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"abstract": "In this article we report a case of stiff, neglected extreme recurvatum knee deformity in a 17-year-old female. This is the first reported case in the literature of an acquired ligamentous stiff extreme knee recurvatum following manipulation under anesthesia and botulinum neurotoxin injection. Μodified Judet quadricepsplasty combined with Ilizarov external hinged frame fixation was implemented. This dual technique can be considered as a rational approach for such an extreme deformity as it stabilizes, progressively corrects, and prevents recurrence. A patellar tendon rupture caused by the increasing tension of the extensor mechanism following the correction was treated successfully using a cadaveric Achilles tendon allograft.",
"affiliations": "Department of Orthopaedic Surgery, Medical School, Democritus University of Thrace, University General Hospital of Alexandroupolis, Alexandroupolis, Greece. Electronic address: tilkerorth@icloud.com.;Medical School, Democritus University of Thrace, University General Hospital of Alexandroupolis, Alexandroupolis, Greece.;Department of Orthopaedics, Democritus University of Thrace, University General Hospital of Alexandroupolis, Alexandroupolis, Greece.;Department of Orthopaedics, Democritus University of Thrace, University General Hospital of Alexandroupolis, Alexandroupolis, Greece.;Department of Orthopaedics, Democritus University of Thrace, University General Hospital of Alexandroupolis, Alexandroupolis, Greece.;Department of Orthopaedics, Democritus University of Thrace, University General Hospital of Alexandroupolis, Alexandroupolis, Greece.;Department of Orthopaedic Surgery, Medical School, Democritus University of Thrace, University General Hospital of Alexandroupolis, Alexandroupolis, Greece.",
"authors": "Tilkeridis|Konstantinos|K|;Diamantidis|Dimitrios|D|;Keskinis|Anthimos|A|;Paraskevopoulos|Konstantinos|K|;Chatzipapas|Christos|C|;Gagali|Kenan|K|;Ververidis|Athanasios N|AN|",
"chemical_list": "D001905:Botulinum Toxins",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.knee.2021.03.008",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0968-0160",
"issue": "30()",
"journal": "The Knee",
"keywords": "Ilizarov frame; Knee genu recurvatum; Manipulation under anesthesia; Patellar tendon reconstruction; Patellar tendon rupture; Quadricepsplasty",
"medline_ta": "Knee",
"mesh_terms": "D000125:Achilles Tendon; D000293:Adolescent; D000758:Anesthesia; D001905:Botulinum Toxins; D005260:Female; D006801:Humans; D018889:Ilizarov Technique; D007717:Knee; D019637:Orthopedic Procedures; D017847:Patellar Ligament; D019651:Reconstructive Surgical Procedures; D012421:Rupture; D013708:Tendon Injuries; D014184:Transplantation, Homologous",
"nlm_unique_id": "9430798",
"other_id": null,
"pages": "35-40",
"pmc": null,
"pmid": "33836302",
"pubdate": "2021-06",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Extreme stiff knee recurvatum following manipulation under anesthesia and botulinum neurotoxin injection.",
"title_normalized": "extreme stiff knee recurvatum following manipulation under anesthesia and botulinum neurotoxin injection"
} | [
{
"companynumb": "GR-MDD US OPERATIONS-MDD202104-000790",
"fulfillexpeditecriteria": "1",
"occurcountry": "GR",
"patient": {
"drug": [
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RIMABOTULINUMTOXINB"
},
"drugaddi... |
{
"abstract": "Osteoporosis is a key health problem in postmenopausal women with high social and economic impact. Decreased bone mineral density (BMD) and deterioration of bone microarchitecture may occur also as a result of long-term glucocorticoid treatment (GCT) of autoimmune or inflammatory conditions. Denosumab specifically inhibits the binding of the receptor activator of nuclear factor-κB to its ligand, thus preventing osteoclast activation and bone resorption. The efficacy and safety of denosumab, administered subcutaneously as 60 mg, once every six months for 12 months, were evaluated in 60 patients with postmenopausal osteoporosis (PMO) divided into two groups. The GCT group included 30 patients receiving concomitant glucocorticoid therapy and the non-GCT group included 30 patients that did not receive GCT. In the non-GCT group, the 12-month treatment with denosumab resulted in BMD increase of 6.1% and 2.8% in lumbar spine and hip, respectively. T-score increased by 13.1% and 5.6% in both, the lumbar spine and hip. A slight rise in the Trabecular Bone Score (TBS) of 0.3% was observed. Bone pain was markedly reduced by 56.2%. In the GCT group, denosumab therapy increased BMD with 5.8% and 2.3% in lumbar spine and hip, respectively. T-score of lumbar spine and hip significantly increased by 14.0% and 4.4%, and the TBS rose by 5%. Bone pain was reduced by 53.6%. These data confirm the available knowledge on denosumab efficacy and safety in women with PMO and also provide new insights into its therapeutic potential in patients with osteoporosis related to a long-term corticosteroid treatment.",
"affiliations": "Clinic of Rheumatology, Medical University , Sofia , Bulgaria.;Clinic of Rheumatology, Medical University , Sofia , Bulgaria.;Clinic of Rheumatology, Medical University , Sofia , Bulgaria.;Rheumatology Center 'Sveta Irina' , Sofia , Bulgaria.;Clinic of Rheumatology, Medical University , Sofia , Bulgaria.",
"authors": "Petranova|Tzvetanka|T|;Sheytanov|Ivan|I|;Monov|Simeon|S|;Nestorova|Rodina|R|;Rashkov|Rasho|R|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1080/13102818.2014.967827",
"fulltext": "\n==== Front\nBiotechnol Biotechnol EquipBiotechnol. Biotechnol. EquipTBEQtbeq20Biotechnology, Biotechnological Equipment1310-28181314-3530Taylor & Francis 96782710.1080/13102818.2014.967827Article; Medical BiotechnologyDenosumab improves bone mineral density and microarchitecture and reduces bone pain in women with osteoporosis with and without glucocorticoid treatment Petranova Tzvetanka \na\n\n*\nSheytanov Ivan \na\nMonov Simeon \na\nNestorova Rodina \nb\nRashkov Rasho \na\na Clinic of Rheumatology, Medical University, Sofia, Bulgariab Rheumatology Center ‘Sveta Irina’, Sofia, Bulgaria* Corresponding author. Email: rilski@rilski.com2 11 2014 17 10 2014 28 6 1127 1137 7 5 2014 14 5 2014 © 2014 The Author(s). Published by Taylor & Francis.2014The Author(s)This is an Open Access article distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0/, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The moral rights of the named author(s) have been asserted.Osteoporosis is a key health problem in postmenopausal women with high social and economic impact. Decreased bone mineral density (BMD) and deterioration of bone microarchitecture may occur also as a result of long-term glucocorticoid treatment (GCT) of autoimmune or inflammatory conditions. Denosumab specifically inhibits the binding of the receptor activator of nuclear factor-κB to its ligand, thus preventing osteoclast activation and bone resorption. The efficacy and safety of denosumab, administered subcutaneously as 60 mg, once every six months for 12 months, were evaluated in 60 patients with postmenopausal osteoporosis (PMO) divided into two groups. The GCT group included 30 patients receiving concomitant glucocorticoid therapy and the non-GCT group included 30 patients that did not receive GCT. In the non-GCT group, the 12-month treatment with denosumab resulted in BMD increase of 6.1% and 2.8% in lumbar spine and hip, respectively. T-score increased by 13.1% and 5.6% in both, the lumbar spine and hip. A slight rise in the Trabecular Bone Score (TBS) of 0.3% was observed. Bone pain was markedly reduced by 56.2%. In the GCT group, denosumab therapy increased BMD with 5.8% and 2.3% in lumbar spine and hip, respectively. T-score of lumbar spine and hip significantly increased by 14.0% and 4.4%, and the TBS rose by 5%. Bone pain was reduced by 53.6%. These data confirm the available knowledge on denosumab efficacy and safety in women with PMO and also provide new insights into its therapeutic potential in patients with osteoporosis related to a long-term corticosteroid treatment.\n\nKeywords\ndenosumabpostmenopausal osteoporosisglucocorticoid treatmentBMDTBSbone pain\n==== Body\nIntroduction\nOsteoporosis (OP) is a public health problem representing a common bone disease characterized by bone loss and structural deterioration of bone tissue. OP can lead to numerous other clinical and health-related consequences, including fracture, the need for long-term care and excess mortality. The reduced bone density associated with the disorder is a major risk factor for fracture, especially of the hip, spine and wrist.[1] OP is often referred to as a silent disease, as many individuals do not realize that they have the disease until a fracture occurs. OP-related fractures impose a heavy burden on individuals and on society, as they often lead to a variety of physical and psychological consequences, including future fractures, depression, functional impairment, pain and disability.[2] In postmenopausal osteoporosis (PMO), receptor activator of nuclear factor-κB ligand (RANKL) is directly associated with osteoclast-mediated bone resorption.[3,4] Osteoprotegerin binds to RANKL and is directly involved in the regulation of the RANK-RANKL pathway.[5]\n\nOP may occur as a secondary disease and is one of the most devastating side-effects of glucocorticoid (GC) use and is associated with substantial morbidity.[6] GCs are frequently used for the treatment of a variety of diseases, such as rheumatoid arthritis, systemic lupus erythematosus, polymyalgia rheumatica, inflammatory bowel disease and chronic obstructive pulmonary disease. They are widely used because of their anti-inflammatory and immunosuppressive effects. Bone loss related to a long-term corticoid treatment is associated with elevated fracture incidence. It is estimated that fractures occur in 30%–50% of patients receiving a long-term GC therapy, which may have a substantial negative impact on the quality of life.[7]\n\nDenosumab (Prolia®) is indicated for treatment of OP in postmenopausal women at increased risk of fractures. Prolia® significantly reduces the risk of vertebral, non-vertebral and hip fractures.[8] The mechanism of action of denosumab leads to rapid and maximal reductions in bone resorption throughout the trabecular and cortical compartments.[9] Denosumab is a fully human monoclonal antibody that potently blocks the binding of RANKL to its osteoclast-derived receptor (RANK), an interaction that is required for osteoclast formation, activation and survival. By blocking this receptor binding, denosumab potently inhibits osteoclast-mediated bone resorption. This mechanism differs from that of bisphosphonates, which act via inhibition of the enzyme farnesyl pyrophosphate synthase, leading to decreased osteoclast activity and increased osteoclast apoptosis.[10]\n\nDenosumab has already been established as an attractive new therapeutic agent for patients with increased fracture risk due to long-term GC treatment with renal failure and for GC-treated patients with rheumatoid arthritis. In a 12-month, placebo-controlled trial in patients with rheumatoid arthritis concurrently receiving treatment with GCs or bisphosphonates, denosumab therapy was shown to increase bone mineral density (BMD) and reduce bone turnover markers.[11] It has been suggested that denosumab may be considered for GC-treated patients with renal insufficiency and stable serum calcium levels who are not candidates for bisphosphonates or teriparatide. Moreover, the ease of administration as a subcutaneous injection every six months may increase patients’ compliance.[12]\n\nThe aim of this study was to evaluate the efficacy and safety of denosumab treatment on BMD, Trabecular Bone Score (TBS), T-score, Fracture Risk Assessment Tool (FRAX) and bone pain in patients with PMO with or without corticoid treatment.\n\nMaterials and methods\nSubjects\nPatients were divided into two groups: non-GCT group – women with PMO that did not receive GC therapy (n = 30); and GCT group – women with PMO receiving concomitant glucocorticoid treatment (GCT) (n = 30). All included patients had BMD score lower than –2.5 both at the lumbar spine and total hip and were treated with 60 mg denosumab s.c. once per six months, with Ca and vitamin D supplementation as per product indication.[8] In the non-GCT group, 23% of the patients had a concomitant rheumatology disease and 6.6% had an endocrine disease. Forty-seven per cent of the patients had received a previous OP treatment. Patients who had a previous osteoporotic fracture (either wrist, lumbar or proximal femur) represented 20% of this study group. With regard to the GCT group, 97% of the subjects had a concomitant rheumatology disease and 3% had an endocrine disease. Previous fractures had occurred among 50% of these patients (Table 1).\nTable 1. Patients’ baseline characteristics and demographics.\n\n#\tPatients not treated with corticosteroids\tPatients treated with corticosteroids\t\nFemale, n (%)\t30 (100)\t30 (100)\t\nRace/ethnicity, n (%)\t \t \t\n White\t30 (100)\t30 (100)\t\nAge (yr), mean (SD)\t67.5 (9.0)\t66.7 (7.9)\t\nAge (yr) of menopause (SD)\t47 (3.0)\t48.2 (2.3)\t\nOsteoporosis occurrence (yr)\t63 (8.3)\t61 (7.5)\t\nHeight (cm), mean (SD)\t158 (5.9)\t157 (5.7)\t\nWeight (kg), mean (SD)\t59 (14.1)\t68 (12.7)\t\nSmoking (Yes/No/Missing (%))\t13/80/7\t13/77/10\t\nFamily predisposition, fractures (Yes/No (%))\t27/73\t20/80\t\nRheumatology disease (Yes/No (%))\t23/77\t97/3\t\nEndocrine disease (Yes/No (%))\t6.6/93.4\t3/97\t\nTreatment with cortisone drug (%)\tNo (100)\tYes (100)\t\nAdministration of other medications (Yes/No (%))\t20/80\t90/10\t\nFractures, total number (% of pts)\t0–3 (20)\t0–4 (50)\t\nLumbar fractures\t0–2\t0–7\t\nWrist fractures\t0–2\t0–1\t\nFractures of proximal femur\t0–1\t0\t\nPrevious osteoporosis treatment (Yes/No (%))\t46.6/53.4\t53.3/46.6\t\nCa and vitamin D administration (Yes/NA (%))\t43.3/56.7\t70/30\t\nLumbar spine T-score, n (%)\t \t \t\n ≤−2.5\t27 (83)\t24 (80)\t\n >−2.5\t3 (17)\t6 (20)\t\nTotal hip T-score, n (%)\t \t \t\n ≤−2.5\t13 (43.3)\t19 (63)\t\n >−2.5\t15 (50)\t11 (37)\t\n Missing\t2 (6.7)\t0\t\nTBS, mean (SD)\t1.292 (0.08)\t1.168 (0.12)\t\nCalcium (mmol/L), mean (SD)§\t2.35 (0.1)\t2.37 (0.1)\t\nPhosphorus (mmol/L), mean (SD)§\t1.17 (0.2)\t1.13 (0.2)\t\nBone-specific alkaline phosphatase (U/l), mean (SD)§\t90.8 (41.2)\t88 (67)\t\nIntact PTH (pg/ml), mean (SD)§\t48.9 (14.9)\t47.8 (14.3)\t\nBeta-CTx, mean (SD)§\t0.43 (0.3)\t0.62 (1.4)\t\nOsteocalcin§\t24.8 (9.0)\t16.4 (8.0)\t\nFractures after treatment initiation, n (%)\t1 (3.3)\t3 (10)\t\n\n§Mean (SD) or reference range for normal values: 35 (15) nmol/mmol for urine NTX/creatinine (premenopausal women); 0.321 (0.155) ng/ml for serum CTx; 7.3–22.4 g/l for bone-specific alkaline phosphatase; 8.4–10.3 mg/dl for albumin-adjusted calcium; and 10–65 pg/ml for iPTH.\n\n\n\n\nDXA, BMD and TBS assessments\nFor all patients, BMD assessments were performed at baseline and after 12 months for the lumbar spine and total hip. BMD was measured by a Lunar Prodigy® Primo (GE Healthcare, Caserta, Italy) osteodensitometer. A new software program (TBS iNsight® v1.9, Med-Imaps, Pessac, France) was applied to the standard lumbar spine Dual-energy X-ray absorptiometry (DXA) scans to determine their TBS indexes. Lumbar spine scans included L1–L4 vertebrae. The scanner precision (precision error), together with the quality and reliability of individual scans, was measured using the LSC (least significant change) calculation. The precision error measured for the osteodensitometer used in the present work was 0.015 g/cm2 for posterior–anterior spine (LSC of 0.042 g/cm2) and 0.008 g/cm2 for the femoral neck (LSC of 0.022 g/cm2) which was close to the minimum acceptable precision for an individual technologist.[13]\n\nFRAX measurement and fracture risk assessment\nThe fracture risk was assessed for all patients in both groups (n = 30 subjects per group) using the online FRAX® tool at http://www.shef.ac.uk/FRAX/tool.jsp. At baseline, the estimated risk of major osteoporotic fracture and for hip fracture was 9.7% and 5.0% in the non-GCT group and 34% and 14% for the GCT group, respectively.\n\nAssessment of bone pain\nBone pain was evaluated by a visual analogue scale (VAS). Pain scores were assessed at baseline and after 12 months of treatment. Pain was measured using a 100-mm VAS with 0 representing ‘no pain’ and 100 representing ‘severe pain’.[14]\n\nStatistical analysis\nThe analysis was performed using the T-test for establishment of difference of mean values. Results were presented as mean statistical values of the analysed parameters: BMD; T-score; TBS; and values obtained from the VAS for assessing bone pain (comparison was made between the measurements at baseline and at month 12). Standard deviations and p-values are presented for each investigated parameter with a significance level of p ≤ 0.05. Percentage changes from baseline to the 12th month for all measured parameters are also presented (Figures 1–8).\nFigure 1. Change in BMD and T-score of lumbar spine after 12-month treatment with denosumab (non-GCT group). (A) Change in BMD. Data are presented as a comparison between mean values of BMD (g/cm2) at baseline and at the 12th month of treatment with a percent change of 6.1 and level of significance of p = 0.2. (B) Change in T-score. Comparison between mean values of T-score at baseline vs. T-score at month 12 of treatment with a significant change of 13.1%, p < 0.05.\n\n\nFigure 2. Change in BMD and T-score of lumbar spine after 12-month treatment with denosumab (GCT group). (A) Change in BMD. Data are presented as a comparison between mean values of BMD (g/cm2) at baseline and at the 12th month of treatment with a percent change of 5.8% and level of significance of p = 0.2. (B) Change in T-score. Comparison between mean values of T-score at baseline vs. T-score at month 12 of treatment with a significant change of 14.0%, p = 0.03.\n\n\nFigure 3. Change in BMD and T-score of total hip after 12-month treatment with denosumab (non-GCT group). (A) Change in BMD. Data are presented as a comparison between mean values of BMD (g/cm2) at baseline and at the 12th month of treatment with a percent change of 2.8% and level of significance of p = 0.2. (B) Change in T-score. Comparison between mean values of T-score at baseline vs. T-score at month 12 of treatment with a significant change of 5.6%, p = 0.01.\n\n\nFigure 4. Change in BMD and T-score of total hip after 12-month treatment with denosumab (GCT group). (A) Change in BMD. Data are presented as a comparison between mean values of BMD (g/cm2) at baseline and at the 12th month of treatment with a percent change of 2.3% and level of significance of p = 0.2. (B) Change in T-score. Comparison between mean values of T-score at baseline vs. T-score at month 12 of treatment with a significant change of 4.4%, p = 0.01.\n\n\nFigure 5. Effect of denosumab on TBS. (A) Non-GCT group. Comparison between mean TBS values at baseline and mean TBS values at the 12th month of denosumab therapy with a percent change of 0.3% and p = 0.1. (B) GCT group. Comparison between mean TBS values at baseline and mean TBS values at the 12th month of denosumab therapy with a percent change of 5.0% and p = 0.1.\n\n\nFigure 6. Effect of denosumab on fracture risk reduction. Data are presented as mean values (baseline and at the 12 month) of fracture risk for major osteoporotic and hip fracture, respectively, as measured by the FRAX tool. (A) Non-GCT group. (B) GCT group.\n\n\nFigure 7. Effect of denosumab on bone pain. (A) Non-GCT group. Pain levels are presented as mean values of pain scores (VAS) assessed at baseline and after 12 months of treatment with a significant change of 56.2%, p < 0.01. (B) GCT group. Pain levels are presented as mean values of pain scores (VAS) assessed at baseline and after 12 months of treatment with a significant change of 53.6%, p < 0.01.\n\n\nFigure 8. Correlation between BMD change (lumbar spine and hip) and Beta-CTx. Patients were divided into four groups on the basis of their baseline Beta-CTx measures. Data are presented as mean values of baseline Beta-CTx (per group) and mean BMD change (lumbar spine and hip, also per group) at month 12. (A) Non-GCT group. (B) GCT group.\n\n\n\n\nResults and discussion\nOP is a common clinical condition, resulting in decreased bone strength, increased fracture risk and low quality of life. Currently, there is a great amount of evidence about the correlation between fracture risk and bone parameters such as BMD, T-score, TBS, bone turnover markers and bone pain. BMD is a key factor continuously used for demonstration of bone mass change in response to different anti-osteoporotic treatments. On the other hand, TBS reflects the status of bone microarchitecture.\n\nChanges of BMD and T-score of lumbar spine from baseline to month 12\nIn the non-GCT group, denosumab increased the BMD of lumbar spine at month 12 compared with the baseline BMD values in 93.3% of all patients. A percent change of 6.1% in BMD favouring denosumab treatment was measured at the end of observation. In correlation with the increase of BMD at the lumbar spine, the T-score was improved in 96.6% of patients, resulting in a significant change of 13.1% compared to the baseline T-score mean value (Figure 1). For the GCT group, BMD of lumbar spine was increased at month 12 after denosumab treatment in 96.6% of all patients compared with the baseline BMD values. A percent change of 5.8 in BMD favouring denosumab treatment was measured at the end of observation. The T-score was significantly improved in 96.6% of patients with 14.0% compared to the baseline T-score mean value (Figure 2).\n\nThe one-year clinical experience presented herein showed a clear trend for increase of BMD in the two groups that were managed: the GCT and non-GCT groups. Moreover, both groups showed a similar extent of the BMD increase despite bone localization, as well as between the levels of change. The results showed that in the non-GCT group, BMD of lumbar spine increased by 6.1% at month 12, and similarly, in the GCT group this percent change was 5.8%. BMD of total hip in the non-GCT and GCT groups increased up to month 12 by 2.8% and 2.3%, respectively. When the two groups were compared, a higher increase of BMD of lumbar spine than in the BMD of total hip was observed.\n\nChanges of BMD and T-score of total hip from baseline to month 12\nIn the non-GCT group, 22 patients (73.3%) had a BMD increase of total hip at month 12. There was a 2.8% increase in the BMD at the end of observation in comparison with the mean baseline values. Similarly to the results related to the T-score change at lumbar spine, the T-score of total hip also changed in corresponding proportion to the increase of BMD. There was a significant positive change of 5.6% in the T-score of total hip, determined in 80% of the patients as compared with their baseline T-score values (Figure 3).\n\nIn the GCT group, at month 12, 83.3% had a BMD increase of total hip. There was a 2.3% increase in the BMD at the end of observation in comparison with the mean baseline values. T-score of total hip also changed in corresponding proportion to the increase of BMD. There was a significant positive change of 4.4% in the T-score of total hip, determined in 83.3% of the patients as compared with their baseline T-score values (Figure 4).\n\nGenerally, T-score changed in a similar extent to BMD. In both groups, T-score showed a significant and constant increase. In the non-GCT group, at month 12, T-score of lumbar spine increased by 13.1% and in the GCT group, this increase was by 14.0%.\n\nChange in TBS\nIn the non-GCT group, the treatment of osteoporotic postmenopausal women with denosumab for 12 months led to an increase of TBS by 0.3%. For the one-year treatment period, this increase was documented in 70.0% of all patients. In the GCT group, TBS changed by 5.0% as compared to the baseline mean value. This change was observed in 76.6% of all patients (Figure 5). Interestingly, there was a distinct change in TBS between the two observed groups. This finding is in correlation with the concept that TBS provides distinct information, independent of BMD and can be used as an additional and substantive factor for assessing bone structure, quality and treatment effect.[15] Our results, together with the fact that TBS influences fracture risk, suggest that this novel technique may have a role in managing patients with OP.\n\nFracture risk reduction in response to denosumab treatment at month 12\nIt was obvious that the patients from the GCT group had a higher risk of major osteoporotic and hip fracture at baseline (34% and 14%, respectively) as measured by the FRAX tool. It is most likely related to the long-term exposure of these patients to corticoid treatment. In opposite, the fracture risk reduction that was measured at the 12th month of denosumab treatment was lower in that group (1.2% of major OP fractures and 1.8% of hip fractures, respectively), showing a slower bone recovery in comparison to the non-GCT group which is in correlation with the data on BMD and T-score showing trends for increase. In the non-GCT group, the measured fracture risk at baseline as 9.7% and 5.0% for major OP and hip fracture, respectively, was reduced after 12 months of treatment with 2.1% and 4.0%, respectively. It is suggested that these reduction rates will increase significantly for a longer treatment period (Figure 6).\n\nBone pain reduction\nDenosumab treatment exhibited a substantial decrease in bone pain at month 12 as evaluated by the patients using VAS. This reduction was observed and reported by all patients from both the non-GCT and GCT groups with an average percent reduction of 56.2% and 53.6%, respectively (Figure 7).\n\nMarkers of bone turnover\nAn additional analysis of the correlation between BMD changes (both for lumbar spine and hip) and Beta-CTx in the two groups was performed. It demonstrated that BMD increases and keeps equal levels of improvement despite the baseline value of Beta-CTx (Figure 8). The current results are in accordance with already published data on denosumab efficacy on the increase of BMD in patients with rheumatoid disease. Denosumab treatment led to a significant increase in BMD at the lumbar spine, total hip, femoral neck and trochanter. In addition, compared with placebo, denosumab treatment reduced the cartilage turnover marker C-telopeptide of type II collagen (CTx-II)/creatinine at 3 months, but not at 6 and 12 months.[16]\n\nSafety\nDenosumab treatment was not discontinued due to safety reasons at any of the patients. One patient from the non-GCT group (3.3%) and three patients (10%) from the GCT group experienced fractures after the initiation of treatment. In general, denosumab was well tolerated by all patients and a good patient compliance and treatment adherence was observed.\n\nConclusions\nOur clinical data showed that 12-month treatment with denosumab increased BMD at lumbar spine and total hip, and reduced bone pain in women with OP regardless of its origin, postmenopausal or related to corticoid treatment. Both treatment groups achieved similar levels of increase in BMD and T-score of lumbar spine and total hip. Only, TBS appeared to be differently influenced by the treatment of the two groups, which comes as a confirmation of the suggestion that TBS represents an independent bone measure. The present data suggest that denosumab could be used as an effective and safe therapeutic option in patients not only with PMO but also with secondary OP related to long-term GCT.\n==== Refs\nReferences\nDempster DW Osteoporosis and the burden of osteoporosis-related fractures Am J Manag Care 2011 17 S164 S169 21761955 \nColon-Emeric CS Saag KG Osteoporotic fractures in older adults Best Pract Res Clin Rheumatol. 2006 20 4 695 706 16979533 \nLacey DL Timms E Tan HL Kelley MJ Dunstan CR Burgess T Elliott R Colombero A Elliott G Scully S Hsu H Sullivan J Hawkins N Davy E Capparelli C Eli A Qian YX Kaufman S Sarosi I Shalhoub V Senaldi G Guo J Delaney J Boyle WJ Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation Cell. 1998 93 165 176 9568710 \nDelmas PD Clinical potential of RANKL inhibition for the management of postmenopausal osteoporosis and other metabolic bone diseases J Clin Densitom. 2008 11 325 338 18375161 \nSimonet WS Lacey DL Dunstan CR Kelley M Chang MS Luthy R Nguyen HQ Wooden S Bennett L Boone T Shimamoto G DeRose M Elliott R Colombero A Tan HL Trail G Sullivan J Davy E Bucay N Renshaw-Gegg L Hughes TM Hill D Pattison W Campbell P Sander S Van G Tarpley J Derby P Lee R Boyle WJ Osteoprotegerin: a novel secreted protein involved in the regulation of bone density Cell. 1997 89 309 319 9108485 \nBultink IEM Baden M Lems WF Glucocorticoid-induced osteoporosis: an update on current pharmacotherapy and future directions Expert Opin Pharmacother. 2013 14 2 185 197 23317448 \nCanalis E Mazziotti G Giustina A Bilezikian JP Glucocorticoid-induced osteoporosis: pathophysiology and therapy Osteoporos Int. 2007 18 1319 1328 17566815 \nProlia Denosumab 60 mg. Summary of Product Characteristics \nBaron R Ferrari S Russell RG Denosumab and bisphosphonates: different mechanisms of action and effects Bone. 2011 48 677 692 21145999 \nFisher JE Rodan GA Reszka AA \nIn vivo effects of bisphosphonates on the osteoclast mevalonate pathway Endocrinology. 2000 141 4793 4796 11108295 \nDore RK Cohen SB Lane NE Palmer W Shergy W Zhou L Wang H Tsuji W Newmark R Denosumab RA Study Group Effects of denosumab on bone mineral density and bone turnover in patients with rheumatoid arthritis receiving concurrent glucocorticoids or bisphosphonates Ann Rheum Dis. 2010 69 872 875 19734132 \nWeinstein RS G1ucocorticoid-Induced osteoporosis and osteonecrosis Endocrinol Metab Clin North Am. 2012 41 595 611 22877431 \nSornay-Rendu E Munoz F Duboeuf F Delmas PD Rate of forearm bone loss is associated with an increased risk of fracture independently of bone mass in postmenopausal women: the OFELY study J Bone Mineral Res 2005 20 1929 1935 \nKwok T Pope JE Minimally important difference for patient-reported outcomes in psoriatic arthritis: health assessment questionnaire and pain, fatigue, and global visual analog scales J Rheumatol. 2010 37 1024 1028 20231193 \nHans D Goertzen A Krieg M-A Leslie W Bone microarchitecture assessed by TBS predicts osteoporotic fractures independent of bone density: the Manitoba study J Biomed Mater Res. 2011 26 2762 2769 \nCohen SB Dore RK Lane NE Ory PA Peterfy CG Sharp JT van der Heijde D Zhou L Tsuji W Newmark R Denosumab Rheumatoid Arthritis Study Group Denosumab treatment effects on structural damage, bone mineral density, and bone turnover in rheumatoid arthritis Arthritis Rheumatol. 2008 58 1299 1309\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1310-2818",
"issue": "28(6)",
"journal": "Biotechnology, biotechnological equipment",
"keywords": "BMD; TBS; bone pain; denosumab; glucocorticoid treatment; postmenopausal osteoporosis",
"medline_ta": "Biotechnol Biotechnol Equip",
"mesh_terms": null,
"nlm_unique_id": "101128940",
"other_id": null,
"pages": "1127-1137",
"pmc": null,
"pmid": "26019600",
"pubdate": "2014-11-02",
"publication_types": "D016428:Journal Article",
"references": "21761955;21887701;20231193;19734132;23317448;16979533;9108485;11108295;9568710;16234965;17566815;22877431;18438830;18375161;21145999",
"title": "Denosumab improves bone mineral density and microarchitecture and reduces bone pain in women with osteoporosis with and without glucocorticoid treatment.",
"title_normalized": "denosumab improves bone mineral density and microarchitecture and reduces bone pain in women with osteoporosis with and without glucocorticoid treatment"
} | [
{
"companynumb": "BG-AMGEN-BGRSP2020164006",
"fulfillexpeditecriteria": "2",
"occurcountry": "BG",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CHOLECALCIFEROL"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nThe objective of this study was to determine the cardiac safety of high cumulative doses of pegylated liposomal doxorubicin (PLD) in patients with gynecologic malignancies and the need for routine evaluation of left ventricular ejection fraction (LVEF).\n\n\nMETHODS\nData were collected for all patients treated with PLD with at least one evaluation of LVEF with either Multi-Gated Acquisition (MUGA) scan or echocardiogram from January 2006 to May 2012. Evaluation of LVEF was used to detect PLD-related cardiac toxicity (defined as a decline in LVEF of greater than 10% compared to baseline measurements).\n\n\nRESULTS\nA total of 141 patients were included. Twenty-two patients were treated with a cumulative dose of 500 mg/m(2) or more, and five patients with 1000 mg/m(2) or more. Ten patients (7%) had a reduction in LVEF of greater than 10%, 38 had no significant change or increase in LVEF throughout the duration of treatment, and 93 did not require a follow-up evaluation of LVEF. The LVEFs of two patients dropped below 50% at cumulative doses of 1110 mg/m(2) and 1670 mg/m(2); one began with a baseline of 52%.\n\n\nCONCLUSIONS\nOnly one patient had a clinically significant decrease in LVEF at a cumulative dose of 1670 mg/m(2), suggesting that PLD does not carry a significant risk of cardiotoxicity, as evidenced by the stability of LVEF even after treatment with large cumulative doses. Routine surveillance of LVEF does not seem to be necessary or cost effective in the absence of other risk factors.",
"affiliations": "Department of Obstetrics and Gynecology, Greenville Hospital System University Medical Center, Greenville, SC 29605, USA. SGill2@ghs.org",
"authors": "Gill|Sarah E|SE|;Savage|Kari|K|;Wysham|Weiya Z|WZ|;Blackhurst|Dawn W|DW|;Winter|William E|WE|;Puls|Larry E|LE|",
"chemical_list": "D000903:Antibiotics, Antineoplastic; C506643:liposomal doxorubicin; D011092:Polyethylene Glycols; D004317:Doxorubicin",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0090-8258",
"issue": "129(3)",
"journal": "Gynecologic oncology",
"keywords": null,
"medline_ta": "Gynecol Oncol",
"mesh_terms": "D000903:Antibiotics, Antineoplastic; D004317:Doxorubicin; D016903:Drug Monitoring; D004452:Echocardiography; D005260:Female; D015637:Gated Blood-Pool Imaging; D006321:Heart; D006331:Heart Diseases; D006801:Humans; D060046:Maintenance Chemotherapy; D008875:Middle Aged; D011092:Polyethylene Glycols; D012189:Retrospective Studies; D013318:Stroke Volume; D016277:Ventricular Function, Left",
"nlm_unique_id": "0365304",
"other_id": null,
"pages": "544-7",
"pmc": null,
"pmid": "23523653",
"pubdate": "2013-06",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Continuing routine cardiac surveillance in long-term use of pegylated liposomal doxorubicin: is it necessary?",
"title_normalized": "continuing routine cardiac surveillance in long term use of pegylated liposomal doxorubicin is it necessary"
} | [
{
"companynumb": "US-JNJFOC-20130516190",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DOXORUBICIN HYDROCHLORIDE"
},
"drugadditional": n... |
{
"abstract": "BACKGROUND\nMetformin, widely used in the treatment of type 2 diabetes mellitus, reduces the risk of cancer and relapse after treatment. Fertility-sparing treatment for endometrial cancer (EC) with progestin is associated with a high chance of disease regression, and the high relapse rate continues to be a problem. We assessed the efficacy of metformin in preventing recurrence after medroxyprogesterone acetate (MPA) as fertility-sparing treatment for atypical endometrial hyperplasia (AEH) and EC.\n\n\nMETHODS\nThis phase II study enrolled 17 patients with AEH and 19 patients with EC limited to the endometrium (age, 20-40 years). MPA (400 mg/day) and metformin (750-2250 mg/day) were administered for 24-36 weeks to achieve a complete response (CR). Metformin was administered until conception, even after MPA discontinuation. The primary end point was relapse-free survival (RFS) after remission. We analyzed all efficacy end points in the full analysis set.\n\n\nRESULTS\nThe body mass index was ≥25 kg/m(2) in 27 patients (mean, 31 kg/m(2); range, 19-51 kg/m(2)), and the homeostasis model assessment for insulin resistance index was ≥2.5 in 24 patients (mean, 4.7; range, 0.7-21). Two patients showed progression at 12 weeks [6%; 95% confidence interval (CI) 2-18]. At 36 weeks, 29 (81%; 95% CI 65-90) patients achieved CR, and 5 (14%; 95% CI 6-29) patients achieved partial response. During a median follow-up of 38 months (range, 9-66 months) after remission, relapse was confirmed in three of the patients who had achieved CR (relapse rate, 10%). The 3-year estimated RFS rate was 89%. No patients experienced severe toxicity.\n\n\nCONCLUSIONS\nMetformin inhibited disease relapse after MPA therapy. The combination of metformin and MPA in EC treatment should be studied further.\n\n\nBACKGROUND\nUMIN 000002210.",
"affiliations": "Department of Reproductive Medicine, Graduate School of Medicine, Chiba University, Chiba antira@faculty.chiba-u.jp.;Clinical Research Center, Chiba University Hospital, Chiba.;Department of Molecular Pathology, Graduate School of Medicine, Chiba University, Chiba, Japan.;Clinical Research Center, Chiba University Hospital, Chiba.;Clinical Research Center, Chiba University Hospital, Chiba.;Department of Reproductive Medicine, Graduate School of Medicine, Chiba University, Chiba.",
"authors": "Mitsuhashi|A|A|;Sato|Y|Y|;Kiyokawa|T|T|;Koshizaka|M|M|;Hanaoka|H|H|;Shozu|M|M|",
"chemical_list": "D018931:Antineoplastic Agents, Hormonal; D008687:Metformin; D017258:Medroxyprogesterone Acetate",
"country": "England",
"delete": false,
"doi": "10.1093/annonc/mdv539",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0923-7534",
"issue": "27(2)",
"journal": "Annals of oncology : official journal of the European Society for Medical Oncology",
"keywords": "endometrial cancer; fertility-sparing treatment; insulin resistance; medroxyprogesterone acetate; metformin",
"medline_ta": "Ann Oncol",
"mesh_terms": "D000328:Adult; D018931:Antineoplastic Agents, Hormonal; D000971:Antineoplastic Combined Chemotherapy Protocols; D004714:Endometrial Hyperplasia; D016889:Endometrial Neoplasms; D004717:Endometrium; D005260:Female; D005298:Fertility; D059247:Fertility Preservation; D006801:Humans; D007333:Insulin Resistance; D017258:Medroxyprogesterone Acetate; D008687:Metformin; D009364:Neoplasm Recurrence, Local; D011446:Prospective Studies; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "9007735",
"other_id": null,
"pages": "262-6",
"pmc": null,
"pmid": "26578736",
"pubdate": "2016-02",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Phase II study of medroxyprogesterone acetate plus metformin as a fertility-sparing treatment for atypical endometrial hyperplasia and endometrial cancer.",
"title_normalized": "phase ii study of medroxyprogesterone acetate plus metformin as a fertility sparing treatment for atypical endometrial hyperplasia and endometrial cancer"
} | [
{
"companynumb": "JP-MYLANLABS-2016M1020529",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ASPIRIN"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nPatients with an acute ischemic stroke (AIS) following cardiac catheterization (CC) generally do not receive intravenous thrombolysis [intravenous tissue plasminogen activator (IV-tPA)] as it is contraindicated due to the coagulopathy related to the heparin used during the procedure. We report a case of AIS successfully treated with IV thrombolysis following protamine reversal of heparin effect.\n\n\nMETHODS\nAn 87-year-old man with diabetes mellitus, hypertension, neurofibromatosis, and hyperlipidemia underwent elective transradial CC following an abnormal stress test. He had 2 drug-eluting stents for severe stenosis of mid-circumflex and right coronary arteries and received heparin 13,000 IU during procedure. He developed acute left hemiparesis with initial NIH stroke scale (NIHSS) of 4. Computed tomographic scan of the brain and computed tomographic angiogram of head and neck were unremarkable. Bedside activated clotting time was 181. Protamine 40 mg was administered and 30 minutes later, the activated clotting time level was normalized. IV-tPA was administered at 4 hours 25 minutes from his last known well. Within 15 minutes, his NIHSS was 0. Magnetic resonance imaging of brain showed no acute infarction 24 hours after stroke.\n\n\nCONCLUSIONS\nThere are limited reports of protamine reversal of heparin before IV-tPA administration. To our knowledge, there are only 6 AIS cases including ours. Three cases received 0.6 mg/kg of tPA dose. All have favorable outcomes and no intracranial hemorrhage was reported. Protamine reversal of heparin for AIS after CC seems to be safe. Further studies are needed to confirm the therapeutic safety and efficacy of this strategy.",
"affiliations": "Aurora St. Luke's Medical Center, Aurora Neuroscience Innovation Institute.;Aurora Cardiovascular Services, St. Luke's Medical Center.;Aurora Sinai Medical Center, Aurora Research Institute, Milwaukee, WI.;Aurora St. Luke's Medical Center, Aurora Neuroscience Innovation Institute.;Aurora St. Luke's Medical Center, Aurora Neuroscience Innovation Institute.;Aurora St. Luke's Medical Center, Aurora Neuroscience Innovation Institute.;Aurora St. Luke's Medical Center, Aurora Neuroscience Innovation Institute.;Marian University College of Osteopathic Medicine, Indianapolis, IN.;Aurora St. Luke's Medical Center, Aurora Neuroscience Innovation Institute.",
"authors": "Warner|Danielle S|DS|;Schwartz|Bryan G|BG|;Babygirija|Reji|R|;Rovin|Richard A|RA|;Kassam|Amin B|AB|;Biddick|Lindsay|L|;Sajjad|Rehan|R|;Chohan|Adil|A|;Panichpisal|Kessarin|K|",
"chemical_list": "D005343:Fibrinolytic Agents; D006494:Heparin Antagonists; D011479:Protamines; D006493:Heparin",
"country": "United States",
"delete": false,
"doi": "10.1097/NRL.0000000000000204",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1074-7931",
"issue": "23(6)",
"journal": "The neurologist",
"keywords": null,
"medline_ta": "Neurologist",
"mesh_terms": "D000369:Aged, 80 and over; D002545:Brain Ischemia; D006328:Cardiac Catheterization; D005343:Fibrinolytic Agents; D006493:Heparin; D006494:Heparin Antagonists; D006801:Humans; D008297:Male; D011479:Protamines; D020521:Stroke; D016896:Treatment Outcome",
"nlm_unique_id": "9503763",
"other_id": null,
"pages": "194-196",
"pmc": null,
"pmid": "30379743",
"pubdate": "2018-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Thrombolysis After Protamine Reversal of Heparin for Acute Ischemic Stroke After Cardiac Catheterization: Case Report and Literature Review.",
"title_normalized": "thrombolysis after protamine reversal of heparin for acute ischemic stroke after cardiac catheterization case report and literature review"
} | [
{
"companynumb": "US-HIKMA PHARMACEUTICALS USA INC.-US-H14001-18-08365",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "HEPARIN SODIUM"
},
... |
{
"abstract": "BACKGROUND\nPyrexia is a physiological response through which the immune system responds to infectious processes. Hyperpyrexia is known to be neurodegenerative leading to brain damage. Some of the neurotoxic effects of hyperpyrexia on the brain include seizures, decreased cognitive speed, mental status changes, coma, and even death. In the clinical management of hyperpyrexia, the goal is to treat the underlying cause of elevated temperature and prevent end organ damage.\n\n\nMETHODS\nThis case illustrates a 39-year-old white American man referred from another medical facility where he had undergone an upper gastrointestinal tract diagnostic procedure which became complicated by blood aspiration and respiratory distress. During hospitalization, he developed a core body temperature of 41.6 °C (106.9 °F) leading to cognitive decline and coma with a Glasgow Coma Score of 3. Levetiracetam and amantadine were utilized effectively for preserving and restoring neurocognitive function. Prior studies have shown that glutamate levels can increase during an infectious process. Glutamate is an excitatory neurotransmitter that is utilized by the organum vasculosum laminae terminalis through the neuronal excitatory system and causes an increase in body temperature which can lead to hyperpyrexia. Similar to neurogenic fevers, hyperpyrexia can lead to neurological decline and irreversible cognitive dysfunction. Inhibition of the glutamate aids a decrease in excitatory states, and improves the brain's regulatory mechanism, including temperature control. To further improve cognitive function, dopamine levels were increased with a dopamine agonist.\n\n\nCONCLUSIONS\nWe propose that a combination of levetiracetam and amantadine may provide neuroprotective and neurorestorative properties when administered during a period of hyperpyrexia accompanied by any form of mental status changes, particularly if there is a decline in Glasgow Coma Score.",
"affiliations": "Department of Internal Medicine, Larkin Community Hospital, Graduate Medical Education, 7000 SW 62nd Avenue, Suite 401, South Miami, FL, 33142, USA.;Department of Psychiatry, Larkin Community Hospital, Graduate Medical Education, 7000 SW 62nd Avenue, Suite 401, South Miami, FL, 33142, USA. aakinyemi@larkinhospital.com.;Division of Clinical & Translational Research, Larkin Community Hospital, South Miami, FL, USA.;Department of Internal Medicine, Larkin Community Hospital, Graduate Medical Education, 7000 SW 62nd Avenue, Suite 401, South Miami, FL, 33142, USA.",
"authors": "Sterkel|Samantha|S|;Akinyemi|Akinboyede|A|;Sanchez-Gonzalez|Marcos A|MA|;Michel|George|G|",
"chemical_list": "D000927:Anticonvulsants; D015259:Dopamine Agents; D018698:Glutamic Acid; D000077287:Levetiracetam; D000547:Amantadine; D010889:Piracetam",
"country": "England",
"delete": false,
"doi": "10.1186/s13256-017-1204-8",
"fulltext": "\n==== Front\nJ Med Case RepJ Med Case RepJournal of Medical Case Reports1752-1947BioMed Central London 120410.1186/s13256-017-1204-8Case ReportPreserving brain function in a comatose patient with septic hyperpyrexia (41.6 °C): a case report Sterkel Samantha 954-309-2558305-284-7608smousset@larkinhospital.com 1Akinyemi Akinboyede 404-304-5002305-284-7608aakinyemi@larkinhospital.com 2Sanchez-Gonzalez Marcos A. masanchez@larkinhospital.com 3Michel George gmichel@larkinhospital.com 11 0000 0004 0427 8827grid.415823.9Department of Internal Medicine, Larkin Community Hospital, Graduate Medical Education, 7000 SW 62nd Avenue, Suite 401, South Miami, FL 33142 USA 2 0000 0004 0427 8827grid.415823.9Department of Psychiatry, Larkin Community Hospital, Graduate Medical Education, 7000 SW 62nd Avenue, Suite 401, South Miami, FL 33142 USA 3 0000 0004 0427 8827grid.415823.9Division of Clinical & Translational Research, Larkin Community Hospital, South Miami, FL USA 13 2 2017 13 2 2017 2017 11 4024 8 2016 6 1 2017 © The Author(s). 2017\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nPyrexia is a physiological response through which the immune system responds to infectious processes. Hyperpyrexia is known to be neurodegenerative leading to brain damage. Some of the neurotoxic effects of hyperpyrexia on the brain include seizures, decreased cognitive speed, mental status changes, coma, and even death. In the clinical management of hyperpyrexia, the goal is to treat the underlying cause of elevated temperature and prevent end organ damage.\n\nCase presentation\nThis case illustrates a 39-year-old white American man referred from another medical facility where he had undergone an upper gastrointestinal tract diagnostic procedure which became complicated by blood aspiration and respiratory distress. During hospitalization, he developed a core body temperature of 41.6 °C (106.9 °F) leading to cognitive decline and coma with a Glasgow Coma Score of 3. Levetiracetam and amantadine were utilized effectively for preserving and restoring neurocognitive function. Prior studies have shown that glutamate levels can increase during an infectious process. Glutamate is an excitatory neurotransmitter that is utilized by the organum vasculosum laminae terminalis through the neuronal excitatory system and causes an increase in body temperature which can lead to hyperpyrexia. Similar to neurogenic fevers, hyperpyrexia can lead to neurological decline and irreversible cognitive dysfunction. Inhibition of the glutamate aids a decrease in excitatory states, and improves the brain’s regulatory mechanism, including temperature control. To further improve cognitive function, dopamine levels were increased with a dopamine agonist.\n\nConclusions\nWe propose that a combination of levetiracetam and amantadine may provide neuroprotective and neurorestorative properties when administered during a period of hyperpyrexia accompanied by any form of mental status changes, particularly if there is a decline in Glasgow Coma Score.\n\nKeywords\nHyperpyrexiaLevetiracetamGlutamateOrganum vasculosum laminae terminalisNeuroprotectionAmantadineGlasgow Coma Scoreissue-copyright-statement© The Author(s) 2017\n==== Body\nBackground\nFever is a natural regulatory protective mechanism through which the human body counteracts physiological insults. Causes of fever include infections, traumatic brain injury, thalamic injury, dehydration, tissue destruction, and thromboembolism [1, 2]. Conversely, hyperpyrexia or body temperature greater than or equal to 41.5 °C (106.7 °F) may lead to pathological complications including detrimental mental status changes, neuronal brain injury, cognitive decline, coma, and even death [2]. Causes of hyperpyrexia include neuroleptic malignant syndrome, heat stroke, amphetamine overdose, serotonin syndrome, infections, and sepsis [2]. In a study conducted by Minamisawa et al. [3], it was shown that hyperpyrexia induced pannecrosis as well as damage to the neocortex, caudoputamen, and substantia nigra pars reticulate, which are responsible for dopamine activity. These areas of the brain are involved in conscious reasoning, spatial orientation, sensation to all modalities, movement regulation, and learning [3]. Regulation of neuronal excitability occurs in the brain via balancing of gamma-aminobutyric acid (GABA) and glutamate decarboxylase [4, 5]. Glutamate is a major excitatory neurotransmitter in the brain and serves as a precursor for the synthesis of GABA, which can be inversely metabolized back to glutamate via the tricarboxylic acid (TCA) cycle [6]. Dysfunction of neuronal activities in hypoxia, however, causes poor regulation of TCA cycle causing uncontrolled release of glutamate which becomes toxic to neurons and thus inducing further neuronal necrosis in the brain [7].\n\nHyperpyrexia of infectious origin is discussed in this case in combination with the pharmacological interventions utilized following a severe mental status decline leading to a comatose state. A combination of levetiracetam and amantadine were successfully utilized. Here, we demonstrate the beneficial effect of neuroprotective agents in fever regulation via the organum vasculosum laminae terminalis (OVLT) and its function in fever regulation in a patient with brain injury resulting from hyperpyrexia. The OVLT glutamate spike has been studied in animals showing a rise in glutamate levels prior to measurable increase in body temperature [8]. This suggests a link between hyperpyrexia and OVLT involvement in temperature regulation via glutamate release [9]. While levetiracetam is a known antiepileptic agent, its impact on regulating the integrity of the blood–brain barrier function following hyperpyrexia in a comatose state has not been well documented in humans [10]. Levetiracetam is documented with a known mechanism of action in neuronal glutamate regulation in seizure disorder via inhibition of presynaptic calcium channels [11]. Following the assessment and review of this case, we suggest that in patients with hyperpyrexia and cognitive decline, a combination of amantadine and levetiracetam could be beneficial for preserving neuronal survival and restoring cognitive function.\n\nCase presentation\nA 39-year-old white American man with a past medical history of hypertension, hyperlipidemia, and major depressive disorder presented to our facility after being transferred from another facility following an attempted suicide. He presented to our intensive care unit; he was intubated due to respiratory distress and hypoxic-anoxic brain injury, secondary to complications of sharp foreign object ingestion as a means of suicide attempt. According to collateral information retrieved from the sending facility, he was seen aspirating blood while undergoing esophagogastroduodenoscopy (EGD) thus requiring emergency intubation. On admission to our facility, an abdominal X-ray showed no evidence of foreign object ingestion. Another EGD was performed at our facility to investigate upper gastric bleeding which revealed a 2 cm ulcer at the base of his esophagus, which was cauterized resulting in control of the hemorrhage. An abdominal axial computed tomography (CT) scan performed on hospital day 18 showed evidence of a foreign object in his descending colon which was later expulsed via bowel movement on day 20. Per transfer records received at our facility, medications included amlodipine 5 mg orally daily, simvastatin 10 mg orally daily, gemfibrozil 600 mg orally twice a day, and niacin 500 mg daily. According to the history obtained from members of his family, there were no reported medication allergies and no past non-prescribed substance use history.\n\nWithin hours of admission to our intensive care unit, his mental status progressively declined due to hypoxic-anoxic brain injury reaching a Glasgow Coma Score (GCS) of 6. On physical examination there was no eye opening response, no verbal response, and he only merely withdrew from painful stimuli. There was neither decorticate nor decerebrate posturing at the time of examination. Lung auscultation revealed decreased breath sounds in bilateral lung bases. His abdomen was distended, obese, with decreased bowel sounds in all four quadrants and tympanic to percussion. His white blood cell (WBC) count was elevated at 14.9 (103/uL), with 83.6 % neutrophil predominance. A chest X-ray showed bilateral pleural effusion. A sputum culture was positive for Klebsiella pneumonia. His clinical picture was consistent with aspiration pneumonitis with severe hypoxia which later decompensated to ventilator-associated pneumonia with methicillin-resistant Staphylococcus aureus (MRSA) pneumonia (as seen on sputum culture), which thus made him ventilator dependent due to decreased respiratory drive. His treatment was a combination of levofloxacin 750 mg administered intravenously daily, piperacillin/tazobactam 3.375 mg every 6 hours, and vancomycin 1 gram daily. On day 8, a maximum core temperature (Tmax) of 39.6 °C (103.3 °F) was recorded rectally. He had no motor response to painful stimuli, no eye opening, nor verbal response despite being off all sedating agents. His blood culture at this time was positive for Candida albicans and, as a result, micafungin 100 mg administered intravenously daily was initiated. While on this regimen, on day 9, a temperature of 41.6 °C (106.9 °F) was recorded with a GCS of 3. Acetaminophen 650 mg was administered rectally; cooling blankets and multiple ice packs were applied to his groin, axillae, and neck regions resulting in a decrease in his body temperature to 37.8 °C (100.1 °F) within 8 hours of intervention. He continued to have fever on a daily basis with no improvement in cognitive functioning as he remained comatose. On hospital day 11, he had become flaccid and was considered to be in a vegetative state as evidenced by an electroencephalogram (EEG) study, which showed diffuse slowing consistent with encephalopathy with very poor prognosis. His WBC count increased to 27.9 (103/uL) and he remained in a state of septicemia. Due to multiple failed attempts to wean him off the ventilator, a tracheostomy was performed on day 14 and a percutaneous endoscopic gastrostomy (PEG) tube was placed on day 17. Given his neurological decline, a lumbar puncture was considered for cerebrospinal fluid (CSF) analysis. However, he was already on broad spectrum antibiotics, therefore, the benefits from CSF analysis would have been undermined by antibiotic coverage.\n\nAfter concerted deliberations over the trial of levetiracetam as a neuroprotective and antiepileptic agent, the decision was made on day 29 to administer 500 mg of the medication via a PEG tube at bedtime. Within 48 hours of administration, he was awake and alert but remained disoriented to person, place, and time. His GCS improved from 3 to 14 and he was able to respond to painful stimuli from his lower extremities up to his knees. Amantadine 50 mg/ml via a PEG tube every morning was started for neurocognitive stimulation as he was noted to have decreased cognitive speed measured grossly during conversation evidenced by increased latency of response when questioned. On hospital day 38 (9 days after levetiracetam 500 mg initiation), he was able to communicate verbally, although with difficulties with phonation even with a Passy-Muir valve. There was orientation to person and place but not to time. His body temperature was 37.3 °C (99.1 °F) without antipyretic agents, while his WBC remained elevated at 20.9 (103/uL) showing persistence of infection.\n\nThe finding of a neurological examination was consistent with critical illness polyneuropathy, as he had no motor function below the clavicle after surviving the profound neurological impairment induced by hyperpyrexia. His pain sensation remained intact, he responded to sharp and dull touch sensations, and he responded to vibrations. He was noted to have decreased cognitive speed; therefore, he required neurocognitive stimulation. Amantadine was initiated on day 34, resulting in improved cognitive functioning with noted increased cognitive speed during conversation. Amantadine was increased to 100 mg/ml via a PEG tube for enhancement of neuroprotection on day 41.\n\nHe was weaned off a ventilator, then transferred to our medical floor and eventually discharged. Extensive rehabilitation was recommended for neuromusculoskeletal strengthening in all his extremities. A CT scan showed diffuse brain atrophy disproportionate to his chronological age; thus consistent with hypoxic ischemic brain injury.\n\nFollowing cognitive recovery, he was awake, alert, and oriented to time, place, person, and situation. He remained with a motor strength of 0/5 bilaterally in upper and lower extremities proximally and distally, secondary to critical illness polyneuropathy; however, he had intact temperature and pain sensation to all modalities in the upper and lower extremities, chest, abdomen, and face. He was seen on follow-up evaluation 6 months following initial encounter and he remained cognitively intact.\n\nDiscussion\nBody temperatures can be classified into different stages: hypothermia <35 °C (<95 °F), normal 36.5 to 37.5 °C (97.7 to 99.5 °F), fever 37.5 to 38.3 °C (99.5 to 100.9 °F), and hyperpyrexia 38.0 to 41.5 °C (100.4 to 106.7 °F) [2]. Of interest, neuronal damage may occur at the range of hyperthermia [12]. Significant in this case is an appreciable Tmax of 41.6 °C (106.9 °F) followed by further neurocognitive decline from GCS 6 to GCS 3 within hours of increased core body temperature leading to coma and a persistent vegetative state, which posed a very poor recovery prognosis. In the event of hyperpyrexia, endoplasmic reticular stress occurs due to denaturing of the inherent polypeptide chains, nuclei carrying genetic information, and mitochondria [12]. In burn injuries, there is rapid destruction of polypeptides; however, in hyperpyrexia, as narrated in this case for instance, temperature raises gradually causing gradual dysfunction in the neuronal polypeptide chains [12]. One of the most evident indications of intracranial neuronal interference as noted in this case is decline in mental status and coma, which was supported by an EEG finding consistent with encephalopathy.\n\nThe OVLT is a brain structure present in the anteroventral third ventricle, which is connected to the median preoptic nucleus in the hypothalamus, which helps in regulating temperature, thirst, and vasopressin secretion [13]. The OVLT utilizes glutamate in creating neuronal excitation and action potential required in initiating temperature increase [8, 14]. Glutamate levels are known to increase slightly prior to a rise in body temperature during infectious processes [9]. Studies performed on rabbits showed evidence of OVLT glutamate spikes when staphylococcal enterotoxin A was injected [9]. In our case, while there was physiologic fever response given the presence of multiple infections, hyperpyrexia ensued thus damaging neuronal functioning as evidenced by the further decrease in GCS from 6 to 3 following a documented temperature of 41.6 °C (106.9 °F). Excess availability of glutamate in a brain with neuronal necrosis causes temperature regulation impairment thus mimicking a neurogenic fever which is difficult to regulate [14].\n\nAs observed in this case, following the noted rise in core body temperature, there was a decline in cognitive function predisposing our patient to further irreversible cognitive dysfunction similar to what is seen in neurogenic fever. Given that there were multiple sources of identified infections, which were poorly manageable using antibiotics, it was necessary to protect cognitive function by means of decreasing the amount of glutamate that was being produced in his brain. Werner et al. [15] documented that glutamate’s excitotoxicity mediated by the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate-type of glutamate receptors is known to cause damage to the neurons and the oligodendrocytes in the central nervous system. In this case, a similar scenario is proposed based on the finding of changes in mental status. The choice of levetiracetam was made for the purpose of decreasing the excitogenic effects of glutamate; it was found to be effective within 48 hours of administration as our patient became awake and alert following a prior comatose state for 21 days.\n\nAs an antiepileptic agent, levetiracetam functions by binding to neuronal synaptic vesicle glycoprotein 2A and inhibiting presynaptic calcium channels which leads to decreased cell excitation [11]. Prolonged excitatory states with glutamate release from brain neurons occur in anoxic-hypoxic brain injury via unregulated release of neurotransmitters from the vesicles where they are normally stored [16]. In hyperpyrexia, the excitatory states with continuous release of neurotransmitters further induce necrosis which usually can be noticed on CT imaging within 14 days of initial injury [17, 18] (Fig. 1). As further necrosis occurs, more glutamate is released from damaged neurons causing more excitatory states in the brain causing further cognitive decline and coma due to excitatory neuronal states. Excitogenicity caused by the release of glutamate after any form of brain injury occurs due to reactive oxygen stress, which occasionally causes epileptogenic foci in patients [19, 20]. In this case, our patient had hypoxic ischemic brain injury and brain atrophy as seen on CT imaging. Levetiracetam inhibits glutamate transmission through presynaptic P/Q-type calcium channels thus decreasing neuronal excitation [21]. The inhibition of glutamate release in our patient’s brain led to improvement and preservation in brain function by decreasing excitatory states in his brain and assisting in improved fever regulation. Hence, we theorize that the inhibition of action potential via utilization of levetiracetam halted the progression of neuronal damage in this patient thus preserving cognitive function despite a temperature of 41.6 °C (106.9 °F).Fig. 1 Computed tomography scan of brain without contrast showing brain atrophy disproportionately advanced for patient’s age. Arrows pointing to areas of atrophy\n\n\n\n\nIn the absence of pharmacological intervention with levetiracetam, a comatose state would have continued with persistent vegetative state given the excitatory state caused by glutamate release from damaged neurons; his comatose state would have become irreversible without intervention. As shown by his positive response to the regimen with levetiracetam within 48 hours of treatment, there is evidence to support that the treatment response in this patient was due to our pharmacological intervention. Without the prescribed regimental intervention, he had remained in a vegetative state for 21 days. However, within 9 days of treatment with levetiracetam, his cognitive function improved to the point that he was out of a comatose state and able to verbalize complaints (Fig. 2). Sepsis remained despite the cognitive intervention; leukocytosis persisted due to septic emboli from endocarditis requiring aortic valve replacement which was not performed during admission. He remained on antibiotic treatment even after discharge from our hospital and remained with persistent leukocytosis (Table 1).Fig. 2 \na Changes in core temperature. b Glasgow Coma Score. c Immune response before and after levetiracetam administration. WBC white blood cells\n\n\nTable 1 Choice of antibiotics based on antibiotics sensitivity studies\n\nDay\tWBC count (Range)\tTemperature maximum\tAntibiotic regimen based on culture and sensitivity studies\tMicroorganism\t\n1–7\t11.9–18.6\t37.1 °C (98.7 °F)\tPiperacillin-tazobactam 3.375 g intravenously Q 8 hours. Vancomycin 1 g intravenously Q 12 hours\t\nK. pneumoniae – sputum\t\n8–13\t10.6–29.5\t41.6 °C (106.9 °F)\tLevofloxacin 500 mg intravenously Q 48 hours. Micafungin 100 mg intravenously Q daily\t\nK. pneumoniae – sputum. C. albicans – blood\t\n14–22\t9.1–22.1\t38.9 °C (102 °F)\tLevofloxacin 500 mg intravenously Q 48 hours\t\nC. albicans – blood and sputum\t\n23–30\t12.1–20.9\t39.7 °C (103.4 °F)\tFluconazole 100 mg/50 ml, 100 mg Q 24 hours\t\nC. albicans – blood\t\n31–41\t13.9–29.7\t36.7–39.4 °C (98–103 °F)\tLevofloxacin 500 mg intravenously Q 48 hours. Piperacillin-tazobactam 3.375 g intravenously Q 8 hours\t\nP. aeruginosa – stool and wound\t\n42–49\t12.6–17.5\t36.7–39.4 °C (98–103 °F)\tDaptomycin 500 mg intravenously Q 8 hours\t\nS. epidermidis – skin, stool, blood\t\n50–57\t7.2–17.5\t36.8–39.4 °C (98.3–102.9 °F)\tMetronidazole 500 mg intravenously Q 8 hours. Linezolid 600 mg/300 ml Q 12 hours\tMRSA – sputum. C. difficile – stool\t\n58–67\t10.1–15.9\t36.5–37.6 °C (97.7–99.7 °F)\tLevofloxacin 750 mg intravenously Q 24 hours. Daptomycin 500 mg intravenously Q 8 hours\tMRSA – sputum\t\n68–78\t7.3–18.2\t36.5–39.0 °C (97.7–102.2 °F)\tVancomycin 1 g intravenously Q 12 hours. Imipenem 500 mg intravenously Q 8 hours\tMRSA – Blood\t\nC. albicans Candida albicans, C. difficile Clostridium difficile, K. pneumonia Klebsiella pneumoniae, MRSA methicillin-resistant Staphylococcus aureus, P. aeruginosa Pseudomonas aeruginosa, Q every, S. epidermidis Staphylococcus epidermidis, WBC white blood cells\n\n\n\n\nThe role of amantadine in this case was that of neurocognitive stimulation via dopamine agonist effects. In addition, amantadine has neuroprotective properties via inhibition of glutamatergic N-methyl-D-aspartate (NMDA) receptor reducing the release of proinflammatory factors from activated microglia and increasing the expression of glial cell line-derived neurotrophic factor (GNDF) in astroglia. Wakefulness, a function associated with dopamine, was further improved with the use of amantadine in this patient [22, 23].\n\nPrior to treatment with amantadine, our patient was noted to have increased latency of response to questions following recovery from comatose state. Following initiation of amantadine 50 mg/mL via PEG tube daily on day 34 and 100 mg/mL via PEG tube daily on day 41, there was improvement in his cognitive speed as measured by improvement in speed of response, ability to initiate conversations, and spontaneous report of complaints. His GCS was 15 following the combined pharmacological intervention with levetiracetam and amantadine.\n\nLimitations\nOur inability to obtain a magnetic resonance imaging (MRI) of his brain due to unavailability at our facility limits our evaluation of the structures of his brain following recovery from a coma. CSF analyses were not able to be obtained because he was on broad spectrum antibiotics and it was not deemed medically necessary at the time.\n\nConclusions\nPhysicians should be aware that the combination of hyperpyrexia and cognitive changes including coma cause poor recovery due to neuronal brain damage. The utilization of levetiracetam and amantadine may provide neuroprotective and neurorestorative effects following hyperpyrexia with coexisting cognitive decline. Our case depicts the successful use of both medications in restoring cognitive function following hyperpyrexia with extensive comatose state. Given the successful recovery achieved in this case, we suggest that further research, such as randomized controlled trials, need to be explored in similar cases to harness the benefits of the conceptualization depicted in this case report.\n\nAbbreviations\nCSFCerebrospinal fluid\n\nCTComputed tomography\n\nEEGElectroencephalogram\n\nEGDEsophagogastroduodenoscopy\n\nGABAGamma-aminobutyric acid\n\nGCSGlasgow Coma Score\n\nGNDFGlial cell line-derived neurotrophic factor\n\nMRIMagnetic resonance imaging\n\nMRSAMethicillin-resistant Staphylococcus aureus\n\n\nNMDAN-methyl-D-aspartate\n\nOVLTOrganum vasculosum laminae terminalis\n\nPEGPercutaneous endoscopic gastrostomy\n\nTCATricarboxylic acid\n\nTmaxMaximum core temperature\n\nWBCWhite blood cell\n\nAcknowledgements\nWe thank Dr JD Suarez, MD – family medicine physician – for guiding the treatment plan in this case.\n\nFunding\nThere is no external source of funding.\n\nAvailability of data and materials\nSupporting materials are available only for testing by reviewers in a way that preserves our index patient’s anonymity.\n\nAuthors’ contributions\nBoth SS and AA performed the bibliographic search and drafted the paper; MASG contributed to conception, analysis, and interpretation of data and reviewed the paper; GM reviewed the paper for important intellectual content. All authors read and approved the paper.\n\nCompeting interests\nThe authors declared no potential conflict of interests with respect to the research, authorship, and/or publication of this paper. The work on the present paper was not funded by any source.\n\nConsent for publication\nWritten informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nEthics approval and consent to participate\nNot applicable.\n==== Refs\nReferences\n1. Lee-Chiongr TL Stitt JT Disorders of temperature regulation Compr Ther 1995 21 12 697 704 8789133 \n2. Loscalzo J, Fauci A, Braunwald E, Dennis KL, Hauser SL, Longo DL. Chapter 17, Fever versus hyperthermia. Harrison’s principles of internal medicine. McGraw-Hill Medical; 2008. ISBN 0-07-146633-9.\n3. Minamisawa H Smith ML Siesjö BK The effect of mild hyperthermia and hypothermia on brain damage following 5, 10, and 15 minutes of forebrain ischemia Ann Neurol 1990 28 1 28 33 10.1002/ana.410280107 \n4. Gale K Role of the substantia nigra in GABA-mediated anticonvulsant actions Adv Neurol 1986 44 343 64 3010676 \n5. Treiman DM GABAergic mechanisms in epilepsy Epilepsia 2001 42 3 8 12 10.1046/j.1528-1157.2001.042suppl.3008.x 11520315 \n6. Schousboe A Scafidi S Bak LK Waagepetersen HS McKenna MC Glutamate metabolism in the brain focusing on astrocytes Adv Neurobiol 2014 11 13 30 10.1007/978-3-319-08894-5_2 25236722 \n7. Rothman SM Olney JW Glutamate and the pathophysiology of hypoxic-ischemic brain damage Ann Neurol 1986 19 2 105 11 10.1002/ana.410190202 2421636 \n8. Zeisberger E Merker G Circumventricular organs and brain fluid environment – molecular and functional aspects Prog Brain Res 1992 91 1 403 8 10.1016/S0079-6123(08)62359-6 1410426 \n9. Huanga WT Tsaib SM Lin MT Involvement of brain glutamate release in pyrogenic fever Neuropharmacology 2001 41 7 811 8 10.1016/S0028-3908(01)00120-4 11684145 \n10. Ahishali B Kaya M Effects of levetiracetam on blood–brain barrier disturbances following hyperthermia-induced seizures in rats with cortical dysplasia Life Sci 2010 87 19–22 609 19 10.1016/j.lfs.2010.09.014 20875430 \n11. Vogl C Mochida S Wolff C Whalley BJ Stephens GJ The synaptic vesicle glycoprotein 2A ligand levetiracetam inhibits presynaptic Ca2+ channels through an intracellular pathway Mol Pharmacol 2012 82 2 199 208 10.1124/mol.111.076687 22554805 \n12. White MG Luca LE Nonner D Saleh O Hu B Barrett EF Barrett JN Cellular mechanisms of neuronal damage from hyperthermia Prog Brain Res 2007 162 347 71 10.1016/S0079-6123(06)62017-7 17645927 \n13. Fry M Ferguson AV The sensory circumventricular organs: Brain targets for circulating signals controlling ingestive behavior Physiol Behav 2007 91 4 413 23 10.1016/j.physbeh.2007.04.003 17531276 \n14. Brann DW Glutamate: a major excitatory transmitter in neuroendocrine regulation Neuroendocrinology 1995 51 3 213 25 \n15. Werner P Pitt D Raine CS Glutamate excitotoxicity – a mechanism for axonal damage and oligodendrocyte death in Multiple Sclerosis? J Neural Transm Suppl 2000 60 375 85 \n16. McAllister TW Neurobiological consequences of traumatic brain injury Dialogues Clin Neurosci 2011 13 3 287 300 22033563 \n17. MacDonald JF Xiong ZG Jackson MF Paradox of Ca2+ signaling, cell death and stroke Trends Neurosci 2006 29 2 75 81 10.1016/j.tins.2005.12.001 16376999 \n18. Falini A Barkovich AJ Calabrese G Origgi D Triulzi F Scotti G Progressive brain failure after diffuse hypoxic ischemic brain injury: a serial MR and proton MR spectroscopic study AJNR Am J Neuroradiol 1998 19 4 648 52 9576649 \n19. Mrozek S Vardon F Geeraerts T Brain temperature: physiology and pathophysiology after brain injury Anesthesiol Res Pract 2012 2012 1 13 10.1155/2012/989487 \n20. Gupta YK Gupta M Post traumatic epilepsy: a review of scientific evidence Indian J Physiol Pharmacol 2006 50 1 7 16 16850898 \n21. Lee CY Chen CC Liou HH Levetiracetam inhibits glutamate transmission through presynaptic P/Q-type calcium channels on the granule cells of the dentate gyrus Br J Pharmacol 2009 158 7 1753 62 10.1111/j.1476-5381.2009.00463.x 19888964 \n22. Sawyer E Mauro LS Ohlinger MJ Amantadine enhancement of arousal and cognition after traumatic brain injury Ann Pharmacother 2008 42 2 247 52 10.1345/aph.1K284 18212258 \n23. Laupland KB Shahpori R Kirkpatrick AW Gregson DB Stelfox HT Occurrence and outcome of fever in critically ill adults Crit Care Med 2009 36 5 1531 5 10.1097/CCM.0b013e318170efd3\n\n",
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"keywords": "Amantadine; Glasgow Coma Score; Glutamate; Hyperpyrexia; Levetiracetam; Neuroprotection; Organum vasculosum laminae terminalis",
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"mesh_terms": "D000328:Adult; D000547:Amantadine; D000927:Anticonvulsants; D001921:Brain; D001930:Brain Injuries; D003072:Cognition Disorders; D003128:Coma; D015259:Dopamine Agents; D004359:Drug Therapy, Combination; D018698:Glutamic Acid; D006801:Humans; D000077287:Levetiracetam; D008297:Male; D008305:Malignant Hyperthermia; D010889:Piracetam; D014057:Tomography, X-Ray Computed",
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"title": "Preserving brain function in a comatose patient with septic hyperpyrexia (41.6 °C): a case report.",
"title_normalized": "preserving brain function in a comatose patient with septic hyperpyrexia 41 6 c a case report"
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"abstract": "We retrospectively investigated drug retention rate (DRR) and reasons for discontinuation of seven biologic disease-modifying anti-rheumatic drugs (bDMARDs) in Takayasu's arteritis (TA) in a real-world setting.\n\n\n\nTA patients followed-up in our center fulfilling the 1990 ACR criteria and treated with ≥1 bDMARD were selected. Data about disease duration, number of bDMARDs, reasons for bDMARDs discontinuation, and concomitant conventional synthetic (cs)DMARDs were collected. Survival curves were examined by the Kaplan-Meier method and compared using a stratified log-rank test. 24-month DRR was calculated. Hazard ratio (HR) for concomitant csDMARDs and for previous bDMARDs was evaluated. A comparative sub-analysis between anti-TNFα drugs and tocilizumab was performed.\n\n\n\nWe identified 50 patients and 86 bDMARD-courses. No significant differences were observed in age and disease duration between the seven groups. Infliximab was the most frequent first-line bDMARD (78.6%). At bDMARDs initiation, all patients were prescribed prednisone (mean dose, 13.5 ± 10.3 mg/day) and 85.2% concomitant csDMARD therapy. 43% of treatment courses were stopped by 24 months. Golimumab had the highest DRR (71.4%), followed by infliximab (69%), adalimumab (56.3%), abatacept (50%), tocilizumab (41.1%), anakinra (0%) and rituximab (0%), p = 0.016. Concomitant csDMARDs therapy showed positive effects on DRR (HR=2.87, 95% CI=1.19-6.92, p = 0.019). Anti-TNFα drugs had significantly higher DRR compared to tocilizumab (67.2% vs 41.1%, p = 0.028). Even in these subgroups, csDMARDs showed positive effects on DRR (HR=3.79, 95% CI=1.49-9.6, p = 0.005).\n\n\n\nAnti-TNFα agents had the highest DRR overall and a higher DRR in a head-to-head comparison with tocilizumab. Concomitant csDMARDs had a significant positive effect on bDMARDs DRR.",
"affiliations": "Unit of Immunology, Rheumatology, Allergy and Rare diseases, IRCCS San Raffaele Hospital, Milan, Italy; Vita-Salute San Raffaele University, Via Olgettina 60, 20132 Milan, Italy. Electronic address: campochiaro.corrado@hsr.it.;Unit of Immunology, Rheumatology, Allergy and Rare diseases, IRCCS San Raffaele Hospital, Milan, Italy; Vita-Salute San Raffaele University, Via Olgettina 60, 20132 Milan, Italy.;Unit of Immunology, Rheumatology, Allergy and Rare diseases, IRCCS San Raffaele Hospital, Milan, Italy; Vita-Salute San Raffaele University, Via Olgettina 60, 20132 Milan, Italy.;Unit of Immunology, Rheumatology, Allergy and Rare diseases, IRCCS San Raffaele Hospital, Milan, Italy; Vita-Salute San Raffaele University, Via Olgettina 60, 20132 Milan, Italy.;Unit of Immunology, Rheumatology, Allergy and Rare diseases, IRCCS San Raffaele Hospital, Milan, Italy; Vita-Salute San Raffaele University, Via Olgettina 60, 20132 Milan, Italy.;Unit of Immunology, Rheumatology, Allergy and Rare diseases, IRCCS San Raffaele Hospital, Milan, Italy.;Unit of Immunology, Rheumatology, Allergy and Rare diseases, IRCCS San Raffaele Hospital, Milan, Italy; Vita-Salute San Raffaele University, Via Olgettina 60, 20132 Milan, Italy.",
"authors": "Campochiaro|Corrado|C|;Tomelleri|Alessandro|A|;Sartorelli|Silvia|S|;Cavalli|Giulio|G|;De Luca|Giacomo|G|;Baldissera|Elena|E|;Dagna|Lorenzo|L|",
"chemical_list": "D018501:Antirheumatic Agents; D001685:Biological Factors; D000079424:Tumor Necrosis Factor Inhibitors",
"country": "United States",
"delete": false,
"doi": "10.1016/j.semarthrit.2020.01.005",
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"issn_linking": "0049-0172",
"issue": "50(3)",
"journal": "Seminars in arthritis and rheumatism",
"keywords": "Anti-TNF; Biologic agents; Retention rate; Takayasu arteritis; Tocilizumab; Treatment",
"medline_ta": "Semin Arthritis Rheum",
"mesh_terms": "D000328:Adult; D018501:Antirheumatic Agents; D001685:Biological Factors; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D055118:Medication Adherence; D008875:Middle Aged; D012189:Retrospective Studies; D013625:Takayasu Arteritis; D000079424:Tumor Necrosis Factor Inhibitors",
"nlm_unique_id": "1306053",
"other_id": null,
"pages": "509-514",
"pmc": null,
"pmid": "32088012",
"pubdate": "2020-06",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Drug retention and discontinuation reasons between seven biologics in patients with Takayasu arteritis.",
"title_normalized": "drug retention and discontinuation reasons between seven biologics in patients with takayasu arteritis"
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"companynumb": "IT-ROCHE-2667322",
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"activesubstancename": "ANAKINRA"
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"abstract": "Spondylodiscitis due to Candida is a rare complication from hematogenic dissemination of infection caused by this fungus. We present an atypical case of spondylodiscitis caused by this germ that occurred after chest contusion and progressed with necrotizing fasciitis of the anterior region of the chest and osteomyelitis of the sternum. Through contiguity, it also affected the upper thoracic spine. The patient evolved with neurological alterations and recovered satisfactorily after appropriate treatment with surgical decompression of the spinal cord and specific antibiotic therapy.",
"affiliations": "Orthopedics and Traumatology Service, Hospital de Clínicas, Universidade Federal do Paraná (UFPR), Curitiba, PR, Brazil; Hospital do Trabalhador, Universidade Federal do Paraná (UFPR), Curitiba, PR, Brazil.;Orthopedics and Traumatology Service, Hospital de Clínicas, Universidade Federal do Paraná (UFPR), Curitiba, PR, Brazil; Hospital do Trabalhador, Universidade Federal do Paraná (UFPR), Curitiba, PR, Brazil.;Orthopedics and Traumatology Service, Hospital de Clínicas, Universidade Federal do Paraná (UFPR), Curitiba, PR, Brazil; Hospital do Trabalhador, Universidade Federal do Paraná (UFPR), Curitiba, PR, Brazil.;Orthopedics and Traumatology Service, Hospital de Clínicas, Universidade Federal do Paraná (UFPR), Curitiba, PR, Brazil; Hospital do Trabalhador, Universidade Federal do Paraná (UFPR), Curitiba, PR, Brazil.;Orthopedics and Traumatology Service, Hospital de Clínicas, Universidade Federal do Paraná (UFPR), Curitiba, PR, Brazil; Hospital do Trabalhador, Universidade Federal do Paraná (UFPR), Curitiba, PR, Brazil.",
"authors": "Kulcheski|Álynson Larocca|ÁL|;Graells|Xavier Soler|XS|;Benato|Marcel Luiz|ML|;Santoro|Pedro Grein Del|PG|;Sebben|André Luis|AL|",
"chemical_list": null,
"country": "Brazil",
"delete": false,
"doi": "10.1016/j.rboe.2015.10.005",
"fulltext": "\n==== Front\nRev Bras OrtopRev Bras OrtopRevista Brasileira de Ortopedia2255-4971Elsevier S2255-4971(15)00147-010.1016/j.rboe.2015.10.005Case ReportFungal spondylodiscitis due to Candida albicans: an atypical case and review of the literature☆ Espondilodiscite fúngica por Candida albicans: um caso atípico e revisão da literatura Kulcheski Álynson Larocca alylarocca@gmail.comalynson_larocca@hotmail.comab⁎Graells Xavier Soler abBenato Marcel Luiz abSantoro Pedro Grein Del abSebben André Luis aba Orthopedics and Traumatology Service, Hospital de Clínicas, Universidade Federal do Paraná (UFPR), Curitiba, PR, Brazilb Hospital do Trabalhador, Universidade Federal do Paraná (UFPR), Curitiba, PR, Brazil⁎ Corresponding author. alylarocca@gmail.comalynson_larocca@hotmail.com18 10 2015 Nov-Dec 2015 18 10 2015 50 6 739 742 18 8 2014 14 11 2014 © 2015 Sociedade Brasileira de Ortopedia e Traumatologia. Published by Elsevier Editora Ltda. All rights reserved.2015Sociedade Brasileira de Ortopedia e TraumatologiaThis is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Spondylodiscitis due to Candida is a rare complication from hematogenic dissemination of infection caused by this fungus. We present an atypical case of spondylodiscitis caused by this germ that occurred after chest contusion and progressed with necrotizing fasciitis of the anterior region of the chest and osteomyelitis of the sternum. Through contiguity, it also affected the upper thoracic spine. The patient evolved with neurological alterations and recovered satisfactorily after appropriate treatment with surgical decompression of the spinal cord and specific antibiotic therapy.\n\nResumo\nA espondilodiscite por Candida albicans é uma rara complicação da disseminação hematogênica da infecção por esse fungo. Apresentamos um caso atípico de espondilodiscite por esse germe ocorrido após trauma contuso torácico que cursou com fasceíte necrotizante da região anterior do tórax, osteomielite de esterno e, por contiguidade, afetou a coluna vertebral torácica alta. O paciente evoluiu com alteração neurológica e recuperou-se satisfatoriamente após tratamento adequado com descompressão medular cirúrgica e antibioticoterapia específica.\n\nKeywords\nCandida albicansDiscitisSpinal diseasesPalavras-chave\nCandida albicansDisciteDoenças da coluna vertebral\n==== Body\nIntroduction\nSpinal cord infections are rare and comprise approximately 1% of bone infectious involvement.1 Most of these infections are of pyogenic or tuberculous origin. Fungal infections are increasing, but are still extremely rare and occur more as opportunistic infections in immunocompromised individuals.2 Despite the increased frequency, infection by Candida albicans is not common.3 We report an unusual case of thoracic spondylodiscitis caused by C. albicans. The literature was reviewed, aiming to better understanding the subject.\n\nCase report\nThe patient was a 39-year-old homeless, chronic alcoholic male individual. He fell two meters to the ground in October 2012. He was treated in a trauma hospital, where he showed signs of septic shock, hyperemia and crackles in the sternal region, with 10 cm in diameter. Chest radiography and computed tomography (CT) showed pre-sternal subcutaneous emphysema and signs of sternum fracture, and culminated with a diagnosis of anterior chest wall necrotizing fasciitis (Fig. 1). Surgical debridement was performed in this region. The result of the of sternum soft tissue culture was positive for multisensitive Escherichia coli and the result of the sternal bone fragment culture for C. albicans was positive. Treatment with fluconazole (6 mg/kg/day) and Ciprofloxacin (400 mg 12/12 h) was started and drug use was scheduled for six months, initially intravenously and, after clinical improvement, by oral route. The patient developed vertebral osteomyelitis signs, with decreased height of the vertebral bodies and discs at the thoracic spine levels of T4–T5–T6 (Fig. 2). The patient was paralyzed, with altered sensitivity at the T4 level, compatible with Frankel B. Initial Cobb angle of 68° (Fig. 3) was observed. The patient underwent thoracotomy, which disclosed a spinal abscess and a large amount of purulent secretion. A corpectomy was performed from T4 to T6 with autologous iliac graft replacement and comprehensive spinal decompression in T4. There was improvement of pain complaints in the thoracic spine, with fever disappearance and improvement to Frankel C. At a second procedure, he was submitted to posterior fixation and arthrodesis with pedicle screws at the level of the thoracic spine from T3 to T7 (Fig. 4).\n\nPostoperatively, he showed improvement of 13° of kyphosis in the Cobb angle and remained at 55° (Fig. 4, Fig. 5). After eight months of the diagnosis, the patient showed improvement of the neurological level to Frankel D at the T4 level. Upon assessment at 12 months after the first diagnosis, the wounds were healed and he showed significant improvement in the thoracic kyphosis (Fig. 5). The patient was well, communicative, independent in relation to self-care, and managed to perform his activities without assistance or difficulty. During hospitalization the Oswestry Disability Index 2.0 was applied preoperatively and after the definitive surgical procedure. Preoperatively, he scored 70% and was classified as disabled. Postoperatively, the index was 25%, which showed good results in the pain/disability item.\n\nDiscussion\nDespite the increase in the frequency of fungemia, infection by C. albicans is also a rare cause of spinal infection.3 The main risk factors are: prior antibiotic therapy, ICU stay, long-term catheter use, corticosteroids, intravenous drugs, transplants and chemotherapy.1, 2, 4, 5 In our case, the patient was alcoholic, homeless and immunocompromised.\n\nThe most common location of spondylodiscitis by Candida is in the lumbar spine, and the presence of neurological deficit is infrequent.2\n\nIn 2001, Miller6 described 59 cases of spinal infection by Candida, 33 affecting the lumbar spine, 17 the chest, three the cervical and six both the thoracic and lumbar spine.\n\nIn our case, the upper thoracic region was affected and there was neurological deficit, in contrast to the literature. This condition is usually insidious. The most useful clinical finding is pain in the affected area, both bone and paravertebral types.7 The paraplegia was noteworthy in our case. An association was observed between chest trauma and the spinal injury, a fact validated by literature.8\n\nWhen C. albicans affects the spine, it usually causes disk narrowing, destruction of the endplates and the subjacent vertebral bone.4 These imaging findings are consistent with what we found in our case.\n\nThe optimized management of spinal infections by Candida remains unclear. Case reports such as this one help to increase the experience in the management and treatment of this disease.\n\nSurgical treatment is not required in spondylodiscitis by Candida. However, it should be performed in cases where there is neurological deficit and vertebral instability.4, 5 In the present report, the patient had neurological deficit (Frankel B) and vertebral instability, characterized by kyphosing of the thoracic spine.\n\nClinical treatment is carried out with antifungal drugs, using amphotericin B or fluconazole. One proposed treatment consists of 6–10 weeks of Amphotericin B IV at a dose of 0.5–0.6 mg/kg/day.9 Studies have shown that Fluconazole is as effective as amphotericin, showing higher safety and tolerability. In our institution, we chose to carry out the treatment with fluconazole.\n\nStudies have documented that diagnostic delay is common.10 That is attributed to the rare occurrence and difficulty in cultivating the microorganisms. It has been suggested that a delay in the start of antifungal therapy is associated with a worse outcome, particularly the neurological one.10 We believe that our success was due to the early diagnosis and confirmation by biopsy and the sternum bone culture, as well as the identification of spinal cord compression. The treatment was promptly carried out with spinal decompression, rapid microbiological results and start of specific antifungal treatment.\n\nSpondylodiscitis by Candida should be considered in immunocompromised patients. The definitive diagnosis is achieved through isolation of C. albicans in blood or cultures. The antifungal treatment often results in the cure, even in cases of delayed diagnosis. When there is neurological instability or deficit, surgical treatment should be considered.\n\nConflicts of interest\nThe authors declare no conflicts of interest.\n\n☆ Study carried out at the Orthopedics and Traumatology Service, Hospital de Clínicas, Universidade Federal do Paraná (UFPR) and Hospital do Trabalhador, Universidade Federal do Paraná (UFPR), Curitiba, PR, Brazil.\n\nFig. 1 Initial aspect of the sternum lesion.\n\nFig. 2 CT scans in the sagittal, axial and coronal sections.\n\nFig. 3 Cobb angle in the preoperative period between T2 and T7.\n\nFig. 4 postoperative AP and profile radiographies.\n\nFig. 5 Clinical evolution 12 months after the initial diagnosis.\n==== Refs\nReferences\n1 Ghanayem A.J. Zdeblick T.A. Cervical spine infections Orthop Clin North Am 27 1 1996 53 67 8539053 \n2 Broner F.A. Garland D.E. Zigler J.E. Spinal infections in the immunocompromised host Orthop Clin North Am 27 1 1996 37 46 8539051 \n3 Johnson M.D. Perfect J.R. Fungal infections of the bones and joints Curr Infect Dis Rep 3 5 2001 450 460 11559466 \n4 Gathe J.C. Jr. Harris R.L. Garland B. Bradshaw M.W. Williams T.W. Jr. Candida osteomyelitis. Report of five cases and review of the literature Am J Med 82 5 1987 927 937 3555067 \n5 Almekinders L.C. Greene W.B. Vertebral Candida infections. A case report and review of the literature Clin Orthop Relat Res 267 1991 174 178 2044273 \n6 Miller D.J. Mejicano G.C. Vertebral osteomyelitis due to Candida species: case report and literature review Clin Infect Dis 33 4 2001 523 530 11462190 \n7 Smith A.S. Blaser S.I. Infectious and inflammatory processes of the spine Radiol Clin North Am 29 4 1991 809 827 2063006 \n8 Graells X.S. Zaninelli E.M. Collaço I.A. Nasr A. Cecílio W.A.C. Borges G.A. Thoracic injuries and spinal trauma: a complex association Coluna/Columna 7 1 2008 8 13 \n9 Rex J.H. Walsh T.J. Sobel J.D. Filler S.G. Pappas P.G. Dismukes W.E. Practice guidelines for the treatment of candidiasis. Infectious Diseases Society of America Clin Infect Dis 30 4 2000 662 678 10770728 \n10 Frazier D.D. Campbell D.R. Garvey T.A. Wiesel S. Bohlman H.H. Eismont F.J. Fungal infections of the spine. Report of eleven patients with long-term follow-up J Bone Joint Surg Am 83 4 2001 560 565 11315785\n\n",
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"journal": "Revista brasileira de ortopedia",
"keywords": "Candida albicans; Discitis; Spinal diseases",
"medline_ta": "Rev Bras Ortop",
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"title": "Fungal spondylodiscitis due to Candida albicans: an atypical case and review of the literature.",
"title_normalized": "fungal spondylodiscitis due to candida albicans an atypical case and review of the literature"
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"abstract": "We evaluated results of temozolomide (TMZ) therapy in six patients, aged 34-78 years, presenting aggressive pituitary tumors. In all the patients tested O(6)-methylguanine-DNA methyltransferase (MGMT) immunoexpression in surgical specimens was absent. Patients received temozolomide 140-320 mg/day for 5 days monthly for at least 3 months. In two patients minimum time for evaluation could not be reached because of death in a 76-year-old man with a malignant prolactinoma and of severe neutro-thrombopenia in a 47-year-old woman with nonfunctioning pituitary adenoma. In two patients (a 34-year-old acromegalic woman and a 39-year-old woman with Nelson's syndrome) no response was observed after 4 and 6 months, respectively, and the treatment was stopped. Conversely, two 52- and 42-year-old women with Cushing's disease had long-term total clinical and radiological remissions which persisted after stopping temozolomide. We conclude that TMZ therapy may be of variable efficacy depending on-until now-incompletely understood factors. Cooperative work on a greater number of cases of aggressive pituitary tumors should be crucial to establish the indications, doses, and duration of temozolomide administration.",
"affiliations": "Foundation of Endocrinology, 1425 Buenos Aires, Argentina.;Foundation of Endocrinology, 1425 Buenos Aires, Argentina.;Pathology Laboratory, Hospital Italiano, 1199 Buenos Aires, Argentina.;Division of Endocrinology, Hospital de Clínicas, University of Buenos Aires, 1120 Buenos Aires, Argentina.;Division of Endocrinology, Hospital de Clínicas, University of Buenos Aires, 1120 Buenos Aires, Argentina.;Division of Endocrinology, Hospital de Clínicas, University of Buenos Aires, 1120 Buenos Aires, Argentina.;Division of Endocrinology, Hospital de Clínicas, University of Buenos Aires, 1120 Buenos Aires, Argentina.",
"authors": "Bruno|Oscar D|OD|;Juárez-Allen|Lea|L|;Christiansen|Silvia B|SB|;Manavela|Marcos|M|;Danilowicz|Karina|K|;Vigovich|Carlos|C|;Gómez|Reynaldo M|RM|",
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"fulltext": "\n==== Front\nInt J EndocrinolInt J EndocrinolIJEInternational Journal of Endocrinology1687-83371687-8345Hindawi Publishing Corporation 10.1155/2015/587893Clinical StudyTemozolomide Therapy for Aggressive Pituitary Tumors: Results in a Small Series of Patients from Argentina Bruno Oscar D. \n1\n\n*\nJuárez-Allen Lea \n1\nChristiansen Silvia B. \n2\nManavela Marcos \n3\nDanilowicz Karina \n3\nVigovich Carlos \n3\nGómez Reynaldo M. \n3\n1Foundation of Endocrinology, 1425 Buenos Aires, Argentina2Pathology Laboratory, Hospital Italiano, 1199 Buenos Aires, Argentina3Division of Endocrinology, Hospital de Clínicas, University of Buenos Aires, 1120 Buenos Aires, Argentina*Oscar D. Bruno: bodomingo@intramed.netAcademic Editor: Andre P. Kengne\n\n2015 27 5 2015 2015 58789323 2 2015 6 5 2015 6 5 2015 Copyright © 2015 Oscar D. Bruno et al.2015This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.We evaluated results of temozolomide (TMZ) therapy in six patients, aged 34–78 years, presenting aggressive pituitary tumors. In all the patients tested O6-methylguanine-DNA methyltransferase (MGMT) immunoexpression in surgical specimens was absent. Patients received temozolomide 140–320 mg/day for 5 days monthly for at least 3 months. In two patients minimum time for evaluation could not be reached because of death in a 76-year-old man with a malignant prolactinoma and of severe neutro-thrombopenia in a 47-year-old woman with nonfunctioning pituitary adenoma. In two patients (a 34-year-old acromegalic woman and a 39-year-old woman with Nelson's syndrome) no response was observed after 4 and 6 months, respectively, and the treatment was stopped. Conversely, two 52- and 42-year-old women with Cushing's disease had long-term total clinical and radiological remissions which persisted after stopping temozolomide. We conclude that TMZ therapy may be of variable efficacy depending on—until now—incompletely understood factors. Cooperative work on a greater number of cases of aggressive pituitary tumors should be crucial to establish the indications, doses, and duration of temozolomide administration.\n==== Body\n1. Introduction\nAggressive pituitary tumors are invasive macroadenomas refractory to surgical and medical treatments, showing tendency to continuous growth and implicating a bad vital prognosis [1]. Until some years ago, no therapies were efficacious in treating that kind of tumors. First publications of treatment with the alkylating agent temozolomide (TMZ) appeared in 2006 [2, 3] and since then, variable responses to this drug have been reported in a limited number of cases with tumor volume reduction and control of the disease in some of them. We present here our experience with the use of temozolomide in six patients with different variants of aggressive pituitary tumors.\n\n2. Patients and Methods\nSix patients with intention-to-treat with TMZ, presenting different types of aggressive pituitary tumors, were evaluated. They were 5 women aged 34–52 and one 78-year-old man. They all presented macroadenomas (more than 10 mm) with cavernous sinus invasion, two of them with third par palsies and one with bitemporal hemianopsia. The only male patient had pituitary carcinoma (malignant prolactinoma) with an isolated parietal metastasis which was first biopsied and then surgically excised. All patients had had unsuccessful previous pituitary surgery (from 1 to 5 times), radiotherapy in 3, and conventional drug treatment in 4 of them, aimed at controlling hyperfunction and/or tumor volume (Table 1). The definition of aggressive pituitary tumor was based on clinical grounds (invasive macroadenomas refractory to surgical and medical treatments, showing tendency to continuous growth) as previously stated. We use the denomination pituitary carcinoma when extrapituitary presence of tumor (metastasis) is found. Temozolomide was administered as oral pills in variable doses, from 140 to 320 mg/day for 5 days every month, for at least 3 months before evaluating results. TMZ administration was preceded by the oral intake of ondansetron, as antiemetic prevention. Hematologic and liver function tests were performed before each cycle of therapy. Results of treatment were evaluated by monthly clinical examination and pituitary MRI after at least 3 months of therapy; computerized visual field examination and routine hormone tests were also made, when indicated.\n\nFor determinations of MGMT and marker of cell proliferation Ki67 on pathological specimens, all blocks were formalin buffer fixed and paraffin embedded. Cuts of 3-4 microns were made and stained with hematoxylin and eosin. Immunohistochemical determinations for adenohypophyseal hormones GH, FSH, LH, and TSH were made by using rabbit polyclonal Cell Marque (http://www.cellmarque.com/) antibodies whereas for PRL and ACTH, rabbit polyclonal DAKO (http://www.dako.com/) antibodies were employed. Ki67 and O6-methylguanine-DNA methyltransferase Ab-1 (MGMT) were measured by using mouse monoclonal antibodies from Thermo Scientific (http://www.thermoscientific.com/) in a 1 : 20 dilution. Immunostaining for MGMT was considered negative when lower than 10%.\n\n3. Results\n\nFigure 1 shows a MGMT-negative macrocorticotropinoma study of patient GM as compared to a MGMT-positive glioblastoma. Table 2 shows the results of MGMT and Ki67 immunohistochemistry, individual doses administered, length of therapy, and clinical outcome in the six patients.\n\nDrug therapy effect could not be evaluated in patients JB and SA because they failed to complete a 3-month treatment. JB had a malignant prolactinoma with brain metastases which deceased after the first administration of TMZ and SA developed severe thrombocytopenia and neutropenia after the first cycle of therapy. In two more patients TMZ was stopped after 4 (LC) and 6 (DDO) months of treatment, because it was considered ineffective in reducing tumor size. The two last patients having macrocorticotropinoma and Cushing's disease have been reported in detail elsewhere [4]. They showed clinical response after just 3-4 cycles of administration of TMZ with remission of ocular signs, normalization of cortisol alterations, and significant shrinkage (more than 50%) of the tumors, which completely disappeared one year later and, most interestingly, long time (19–30 months) after stopping therapy the patients remained well with no signs of tumor relapse [4].\n\n4. Discussion\nFrequency of pituitary tumors appears to be higher than previously suspected, as high as 1 in 1000 of the general population [5, 6]. They are usually benign and in most cases controlled by surgery, radiation, or medical treatments. In 2004 the World Health Organization defined as “atypical” those tumors exhibiting a MIB-1 (Ki-67) proliferative index >3%, strong p53 immunoreactivity, and increased mitotic activity [7]. They make up 15% of resected pituitary tumors [8]. Up to 45% of macroadenomas show signs of invasion of the sphenoid or cavernous sinus [9]. The concept of “aggressive” pituitary tumors represents a clinical appreciation to designate tumors that may recur quickly after surgery, grow into the cavernous sinus or skull base, and show resistance to the usual therapeutic means. The name pituitary carcinoma is reserved for those tumors with neural or extraneural metastases which make up less than 1% of the totality of pituitary tumors. It has to be emphasized that they do not show histological differences with other aggressive tumors save for the existence of metastases [10].\n\nSo called silent pituitary adenomas are tumors, mainly gonadotrope, corticotrope, and somatotrope, having an aggressive behavior, with frequent recurrences which made up 9% in 100 samples studied retrospectively [11]. They can be classified as “silent,” with immunohistochemical evidence but no biochemical or clinical evidence of hormone excess, or “clinically silent” with immunohistochemical and biochemical evidence but no clinical evidence of hormone excess.\n\nTemozolomide is an alkylating drug which has been used mainly in the treatment of glioblastoma multiforme but also for colorectal cancer and melanoma [12–14]. This drug has been used for the treatment of pituitary carcinoma and aggressive adenoma from the year 2006 onwards [2, 3]. Its mechanism of action is through sticking an alkyl group to DNA bases, principally guanine, which induces methylation. Subsequently, it provokes the fragmentation of DNA by repairing enzymes in its attempt to replace the alkylated bases [15]. Up to now, around 105 pituitary tumors treated with TMZ have been reported in the literature with variable results (Table 3) [4, 16–53]. More than half (~60%) were aggressive adenomas, the remaining being pituitary carcinomas. Most were functioning tumors, especially corticotropinomas and prolactinomas (~80%). Global efficacy of TMZ therapy oscillated between 55% for aggressive adenomas and 58% for pituitary carcinomas, but it has to be underlined that criteria for efficacy were quite diverse, going from variable reduction to “stabilization” in tumoral size. It has to be remarked that in none of the reported cases a sustained disappearance of tumor after stopping TMZ was described. As far as aggressive macrocorticotropinomas are concerned, we were able to find 37 published cases silent or with overt hypercortisolism. Once again, criteria employed to evaluate response were quite diverse. In just one of those cases [20], the tumor disappeared under treatment but if the patient was treated with a CAPTEM schema (capecitabine plus temozolomide) we cannot know which one of the two drugs was more effective.\n\nDoses of temozolomide usually recommended in neurology are adapted to body surface and oscillate from 150 to 200 mg/m2 [54]. Doses employed in our patients were variable, but generally lower than recommended. It has to be underlined that dose amount was mostly determined by availability following individual medical coverage. Interestingly, patients MC and GM who had total remission received fixed doses of 250 mg/d and 180 mg/d, respectively, while, if adapted to body surface area, those figures should have been 291–388 mg/d for MC and 273–364 mg/d for GM. The role that the DNA repairing systems may play in the effectiveness of temozolomide is controversial, especially concerning MGMT. This enzyme can reverse methylation of the guanine residues, thus antagonizing the effect of the drug. It has been reported that a low expression or the absence of this enzyme strongly correlates with the response to TMZ [15]. This has been challenged by other authors, who failed to find such a correlation [21, 23]. It has been proposed that the preservation of another enzyme system, MSH6 (DNA mismatch repair protein), correlated better with the response to TMZ than the absence of MGMT [23, 54].\n\nIn our series, the five patients in whom we were able to measure MGMT failed to show a significant expression (less than 5%); two of them having aggressive corticotropinoma had excellent clinical responses to temozolomide. Nevertheless, this does not enable us to extrapolate any conclusions at this respect, since two other MGMT-negative patients who completed the minimum period of treatment failed to show a response.\n\nFor a more rational use of TMZ several points deserve clarification: What should be the starting and maintenance doses? How can efficacy be defined? How long should the treatment be given? How big is the mutagenic risk? What is the recurrence risk after stopping TMZ? What is the probability of relapse with resistance to TMZ after stopping a successful therapy?\n\nIn conclusion, although less common, clinically aggressive pituitary tumors are not at all exceptional and pose special therapeutic challenges because surgery and radiotherapy are frequently useless and usual drug therapy is of variable and unpredictable efficacy. So called “silent” tumors appear to be particularly aggressive and, although less frequent, invasive corticotropinomas may present a difficult challenge as well, since besides local complications, they put life at risk because of the metabolic consequences of excess cortisol secretion. Temozolomide may be a salvage drug in selected cases, mainly in prolactinoma and corticotrope tumors. Cooperative work on a greater number of cases of aggressive pituitary tumors should be of the outmost importance to establish the indications, doses, and duration of temozolomide administration.\n\nAcknowledgments\nThe authors are deeply indebted to Drs. Mariano Volpacchio and Santiago Rossi, from the Centro de Diagnóstico Dr. Enrique Rossi, Buenos Aires, who generously provided gratuitous control MRI in patient MC.\n\nDisclosure\nThis paper was presented in part at The Endocrine Society Annual Meeting, Phoenix, AZ, 2013.\n\nConflict of Interests\nThe authors declare that they have no conflict of interests.\n\nFigure 1 The upper panel (a) shows a diffuse positive MGMT control (glioblastoma). The lower panel (b) corresponds to a negative MGMT immunostaining of macrocorticotropinoma in patient GM.\n\nTable 1 Main clinical traits of 6 patients with intention-to-treat with temozolomide.\n\nPatient\tSex\tAge\tTumor type\t\nNumber of previous surgeries\tRxT\tPrevious drug therapy\t\nJB\tM\t78\tPRL Ca\t1\tYes\tCAB\t\nSA\tF\t47\tCNFPA\t3\tNo\tCAB\t\nLC\tF\t34\tGH-oma\t2\tNo\tCAB, SSAs\t\nDDO\tF\t39\tNS\t2\tYes\tNone\t\nCM\tF\t42\tCD\t1\tNo\tNone\t\nGM\tF\t52\tCD\t5\tYes\tKNZ\t\n\nPRLCa: prolactin carcinoma; GH-oma: somatotropinoma; CNFPA: clinically nonfunctioning pituitary adenoma; NS: Nelson' syndrome; CD: Cushing's disease; RxT: radiotherapy; CAB: cabergoline; SSAs: somatostatin analogs; KNZ: ketoconazole.\n\nTable 2 Results of MGMT and Ki67 immunohistochemistry, doses, length of therapy, and clinical outcome in 6 patients with intention-to-treat with TMZ.\n\nPatient\tTumor type\tMGMT\tKi67\tTMZ mg/d\tMonths\tOutcome\t\nJB\tPRL Ca\t(−)\t10%\t140\t1\tDeath\t\nSA\tCNFPA\tND\t2%\t150\t1\tFailure\t\nLC\tGH-oma\t(−)\t3%\t320\t4\tFailure\t\nDDO\tNelson's\t(−)\t1%\t240\t6\tFailure\t\nCM\tCD\t(−)\t6%\t250\t13\tRemission\t\nGM\tCD\t(−)\t4%\t180\t29\tRemission\t\nTable 3 Literature update on aggressive pituitary adenomas and carcinomas.\n\nAuthor, year \n[reference]\tSex/age\tTumor type\tKi67 (%)\tMGMT\tTMZ (mg/m2) & schedule (no. cycles)\tMRI (% shrinkage)\tClinical outcome\t\nThearle et al., 2011 [16]\tM/50\tACTH SA Ad → Ca → NS\t31\tNA\t200 × 5/28 + CAP (4)\tReduced (75)\tDeath \t\n\n\n\t\nDillard et al., 2011 [17]\tM/56\tACTH Ad\t5-6\tNA\t150–200 × 5/28 (4)\tReduced (60)\tCR\t\n\n\n\t\nAnnamalai et al., 2012 [18]\tM/65\tACTH Ca\t5–15\tLow\t200 × 5/28 (15)\tPR of METS\t“Remained well”\t\n\n\n\t\nMoshkin et al., 2011 [19]\tM/46\tACTH SA Ad → Ca\t1–5\t(+)\t200 × 5/28 (16)\tNo change\tProgression\t\n\n\n\t\nZacharia et al., 2014 [20]\tM/50\tACTH Ad\t<5\t(−)\t\n150, 5/28 + CAP (30)\tSD\tPR\t\nF/46\tACTH Ad\t15–20\t(−)\t150, 5/28 + CAP (32)\tCR\tCR\t\nM/44\tACTH Ad\t<5\t(−)\t150, 5/28 (45) + CAP + A-SST\tCR\tCR\t\n\n\n\t\nRaverot et al., 2010 [21] \tM/31\tACTH Ca → NS\t20\t50 (+)\t150–200 × 5/28\tNo change\tNA\t\nM/49\tACTH Ad\t20\t<1\t150–200 × 5/28\tNo change\tNA\t\nM/38\tACTH Ca\t10\t30 (+)\t150–200 × 5/28\tSR\t“Significant response”\t\nF/42\tACTH Ad\t0.5\t0\t150–200 × 5/28 \tSR\t“Significant response”\t\nM/32\tPRL Ca\tNA\tNA\t150–200 × 5/28 (24)\tReduced (60), disappearance of METS\tNA\t\nM/52\tPRL Ad\t0.5\t30\t150–200 × 5/28 (8)\tNo change\tNA\t\nM/54\tPRL Ca\t1\t0\t150–200 × 5/28 (5)\tNo change\tNA\t\nF/30\tPRL Ca\t10\t100\t150–200 × 5/28 (3)\tNo change\tNA\t\n\n\n\t\nBush et al., 2010 [22] \tNA\tNull cell Ad\t<3\t—\t75 × 21/7 (10)\tReduced (20) \tStable\t\nNA\tACTH Ad\t18\t<10\t75 × 21/28 (11)\tReduced (80)\t“Improved”\t\nNA\tNF Ad\t<3\t10–50\t\n75 × 21/(13)\tSD\tSD\t\nNA\tNull cell Ad\t6\t>50\t75 × 21/7 (10)\tSD\tSD\t\nNA\tPRL Ad\tNA\t<10\t75 × 21/7 (11)\tReduced (80)\t“Improved”\t\nNA\tNull cell Ca\t>20\t>50\t75 × 21/7 (2)\tSD × 2 months\tNA\t\nNA\tNull cell Ca\t>20\t<10\t75 × 21/7 (7)\tProgression\tDeath\t\n\n\n\t\nHirohata et al., 2013 [23] \tM/59\tNF Ca\t74.6\t(+)\t150–200 × 5/28 (5)\tPR\tNA\t\nF/42\tACTH Ca\t3.4\t(−)\t150–200 × 5/28 (7)\tPR\tNA\t\nF/60\tPRL Ca\t18.7\t(−)\t150–200 × 5/28 (13)\tCR\tNA\t\nM/23\tNF Ca\t2.5\t(+)\t150–200 × 5/28 (7)\tSD\tNA\t\nF/53\tACTH Ca (Crooke cell)\t2.0\t(+)\t150–200 × 5/28 (20)\tCR\tNA\t\nF/60\tPRL Ca\t27.8\t(+)\t150–200 × 5/28 (12)\tPR\tNA\t\nM/57\tACTH Ca\t10\t(+)\t150–200 × 5/28 (8)\tSD\tNA\t\nF/73\tNF Ca\t5.6\t(−)\t150–200 × 5/28 (22)\tPR\tNA\t\nM/60\tPRL Ca\t40.2\t(−)\t150–200 × 5/28 (24)\tPR\tNA\t\nF/61\tNF Ca\t12.2\t(+)\t75 × 6 weeks + RT \tProgression\tNA\t\nF/66\tPRL Ad\t9.4\t(−)\t75 × 6 weeks + RT\tCR\tNA\t\nF/49\tPRL Ad\t3.9\t(−)\tNA (3)\tProgression\tNA\t\nF/45\tACTH Ad (Crooke cell)\t46.8\t(+)\t150–200 × 5/28 (11)\tPR\tNA\t\n\n\n\t\nLosa et al., 2010 [24] \tM/64\tACTH Ad\tNA\tNA\t150–200 × 5/28\tProgression\tDeath\t\nM/52\tACTH Cd\t1\t(−)\t150–200 × 5/28\t“Response”\tRequired GC therapy\t\nF/55\tACTH Ad → NS\t5\t(−)\t150–200 × 5/28\tSD\tNA\t\nF/53\tACTH Ad\t2.5\t(+)\t150–200 × 5/28\tProgression\tNo change\t\nM/62\tPRL Ad\t9\t(−)\t150–200 × 5/28\tSD\tNA\t\nF/57\tPRL Ad\tNA\tNoninformative\t150–200 × 5/28\t“Response”\t“Improved”\t\n\n\n\t\nMoyes et al., 2009 [25]\tF/64\tACTH Ad → NS\t“High”\t(−)\t200 × 5/28 (6)\t“Marked shrinkage”\t“Improved”\t\n\n\n\t\nTakeshita et al., 2009 [26]\tF/46\tACTH Ca → NS\t~3\t<5 (−)\t150–200 × 5/28 (23)\tCR tumor + METS\tRequired GC therapy\t\n\n\n\t\n\nCurtò et al., 2010 [27]\tM/42\tACTH Ca\t2–18\t<5 (−)\t150–200 × 5/28 (17)\tReduced (>90) \t“Improved”\t\n\n\n\t\nMohammed et al., 2009 [28] \tF/43\tACTH Ad\tNA\t(−)\t150–200 × 5/28 (12)\tPR\t“Improved”\t\nM/60\tACTH Ca → NS\tNA\t(+)\t150–200 × 5/28 (12)\tPR\t“Improved”\t\n\n\n\t\nBode et al., 2010 [29]\tNA\tACTH Ca → NS\tNA\tNA\t150 × 5/28\tPR\tNA\t\n\n\n\t\nJouanneau et al., 2012 [30]\tNA\tSA → Ca\tNA\tNA\t200 × 5/28\tNR\tNA\t\n\n\n\t\nAsimakopoulou et al., 2014 [31]\tF/55\tACTH Ad (Crooke cell)\t1\tNA\t150–200 × 5/28\tCR\tCR\t\n\n\n\t\nBengtsson et al., 2015 [32] \tF/71\tACTH Ad\t50\t90\t150–200 × 5/28\tSD\tNA\t\nF/31\tGH Ad\t7\t9–100\t150–200 × 5/28 (6)\tReduced (50)\tRegrowth after TMZ stop\t\nF/13\tGH Ad\t5\t95\t150–200 × 5/28\tNA\tNA\t\nM/33\tPRL-GH Ad\t23\t10\t150–200 × 5/28 (3)\tReduced (35)\tSD 25 months after TMZ \t\nM/22\tPRL Ad\t8\t90\t150–200 × 5/28 (15)\tReduced (25)\tDeath\t\nM/34\tPRL Ad\t6\t9–100\t150–200 × 5/28 (4)\tStable 40 m after TMZ \tPR\t\nM/45\tPRL Ad\t2\t100\t150–200 × 5/28 (5)\tProgression\tPR\t\nM/55\tPRL Ad\t10\t20\t150–200 × 5/28 (11)\tReduced (66)\tDeath \t\nM/60\tPRL Ad\t2\t9\t150–200 + CAB (21)\tReduced (80)\tDeath\t\nM/68\tPRL Ad\tNA\t \t150–200 × 5/28\tProgression\tDeath\t\nM/23\tPRL Ad\t41\t100\t150–200 × 5/28 (4)\tProgression\tDeath\t\nM/22\tNF Ad \t2\t9\t150–200 × 5/28 (12)\tReduced (55)\tSD 69 m after TMZ \t\nM/45\tNF Ad\t2\t100\t150–200 × 5/28 (18)\tReduced (28) \tNA\t\nF/52\tNF Ad\t10\t90\t150–200 × 5/28 (5)\tProgression\tDeath\t\nM/59\tNF Ad\t10\t90\t150–200 × 5/28 (6)\tProgression\tDeath\t\nM/57\tNF Ad\t3.3\t95\t150–200 × 5/28\tProgression\tDeath\t\nM/51\tACTH Ca\t80\t0–60\t150–200 × 5/28\tNA\tDeath\t\nM/62\tACTH Ca (NS)\t10\t95\t150–200 × 5/28\tNA\tLost to follow-up\t\nM/70\tACTH Ca\t70\t9\t150–200 × 5/28\tNA\tNA\t\nM/46\tGH Ca\t60\t90\t150–200 × 5/28\tNA\tDeath\t\nF/40\tGH Ca\t20\t9\t150–200 × 5/28\tCR\tCR after 48 months\t\nF/49\tPRL-GH Ca\t5\t9\t150–200 × 5/28\tCR\tCR after 91 months\t\nF/32\tPRL Ca\t20\t50\t150–200 × 5/28\tNA\tDeath\t\nF/59\tPRL Ca\t10\tNA\t150–200 × 5/28\tNA\tPR\t\n\n\n\t\nVieira Neto et al., 2013 [33]\tF/54\tGH S Ca\t2.6\t68\t150–200 × 5/28\tSD\tNA\t\n\n\n\t\nMorokuma et al., 2012 [34]\tM/58\tNF Ca/NEM-1\t7.6\t(−)\t75/d × 42 days; then 192 × 5/28 + RT (20)\t“Visibly declined”\t“Improved” \t\n\n\n\t\nZhong et al., 2014 [35]\tF/30\tNF Ad\t20\tNA\t200/d × 5/4 consecutive weeks/2 months + RT (4)\tCR\tNA\t\n\n\n\t\nSyro et al., 2009 [36]\tM/70\tGn Ad\t2–6\t30–>50\t200 × 5/28 (6)\t“Minor reduction” and intratumoral necrosis\tDeath\t\n\n\n\t\nHagen et al., 2009 [37] \tF/48\tPRL Ad to mixed PRL-GH Ad to Ca\t5\t(−)\t150–200 + CAB/STT-A\tReduced (62)\t“Improved”\t\nM/60\tPRL Ad\t~2\t(−)\t150–200 + CAB\tReduced (80)\t“Improved”\t\nM/20\tNF Ad\t~2\tFew (+)\t150–200\tReduced (55)\t“Improved”\t\n\n\n\t\nMendola et al., 2014 [38]\tM/58\tNS Ca\t10\tNA\t160 × 5/28 (1)\tNo\tNo change\t\n\n\n\t\nStrowd et al., 2015 [39]\tF/44\tPRL Ad\tNA\tNA\t150–200 × 5/28 (3 months)\t“Reduction in tumor size”\tPR\t\n\n\n\t\nCeccato et al., 2015 [40] \tF/67\tNF Ad\t<3\tNA\t150–200 × 5/28\tProgression\tNo change\t\nF/39\tGH Ad\t<3\tNA\t150–200 × 5/28\tProgression\tNo change\t\nM/40\tNF Ad\t<3\tNA\t150–200 × 5/28\tDecreased (49) \tNA\t\nM/32\tACTH Ad\t<3\tNA\t150–200 × 5/28\tDecreased (63) \tNo change\t\nM/47\tNF Ad → ACTH\t<3\tNA\t150–200 × 5/28 + pasireotide\tDecreased (21)\tNo change\t\n\n\n\t\nPhilippon et al., 2012 [41]\tM/41\tPRL Ca/MEN-1\tNA\tNA\t200 × 5/28 (24)\tDecreased (62) \t“Improved”\t\n\n\n\t\nFadul et al., 2006 [42]\tM/38\tNF Ca \t1\tNA\t200 × 5/23 (12)\tPR \tPR\t\nM/26\tPRL Ca\t10\t \t200 × 5/23 (10)\tPR\tPR\t\n\n\n\t\nKovacs et al., 2007 [43]\tM/46\tPRL Ca\t40–60\tNA\t200 × 5/28 (7)\t“Shrinkage”\t“Improved”\t\n\n\n\t\nCornell et al., 2013 [44]\tM/40\tACTH Ad\t5–7\tNA\t200 × 5/28 (3)\tProgression\tNo change\t\n\n\n\t\nPhillips et al., 2012 [45]\tM/25\tPRL Ad\t23\tNA\t350 × 5 (1)\tNo change\tDeath\t\n\n\n\t\nRotondo et al., 2012 [46]\tF/49\tCrooke cell Ad\t5–8\t(−)\t85 p.o daily + SRT\tNA\tNA\t\n\n\n\t\nArnold et al., 2012 [47]\tF/61\tACTH Ca\tNA\tNA\tNA (12)\t“Resolved” \tPR \t\n\n\n\t\nMorin et al., 2012 [48]\tM/22\tGH Ad\t3-4\tNA\t200 × 5/28 (5)\tNo change\tIncreased signs\t\n\n\n\t\nWhitelaw et al., 2012 [49] \tM/34\tPRL Ad\t15\t(−)\t200 × 5/28 (6)\t“Dramatic reduction”\t“Significant improvement”\t\nM/32\tPRL Ad\t8\t(−)\t200 × 5/28 (6)\t“Substantial reduction”\t“Significant improvement” \t\nM/13\tPRL Ad\t4\t(−)\t200 × 5/28 (12)\tPR\tPR\t\n\n\n\t\nErsen et al., 2012 [50]\tNA\tGn Ad\tNA\tTwo zones: (−) and (+), 60%\t200 × 5/28 (14)\tSD\t“Clinical improvement”\t\n\n\n\t\nScheithauer et al., 2012 [51]\tF/13 months\tPituitary blastoma \tNA\tVaried from 40 to 60%\t100 × 5/28 (12 + 6)\tProgression\tNA\t\n\n\n\t\nOrtiz et al., 2012 [52]\tM/38\tACTH Ad → Ca\tNA\tHigh\t200 × 5/28 (8)\tNo change\tProgression\t\n\n\n\t\nBatisse et al., 2013 [53]\tM/47\tGH Ad\t(−)\tHigh\t200 × 5/28 (3)\tProgression\tNo significant response\t\n\n\n\t\nBruno et al., 2015 [4] \tF/52\tACTH Ad\t6\t(−)\t150–200 × 5/28 (29)\tCR \tCR\t\nF/42\tACTH Ad\t4\t(−)\t150–200 × 5/28 (12)\tCR\tCR\t\nAd: adenoma; Ca: carcinoma; SA: silent adenoma; NS: Nelson's syndrome; NF: nonfunctioning; PRL: lactotrope; ACTH: corticotrope; GH: somatotrope; Gn: gonadotrope; MRI: magnetic resonance imaging; NA: not available; RT: radiotherapy; CR: complete response; PR: partial response; SR: “significant” reduction; METS: metastases; SD: stable disease; CAB: cabergoline; STT-A: somatostatin agonist; CAP: capecitabine; →: change; (og): ongoing.\n==== Refs\n1 Colao A. Grasso L. F. S. Pivonello R. Lombardi G. Therapy of aggressive pituitary tumors Expert Opinion on Pharmacotherapy 2011 12 10 1561 1570 10.1517/14656566.2011.568478 2-s2.0-79958758987 21434849 \n2 Lim S. Shahinian H. Maya M. M. Yong W. Heaney A. P. Temozolomide: a novel treatment for pituitary carcinoma The Lancet Oncology 2006 7 6 518 520 10.1016/s1470-2045(06)70728-8 2-s2.0-33744501578 16750503 \n3 Syro L. V. Uribe H. Penagos L. C. Antitumour effects of temozolomide in a man with a large, invasive prolactin-producing pituitary neoplasm Clinical Endocrinology 2006 65 4 552 553 10.1111/j.1365-2265.2006.02653.x 2-s2.0-33748799412 16984254 \n4 Bruno O. D. Juárez-Allen L. Christiansen S. B. Danilowicz K. Long-lasting complete remission after therapy with temozolomide in two patients with macrocorticotropinoma causing Cushing's disease Clinical Endocrinology 2015 10.1111/cen.12727 \n5 Daly A. F. Rixhon M. Adam C. Dempegioti A. Tichomirowa M. A. Beckers A. High prevalence of pituitary adenomas: a cross-sectional study in the province of Liège, Belgium Journal of Clinical Endocrinology and Metabolism 2006 91 12 4769 4775 10.1210/jc.2006-1668 2-s2.0-33845489470 16968795 \n6 Fernandez A. Karavitaki N. Wass J. A. H. Prevalence of pituitary adenomas: a community-based, cross-sectional study in Banbury (Oxfordshire, UK) Clinical Endocrinology 2010 72 3 377 382 10.1111/j.1365-2265.2009.03667.x 2-s2.0-76649132060 19650784 \n7 Lloyd R. J. Kovacs K. Young W. F. Jr. DeLellis R. A. Lloyd R. V. Heitz P. U. Tumours of the pituitary gland Pathology and Genetics of Endocrine Tumours 2004 Lyon, France International Agency for Research and Cancer (IARC) 9 48 \n8 Zada G. Woodmansee W. W. Ramkissoon S. Amadio J. Nose V. Laws E. R. Jr. Atypical pituitary adenomas: incidence, clinical characteristics, and implications Journal of Neurosurgery 2011 114 2 336 344 10.3171/2010.8.jns10290 2-s2.0-79551711233 20868211 \n9 Meij B. P. Lopes M.-B. S. Ellegala D. B. 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SOM230 (Pasireotide) and temozolomide achieve sustained control of tumour progression and ACTH secretion in pituitary carcinoma with widespread metastases Experimental and Clinical Endocrinology and Diabetes 2010 118 10 760 763 10.1055/s-0030-1253419 2-s2.0-78349239330 20496311 \n30 Jouanneau E. Wierinckx A. Ducray F. New targeted therapies in pituitary carcinoma resistant to temozolomide Pituitary 2012 15 1 37 43 10.1007/s11102-011-0341-0 2-s2.0-84858160987 21858654 \n31 Asimakopoulou A. Tzanela M. Koletti A. Kontogeorgos G. Tsagarakis S. Long-term remission in an aggressive Crooke cell adenoma of the pituitary, 18 months after discontinuation of treatment with temozolomide Clinical Case Reports 2014 2 1 1 3 10.1002/ccr3.39 25356225 \n32 Bengtsson D. Schrøder H. D. Andersen M. Long-term outcome and MGMT as a predictive marker in 24 patients with atypical pituitary adenomas and pituitary carcinomas given treatment with temozolomide The Journal of Clinical Endocrinology & Metabolism 2015 100 4 1689 1698 10.1210/jc.2014-4350 25646794 \n33 Neto L. Chimelli L. Pereira P. D. M. The role of temozolomide in the treatment of a patient with a pure silent pituitary somatotroph carcinoma Endocrine Practice 2013 19 6 e145 e149 10.4158/ep12400.cr 2-s2.0-84888882564 23807517 \n34 Morokuma H. Ando T. Hayashida T. A case of nonfunctioning pituitary carcinoma that responded to temozolomide treatment Case Reports in Endocrinology 2012 2012 5 645914 10.1155/2012/645914 \n35 Zhong C. Yin S. Zhou P. Jiang S. Pituitary atypical adenoma or carcinoma sensitive to temozolomide combined with radiation therapy: a case report of early identification and management Turkish Neurosurgery 2014 24 6 963 966 10.5137/1019-5149.jtn.9629-13.1 25448217 \n36 Syro L. V. Scheithauer B. W. Ortiz L. D. Effect of Temozolomide in a patient with recurring oncocytic gonadotrophic pituitary adenoma Hormones 2009 8 4 303 306 10.14310/horm.2002.1247 2-s2.0-74849098857 20045804 \n37 Hagen C. Schroeder H. D. Hansen S. Hagen C. Andersen M. Temozolomide treatment of a pituitary carcinoma and two pituitary macroadenomas resistant to conventional therapy European Journal of Endocrinology 2009 161 4 631 637 10.1530/EJE-09-0389 2-s2.0-70349771361 19654234 \n38 Mendola M. Passeri E. Ambrosi B. Corbetta S. Multiple cerebral hemorrhagic foci from metastases during temozolomide treatment in a patient with corticotroph pituitary carcinoma The Journal of Clinical Endocrinology & Metabolism 2014 99 8 2623 2624 10.1210/jc.2014-1183 24823463 \n39 Strowd R. E. Salvatori R. Laterra J. J. Temozolomide retreatment in a recurrent prolactin-secreting pituitary adenoma: Hormonal and radiographic response Journal of Oncology Pharmacy Practice 2015 10.1177/1078155215569556 \n40 Ceccato F. Lombardi G. Manara R. Temozolomide and pasireotide treatment for aggressive pituitary adenoma: expertise at a tertiary care center Journal of Neuro-Oncology 2015 122 1 189 196 10.1007/s11060-014-1702-0 25555563 \n41 Philippon M. Morange I. Barrie M. Long-term control of a MEN1 prolactin secreting pituitary carcinoma after temozolomide treatment Annales d'Endocrinologie 2012 73 3 225 229 10.1016/j.ando.2012.03.001 2-s2.0-84863850783 \n42 Fadul C. E. Kominsky A. L. Meyer L. P. Long-term response of pituitary carcinoma to temozolomide. Report of two cases Journal of Neurosurgery 2006 105 4 621 626 10.3171/jns.2006.105.4.621 2-s2.0-33749537681 17044568 \n43 Kovacs K. Horvath E. Syro L. V. Temozolomide therapy in a man with an aggressive prolactin-secreting pituitary neoplasm: morphological findings Human Pathology 2007 38 1 185 189 10.1016/j.humpath.2006.07.014 2-s2.0-33845338456 17056093 \n44 Cornell R. F. Kelly D. F. Bordo G. Chemotherapy-induced regression of an adrenocorticotropin-secreting pituitary carcinoma accompanied by secondary adrenal insufficiency Case Reports in Endocrinology 2013 2013 10 675298 10.1155/2013/675298 \n45 Phillips J. East H. E. French S. E. What causes a prolactinoma to be aggressive or to become a pituitary carcinoma? Hormones 2012 11 4 477 482 10.14310/horm.2002.1380 2-s2.0-84871998498 23422771 \n46 Rotondo F. Cusimano M. Scheithauer B. W. Coire C. Horvath E. Kovacs K. Atypical, invasive, recurring Crooke cell adenoma of the pituitary Hormones 2012 11 1 94 100 2-s2.0-84859040583 22450349 \n47 Arnold P. M. Ratnasingam D. O'Neil M. F. Johnson P. L. Pituitary carcinoma recurrent to the lumbar intradural extramedullary space: case report The Journal of Spinal Cord Medicine 2012 35 2 118 121 10.1179/2045772311y.0000000055 2-s2.0-84858995774 22333938 \n48 Morin E. Berthelet F. Weisnagel J. Bidlingmaier M. Serri O. Failure of temozolomide and conventional doses of pegvisomant to attain biochemical control in a severe case of acromegaly Pituitary 2012 15 1 97 100 10.1007/s11102-010-0232-9 2-s2.0-79959922097 20407837 \n49 Whitelaw B. C. Dworakowska D. Thomas N. W. Temozolomide in the management of dopamine agonist-resistant prolactinomas Clinical Endocrinology 2012 76 6 877 886 10.1111/j.1365-2265.2012.04373.x 2-s2.0-84860189379 22372583 \n50 Ersen A. Syro L. V. Penagos L. Non-uniform response to temozolomide therapy in a pituitary gonadotroph adenoma The Canadian Journal of Neurological Sciences 2012 39 5 683 685 10.1017/s0317167100018242 2-s2.0-84868258861 23066557 \n51 Scheithauer B. W. Horvath E. Abel T. W. Pituitary blastoma: a unique embryonal tumor Pituitary 2012 15 3 365 373 10.1007/s11102-011-0328-x 2-s2.0-84867396555 21805093 \n52 Ortiz L. D. Syro L. V. Scheithauer B. W. Anti-VEGF therapy in pituitary carcinoma Pituitary 2012 15 3 445 449 10.1007/s11102-011-0346-8 2-s2.0-84867398371 21918831 \n53 Batisse M. Raverot G. Maqdasy S. Aggressive silent GH pituitary tumor resistant to multiple treatments, including temozolomide Cancer Investigation 2013 31 3 190 196 10.3109/07357907.2013.775293 2-s2.0-84875034854 23477586 \n54 Matsuno A. Murakami M. Hoya K. Molecular status of pituitary carcinoma and atypical adenoma that contributes the effectiveness of temozolomide Medical Molecular Morphology 2014 47 1 1 7 10.1007/s00795-013-0050-z 2-s2.0-84897028439 23955641\n\n",
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"title": "Temozolomide Therapy for Aggressive Pituitary Tumors: Results in a Small Series of Patients from Argentina.",
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"abstract": "Allogeneic hematopoietic stem-cell transplantation and solid-organ transplantation are associated with an increased risk of secondary neoplasms. Indeterminate cell histiocytosis (ICH) is a rare disease composed of so-called indeterminate cells, an alleged cutaneous dendritic cell subset displaying histological and some ultrastructural and immunophenotypic features of Langerhans cells but lacking Birbeck granules. We report a case of cutaneous ICH occurring after allogeneic hematopoietic stem-cell transplantation for a myelodysplastic syndrome in a 56-year-old man. Microsatellite analysis demonstrated that the neoplastic cells were derived from the donor's hematopoietic system. This case broadens the spectrum of complications after stem-cell transplantation and demonstrates that cutaneous ICH in the setting of myelodysplastic syndromes may have a nonrelated origin to dysplastic myeloid cells.",
"affiliations": "*Department of Pathology, Hospital Universitario de Salamanca, Salamanca, Spain;†Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain;‡Dermatology Service, Hospital Universitario de Salamanca, Salamanca, Spain; and§Hematology Service, Hospital Universitario de Salamanca, Salamanca, Spain.",
"authors": "Santos-Briz|Angel|A|;Román|Concepción|C|;Corral|Rocío|R|;de Dios|Alvaro|A|;Vázquez|Lourdes|L|;Ludeña|María D|MD|",
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"journal": "The American Journal of dermatopathology",
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"mesh_terms": "D018380:Hematopoietic Stem Cell Transplantation; D015614:Histiocytosis; D006801:Humans; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes; D012871:Skin Diseases",
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"pubdate": "2017-09",
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"title": "Cutaneous Indeterminate Cell Histiocytosis of Donor Origin After Allogeneic Hematopoietic Stem-Cell Transplantation.",
"title_normalized": "cutaneous indeterminate cell histiocytosis of donor origin after allogeneic hematopoietic stem cell transplantation"
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"abstract": "BACKGROUND\nChemical coping is an inappropriate method for dealing with stress through the use of opioids; it is considered the stage prior to abuse and dependence. In patients with cancer, it is important to evaluate the risk of chemical coping when using opioids. There are some pediatric opioid use-related tolerances and addictions; however, no mention of chemical coping has been found.\n\n\nMETHODS\nWe present a case of an 11-year-old Japanese boy with acute lymphocytic leukemia. After transplantation, he complained of abdominal and articular pain, which are considered as symptoms of graft-versus-host disease; thus, opioid therapy was initiated, and the dose was gradually increased for pain management, resulting in a high dose of 2700 μg/day of fentanyl (4200-4700 μg/day including the rescue dose). After switching from fentanyl to oxycodone injections, he continued to experience pain, and there was no change in the frequency of oxycodone rescue doses. Physically, his pain was considered to have alleviated; thus, there was the possibility of mental anxiety resulting in the lowering of pain threshold and the possibility of chemical coping. Mental anxiety and stress with progress through schooling was believed to have resulted in chemical coping; thus, efforts were made to reduce the boy's anxiety, and opioid education was provided. However, dose reduction was challenging. Ultimately, with guidance from medical care providers, the opioid dose was reduced, and the patient was successfully weaned off opioids.\n\n\nCONCLUSIONS\nWhen chemical coping is suspected in pediatric patients, after differentiating from pseudo-addiction, it might be necessary to restrict the prescription for appropriate use and to provide opioid education while taking into consideration the emotional background of the patient that led to chemical coping.",
"affiliations": "Department of Anesthesiology and Critical Care Medicine, Hokkaido University Graduate School of Medicine, Hokkaido, Japan. moto_m829@yahoo.co.jp.;Hokkaido University Hospital Cancer Center, Hokkaido, Japan.;Department of Anesthesiology and Critical Care Medicine, Hokkaido University Graduate School of Medicine, Hokkaido, Japan.",
"authors": "Miura|Mototsugu|M|;Tsuruga|Kenkichi|K|;Morimoto|Yuji|Y|",
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"fulltext": "\n==== Front\nJ Med Case RepJ Med Case RepJournal of Medical Case Reports1752-1947BioMed Central London 227310.1186/s13256-019-2273-7Case ReportA pediatric cancer patient with suspected chemical coping following high-dose opioid therapy: a case report Miura Mototsugu +81-01-706-7861moto_m829@yahoo.co.jp 1Tsuruga Kenkichi ktsuruga@med.hokudai.ac.jp 2Morimoto Yuji morim2@med.hokudai.ac.jp 11 0000 0001 2173 7691grid.39158.36Department of Anesthesiology and Critical Care Medicine, Hokkaido University Graduate School of Medicine, Hokkaido, Japan 2 0000 0004 0378 6088grid.412167.7Hokkaido University Hospital Cancer Center, Hokkaido, Japan 30 11 2019 30 11 2019 2019 13 35328 5 2019 24 9 2019 © The Author(s). 2019Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nChemical coping is an inappropriate method for dealing with stress through the use of opioids; it is considered the stage prior to abuse and dependence. In patients with cancer, it is important to evaluate the risk of chemical coping when using opioids. There are some pediatric opioid use-related tolerances and addictions; however, no mention of chemical coping has been found.\n\nCase presentation\nWe present a case of an 11-year-old Japanese boy with acute lymphocytic leukemia. After transplantation, he complained of abdominal and articular pain, which are considered as symptoms of graft-versus-host disease; thus, opioid therapy was initiated, and the dose was gradually increased for pain management, resulting in a high dose of 2700 μg/day of fentanyl (4200–4700 μg/day including the rescue dose). After switching from fentanyl to oxycodone injections, he continued to experience pain, and there was no change in the frequency of oxycodone rescue doses. Physically, his pain was considered to have alleviated; thus, there was the possibility of mental anxiety resulting in the lowering of pain threshold and the possibility of chemical coping. Mental anxiety and stress with progress through schooling was believed to have resulted in chemical coping; thus, efforts were made to reduce the boy’s anxiety, and opioid education was provided. However, dose reduction was challenging. Ultimately, with guidance from medical care providers, the opioid dose was reduced, and the patient was successfully weaned off opioids.\n\nConclusions\nWhen chemical coping is suspected in pediatric patients, after differentiating from pseudo-addiction, it might be necessary to restrict the prescription for appropriate use and to provide opioid education while taking into consideration the emotional background of the patient that led to chemical coping.\n\nKeywords\nChemical copingOpioidPediatricPseudo-addictionAnxietyissue-copyright-statement© The Author(s) 2019\n==== Body\nBackground\nChemical coping was first proposed by Bruera et al. in 1995 as “an inappropriate method of dealing with stress through the use of drugs seen in patients suffering from terminal-phase cancer” [1]. In recent years, chemical coping using opioids to deal with psychological and spiritual distress has been considered the stage prior to abuse and dependence [2]. In patients with cancer who are receiving opioid therapy, a history of alcohol dependence and drug abuse, age < 65 years, psychiatric disturbance, high emotional stress, and limited coping mechanisms are considered as risk factors for chemical coping [2–5]. In a previous report, 18% of adult patients with cancer who were receiving opioids exhibited signs of chemical coping upon evaluation by a palliative care specialist [6].\n\nSimple screening tools, such as the CAGE questionnaire [7] and the Screener and Opioid Assessment for Patients with Pain [8], may be used to assess the risk of chemical coping [3, 9]. However, these assessment tools have been developed on the basis of tools used for alcohol dependency, and whether they can be used in children remains unknown. Appropriate methods of assessment and treatment have not been established yet; in fact, there are some pediatric opioid use-related tolerances and addictions; however, no mention of chemical coping has been found. We report our experience with a pediatric patient with cancer suspected of chemical coping and in whom opioid dose reduction was difficult.\n\nCase presentation\nOur patient was an 11-year-old Japanese boy (height 141 cm, weight 36.5 kg) with acute lymphocytic leukemia. Since the onset of acute lymphocytic leukemia, he had received early-stage intensive chemotherapy, remission therapy, and maintenance therapy; however, because he had a positive test result for minor breakpoint cluster region, umbilical cord blood transplantation was performed. After transplantation, he complained of abdominal and articular pain; his abdominal pain was accompanied by frequent diarrhea. These were considered to represent gastrointestinal symptoms of graft-versus-host disease (GVHD); thus, opioid therapy was initiated. For long-term opioid therapy, few opioid medications provide information on the label regarding the safety and effectiveness of the drug in pediatric patients [10]. We selected fentanyl because chemotherapy for leukemia predisposes the patient to renal dysfunction, and it is considered effective because it has high selectivity for mu 1 receptors in the treatment of mucosal pain [11, 12]. However, the dose of fentanyl was gradually increased for pain management, resulting in dose as high as 2300 μg/day, which required intervention from the palliative care team.\n\nAt the time of intervention, the patient was isolated in a sterilized room after transplantation. In addition to the major complaint of pain in the lower left abdomen, upon palpation, the patient complained of pressure pain throughout the abdomen; he also complained of joint pain in the legs when the abdominal pain intensified. Computed tomography revealed changes showing pancreatitis and mild intestinal edema, which was considered to be a sign of GVHD (Fig. 1).\nFig. 1 Abdominal imaging findings. a Ring-shaped calcification with findings of old fat necrosis in the pancreatic tail (arrow). b Mild intestinal edema (graft-versus-host disease findings)\n\n\n\nGiven the intense acute pain caused by GVHD, the fentanyl dose was increased again to 2700 μg/day; however, the frequency of the rescue dose for pain (equivalent to 1-h dose of continuous infusion) did not decrease below 15 times per day, and continuously increasing the dose did not reduce the frequency of the rescue dose. After the opioid was switched to 90 mg/day of oxycodone injections, the patient continued to experience pain, and there was no change in the frequency of oxycodone rescue doses (Table 1).\nTable 1 Progress tabel\n\nAfter umbilical cord blood transplant\tSymptom, event\tOpioid dose for scheduled use\tNumber of rescues (continuous infusion at an elevated rate)\tAnalgesic adjuvant\t\nDay 13\tIntervention by the palliative care team\tFentanyl 2300 μg\t16\t\t\nDay 17\tArticular pain in lower limbs in addition to pain in the pain in the left lower abdomen; nausea and fatigue due to GVHD (and opioids?)\tFentanyl2700 μg\t19\t\t\nDay 19\tDiarrhea improved from watery stools to soft stools, but abdominal pain remained unchanged; the opioid was switched to oxycodone for injection.\tOxycodone for injection 90 mg\t14\t\t\nDay 21\tAfter switching, complaint of pain continued, and the number of rescues remained unchanged.\tOxycodone for injection90 mg\t12\t\t\nDay 24\t\tOxycodone for injection100 mg\t16\t\t\nDay 27\tFor attending school (in the hospital), syringe pump administration was switched to patient-controlled analgesia.\tOxycodone for injection100 mg\t18\t\t\nDay 28\tThe patient showed a tendency toward constipation, and laxatives were adjusted, including naldemedine.\tOxycodone for injection100 mg\t15\t\t\nDay 44 (early in March)\tThe patient expressed anxiety about entering junior high school; nausea and fatigue intensified.\tOxycodone for injection84 mg\t13\t\t\nDay 53\tThe patient exhibited strong resistance to dose reduction because of fear of possible intensified pain: “No one knows how I am feeling.”\tOxycodone for injection72 mg\t14\t\t\nDay 64\tMultidisciplinary conference\tOxycodone for injection72 mg\t13\tDuloxetine 10 mg\t\nDay 83\tOfficial entrance ceremony of junior high school (outside the hospital); oral immediate-release oxycodone preparation was prescribed.\tOxycodone for injection72 mg\t12\tDuloxetine 20 mg\t\nDay 97\tOral immediate-release oxycodone preparation was discontinued; dose reduction was started without telling the dose for scheduled use after consent was obtained from the patient and his mother.\tOxycodone for injection60 mg\t12\tDuloxetine 20 mg\t\nDay 105\tThe patient stayed out (his home) overnight on weekends.\tOxycodone for injection54 mg\t16\tDuloxetine 20 mg\t\nDay 119\tThe number of rescues did not decrease, but pain did not intensify after reducing the dose for scheduled use.\tOxycodone for injection48 mg\t11\tDuloxetine 20 mg\t\nDay 121\t\tOxycodone for injection42 mg\t10\tDuloxetine 20 mg\t\nDay 134\t\tOxycodone for injection30 mg\t6\tDuloxetine 20 mg\t\nDay 136\t\tOxycodone for injection18 mg\t11\tDuloxetine 20 mg\t\nDay 137\t\tOxycodone for injection12 mg\t8\tDuloxetine 20 mg\t\nDay 139\t\tOxycodone for injection6 mg\t13\tDuloxetine 20 mg\t\nDay 143\t\tOxycodone for injection3 mg\t8\tDuloxetine 20 mg\t\nDay 148\tNo complaint of pain; acetaminophen 200 mg and ibuprofen 100 mg were prescribed.\tDiscontinued\t\tDuloxetine 20 mg\t\nDay 168\tDischarged to home\t\t\tDuloxetine 20 mg\t\nDay 180\tNo complaint of pain at the outpatient visit; analgesic agents were discontinued, including duloxetine.\t\t\tDiscontinued\t\nGVHD Graft-versus-host disease\n\n\n\nThe patient’s general condition improved, and he did not require isolation. Despite attending school in the hospital, there was no improvement in his complaints of pain, and just before entering junior high school, he expressed anxiety about friends, learning, and whether he would be understood by the teachers. Considering the possibility of opioid overdose in response to complaints of nausea and fatigue, dose reduction was planned; however, he exhibited strong resistance. Furthermore, he became irritable, and his mental instability became evident as exhibited by violent outbursts.\n\nComputed tomography revealed no findings that caused physical pain. His pain was considered to have alleviated; thus, health professionals involved in his care (that is, pediatrician, pediatric psychiatrist, palliative care team, ward nurse, child medical care support provider, and childcare worker) examined the possibility of mental anxiety resulting in the lowering of pain threshold and the possibility of chemical coping.\n\nExpecting to use less opioid, we initiated duloxetine, which exerts an antidepressive effect and adjuvant analgesic effect, at a dose of 10 mg/day. Furthermore, to address the patient’s mental anxiety, a meeting was held with the teacher whose class the patient was expected to attend. The new school staff cooperated so that the patient could attend the same class as his good friends. To address the patient’s drug use, upon suspicion that the sudden increase in blood concentration due to administration of rescue doses of opioid injections could have caused chemical coping, switching to oral opioids was attempted; however, on a pain scale (scale of 0 to 5), the patient assessed that the rescue doses of intravenous oxycodone had reduced his pain from 5 to 1.2 points, whereas the oral oxycodone immediate-release preparation had only reduced pain from 5 to 4.5 points; thus, switching to oral drugs was not successful.\n\nWe believed that the rescue dose of intravenous oxycodone resulted in a sudden increase in blood concentration, and the administration of the rescue dose could have been a coping behavior. An explanation regarding opioids in general and the possibility that the number of rescues will not decrease for purposes other than analgesia (such as antianxiety) was shared with the patient and his family members who provided the consent; thereafter, we decided to lower the concentration of intravenous oxycodone without informing the patient of the timing of dose reduction.\n\nAfter approximately 1 month, the intravenous oxycodone dose was gradually reduced to 3 mg/day; however, there was no major change in the frequency of rescue doses. After the patient was informed that the intravenous oxycodone had been reduced to a dose that had been ineffective as an analgesic, we prescribed 200 mg of acetaminophen and 100 mg of ibuprofen to be taken as needed. Subsequently, oxycodone infusion was discontinued, and the patient did not complain of pain. Thereafter, he expressed no desire for opioid use and was discharged. Currently, he is being treated on an outpatient basis and is opioid-free.\n\nDiscussion and conclusions\nOur patient complained of intense pain that was medically difficult to explain, and he requested frequent rescue doses of continuous oxycodone infusion. With the suspicion of chemical coping, we were able to wean the patient from opioids through psychological care and gradually reducing the oxycodone dosage.\n\nWhen chemical coping is suspected, it is important to differentiate pseudo-addiction, opioid tolerance, and opioid-induced hyperpathia [13]. Pseudo-addiction is defined as the state in which the patient excessively or dramatically complains of pain and frequently seeks analgesics to escape from the inadequately controlled pain [13], which, if misdiagnosed, can lead to insufficient control of pain in a pseudo-dependent patient. In our patient, given the presence of pain associated with GVHD following umbilical cord blood transplantation, pseudo-addiction could explain why there was no change in the complaints of pain despite increasing the opioid dose and the frequency of rescue doses during pain. However, even after mucositis symptoms such as stomatitis and diarrhea improved, the reason that the opioid dose was not reduced might be attributed to chemical coping through the administration of rescue doses of intravenous opioids, which was largely affected by psychological factors such as fear that opioid dose reduction would intensify abdominal pain, loneliness during isolation because of an immunocompromised state, anxiety about entering junior high school, and actual coping behavior (that is, pressing the rescue dose button). However, the possibility of tolerance and opioid-induced hyperalgesia could not be completely ruled out.\n\nTo prevent chemical coping, accurately evaluating pain upon opioid introduction, clarifying patient’s history, and verifying whether the frequency of rescue doses has decreased and whether pain is alleviated upon regularly increasing the opioid dose are necessary. When chemical coping is suspected, the health care team may need to be proactive in addressing the patient’s emotional needs, providing proper education on safe opioid use, and monitoring the patient for aberrant behaviors [14].\n\nOur patient was a boy in whom a screening tool was not used at the time of opioid introduction. However, upon suspecting chemical coping, a multidisciplinary conference was held, including a palliative care team, in which the mental status of the patient was shared and a team of medical staff was formed to look after the patient. By reducing the patient’s anxiety through organizing entry into junior high school, we were able to reduce his desire for rescue doses. Education regarding the safe use of opioids was provided by the palliative care specialist. The patient was switched to oral immediate-release oxycodone with the aim of weaning him off continuous drip therapy; however, this attempt failed. Hence, compulsory opioid dose reduction was implemented with the consent of the patient and his family members.\n\nBarglow examined countermeasures for opioid overdose, including improper use, and divided them into three categories (that is, demand reduction [counseling and education about proper opioid use], supply reduction [restricting prescriptions and access so that the patient uses the appropriate dose for pain relief], and harm reduction [medication-assisted treatment {MAT}]) [15]. In our patient, the opioid dosage could not be reduced through demand reduction, but it could be reduced through supply reduction; however, we believe that further examination is warranted to determine whether demand reduction results in poorer treatment outcomes for chemical coping in pediatric patients than in adults. In contrast, MAT for opioid use disorder in adolescents has been reported [16]; thus, dose reduction through MAT using drugs such as buprenorphine might be a good treatment option for chemical coping in children.\n\nAbbreviations\nGVHDGraft-versus-host disease\n\nMATMedication-assisted treatment\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAcknowledgements\nNot applicable.\n\nAuthors’ contributions\nAll authors read and approved the final manuscript.\n\nFunding\nThis research received no specific grant from any funding agency in the public, commercial, or not-for-profit sector.\n\nAvailability of data and materials\nNot applicable.\n\nEthics approval and consent to participate\nNot applicable.\n\nConsent for publication\nWritten informed consent was obtained from the patient’s legal guardian(s) for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n==== Refs\nReferences\n1. Bruera E Moyano J Seifert L Fainsinger RL Hanson J Suarez-Almazor M The frequency of alcoholism among patients with pain due to terminal cancer J Pain Symptom Manag 1995 10 599 603 10.1016/0885-3924(95)00084-4 \n2. Fabbro ED Assessment and management of chemical coping in patients with cancer J Clin Oncol 2014 32 1734 1738 10.1200/JCO.2013.52.5170 24799476 \n3. Dhalla S Kopec JA The CAGE questionnaire for alcohol misuse: a review of reliability and validity studies Clin Invest Med 2007 30 33 41 10.25011/cim.v30i1.447 17716538 \n4. Edlund MJ Steffick D Hudson T Harris KM Sullivan M Risk factors for clinically recognized opioid abuse and dependence among veterans using opioids for chronic noncancer pain Pain 2007 129 355 362 10.1016/j.pain.2007.02.014 17449178 \n5. Boscarino JA Rukstalis M Hoffman SN Risk factors for drug dependence among out-patients on opioid therapy in a large US health-care system Addiction 2010 105 1776 1782 10.1111/j.1360-0443.2010.03052.x 20712819 \n6. Kwon JH Tanco K Hui D Wong A Seo L Liu D Frequency, predictors, and medical record documentation of chemical coping among advanced cancer patients Oncologist 2015 20 692 697 10.1634/theoncologist.2015-0012 25933929 \n7. Ewing JA Detecting alcoholism: the CAGE questionnaire JAMA 1984 252 1905 1907 10.1001/jama.1984.03350140051025 6471323 \n8. Akbik H Butler SF Budman SH Fernandez K Katz NP Jamison RN Validation and clinical application of the Screener and Opioid Assessment for Patients with Pain (SOAPP) J Pain Symptom Manag. 2006 32 287 293 10.1016/j.jpainsymman.2006.03.010 \n9. Kircher S Zacny J Apfelbaum SM Passik S Kirsch K Burbage M Understanding and treating opioid addiction in a patient with cancer pain J Pain. 2011 12 1025 1031 10.1016/j.jpain.2011.07.006 21968264 \n10. Dowell D Haegerich TM Chou R CDC guideline for prescribing opioids for chronic pain — United States, 2016 MMWR Recomm Rep. 2016 65 1 49 10.15585/mmwr.rr6501e1. 26987082 \n11. Strupp C Sudhoff T Germing U Hunerliturkoglu A Schneider P Niederste-Hollenberg A Transdermal fentanyl during high-dose chemotherapy and autologous stem cell support Oncol Rep. 2000 7 659 661 10767386 \n12. Kim JG Sohn SK Kim DH Baek JH Chae YS Bae NY Effectiveness of transdermal fentanyl patch for treatment of acute pain due to oral mucositis in patients receiving stem cell transplantation Transplant Proc. 2005 37 4488 4491 10.1016/j.transproceed.2005.11.038 16387151 \n13. Kwon JH Tanco K Hui D Reddy A Bruera E Chemical coping versus pseudoaddiction in patients with cancer pain Palliat Support Care. 2014 12 413 417 10.1017/S1478951513001351 24524251 \n14. Kwon JH Hui D Bruera E A pilot study to define chemical coping in cancer patients using the Delphi method J Palliat Med. 2015 18 703 706 10.1089/jpm.2014.0446 25922879 \n15. Barglow P The opioid overdose epidemic: evidence-based interventions Am J Addict. 2018 27 605 607 10.1111/ajad.12823 30311993 \n16. American Academy of Pediatrics, Committee on Substance Use and Prevention Medication-assisted treatment of adolescents with opioid use disorders Pediatrics 2016 138 3 e20161893 10.1542/peds.2016-1893 27550978\n\n",
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"issn_linking": "1752-1947",
"issue": "13(1)",
"journal": "Journal of medical case reports",
"keywords": "Anxiety; Chemical coping; Opioid; Pediatric; Pseudo-addiction",
"medline_ta": "J Med Case Rep",
"mesh_terms": "D015746:Abdominal Pain; D000701:Analgesics, Opioid; D002648:Child; D005312:Fetal Blood; D006086:Graft vs Host Disease; D006801:Humans; D008297:Male; D009293:Opioid-Related Disorders; D059408:Pain Management; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "101293382",
"other_id": null,
"pages": "353",
"pmc": null,
"pmid": "31783905",
"pubdate": "2019-11-30",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "24799476;30311993;6471323;16387151;10767386;20712819;27550978;17716538;25922879;24524251;26987082;21968264;25933929;16939853;8594120;17449178",
"title": "A pediatric cancer patient with suspected chemical coping following high-dose opioid therapy: a case report.",
"title_normalized": "a pediatric cancer patient with suspected chemical coping following high dose opioid therapy a case report"
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"companynumb": "JP-ALKEM LABORATORIES LIMITED-JP-ALKEM-2019-10694",
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"activesubstancename": "OXYCODONE HYDROCHLORIDE"
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"abstract": "BACKGROUND\nFor phosphodiesterase type 5 (PDE5) inhibitors, such as sildenafil, the only approved indication in women is for pulmonary arterial hypertension. These drugs are increasingly being proposed and tested for treatment of female infertility and complications in pregnancy. However, the extent of use of PDE5 inhibitors in the general pregnant population over the last decades is unknown. Therefore, we conducted a descriptive cohort study using data from the population health registers in the Scandinavian countries.\n\n\nMETHODS\nBy linking the Medical Birth Registers and the Prescribed Drug Registers in Denmark (1997-2017), Norway (2004-2017), and Sweden (2006-2016), women with filled prescriptions of PDE5 inhibitors in outpatient settings in the 90 days before the date of last menstrual period and/or during pregnancies were identified. With additional linkage to the National Patient Registers, information on maternal, pregnancy, and infant characteristics, co-morbidities, and co-medication was collected and described.\n\n\nRESULTS\nAmong over 3 million singleton pregnancies, only 77 were pregnancies in women who had at least one filled prescription of a PDE5 inhibitor within the 90 days before the start of pregnancy to delivery. Prescription fills most often occurred before the last menstrual period and in the first trimester, with very few occurring later in pregnancy. Sildenafil was the most used PDE5 inhibitor. Among pregnant women using PDE5 inhibitors, 44% were 35 years of age or older, eight had a cardiovascular diagnosis, and three specifically had a diagnosis of pulmonary arterial hypertension. Among the infants born to mothers using PDE5 inhibitors, nine were born preterm, six were small-for-gestational age, five had an Apgar score at 5 minutes below 8, 18 were admitted to the Neonatal Intensive Care Unit, and eight had respiratory and cardiovascular conditions.\n\n\nCONCLUSIONS\nFew women used PDE5 inhibitors in outpatient settings before or during pregnancy in the Scandinavian countries in the last decades. Only a small proportion had a diagnosis for pulmonary arterial hypertension, suggesting off-label use in the remaining users. Use was predominantly in mothers over age 35 years. The safety of fetal exposure to sildenafil and other PDE5 inhibitors in pregnancy has not been established. As maternal age continues to increase and additional uses of PDE5 inhibitors are investigated, the safety of these drugs in pregnancy should be thoroughly evaluated.",
"affiliations": "Department of Medicine Solna, Center for Pharmacoepidemiology, Karolinska Institutet, Stockholm, Sweden.;Department of Medicine Solna, Center for Pharmacoepidemiology, Karolinska Institutet, Stockholm, Sweden.;Department of Global Public Health and Primary Care, University of Bergen, Bergen, Norway.;Department of Clinical Biochemistry and Pharmacology, Odense University Hospital, Odense, Denmark.;Department of Clinical Biochemistry and Pharmacology, Odense University Hospital, Odense, Denmark.;Department of Chronic Diseases and Ageing, Norwegian Institute of Public Health, Oslo, Norway.;Department of Medicine Solna, Center for Pharmacoepidemiology, Karolinska Institutet, Stockholm, Sweden.;Department of Medicine Solna, Center for Pharmacoepidemiology, Karolinska Institutet, Stockholm, Sweden.",
"authors": "Cesta|Carolyn E|CE|https://orcid.org/0000-0001-5759-9366;Segovia Chacón|Silvia|S|https://orcid.org/0000-0003-0210-5829;Engeland|Anders|A|https://orcid.org/0000-0001-5620-9207;Broe|Anne|A|https://orcid.org/0000-0002-4149-8808;Damkier|Per|P|https://orcid.org/0000-0003-0591-7187;Furu|Kari|K|https://orcid.org/0000-0003-2245-0179;Kieler|Helle|H|https://orcid.org/0000-0001-9338-7133;Karlsson|Pär|P|https://orcid.org/0000-0002-7177-1713",
"chemical_list": "D058986:Phosphodiesterase 5 Inhibitors; D000068677:Sildenafil Citrate",
"country": "United States",
"delete": false,
"doi": "10.1111/aogs.14251",
"fulltext": null,
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"issn_linking": "0001-6349",
"issue": "100(11)",
"journal": "Acta obstetricia et gynecologica Scandinavica",
"keywords": "drug utilization; pharmacoepidemiology; phosphodiesterase type 5 inhibitors; pregnancy; sildenafil",
"medline_ta": "Acta Obstet Gynecol Scand",
"mesh_terms": "D000328:Adult; D005260:Female; D006801:Humans; D058986:Phosphodiesterase 5 Inhibitors; D011247:Pregnancy; D012042:Registries; D012537:Scandinavian and Nordic Countries; D000068677:Sildenafil Citrate",
"nlm_unique_id": "0370343",
"other_id": null,
"pages": "2111-2118",
"pmc": null,
"pmid": "34453753",
"pubdate": "2021-11",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": null,
"title": "Use of sildenafil and other phosphodiesterase type 5 inhibitors among pregnant women in Scandinavia.",
"title_normalized": "use of sildenafil and other phosphodiesterase type 5 inhibitors among pregnant women in scandinavia"
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"companynumb": "SE-ALKEM LABORATORIES LIMITED-SE-ALKEM-2021-05696",
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"actiondrug": "6",
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"activesubstancename": "SILDENAFIL"
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"abstract": "To report a case of severe dystrophic calcification in maxillary sinus of a child with liver transplantation and dental organs pigmented by hyperbilirubinemia.\n\n\n\nfemale patient, 12 years old, with liver transplantation performed at the age of 7 due to extrahepatic biliary atresia (EHBA). The patient was receiving the immunosuppressant tacrolimus (2 mg daily). Intraoral clinical exam showed tooth green pigmentation by bilirubin. Cone-beam volumetric computed tomography (CT) was performed to verify radiographic density of pigmented dental elements. Hounsfield scale measurement did not show changes in radiographic density of dental structures. However, CT scan showed intense dystrophic calcification in the maxillary sinus region.\n\n\n\nCT scan indicated relevant radiographic findings, with radiopacity of the maxillary sinus due to fungal or non-fungal sinusitis. This case report highlights the presence of radiographic image associated with acute infectious processes that could compromise the systemic state of immunosuppressed patients.",
"affiliations": "Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, SP, Brasil.;Universidade de São Paulo, São Paulo, SP, Brasil.;Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, SP, Brasil.;Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, SP, Brasil.",
"authors": "Macedo|Adriana Furtado de|AF|;Costa|Claudio|C|;Mattar|Regina Helena Guedes da Motta|RHGDM|;Azevedo|Ramiro Anthero de|RA|",
"chemical_list": "D001663:Bilirubin",
"country": "Brazil",
"delete": false,
"doi": "10.1590/1984-0462/;2018;36;1;00012",
"fulltext": "\n==== Front\nRev Paul PediatrRev Paul PediatrrppRevista Paulista de Pediatria0103-05821984-0462Sociedade de Pediatria de São Paulo 10.1590/1984-0462/;2018;36;1;00012Relatos de CasoDYSTROPHIC CALCIFICATION OF MAXILLARY SINUS IN PEDIATRIC PATIENTS WITH\nLIVER TRANSPLANTATION AND PIGMENTATION OF DENTAL ORGAN CALCIFICAÇÃO DISTRÓFICA EM SEIO MAXILAR DE PACIENTE PEDIÁTRICO COM\nTRANSPLANTE HEPÁTICO E PIGMENTAÇÃO DO ÓRGÃO DENTAL de Macedo Adriana Furtado \na\n\nb\n*Costa Claudio \nc\nMattar Regina Helena Guedes da Motta \na\nde Azevedo Ramiro Anthero \na\n\na Escola Paulista de Medicina, Universidade Federal de São Paulo, São\nPaulo, SP, Brasil.\nb Universidade Cruzeiro do Sul, São Paulo, SP, Brazil.\nc Universidade de São Paulo, São Paulo, SP, Brasil.* Autor correspondente. E-mail: adrifmacedo@yahoo.com.br\n(A. F. Macedo).\nConflito de interesses: Os autores declaram não haver conflito de\ninteresses.\n\n17 11 2017 Jan-Mar 2018 36 1 117 120 08 12 2016 11 4 2017 Este é um artigo publicado em acesso aberto sob uma licença Creative\nCommonsABSTRACT\nObjective:\n To report a case of severe dystrophic calcification in maxillary sinus of a child\nwith liver transplantation and dental organs pigmented by hyperbilirubinemia. \n\nCase description:\n female patient, 12 years old, with liver transplantation performed at the age of\n7 due to extrahepatic biliary atresia (EHBA). The patient was receiving the\nimmunosuppressant tacrolimus (2 mg daily). Intraoral clinical exam showed tooth\ngreen pigmentation by bilirubin. Cone-beam volumetric computed tomography (CT) was\nperformed to verify radiographic density of pigmented dental elements. Hounsfield\nscale measurement did not show changes in radiographic density of dental\nstructures. However, CT scan showed intense dystrophic calcification in the\nmaxillary sinus region.\n\nComments:\n CT scan indicated relevant radiographic findings, with radiopacity of the\nmaxillary sinus due to fungal or non-fungal sinusitis. This case report highlights\nthe presence of radiographic image associated with acute infectious processes that\ncould compromise the systemic state of immunosuppressed patients.\n\nRESUMO\nObjetivo:\n Relatar um caso de calcificação distrófica intensa no interior do seio maxilar em\numa criança com transplante hepático e órgãos dentais pigmentados por\nhiperbilirrubinemia. \n\nDescrição do caso:\n Paciente do sexo feminino, 12 anos de idade, com transplante hepático efetuado\naos 7 anos de vida devido à atresia de vias biliares extra-hepática, uso de\ntacrolimus imunossupressor (2 mg diários). No exame clínico intrabucal,\nobservou-se a presença de pigmentação esverdeada no órgão dental por bilirrubina.\nEfetuou-se um exame de tomografia computadorizada volumétrica de feixe cônico para\nanálise da densidade radiográfica dos elementos dentais pigmentados. Mediante\ninterpretação da imagem pela escala de Hounsfield, não foi constatada nenhuma\nalteração na densidade radiográfica das estruturas do órgão dental. No entanto, a\ntomografia computadorizada evidenciou a presença de calcificação distrófica\nintensa em região de seio maxilar. \n\nComentários:\n A alteração de imagem observada no exame de tomografia computadorizada demonstrou\nachado radiográfico relevante, com presença de radiopacidades no interior do seio\nmaxilar decorrentes de sinusites fúngicas ou não fúngicas. O relato desse caso é\nrelevante por apresentar alteração de imagem radiográfica exacerbada associada a\nquadros infecciosos agudos que podem comprometer o estado sistêmico do paciente\nimunossuprimido.\n\nKeywords:\nAdolescentLiver transplantationMaxillary sinusPigmentationDentition, permanentTomography, X-ray computedPalavras-chave:\nAdolescenteTransplante de fígadoSeio maxilarPigmentaçãoDentição permanenteTomografia computadorizada por raios X\n==== Body\nINTRODUCTION\nCalcification is a biochemical process in which deposition of calcium salts occurs;\nhowever, it may happen in unusual sites of human body.\n1\n Pathological calcifications are classified as idiopathic, metastatic, dystrophic\nor intrasinus. These are called idiopathic when calcium builds up in healthy tissues but\nblood calcium level is normal. However, when blood tests positive calcium elevation with\nconsequent ion deposition, metastatic calcification will be present. In dystrophic\ncalcification, there is poor vascularization where calcium deposits, that is, not\nsufficient blood supply; in addition, necrotic tissues and ischemia may be seen on the\nsite.\n1\n It usually occurs in the core of growing tumors, where there is carbon dioxide\ndecrease and extracellular fluid alkalinity increase, resulting in a microenvironment in\nwhich calcium is easily deposited. Intrinsic calcification derives from inflammatory and\ninfectious conditions.\n2\n\n\n\nThe liver is the main organ for intermediate metabolism of proteins, carbohydrates, and\nfats as it metabolizes and excretes toxic substances. Chronic liver disease may alter\nthese functions, especially in the presence of a perinatal inflammatory process\ninitiated in bile ducts, resulting in progressive fibrosclerosis and intra- and\nextrahepatic obstruction.\n3\n\n,\n\n4\n\n,\n\n5\n Hepatic transplantation is often the preferred therapy for a wide range of\nchronic liver diseases.\n6\n After transplantation, calcineurin inhibitors such as cyclosporine and\ntacrolimus are initiated, which dramatically increases the transplanted organ’s\nlifetime.\n6\n Some oral manifestations are relevant and specific to pediatric patients with\nthis systemic disease. Color change in dental enamel and soft tissues is one of them, in\nboth cases presenting greenish pigmentation, as well as enamel hypoplasias, eruption\ndelay, and increased volume of pulp chamber and root canals.\n3\n In order to analyze such alterations, volumetric computed tomography is often\nrequired, as it is classified as the best available method to evaluate hard-tissue\nlesions, especially in the mandible regions.\n7\n\n,\n\n8\n\n\n\nThus, the aim of this paper is to describe the case of a pediatric patient with\ndystrophic calcifications in maxillary sinus and bilirubin dental pigmentations after\nliver transplantation.\n\nCASE DESCRIPTION\nA female patient, 12 years and 9 months old, presented for dental treatment at\nUniversidade Federal de São Paulo (Unifesp), complaining of color change in dental\nenamel. The patient had been born of 40 weeks, by C-section, with intense neonatal\njaundice. Even after phototherapy for three days, the condition showed no remission. At\nthree years of age, she was diagnosed with biliary atresia, and liver transplantation\nwas performed at the age of seven years and 11 months. The immunosuppressive medication\nadministered was tacrolimus, with 1 mg in the morning and 1 mg in the evening.\n\nMixed dentures with greenish pigmentation in dental elements, as well as dental biofilm\nand prolonged retention of the left superior deciduous canine were observed upon\nintraoral examination (Figure 1). Cone beam CT scan\nof the maxilla was performed at Centro de Tomografia Avançada (CTA).\nThe equipment used was an I-CAT (Kavo•) with cone-beam X-ray system, focal\npoint of 0.5 mm, voxel of 0.125 mm, 14-bit gray scale, 17x23 cm field of view (FOV),\nautomatic collimation with pulsed exposure, effective dose of 36 to 74 µSv and\ncylindrical reconstruction. The method consisted of a single exposure using cone-beam\nX-ray, capturing an image of the whole volume with a single exposure and 360° rotation\nof x-ray source around the patient’s head. To perform the tomographic report on the\ndifferent radiographic densities of pigmented teeth, the Hounsfield scale was used in 16\nshades, from light gray to black. CT scan showed prolonged retention of the left\nsuperior deciduous canine (Figure 2) in frontal\nthree-dimensional view, and sagittal sections showed peripheral hyperdense images of\nmaxillary sinus (Figure 3). Upon panoramic\nexamination, peripheral dystrophic calcifications of maxillary sinus were seen (Figure 3).\n\n\nFigure 1: Intraoral view with prolonged retention of left superior deciduous canine\nand greenish pigmentation of teeth.\n\n\n\n\nFigure 2: Frontal three-dimensional image.\n\n\n\n\nFigura 3: (A) Sagittal view showing peripheral dystrophic calcification of maxillary\nsinus; (B) Sagittal view showing peripheral dystrophic calcification of\nmaxillary sinus and onset of new calcification areas in its center; (C)\nPanoramic view showing dystrophic calcifications of maxillary sinus.\n\n\n\nDISCUSSION\nDystrophic calcification in maxillary sinus originates from an inflammatory picture with\nchronicity characteristics and may be related to fungal or non-fungal sinusitis.\nIntrasinus calcium deposits may arise along with non-fungal inflammatory processes such\nas presence of mucocele and bacterial sinusitis.\n2\n Few reports in literature mention non-fungal sinusitis, and differential\ndiagnosis between both conditions is relevant.\n\nThe present report shows absence of differences in radiographic density of pigmented\nteeth in relation to enamel organ, without color change after cone-beam volumetric CT\nscan. This method allows examining the human body in segments with few millimeters of\nthickness, which helps to diagnose pathologies that affect bone tissues, besides being\nnon-invasive, fast and of high diagnostic accuracy, being able to identify and delineate\npathological processes.\n9\n Computed tomography is currently used for oral rehabilitation, delimitation, and\nvisualization of maxillofacial pathologies, but it is still little used to diagnose head\nand neck systemic pathologies.\n9\n\n\n\nAt images, the pigmented dental structure did not show radiographic density difference,\nsuggesting that dental organs with bilirubin chromatic alterations in their structure\ncan be submitted to restorative treatment. This pigmentation is a consequence of the\nhigh concentration of bilirubin in the dentinal tubules.\n3\n Tomographic imaging also showed dystrophic calcifications inside the maxillary\nsinus, with peripheral areas of hyperdensity and hypodense center. The images suggest\nnon-fungal sinusitis, in which calcification is close to the thickened submucosal layer\nof the maxillary sinus, constantly affected by chronic inflammatory conditions.\n2\n Other etiologies cited in relation to this radiographic finding are inflammatory\ndiseases, malignant tumors and benign lesions, mucoceles, and bacterial sinusitis.\n2\n Calcifications in fungal sinusitis occur in the core of maxillary sinus, with\nhyperdensity originating from well-delineated nodular masses arising from the calcium\ndepositions within mycelial mass.\n2\n There is no consensus on the level of thickening of the sinus mucosa that is\nconsidered abnormal, ranging from 2 to 6 mm.\n10\n The radiographic pattern of nonfungal sinusitis differs from fungal sinusitis,\nwhich is characterized by high density in maxillary sinus, bone destruction, and\ninfiltration of adjacent soft tissue, allowing aggravating processes that may lead to\ndeath in immunosuppressed patients.\n2\n In this case, a patient with liver transplantation may present serious clinical\nimplications, once the adequate treatment of infections and sinusitis requires reduction\nor complete elimination of immunosuppression. If low immunosuppression continuation is\nneeded, transplant rejection may occur.\n\nAnother factor to be highlighted in this case is the absence of symptoms, although\ndental pathological processes may potentially induce inflammation in maxillary sinus\nbecause of the proximity of dental floor to the radicular portion.\n10\n The patient had healthy teeth, which shows no relationship between calcification\nand pathological dental processes. Patients with acute sinusitis usually report\nunilateral headache and maxillary algesia in dental region, with sensitive and painful\nteeth; facial edema and thick purulent secretion may occur in chronic sinusitis.\n11\n This finding underlines the importance of conducting a cone-beam CT scan to\ndiagnose orofacial pathologies.\n10\n\n\n\nAlong with results obtained by imaging evaluation, a tailored treatment plan was\ndeveloped based on weekly dental prophylaxis with oral hygiene guidance and dental\nbiofilm disclosure in order to avoid the installation of a gingival inflammatory process\nand the onset of incipient caries lesions. Later on, the deciduous canine was\nextracted.\n\nTherefore, it can be inferred that imaging was fundamental for diagnosis of non-fungal\nsinusitis in immunosuppressed and asymptomatic patient, which allowed the medical team\nto start the treatment for a disease that can aggravate the overall condition of liver\ntransplantation recipient.\n\n\nFunding: This study did not receive funding.\n==== Refs\nREFERÊNCIAS\n1 Jácome AM Abdo EN Aspectos radiográficos das calcificações em tecidos moles da região\nbucomaxilofacial Odontol Clín-Cient 2010 9 25 32 \n2 Yoon JH Na DG Byun HS Koh Yh Chung SK Dong HJ Calcification in Chronic Maxillary Sinusitis: Comparison of CT\nFindings with Histopathologic Results AJNR Am J Neuroradiol 1999 20 571 574 10319962 \n3 Macedo AF Azevedo RA Zanin FA Duarte DA Manifestações bucais e sistêmicas em crianças com doença hepática\ncrônica Rev Gaúcha Odont 2007 55 403 406 \n4 Cauduro SM Atresia biliar extra-hepática métodos diagnósticos J Pediatr (Rio J) 2003 79 107 114 14502330 \n5 Shen QL Chen YJ Wang ZM Zhang TC Pang WB Shu J Assessment of liver fibrosis by Fibroscan as compared to liver biopsy\nin biliary atresia World J Gastroenterol 2015 21 6931 6936 26078570 \n6 Isa HM Mohamed AM Alderazi AE Effect of pediatric liver transplantation on renal\nfunction Saudi J Kidney Dis Transpl 2016 27 1 8 26787559 \n7 Sumida AE Oliveira FA Oliveira HW Uso da tomografia computadorizada (TC) na odontologia: estudo\ncomparativo entre 2 métodos de reformatação da imagem tomográfica na avaliação de\nretenções dentárias na região anterior da maxila Rev Gaúcha Odontol 2002 50 192 196 \n8 Perella A Borsatti MA Tortamano IP Rocha RG Cavalcanti MG Validation of computed tomography protocols for simulated mandibular\nlesions: a comparison study Braz Oral Res 2007 21 165 169 17589653 \n9 Bramante AS Bramante CM Bernadineli N Moraes IG Garcia RB Diagnóstico de defeitos ósseos por meio da radiografia convencional,\ndigital e tomografia helicoidal Rev Port Estomatol Med Dent Cir Maxilofac 2007 48 15 21 \n10 Rege IC Sousa TO Leles CR Mendonça EF Occurrence of maxillary sinus abnormalities detected by cone beam CT\nin asymptomatic patients BMC Oral Health 2012 12 30 30 22883529 \n11 Oliveira RA Pedrazini MC Wassall T Relative area measurement of maxillary sinus by computed\ntomography Rev Gaúcha Odontol 2014 62 111 116\n\n",
"fulltext_license": "CC BY",
"issn_linking": "0103-0582",
"issue": "36(1)",
"journal": "Revista paulista de pediatria : orgao oficial da Sociedade de Pediatria de Sao Paulo",
"keywords": null,
"medline_ta": "Rev Paul Pediatr",
"mesh_terms": "D001663:Bilirubin; D002114:Calcinosis; D002648:Child; D005260:Female; D006801:Humans; D016031:Liver Transplantation; D008443:Maxillary Sinus; D010254:Paranasal Sinus Diseases; D010858:Pigmentation; D011183:Postoperative Complications; D014076:Tooth Diseases",
"nlm_unique_id": "9109353",
"other_id": null,
"pages": "4",
"pmc": null,
"pmid": "29166493",
"pubdate": "2018",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "22883529;17589653;14502330;26078570;10319962;26787559",
"title": "DYSTROPHIC CALCIFICATION OF MAXILLARY SINUS IN PEDIATRIC PATIENTS WITH LIVER TRANSPLANTATION AND PIGMENTATION OF DENTAL ORGAN.",
"title_normalized": "dystrophic calcification of maxillary sinus in pediatric patients with liver transplantation and pigmentation of dental organ"
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... |
{
"abstract": "OBJECTIVE\nAdvanced Ewing sarcomas have poor prognosis. They are defined by early relapse (<24 months after diagnosis) and/or by metastasis to multiple bones or bone marrow (BM). We analyzed risk factors, toxicity and survival in advanced Ewing sarcoma patients treated with the MetaEICESS vs. EICESS92 protocols.\n\n\nMETHODS\nOf 44 patients, 18 patients were enrolled into two subsequent MetaEICESS protocols between 1992 and 2014, and compared to outcomes of 26 advanced Ewing sarcoma patients treated with EICESS 1992 between 1992 and 1996. MetaEICESS 1992 consisted of induction chemotherapy, whole body imaging directed radiotherapy to the primary tumor and metastases, tandem high-dose chemotherapy and autologous rescue. In MetaEICESS 2007 this treatment was complemented by allogeneic stem cell transplantation. EICESS 1992 comprised induction chemotherapy, local therapy to the primary tumor only followed by consolidation chemotherapy.\n\n\nRESULTS\nIn MetaEICESS 8/18 patients survived in complete remission vs. 2/26 in EICESS 1992 (p<0.05). Survival did not differ between MetaEICESS 2007 and MetaEICESS 1992. Three MetaEICESS patients died of complications, all in MetaEICESS 1992. After exclusion of patients succumbing to treatment related complications (n=3), 7/10 patients survived without BM involvement, in contrast to 0/5 patients with BM involvement. This was confirmed in a multivariate analysis. There was no correlation between BM involvement and the number of metastases at diagnosis.\n\n\nCONCLUSIONS\nThe MetaEICESS protocols yield long-term disease-free survival in patients with advanced Ewing sarcoma. Allogeneic stem cell transplantation was not associated with increased death of complications. Bone marrow involvement is a risk factor distinct from multiple bone metastases.",
"affiliations": "Department of Pediatrics and Pediatric Oncology Center, Kinderklinik München Schwabing, Städtisches Klinikum München und Klinikum rechts der Isar, Wilhelm Sander Sarcoma Unit, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.;Department of Pediatrics and Pediatric Oncology Center, Kinderklinik München Schwabing, Städtisches Klinikum München und Klinikum rechts der Isar, Wilhelm Sander Sarcoma Unit, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.;Department of Pediatrics and Pediatric Oncology Center, Kinderklinik München Schwabing, Städtisches Klinikum München und Klinikum rechts der Isar, Wilhelm Sander Sarcoma Unit, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.;Department of Pediatrics and Pediatric Oncology Center, Kinderklinik München Schwabing, Städtisches Klinikum München und Klinikum rechts der Isar, Wilhelm Sander Sarcoma Unit, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.;Department of Pediatrics and Pediatric Oncology Center, Kinderklinik München Schwabing, Städtisches Klinikum München und Klinikum rechts der Isar, Wilhelm Sander Sarcoma Unit, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.;Laboratory for Pediatric Sarcoma Biology, Institute of Pathology, LMU, Munich, Germany.;Department of Radiology, Klinikum Schwabing, Städtisches Klinikum München, Munich, Germany.;Department of Radiation Oncology, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.;Department of Pediatric Hematology and Oncology, Universitätsklinikum Frankfurt, Frankfurt, Germany.;Department of Pediatric Hematology and Oncology, Universitätsklinikum Frankfurt, Frankfurt, Germany.;Department of Pediatric Hematology and Oncology, Universitätsklinikum Frankfurt, Frankfurt, Germany.;Department of Pediatric Oncology, Hematology and Immunology, Olgahospital, Klinikum Stuttgart, Stuttgart, Germany.;Vestische Kinder- und Jugendklinik, Datteln, Universität Witten/Herdecke, Datteln, Germany.;Department of Pediatric Hematology and Oncology, Universitätsklinikum Münster, Münster, Germany.;Department of Pediatric Hematology and Oncology, Universitätsklinikum Münster, Münster, Germany.;Department of Pediatrics and Pediatric Oncology Center, Kinderklinik München Schwabing, Städtisches Klinikum München und Klinikum rechts der Isar, Wilhelm Sander Sarcoma Unit, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.;Department of Pediatrics and Pediatric Oncology Center, Kinderklinik München Schwabing, Städtisches Klinikum München und Klinikum rechts der Isar, Wilhelm Sander Sarcoma Unit, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.",
"authors": "Thiel|Uwe|U|;Wawer|Angela|A|;von Luettichau|Irene|I|;Bender|Hans-Ulrich|HU|;Blaeschke|Franziska|F|;Grunewald|Thomas G P|TG|;Steinborn|Marc|M|;Röper|Barbara|B|;Bonig|Halvard|H|;Klingebiel|Thomas|T|;Bader|Peter|P|;Koscielniak|Ewa|E|;Paulussen|Michael|M|;Dirksen|Uta|U|;Juergens|Heribert|H|;Kolb|Hans-Jochem|HJ|;Burdach|Stefan E G|SE|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.18632/oncotarget.10938",
"fulltext": "\n==== Front\nOncotargetOncotargetOncotargetImpactJOncotarget1949-2553Impact Journals LLC 274868221093810.18632/oncotarget.10938Clinical Research PaperBone marrow involvement identifies a subgroup of advanced Ewing sarcoma patients with fatal outcome irrespective of therapy in contrast to curable patients with multiple bone metastases but unaffected marrow Thiel Uwe 1Wawer Angela 1von Luettichau Irene 1Bender Hans-Ulrich 1Blaeschke Franziska 1Grunewald Thomas G.P. 2Steinborn Marc 3Röper Barbara 410*Bonig Halvard 56Klingebiel Thomas 5Bader Peter 5Koscielniak Ewa 7Paulussen Michael 8Dirksen Uta 9Juergens Heribert 9Kolb Hans-Jochem 1Burdach Stefan E.G. 1101 Department of Pediatrics and Pediatric Oncology Center, Kinderklinik München Schwabing, Städtisches Klinikum München und Klinikum rechts der Isar, Wilhelm Sander Sarcoma Unit, Klinikum rechts der Isar, Technische Universität München, Munich, Germany2 Laboratory for Pediatric Sarcoma Biology, Institute of Pathology, LMU, Munich, Germany3 Department of Radiology, Klinikum Schwabing, Städtisches Klinikum München, Munich, Germany4 Department of Radiation Oncology, Klinikum rechts der Isar, Technische Universität München, Munich, Germany5 Department of Pediatric Hematology and Oncology, Universitätsklinikum Frankfurt, Frankfurt, Germany6 Department of Transfusion Medicine and Immunohematology, Universitätsklinikum Frankfurt, Frankfurt, Germany7 Department of Pediatric Oncology, Hematology and Immunology, Olgahospital, Klinikum Stuttgart, Stuttgart, Germany8 Vestische Kinder- und Jugendklinik, Datteln, Universität Witten/Herdecke, Datteln, Germany9 Department of Pediatric Hematology and Oncology, Universitätsklinikum Münster, Münster, Germany10 Munich Comprehensive Cancer Center, München, GermanyCorrespondence to:Stefan E.G. Burdach,meta-eicess@lrz.tum.de* Present address: Radiation Oncology Clinic, Klinikum Bogenhausen, Städtisches Klinikum München, Munich, Germany\n\n25 10 2016 29 7 2016 7 43 70959 70968 8 2 2016 30 6 2016 Copyright: © 2016 Thiel et al.2016This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Purpose\nAdvanced Ewing sarcomas have poor prognosis. They are defined by early relapse (<24 months after diagnosis) and/or by metastasis to multiple bones or bone marrow (BM). We analyzed risk factors, toxicity and survival in advanced Ewing sarcoma patients treated with the MetaEICESS vs. EICESS92 protocols.\n\nDesign\nOf 44 patients, 18 patients were enrolled into two subsequent MetaEICESS protocols between 1992 and 2014, and compared to outcomes of 26 advanced Ewing sarcoma patients treated with EICESS 1992 between 1992 and 1996. MetaEICESS 1992 consisted of induction chemotherapy, whole body imaging directed radiotherapy to the primary tumor and metastases, tandem high-dose chemotherapy and autologous rescue. In MetaEICESS 2007 this treatment was complemented by allogeneic stem cell transplantation. EICESS 1992 comprised induction chemotherapy, local therapy to the primary tumor only followed by consolidation chemotherapy.\n\nResults\nIn MetaEICESS 8/18 patients survived in complete remission vs. 2/26 in EICESS 1992 (p<0.05). Survival did not differ between MetaEICESS 2007 and MetaEICESS 1992. Three MetaEICESS patients died of complications, all in MetaEICESS 1992. After exclusion of patients succumbing to treatment related complications (n=3), 7/10 patients survived without BM involvement, in contrast to 0/5 patients with BM involvement. This was confirmed in a multivariate analysis. There was no correlation between BM involvement and the number of metastases at diagnosis.\n\nConclusion\nThe MetaEICESS protocols yield long-term disease-free survival in patients with advanced Ewing sarcoma. Allogeneic stem cell transplantation was not associated with increased death of complications. Bone marrow involvement is a risk factor distinct from multiple bone metastases.\n\nEwing sarcomabone metastasisbone marrow metastasisallogeneic stem cell transplantationhigh-dose chemotherapy\n==== Body\nINTRODUCTION\nEwing sarcomas are defined by t(11;22)(q24;q12) derived EWS/ETS fusion oncogenes [1]. They occur in both bone and soft tissue [2]. Advanced Ewing sarcoma comprises early relapse or metastatic to multiple bones (i.e. more than one) or bone marrow (BM) [3, 4]. Overall survival of advanced Ewing sarcoma after ten years is ≤10% [4–6], warranting the study of intensified treatment modalities [6–19]. Moreover, the distinct contribution of BM involvement vs. multiple bone metastases to the dismal prognosis is not defined.\n\nIn the MetaEICESS 1992 protocol we used induction chemotherapy, whole-body MRI (whole-body MRI) and PET based primary and metastatic tumor irradiation combined with autologous stem cell rescue, followed by tandem high-dose chemotherapy with additional autoologous rescue as consolidation [4]. In the prospective MetaEICESS 2007 study, this sequence was complemented by reduced intensity conditioning and allogeneic stem cell transplantation. Results of disease-free survival of both MetaEICESS protocols were compared with advanced Ewing sarcoma patients who received the EICESS 1992 regimen with induction and consolidation chemotherapy and primary tumor radiation only. Furthermore, results of the MetaEICESS 1992 [4] and the EICESS 1992 groups [22] previously published are updated here.\n\nDefinitions\nAdvanced Ewing sarcoma was defined by early relapse (<24 months after diagnosis) and/or by metastatic disease to multiple bones or BM. BM involvement was defined as cytological detection of tumor cells in the BM aspirate. Death of disease comprised any death directly related to disease progression or relapse. Complete remission was defined as lack of tumor evidence. Death of complication was any death attributable to therapy. In this report, disease-free survival was defined as the interval between the date of diagnosis that prompted respective protocol admission until the occurrence of any local or metastatic tumor evidence (or death of complications when indicated). In MetaEICESS 2007 patients we determined a second disease-free interval as well as overall survival which was was defined as the time period from the last allogeneic stem cell transplantation until first relapse, death or last follow-up (compare Supplementary Figure S1).\n\nPATIENTS AND METHODS\n44 patients were assessed in this study: 18 patients enrolled in the two subsequent single-center MetaEICESS 1992 (registered from 1995 to 2000) and 2007 protocols (registered from 2007 to 2014) were compared to 26 controls (EICESS 1992; registered from 1992 to 1996). Eligibility criterion was diagnosis of advanced Ewing sarcoma. The cut off of ≥ 2 bone metastases and/or early relapse (relapse<24 months after diagnosis) was identical to previous studies [4, 23]. Patients were only treated with the according protocol, respectively, and did not switch groups during treatment course. All patients and their legal guardians signed informed consent prior to therapy. Protocol treatment was applied after approval by the institutional review boards according to the precepts established by the Helsinki Conference Declaration.\n\nEICESS 1992\nIn the EICESS group 26 patients with multiple bone metastases at diagnosis (aged 6–37 years; median: 17 years) were registered from 1992 to 1996 and treated according to the EICESS 92 protocol for advanced Ewing sarcoma, as previously described. In order to prevent a selection bias in favor of MetaEICESS and to warrant comparability to patients treated with the MetaEICESS protocols, only data of EICESS 1992 patients who were alive at a median time of 7.5 months after diagnosis, which equals the median time from diagnosis to first high-dose chemotherapy treatment of MetaEICESS 2007 and 1992 groups, were included.\n\nMetaEICESS 1992\n11 patients were diagnosed with advanced Ewing sarcoma between 1992 and 2000. Diagnoses based upon histopathology. Median age at diagnosis that prompted MetaEICESS admission was 16 years (range 6–32 years). These patients were previously described [4]. Median time from diagnosis to first high-dose chemotherapy treatment was 8 months. 3 out of 11 had BM involvement at initial diagnosis (Supplementary Tables S1 and S2). Patients also received high-dose chemotherapy etc. irrespective of remission.\n\nMetaEICESS 2007\nDiagnoses were made between 2007 and 2013 based upon histopathology and detection of translocations. Median age at diagnosis that prompted MetaEICESS admission was 15 years (range 8-17 years). Median time from diagnosis to first high-dose chemotherapy treatment was 5 months. 3 out of 7 patients had BM involvement at initial diagnosis (Supplementary Tables S1 and S2). Patients received high-dose chemotherapy and ensuing treatments irrespective of remission status.\n\nStaging\nFor MetaEICESS 1992 and MetaEICESS 2007 patients, stage and extent of disease were evaluated by cytological examination of BM aspirates, technetium scintigraphy, chest computed tomography positron emission tomography (PET) scans and whole-body MRI [4], which we introduced in 2003 for advanced Ewing sarcoma [6]. For whole body-MRI, short tau (time) inversion recovery and T1-weighted coronal imaging was applied in all patients. Lung disease was assessed by thoracic computed tomography. In EICESS 1992 patients, extent and stage of disease were evaluated by MRI, chest CT, BM aspirates and technetium scintigraphy bone scans.\n\nInduction chemotherapy and local treatment\nAll MetaEICESS patients received induction chemotherapy consisting of four blocks of VIDE (vincristine, ifosfamide, doxorubicin and etoposide) and two blocks of VIE when patients received primary tumor or metastases irradiation.\n\nAutologous stem cell apheresis was conducted after the last two VIDE blocks. Involved lesion irradiation was delivered to the primary tumor (total dose 50-60 Gy), to the lungs (15-18 Gy), and to lymph node as well as multiple osseous metastases (45-50 Gy) in individual combinations. One patient received proton radiation (patient #1), all others received photon therapy. Radio-chemotherapy was followed by autologous stem cell transplantation (Figure 1).\n\nFigure 1 Schematic overview: Treatment strategies for MetaEICESS protocols 1992 and 2007 as well as EICESS 92 High-Risk (HR)\nIn EICESS 1992 20/26 patients received only EVAIA and 6/26 patients received VAIA followed by EVAIA. As local therapy, 7/26 patients received surgery, 18/26 patients received radiation and 6/26 patients received both surgery and irradiation to the primary tumor site, whereas 1/26 patients did not receive local therapy. The total irradiation dose was 40–54 Gy with a general bone dose of 54 Gy, except for 40 Gy to the spine if more than three vertebrae were involved.\n\nMyeloablation and autologous stem cell transplantation\n16/18 MetaEICESS patients received TandemME (MetaEICESS 1992) or ME/TopoTreo (MetaEICESS 2007) and 2 (all MetaEICESS 1992) patients HyperME myeloablation as previously described (Figure 1) [4, 6]. In MetaEICESS 2007 myeloablation consisted of melphalan (30 mg/m2/day on day −7 and −4 before first autologous stem cell transplantation) in combination with etoposide (1800 mg/m2/day on day −2 before first autologous stem cell transplantation) followed by application of topotecan (2 mg/m2/day on day −7 and −3 before second autologous stem cell transplantation) in combination with treosulfan (10 mg/m2/day on day −5 and −3 before second autologous stem cell transplantation). EICESS 1992 patients did not receive myeloablative therapy.\n\nReduced intensity conditioning and allogeneic stem cell transplantation (MetaEICESS 2007)\nAfter tandem high-dose chemotherapy with autologous stem cell transplantation, all MetaEICESS 2007 patients received reduced intensity chemotherapy followed by allogeneic stem cell transplantation with G-CSF mobilized peripheral blood stem cell products from family donors (Figure 1). Reduced intensity chemotherapy regimen consisted of fludarabine (30 mg/m2/day on day −9 and −5 before allogeneic stem cell transplantation) in combination with thiotepa (10 mg/m2/day on day −4 before allogeneic stem cell transplantation) and melphalan (35 mg/m2/day on day −3 and −2 before allogeneic stem cell transplantation). Seven patients received haploidentical grafts, one patient both a fully matched and an HLA 9/10 matched graft. Six patients were allo-transplanted in complete remission, whereas one patient was transplanted with residual disease (Supplementary Table S1).\n\nStatistical analysis\nStatistical differences in were determined using the Graphpad Prism software, version 5.0 as well as R 2.11.0 (The R Foundation for Statistical Computing, Vienna Austria). In univariate analyses, statistical differences in disease-free survival were determined with the Kaplan–Meier method using the log rank (Mantel-Cox) test and the Breslow-Wilcoxon test. In the multivariate analysis, considered independent variables were patient age at diagnosis, gender, protocol (EICESS92 vs MetaEICESS) and BM involvement at diagnosis. Statistical differences were determined using the Wald test. Hazard ratios (HR), standard errors and confidence intervals (CI) are given when appropriate. In order to determine a correlation between BM involvement with the number of bone metastases at diagnosis the two-tailed t-test was used. In all tests p<0.05 was considered statistically significant. Final data base update was conducted on March 1st 2015.\n\nRESULTS\nEngraftment and GvHD (MetaEICESS 2007)\nIn MetaEICESS 2007 6/7 patients engrafted successfully after first transplant. Patient #5 had to be re-transplanted due to rejection. Three patients developed acute GvHD and one patient developed extensive chronic GvHD; Patient #5 developed BK virus induced hemorrhagic cystitis after allogeneic stem cell transplantation and was successfully treated with third party MSC. Two patients suffered adenovirus reactivation.\n\nDisease-free survival\nIn the MetaEICESS 2007 group median disease-free survival was was 28 months (range 11-73). 4/7 (0.57) MetaEICESS 2007 patients were alive in complete remission at a median of 34 months (range 11-88) after diagnosis that prompted MetaEICESS submission. 6/7 patients were in complete remission before allogeneic stem cell transplantation. One patient had progressive disease at the time of allogeneic stem cell transplantation. Median disease-survival after allogeneic stem cell transplantation was 21 months (range 0-64) (Supplementary Figure S1, Supplementary Table S2). Of these, three patients are alive in complete remission for an observation time of over 24 months. 2/6 patients, who were in complete remission at transplant relapsed after allogeneic stem cell transplantation. Patients #1 and #2 with relapse after allogeneic stem cell transplantation received various rescue therapies and survived for 11 months and 33 months after relapse, respectively (Supplementary Table S2).\n\nIn the MetaEICESS 1992 group, 3/11 (0.28) patients were alive at the end of the follow-up period, while 8/11 had died; 3/11 succumbed to treatment related complications and 5/11 to the underlying disease. Of those patients who had succumbed to complications, patient #10 died of treatment-related bacterial sepsis whereas patients #15 and #16 died of treatment-related secondary malignancies (liposarcoma and myelodysplastic syndrome) (Supplementary Table S2). Both latter patients were treated with allogeneic stem cell transplantation as rescue therapy after diagnosis of treatment related secondary malignancies. Median disease-free survival was 40 months (range: 6 months–20 years).\n\nDeath of disease and death of complication rates in the MetaEICESS 2007 vs. MetaEICESS 1992 group were 0.42 vs 0.45 and 0 vs 0.27, respectively. There was no statistical disease-free survival difference between both groups (Supplementary Table S2, Figure 2), however death of complications was lower in MetaEICESS 2007, i.e. with allogeneic stem cell transplantation. Karnofsky-Index was >90 in all survivors.\n\nFigure 2 Disease-free survival in MetaEICESS 2007 (n=7) versus MetaEICESS 1992 (n=11) versus EICESS 1992 (n=26) from the date of diagnosis\nThere was no statistically significant difference (n.s.) between the MetaEICESS 2007 and the MetaEICESS 1992 group. The EICESS 1992 survival curve differed significantly from the MetaEICESS 1992 and 2007 survival curves (Log-rank test, p=0.01; Breslow-Wilcoxon test p<0.01; HR 0.41; CI 0.21 to 0.82).\n\nIn the EICESS 1992 group 2/26 patients, 0.08 remained alive in complete remission at the end of the follow-up period. 24 patients had died, 22/24 of disease, 2/24 of complications. One of the latter two patients with treatment related complications died of secondary malignancy. 6/26 patients had BM involvement at diagnosis, all of whom died of disease. Median disease-free survival was 12.5 months (range 6 months–20 years).\n\nDisease-free survival with the MetaEICESS 1992 and 2007 protocols was significantly better than with the EICESS 1992 protocol (Log-rank test, p=0.01; Breslow-Wilcoxon test p<0.01; HR 0.41; CI 0.21 to 0.82; Figure 2).\n\nBone marrow involvement\n3/7 patients in the MetaEICESS 2007 group and 3/11 in the MetaEICESS 1992 group had BM involvement at diagnosis. In all MetaEICESS patients 0/6 patients with BM involvement survived in contrast to 7/12 without BM involvement. All MetaEICESS patients with initial BM involvement (6/18) died: 3/3 MetaEICESS 2007 as well as 2/3 MetaEICESS 1992 patients with BM involvement died of disease; the third patient with BM involvement in MetaEICESS 1992 died of a secondary malignancy [4, 23]. The difference in disease-free survival between BM involvement vs. no BM involvement among MetaEICESS patients was statistically significant using the Log-rank test (p=0.023; HR 5.1; CI 1.2 to 20.8) but was insignificant using the Breslow-Wilcoxon test (Figure 3A). After exclusion of patients succumbing to treatment related complications (n=3), 5/5 patients with BM involvement in contrast to 2/10 patients without BM involvement had died of disease, leaving 7/10 patients without BM involvement in contrast to 0/5 with BM involvement in complete remission. The difference was statistically significant (Log-rank test p<0.01; Breslow-Wilcoxon test p=0.013; HR 11.3; CI 2.0 to 63.3; Figure 3B). In the EICESS 1992 group 6/26 patients had BM involvement at diagnosis: all of whom died of disease. When patients with bone metastases were excluded, survival fractions were 1.0 for MetaEICESS 2007 (4/4), 0.38 for MetaEICESS 1992 (3/8) and 0.2 (2/20) for EICESS 1992 patients. After exclusion of patients with bone marrow involvement the difference between both MetaEICESS protocols was not significant, whereas the difference between MetaEICESS versus EICESS 1992 remained significant (Log-rank p=0.01; Breslow-Wilcoxon p<0.01). In the whole study population of 44 patients there was no significant correlation between BM involvement and the number of metastases at diagnosis (two-tailed t-test p>0.05).\n\nFigure 3 A. Disease-free survival with BM (n=6) versus without BM involvement (n=12) at diagnosis (MetaEICESS 1992 and 2007; p=0.023; HR 5.1; CI 1.2 to 20.8; Breslow-Wilcoxon test not significant). B. Poor disease-free survival with BM (n=5) versus without BM involvement (n=10) after exclusion of patients succumbing to treatment related complications (Log-rank test p<0.01; Breslow-Wilcoxon test p=0.013; HR 11.3; CI 2.0 to 63.3). n.s.; not significant.\n\nMultivariate analyses\nUpon multivariate analysis, neither age at diagnosis nor gender had an influence on disease-free survival. EICESS 1992 treatment as well as BM involvement at diagnosis was confirmed as risk factors for poor outcome (both p<0.01; Table 1). When MetaEICESS patients were excluded, multivariate analysis within the EICESS 1992 group confirmed BM involvement as a risk factor for poor outcome (Wald test p=0.03, Supplementary Table S3).\n\nTable 1 Multivariate analysis (EICESS1992 and MetaEICESS; n=44); Poor disease-free survival in patients with EICESS 1992 treatment and/or BM involvement at diagnosis (both p<0.01*Wald-Test)\n\tHR\tSE\t95% CI\t*P-value\t\nDisease-free Survival (n=44)\tAge at Diagnosis\t\t\t0.95\t0.03\t0.99 to 1.11\t0.09\t\nGender\tmale\tReference\t\t\t\t0.06\t\n\tfemale\t\t1.84\t0.33\t0.29 to 1.03\t\t\nProtocol\tEICESS 1992\tReference\t\t\t\t<0.01\t\n\tMetaEICESS\t\t0.39\t0.35\t0.19 to 0.77\t\t\nBM Involvement at Diagnosis\tYes\tReference\t\t\t\t<0.01\t\n\tNo\t\t0.33\t0.35\t1.51 to 6.02\t\t\nAbbreviations: BM, bone marrow; HR, Hazard Ratio; SE, Standard Error; CI, Confidence Interval\n\nDISCUSSION\nOur report deals with a new treatment protocol designed for a subgroup of patients with a rare disease with a hitherto dismal prognosis. Herein, we report on the results of our prospective single-center MetaEICESS 1992 and 2007 approaches in comparison to EICESS 1992. Primary and secondary endpoints were disease-free survival and toxicity. Even for the small numbers accumulated in this report (n=44), we had to compare patients treated within a time period of 22 years. This long period may compromise death of complications comparability between groups, e.g. due to improvement in supportive therapy or staging drift e.g. by introduction of PET-CT or possibly the extent of BM sampling. However, our studies continuously employed ≥ 2 metastatic bones as assessed by technetium scintigraphy as the entry criterion to the study and further evaluation by whole-body MRI. To the best of our knowledge, there is no published evidence that PET-CT is more sensitive than the combination of whole-body MRI, PET and BM aspirate in detecting additional bone metastases or BM involvement. Moreover, PET-CT did not affect the entry to our protocol. Our studies provide a unique long term evaluation of a very rare entity whose prognosis remained unchanged in most studies with reliable and sensitive diagnostic criteria conserved over this long term period: whole-body MRI and BM cytology.\n\nA first finding of potential interest was that allogeneic stem cell transplantation does not increase death of complications. This finding contrasts with our previous finding of higher death of complications rates after this therapy modality [14]. This difference may be due to different conditioning.\n\nIn landmark as well as in recent studies, improvement of local therapy has proven crucial in the treatment of advanced Ewing sarcoma patients [11, 20, 24], whereas the role of high-dose chemotherapy regimen with autologous stem cell transplantation in the treatment of advanced Ewing sarcoma patients remains subject to an ongoing discussion [4, 7, 10, 15–17, 25–35]. The conflicting results of various studies including our previous analyses [6, 20] in contrast to the results of Meyers et al. [21] may be due to variation in intensity of local therapy. We cannot rule out that better results in MetaEICESS vs. EICESS are impacted by variation in induction chemotherapy. However this possibility does not compromise our conclusions that the MetaEICESS regimes in total yield a superior result as compared to EICESS.\n\nAssessing the role of allogeneic stem cell transplantation it turned out that despite better toxicity control in MetaEICESS 2007 compared to MetaEICESS 1992, disease-free survival did not differ. This may be due to the higher incidence of BM involvement as a confounding variable in MetaEICESS 2007 3/7 (0.43) vs. 3/11 (0.27) conferring poor prognosis. Thus, MetaEICESS protocols yield long-term survival in advanced Ewing sarcoma patients but do not eliminate the negative impact on disease-free survival of BM involvement. In a recent study, 87 out of 507 (0.17) ES patients with disseminated disease showed BM involvement [30]. While our previous observation that the presence of multiple bone or BM metastases is associated with poor prognosis in ES has been confirmed in this study, the single contribution of multiple bone metastases vs. BM involvement has not been assessed so far. In our study population of 44 patients there was no significant correlation between BM involvement and the number of bone metastases at diagnosis. Of note, Kopp et al. reported recently that BM involvement correlates with the number of bone metastases [3].\n\nGiven the albeit improved but still unsatisfactory results with high dose consolidation necessitating (autologous) rescue we attempted to assess the curative role of haploidentical allogeneic stem cell transplantation in MetaEICESS 2007. Following the prospective analysis we retrospectively discovered BM involvement as a new distinct and independent risk factor beyond multiple bone metastases. The cut-off for multiple bone metastases used here was ≥2. Thus, BM involvement may be indicative of a higher number of multiple bone metastases.\n\nSince the incidence of BM involvement turned out to be higher in MetaEICESS 2007 vs. MetaEICESS 1992, we were not able to clearly assess the potential of allogeneic stem cell transplantation to improve the prognosis of patients with multiple bone metastases but no BM involvement; this remains to be defined. Of note, results of MetaEICESS 2007 were not inferior to MetaEICESS 1992 despite the higher incidence of BM involvement in MetaEICESS 2007. Moreover, results of MetaEICESS 2007 were superior to EICESS92 despite the higher incidence of BM involvement in MetaEICESS 2007.\n\nSo far, BM involvement has not been published as a distinct risk factor beyond multiple bone metastases in advanced Ewing sarcoma. In addition to variation in local therapy, the unknown distribution of the risk factor BM involvement may explain, at least in part, the afore mentioned conflicting results of previous studies e.g. Meyers et al. [21] vs. Burdach et al. [6, 20], Barker et al. [36] and Rasper et al. [7].\n\nTaken together, BM involvement identifies a subgroup of advanced Ewing sarcoma patients with fatal outcome irrespective of therapy whereas advanced Ewing sarcoma patients with multiple bone metastases but without BM involvement may be cured with the MetaEICESS protocols. Allogeneic stem cell transplantation yielded no deaths of complications in this setting and quality of life was good in all survivors in comparison to former analyses [14, 37]. Despite the fact that eligibility criteria were identical, treatment groups were not randomized and not treated contemporaneously. Thus, there may be potential bias in eligibility that may impact the observation that MetaEICESS may be associated with improved outcome. Nevertheless, allogeneic stem cell transplantation warrants future evaluation to improve prognosis in particular of advanced Ewing sarcoma patients without BM involvement, whereas patients with BM involvement require additional novel approaches.\n\nSUPPLEMENTARY FIGURE AND TABLES\n We wish to thank all patients and their families and all treating physicians and nurses for their contribution to this study. We would also like to thank Sarah Petzold for documentation.\n\nCONFLICTS OF INTEREST\n\nSB has an ownership interest in PDL BioPharma, and holds US and EU intellectual properties in gene expression analysis. None of the other authors has any conflict of interest associated with this study.\n\nGRANT SUPPORT\n\nThe study was supported by grants to SB from the Wilhelm Sander-Stiftung (2006.109.1), Else Kröner–Fresenius–Stiftung (P31/08//A123/07) and the Deutsche Kinderkrebsstiftung (DKS 2010.07); SB and UT received a grant from the Federal Ministry of Education and Research Germany (TranSarNet 01GM1104B). T.G.P.G. is supported by a grant from the Deutsche Krebshilfe, the Daimler and Benz Foundation in cooperation with the Reinhard Frank Foundation, by LMU Munich's Institutional Strategy LMUexcellent within the framework of the German Excellence Initiative, and by the ‘Mehr LEBEN für krebskranke Kinder – Bettina-Bräu-Stiftung’. HJ and UD were supported by the Deutsche Krebshilfe (DKH-108128), the Federal Ministry of Education and Research Germany, and HJ, SB, UD, UT by BMBF (TranSaRNet 01GM0869) UD by PROVABES ERA-Net-TRANSCAN (01KT1310) and EEC (602856-2, EU FP7), PanCareLife (602030-2 EU-FP7). EK was supported by Deutsche Krebshilfe (DKS 50-2635) and ITvL by Cura Placida Children's Cancer Research Foundation.\n==== Refs\nREFERENCES\n1 Delattre O Zucman J Plougastel B Desmaze C Melot T Peter M Kovar H Joubert I de Jong P Rouleau G Gene fusion with an ETS DNA-binding domain caused by chromosome translocation in human tumours Nature 1992 359 162 165 1522903 \n2 Cotterill SJ Ahrens S Paulussen M Jurgens HF Voute PA Gadner H Craft AW Prognostic factors in Ewing's tumor of bone: analysis of 975 patients from the European Intergroup Cooperative Ewing's Sarcoma Study Group Journal of clinical oncology 2000 18 3108 3114 10963639 \n3 Kopp LM Hu C Rozo B White-Collins A Huh WW Yarborough A Herzog CE Hingorani P Utility of bone marrow aspiration and biopsy in initial staging of Ewing sarcoma Pediatric blood & cancer 2015 62 12 15 25174337 \n4 Burdach S Thiel U Schoniger M Haase R Wawer A Nathrath M Kabisch H Urban C Laws HJ Dirksen U Steinborn M Dunst J Jurgens H Meta ESG Total body MRI-governed involved compartment irradiation combined with high-dose chemotherapy and stem cell rescue improves long-term survival in Ewing tumor patients with multiple primary bone metastases Bone marrow transplantation 2010 45 483 489 19684633 \n5 Stahl M Ranft A Paulussen M Bolling T Vieth V Bielack S Gortitz I Braun-Munzinger G Hardes J Jurgens H Dirksen U Risk of recurrence and survival after relapse in patients with Ewing sarcoma Pediatric blood & cancer 2011 57 549 553 21442722 \n6 Burdach S Meyer-Bahlburg A Laws HJ Haase R van Kaik B Metzner B Wawer A Finke R Gobel U Haerting J Pape H Gadner H Dunst J Juergens H High-dose therapy for patients with primary multifocal and early relapsed Ewing's tumors: results of two consecutive regimens assessing the role of total-body irradiation Journal of clinical oncology 2003 21 3072 3078 12915596 \n7 Rasper M Jabar S Ranft A Jurgens H Amler S Dirksen U The value of high-dose chemotherapy in patients with first relapsed Ewing sarcoma Pediatric blood & cancer 2014 61 1382 1386 24729428 \n8 Rosenthal J Pawlowska AB High-dose chemotherapy and stem cell rescue for high-risk Ewing's family of tumors Expert review of anticancer therapy 2011 11 251 262 21342043 \n9 Strauss SJ McTiernan A Driver D Hall-Craggs M Sandison A Cassoni AM Kilby A Michelagnoli M Pringle J Cobb J Briggs T Cannon S Witt J Whelan JS Single center experience of a new intensive induction therapy for ewing's family of tumors: feasibility, toxicity, and stem cell mobilization properties Journal of clinical oncology 2003 21 2974 2981 12885818 \n10 Ladenstein R Lasset C Pinkerton R Zucker JM Peters C Burdach S Pardo N Dallorso S Coze C Impact of megatherapy in children with high-risk Ewing's tumours in complete remission: a report from the EBMT Solid Tumour Registry Bone marrow transplantation 1995 15 697 705 7670398 \n11 Haeusler J Ranft A Boelling T Gosheger G Braun-Munzinger G Vieth V Burdach S van den Berg H Juergens H Dirksen U The value of local treatment in patients with primary, disseminated, multifocal Ewing sarcoma (PDMES) Cancer 2010 116 443 450 19924786 \n12 Burdach S Jurgens H High-dose chemoradiotherapy (HDC) in the Ewing family of tumors (EFT) Crit Rev Oncol Hematol 2002 41 169 189 11856593 \n13 Thiel U Wawer A Wolf P Badoglio M Santucci A Klingebiel T Basu O Borkhardt A Laws HJ Kodera Y Yoshimi A Peters C Ladenstein R Pession A Prete A Urban EC No improvement of survival with reduced- versus high-intensity conditioning for allogeneic stem cell transplants in Ewing tumor patients Annals of oncology 2011 22 1614 1621 21245159 \n14 Burdach S van Kaick B Laws HJ Ahrens S Haase R Korholz D Pape H Dunst J Kahn T Willers R Engel B Dirksen U Kramm C Nurnberger W Heyll A Ladenstein R Allogeneic and autologous stem-cell transplantation in advanced Ewing tumors. An update after long-term follow-up from two centers of the European Intergroup study EICESS. Stem-Cell Transplant Programs at Dusseldorf University Medical Center, Germany and St. Anna Kinderspital, Vienna, Austria Annals of oncology 2000 11 1451 1462 11142486 \n15 Luksch R Tienghi A Hall KS Fagioli F Picci P Barbieri E Gandola L Eriksson M Ruggieri P Daolio P Lindholm P Prete A Bisogno G Tamburini A Grignani G Abate ME Primary metastatic Ewing's family tumors: results of the Italian Sarcoma Group and Scandinavian Sarcoma Group ISG/SSG IV Study including myeloablative chemotherapy and total-lung irradiation Annals of oncology 2012 23 2970 2976 22771824 \n16 McTiernan A Driver D Michelagnoli MP Kilby AM Whelan JS High dose chemotherapy with bone marrow or peripheral stem cell rescue is an effective treatment option for patients with relapsed or progressive Ewing's sarcoma family of tumours Annals of oncology 2006 17 1301 1305 16782749 \n17 Oberlin O Rey A Desfachelles AS Philip T Plantaz D Schmitt C Plouvier E Lejars O Rubie H Terrier P Michon J Societe Francaise des Cancers de lE Impact of high-dose busulfan plus melphalan as consolidation in metastatic Ewing tumors: a study by the Societe Francaise des Cancers de l'Enfant Journal of clinical oncology 2006 24 3997 4002 16921053 \n18 Koscielniak E Gross-Wieltsch U Treuner J Winkler P Klingebiel T Lang P Bader P Niethammer D Handgretinger R Graft-versus-Ewing sarcoma effect and long-term remission induced by haploidentical stem-cell transplantation in a patient with relapse of metastatic disease Journal of clinical oncology 2005 23 242 244 15625381 \n19 Lucas KG Schwartz C Kaplan J Allogeneic stem cell transplantation in a patient with relapsed Ewing sarcoma Pediatric blood & cancer 2008 51 142 144 18266223 \n20 Burdach S Jurgens H Peters C Nurnberger W Mauz-Korholz C Korholz D Paulussen M Pape H Dilloo D Koscielniak E Myeloablative radiochemotherapy and hematopoietic stem-cell rescue in poor-prognosis Ewing's sarcoma Journal of clinical oncology 1993 11 1482 1488 8101562 \n21 Meyers PA Krailo MD Ladanyi M Chan KW Sailer SL Dickman PS Baker DL Davis JH Gerbing RB Grovas A Herzog CE Lindsley KL Liu-Mares W Nachman JB Sieger L Wadman J High-dose melphalan, etoposide, total-body irradiation, and autologous stem-cell reconstitution as consolidation therapy for high-risk Ewing's sarcoma does not improve prognosis Journal of clinical oncology 2001 19 2812 2820 11387352 \n22 Paulussen M Craft AW Lewis I Hackshaw A Douglas C Dunst J Schuck A Winkelmann W Kohler G Poremba C Zoubek A Ladenstein R van den Berg H Hunold A Cassoni A Spooner D Results of the EICESS-92 Study: two randomized trials of Ewing's sarcoma treatment--cyclophosphamide compared with ifosfamide in standard-risk patients and assessment of benefit of etoposide added to standard treatment in high-risk patients Journal of clinical oncology 2008 26 4385 4393 18802150 \n23 Paulussen M Ahrens S Burdach S Craft A Dockhorn-Dworniczak B Dunst J Frohlich B Winkelmann W Zoubek A Jurgens H Primary metastatic (stage IV) Ewing tumor: survival analysis of 171 patients from the EICESS studies. European Intergroup Cooperative Ewing Sarcoma Studies Annals of oncology 1998 9 275 281 9602261 \n24 Ng VY Jones R Bompadre V Louie P Punt S Conrad EU 3rd The effect of surgery with radiation on pelvic Ewing sarcoma survival J Surg Oncol 2015 112 861 865 26525492 \n25 Loschi S Dufour C Oberlin O Goma G Valteau-Couanet D Gaspar N Tandem high-dose chemotherapy strategy as first-line treatment of primary disseminated multifocal Ewing sarcomas in children, adolescents and young adults Bone marrow transplantation 2015 50 1083 1088 26030048 \n26 van den Berg H Paulussen M Le Teuff G Judson I Gelderblom H Dirksen U Brennan B Whelan J Ladenstein RL Marec-Berard P Kruseova J Hjorth L Kuhne T Brichard B Wheatley K Craft A Impact of gender on efficacy and acute toxicity of alkylating agent -based chemotherapy in Ewing sarcoma: Secondary analysis of the Euro-Ewing99-R1 trial European journal of cancer 2015 51 2453 2464 26271204 \n27 Diaz MA Lassaletta A Perez A Sevilla J Madero L Gonzalez-Vicent M High-dose busulfan and melphalan as conditioning regimen for autologous peripheral blood progenitor cell transplantation in high-risk ewing sarcoma patients: a long-term follow-up single-center study Pediatric hematology and oncology 2010 27 272 282 20426518 \n28 Ferrari S del Prever AB Palmerini E Staals E Berta M Balladelli A Picci P Fagioli F Bacci G Vanel D Response to high-dose ifosfamide in patients with advanced/recurrent Ewing sarcoma Pediatric blood & cancer 2009 52 581 584 19142994 \n29 Jahnukainen K Kallio P Koivusalo A Saarinen-Pihkala UM High-dose Thiotepa as Consolidation Therapy With Autologous Hematopoietic Stem Cell Transplantation for High-risk Ewing Family Tumors: Single-institution Experience Journal of pediatric hematology/oncology 2015 37 536 542 26207773 \n30 Ladenstein R Potschger U Le Deley MC Whelan J Paulussen M Oberlin O van den Berg H Dirksen U Hjorth L Michon J Lewis I Craft A Jurgens H Primary disseminated multifocal Ewing sarcoma: results of the Euro-EWING 99 trial Journal of clinical oncology 2010 28 3284 3291 20547982 \n31 Rosenthal J Bolotin E Shakhnovits M Pawlowska A Falk P Qian D Oliver C Sato J Miser J Forman S High-dose therapy with hematopoietic stem cell rescue in patients with poor prognosis Ewing family tumors Bone marrow transplantation 2008 42 311 318 18587438 \n32 van Maldegem AM Benson C Rutkowski P Blay JY van den Berg H Placzke J Rasper M Judson I Juergens H Dirksen U Gelderblom H Etoposide and carbo-or cisplatin combination therapy in refractory or relapsed Ewing sarcoma: a large retrospective study Pediatric blood & cancer 2015 62 40 44 25251256 \n33 Al-Faris N Al Harbi T Goia C Pappo A Doyle J Gassas A Does consolidation with autologous stem cell transplantation improve the outcome of children with metastatic or relapsed Ewing sarcoma? Pediatric blood & cancer 2007 49 190 195 17262797 \n34 Laurence V Pierga JY Barthier S Babinet A Alapetite C Palangie T de Pinieux G Anract P Pouillart P Long-term follow up of high-dose chemotherapy with autologous stem cell rescue in adults with Ewing tumor American journal of clinical oncology 2005 28 301 309 15923805 \n35 Hawkins DS Felgenhauer J Park J Kreissman S Thomson B Douglas J Rowley SD Gooley T Sanders JE Pendergrass TW Peripheral blood stem cell support reduces the toxicity of intensive chemotherapy for children and adolescents with metastatic sarcomas Cancer 2002 95 1354 1365 12216105 \n36 Barker LM Pendergrass TW Sanders JE Hawkins DS Survival after recurrence of Ewing's sarcoma family of tumors Journal of clinical oncology 2005 23 4354 4362 15781881 \n37 Thiel U Pirson S Muller-Spahn C Conrad H Busch DH Bernhard H Burdach S Richter GH Specific recognition and inhibition of Ewing tumour growth by antigen-specific allo-restricted cytotoxic T cells Br J Cancer 2011 104 948 956 21407224\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1949-2553",
"issue": "7(43)",
"journal": "Oncotarget",
"keywords": "Ewing sarcoma; allogeneic stem cell transplantation; bone marrow metastasis; bone metastasis; high-dose chemotherapy",
"medline_ta": "Oncotarget",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D001853:Bone Marrow; D001859:Bone Neoplasms; D002648:Child; D003131:Combined Modality Therapy; D018572:Disease-Free Survival; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D009364:Neoplasm Recurrence, Local; D011379:Prognosis; D011446:Prospective Studies; D012074:Remission Induction; D012512:Sarcoma, Ewing; D016019:Survival Analysis; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "101532965",
"other_id": null,
"pages": "70959-70968",
"pmc": null,
"pmid": "27486822",
"pubdate": "2016-10-25",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": "24729428;26525492;25174337;26030048;11142486;11856593;11387352;15923805;20426518;21407224;9602261;20547982;16782749;12885818;19684633;21245159;26271204;19142994;8101562;12216105;10963639;21342043;15781881;7670398;18587438;16921053;18266223;17262797;22771824;19924786;18802150;26207773;12915596;1522903;25251256;15625381;21442722",
"title": "Bone marrow involvement identifies a subgroup of advanced Ewing sarcoma patients with fatal outcome irrespective of therapy in contrast to curable patients with multiple bone metastases but unaffected marrow.",
"title_normalized": "bone marrow involvement identifies a subgroup of advanced ewing sarcoma patients with fatal outcome irrespective of therapy in contrast to curable patients with multiple bone metastases but unaffected marrow"
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"abstract": "Background: Pediatric sarcoidosis is a complex inflammatory disorder with multisystemic manifestations. Kidney involvement in children is rare, and prognostic factors are unknown. Case Report and Methods: We report the case of a 16-year-old girl with multiorgan sarcoidosis and renal involvement. The patient presented with tubulointerstitial nephritis, acute kidney injury (AKI), chest CT disseminated noduli, granulomatous iridocyclitis, giant-cell sialadenitis, and arthralgia. The kidney biopsy revealed non-granulomatous interstitial nephritis. Treatment consisted of initial high-dose methylprednisolone pulse followed by oral prednisolone and methotrexate. Full remission was achieved. In addition, we performed a literature review using PubMed and analyzed data on pediatric renal sarcoidosis cases. Results: We identified 36 cases of pediatric sarcoidosis with renal involvement on presentation and data on the end-of-follow-up glomerular filtration rate (GFR). The data from the literature review showed that renal involvement was slightly more prevalent in males (60%). AKI was present in most of the described patients (84%). Oral prednisolone was used in 35 of 36 cases; in more severe cases, other immunosuppressants were used. We newly identified renal concentration impairment and granulomatous interstitial nephritis as factors with a clear trend toward GFR loss at the end of follow-up, emphasizing the importance of kidney biopsy in symptomatic patients. In contrast, higher GFR at presentation and hypercalcemia were rather favorable factors. According to the identified predictive factors, our patient has a good prognosis and is in remission. Conclusion: The factors indicating a trend toward an unfavorable renal outcome in pediatric sarcoidosis are renal concentration impairment and granulomatous interstitial nephritis at presentation, while a higher GFR is beneficial.",
"affiliations": "Division of Pediatric Nephrology, Department of Pediatrics, Dr. v. Hauner Children's Hospital Ludwig-Maximilians University, Munich, Germany.;Department of Pediatrics, Dr. v. Hauner Children's Hospital Ludwig-Maximilians University, Munich, Germany.;Department of Pediatrics, Dr. v. Hauner Children's Hospital Ludwig-Maximilians University, Munich, Germany.;Division of Pediatric Nephrology, Department of Pediatrics, Dr. v. Hauner Children's Hospital Ludwig-Maximilians University, Munich, Germany.;Institute for Pathology, University Hospital Erlangen, Erlangen, Germany.;Division of Pediatric Nephrology, Department of Pediatrics, Dr. v. Hauner Children's Hospital Ludwig-Maximilians University, Munich, Germany.",
"authors": "Klaus|Richard|R|;Jansson|Annette Friederike|AF|;Griese|Matthias|M|;Seeman|Tomas|T|;Amann|Kerstin|K|;Lange-Sperandio|Bärbel|B|",
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"country": "Switzerland",
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"doi": "10.3389/fped.2021.724728",
"fulltext": "\n==== Front\nFront Pediatr\nFront Pediatr\nFront. Pediatr.\nFrontiers in Pediatrics\n2296-2360\nFrontiers Media S.A.\n\n10.3389/fped.2021.724728\nPediatrics\nCase Report\nCase Report: Pediatric Renal Sarcoidosis and Prognostic Factors in Reviewed Cases\nKlaus Richard 1 †\n\nJansson Annette Friederike 2\nGriese Matthias 2 3\n\nSeeman Tomas 1\nAmann Kerstin 4\n\nLange-Sperandio Bärbel 1 * †\n\n1Division of Pediatric Nephrology, Department of Pediatrics, Dr. v. Hauner Children's Hospital Ludwig-Maximilians University, Munich, Germany\n2Department of Pediatrics, Dr. v. Hauner Children's Hospital Ludwig-Maximilians University, Munich, Germany\n3German Center for Lung Research (DZL), Munich, Germany\n4Institute for Pathology, University Hospital Erlangen, Erlangen, Germany\nEdited by: Vera Hermina Koch, University of São Paulo, Brazil\n\nReviewed by: Rajiv Sinha, Institute of Child Health, India; Yaacov Frishberg, Shaare Zedek Medical Center, Israel\n\n*Correspondence: Bärbel Lange-Sperandio baerbel.lange-sperandio@med.uni-muenchen.de\nThis article was submitted to Pediatric Nephrology, a section of the journal Frontiers in Pediatrics\n\n†ORCID: Richard Klaus orcid.org/0000-0002-2234-4248 Bärbel Lange-Sperandio orcid.org/0000-0001-8898-3459\n\n13 9 2021\n2021\n9 72472814 6 2021\n09 8 2021\nCopyright © 2021 Klaus, Jansson, Griese, Seeman, Amann and Lange-Sperandio.\n2021\nKlaus, Jansson, Griese, Seeman, Amann and Lange-Sperandio\nhttps://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.\nBackground: Pediatric sarcoidosis is a complex inflammatory disorder with multisystemic manifestations. Kidney involvement in children is rare, and prognostic factors are unknown.\n\nCase Report and Methods: We report the case of a 16-year-old girl with multiorgan sarcoidosis and renal involvement. The patient presented with tubulointerstitial nephritis, acute kidney injury (AKI), chest CT disseminated noduli, granulomatous iridocyclitis, giant-cell sialadenitis, and arthralgia. The kidney biopsy revealed non-granulomatous interstitial nephritis. Treatment consisted of initial high-dose methylprednisolone pulse followed by oral prednisolone and methotrexate. Full remission was achieved. In addition, we performed a literature review using PubMed and analyzed data on pediatric renal sarcoidosis cases.\n\nResults: We identified 36 cases of pediatric sarcoidosis with renal involvement on presentation and data on the end-of-follow-up glomerular filtration rate (GFR). The data from the literature review showed that renal involvement was slightly more prevalent in males (60%). AKI was present in most of the described patients (84%). Oral prednisolone was used in 35 of 36 cases; in more severe cases, other immunosuppressants were used. We newly identified renal concentration impairment and granulomatous interstitial nephritis as factors with a clear trend toward GFR loss at the end of follow-up, emphasizing the importance of kidney biopsy in symptomatic patients. In contrast, higher GFR at presentation and hypercalcemia were rather favorable factors. According to the identified predictive factors, our patient has a good prognosis and is in remission.\n\nConclusion: The factors indicating a trend toward an unfavorable renal outcome in pediatric sarcoidosis are renal concentration impairment and granulomatous interstitial nephritis at presentation, while a higher GFR is beneficial.\n\nsarcoidosis\ntubulointerstitial nephritis\nacute kidney injury\ncase report\nprognostic factor analysis\nDeutsche Forschungsgemeinschaft 10.13039/501100001659\n==== Body\npmcIntroduction\n\nSarcoidosis is a systemic inflammatory disease characterized by the formation of non-necrotizing epithelioid cell granulomas with multiorgan affection. The reported incidence is 0.29–0.8 per 100,000 children (1–3). While adult sarcoidosis is often diagnosed in asymptomatic patients by routine chest x-ray, 66–98% of children present with acute symptoms such as fever, fatigue, and multiorgan involvement (1–3). Common manifestations include uveitis/iritis, hilar and peripheral lymphadenopathy, hepatosplenomegaly, arthritis, parenchymal lung disease, and skin rash. To date, the pathophysiology of this multifactorial disorder remains elusive. A combination of genetic factors (e.g., CARD15/NOD2-mutation) and environmental exposure with antigens such as infectious agents—mainly mycobacteria (4), silica, aluminum, or inorganic dusts (5)—is suspected to trigger a CD4+ T-cell response with increased cytokine activities resulting in granuloma formation. Prolonged inflammation may lead to fibrosis and irreversible organ dysfunction (6). Autonomous expression of 1-alpha-hydroxylase and therefore overproduction of 1,25-vitamin D in activated macrophages may result in hypercalcemia and secondary nephrocalcinosis (7). Histological evidence of non-necrotizing epithelioid granulomas with giant cells in affected organs and exclusion of other diagnoses (especially granuloma-causing infections, immunodeficiencies, and oncological entities) establishes the diagnosis. Therapeutic regimens mostly include steroids and add other immunosuppressants either as steroid-sparing agents or in refractory cases (8).\n\nThere are a few collections of cases of pediatric renal sarcoidosis, and so far, no attempt to analyze prognostic factors has been made. To our knowledge, we here present the largest number of collected previously published cases on renal sarcoidosis in children.\n\nCase Report\n\nA 16-year-old girl (52 kg, 158 cm) with no relevant medical history was admitted to our hospital with a 9-day history of bilateral cervical mass, fever resistant to antibiotics, fatigue, and night sweat with suspicion of lymphoma. Examination showed a stable cardiorespiratory condition (blood pressure: 107/70 mmHg) with bilateral, indolent, firm and immobile submandibular mass, and arthralgia in both knees. Vision was mildly blurred; macroscopically, no eye abnormalities were present. Basic laboratory studies including blood count and blood gas analysis were normal besides elevated inflammatory parameters [C-reactive protein (CrP), 17.9 mg/dl; erythrocyte sedimentation rate (ESR), 87 mm/h] (Figure 1A). Chest x-ray showed disseminated nodules and interstitial consolidations. Lymphoma was suspected, and a PET-CT showed increased metabolic activity in the suspected lymph nodes, kidneys, lungs, bronchi, spleen, and bone marrow. Surprisingly, the cervical mass biopsy showed no signs of malignancy, but sialadenitis with epithelioid and giant cells. Acute kidney injury (AKI) developed (KDIGO stage 1), and glomerular filtration rate (GFR) was 57 ml/min/1.73 m2 according to Schwartz formula (9). Maximum serum creatinine was 1.5 mg/dl, and cystatin C was 1.48 mg/l. Urea and electrolytes were in the normal range. There was no proteinuria, no hematuria, and no leukocyturia. Hemoglobin concentration and thrombocyte count were normal, lactate dehydrogenase was not elevated, and complement level was normal. Urinary calcium excretion was within normal limits (1.04 mg/kg/d, N <4 mg/kg/d). Tubulointerstitial nephritis (TIN) with tubular salt wasting (fractional sodium excretion: 2.3%, fractional chloride excretion: 2.5%, and phosphate reabsorption: 78%) and impaired concentration capacity (tubular reabsorption of water 97%, calculated by: (1 – (creatinineserum/creatinineurine) × 100 N >98.5%) were diagnosed. Although the most frequent causes for TIN are drugs and infections, a systemic disease was suspected as the cause for TIN. Ophthalmologic evaluation was performed because of mildly blurred vision and because of suspicion of systemic disease. Presence of granulomatous iridocyclitis suggested sarcoidosis. Kidney biopsy, chest CT, and bronchoscopy with bronchoalveolar lavage (BAL) were performed. The kidney biopsy showed interstitial nephritis with predominantly CD3-positive T cells, but also granulocyte infiltration and acute tubular epithelial damage (Figure 1B). Epithelioid granulomas or necrosis were not found. Glomeruli (including immunohistochemistry for IgA, IgM, C1q, and C3c) and vessels were unaffected; electron microscopy was unremarkable. Bronchoscopy showed granular inflammation of the mucosa with epithelioid cellular granulomas with giant cells. BAL showed predominantly T-cellular inflammation (87%) with a normal CD4/CD8 ratio (3.2, N: 1.0–3.6). Pulmonary function was normal, and chest CT showed disseminated nodules and ground-glass opacity. Pulmonary findings were compatible with sarcoidosis stage III. Treatment was initiated with 300 mg/m2 methylprednisolone intravenously on days 1, 3, and 5 with 80 mg prednisolone orally on days 2, 4, and 6. From day 7, oral prednisolone was continued with 60 mg daily. Oral methotrexate (20 mg weekly) was used because of the multiorgan involvement. Prednisolone was slowly tapered, aiming for a 6-month period to achieve the maintenance dose of 5 mg daily (Figure 1C). One month after therapy initiation, kidney function had already normalized (creatinine, 0.8 mg/dl; GFR, 108 ml/min/1.73 m2; and fractional sodium excretion, 0.9%). After remission, follow-up was continued every 2 months with physical examination, urine analysis, and laboratory studies of inflammatory markers. Because of stable remission and adverse effects of steroids (transiently increased intraocular pressure, cushing syndrome, hair loss, and tremor), tapering was accelerated to reach maintenance dose of 5 mg daily, and methotrexate was terminated. Currently, 7 months after the diagnosis, she is in complete remission with no systemic signs of inflammation and a normal GFR.\n\nFigure 1 (A) Clinical characteristics of our patient at presentation, 3 and 7 months after therapy initiation. (B) ngTIN in our patient, 20x magnification, hematoxylin and eosin (HE) stain. (C) Course of treatment in our patient. d, day; w, week; m, months; MP, methylprednisolone; PRED, prednisolone; MTX, methotrexate.\n\nPatients and Methods\n\nHere, we use a single case for illustration of renal involvement in sarcoidosis as presenting organ and compared it with previously published pediatric cases. We performed a literature review using PubMed with the terms “renal,” “kidney,” “pediatric,” and “sarcoidosis” in various combinations to collect clinical data from published cases of pediatric sarcoidosis in the years 1999–2021. Thirty-six were identified. Pediatric patients with renal sarcoidosis and a specified or calculated GFR at end of follow-up were included. Renal sarcoidosis was defined as histologically proven sarcoidosis in combination with either a renal histology result or with AKI. All cases were already published in smaller series (1, 10–12). Three cases were reported from the pediatric sarcoidosis register in Louisiana (1). Two were excluded because no end-of-follow-up GFR was available. A series from Paris by Coutant et al. identified 11 cases of renal involvement in children with sarcoidosis and additionally summed up 19 single-case reports. These 19 cases were also included (12). Where possible, additional data were compiled from the original reports; otherwise, data from the collection of Coutant were taken (12). Two cases from the collection of Coutant were excluded because neither biopsy data nor end-of-follow-up GFR was available; two cases were excluded because our criteria for renal sarcoidosis were not met. Hobbs et al. reported one case and reviewed two cases (11). Wang et al. reported one case themselves and reviewed another eight single cases, two overlapping with Hobbs. One was excluded because of no GFR at end of follow-up or serum creatinine was provided (10). Collected data for each patient included age, sex, GFR at presentation, presence of AKI, hematuria, leukocyturia, proteinuria, concentration impairment/polyuria, hypercalcemia, biopsy result, duration of follow-up, and GFR at end of follow-up (Supplementary Table 1). Biopsy result was categorized into three possible categories: “granulomatous interstitial nephritis (GIN),” “non-granulomatous tubulointerstitial nephritis (ngTIN),” and “other.” If GFR was reported as normal at the end of follow-up but no numeric value was specified, a GFR of 100 ml/min/1.73 m2 was assumed for calculations (14 cases). If end-stage renal disease or death was reported, we used a GFR of 0 ml/min/1.73 m2 for calculations (five cases). If only serum creatinine was recorded, Schwartz-formula was used (9). If no height was recorded, a height of the 50th percentile was assumed (two cases); if no follow-up height was recorded, growth along the last specified percentile was assumed but adjusted for the increased age at end of follow-up (four cases). Not all case collections or original cases provided definitions for the clinical symptoms such as renal concentration impairment or proteinuria, but sometimes only indicated whether they were present or not. Hence, they were included as they were recorded in the original articles. If polyuria was diagnosed, it was recorded as concentration impairment. Therapy not specified beyond “steroids” was recorded as “oral prednisolone” (three cases).\n\nStatistical Analysis\n\nTo determine the influence on the end-of-follow-up GFR in the reported cases, univariate linear regression was performed using SPSS v27. For AKI, hematuria, proteinuria, leukocyturia, concentration impairment, and hypercalcemia, absence of these symptoms was used as baseline. For the biopsy result, GIN was compared to ngTIN as baseline since all biopsies had an abnormal histology as proof of renal involvement, and from a clinical point of view, ngTIN was considered the less severe histology.\n\nResults\n\nA total of 36 cases with pediatric sarcoidosis and renal involvement were included in the statistical analysis (Figure 2A). Data of all included and excluded cases can be found in Supplementary Table 1. Mean age of onset was 10.5 ± 4.6 years. The male-to-female ratio was 18:11 (seven unspecified); hence, 62% of patients with a reported gender were male. The spectrum of renal symptoms was broad and included hematuria (9/23), proteinuria (23/30), hypercalcemia (16/34), leukocyturia (10/21), and impaired renal concentration capacity (13/24). In the majority of cases, AKI was present (30/35) (Figure 2A). GFR at presentation was reported in 29 of 36 cases with a mean of 52 ± 36 ml/min/1.73 m2. Renal biopsies mainly revealed GIN (24) or ngTIN (5). Two showed nephrocalcinosis, and one membranous nephropathy; in four cases, no biopsy specimen was obtained. Follow-up period was 3.3 ± 2.9 years (specified in 28/36 cases). The mean GFR at the end of follow-up was 77 ± 43 ml/min/1.73 m2. One patient received no treatment because of spontaneous resolution, and all other patients received at least oral prednisolone. Dosages varied, and therapy duration was many months to years. In more severe cases, intravenous methylprednisolone pulse or other immunosuppressants were added (Figure 2B). Under the mentioned therapies, only five patients had a relevant GFR loss, and four progressed to end-stage renal disease (Figure 2C). Concentration impairment (−34 ± 17 ml/min/1.73 m2, p = 0.06) and GIN in biopsy (−32 ± 21 ml/min/1.73 m2, p = 0.14) showed trends to negatively predict end-of-follow-up-GFR (Figure 2D). Presence of hypercalcemia showed a trend to positively influence end-of-follow-up GFR (+19 ± 33 ml/min/1.73 m2, p = 0.56). Another positive predictive feature was the GFR at presentation, which had an unstandardized B-value of 0.43 ± 0.22 ml/min/1,73 m2 (p = 0.06) in the linear regression. This implies that the end-of-follow-up GFR is improved by 0.43 ml/min/1.73 m2 min per 1 ml/min/1.73 m2 increased GFR at presentation. Detailed results of the individual univariate linear regressions can be found in Supplementary Table 2.\n\nFigure 2 (A) Clinical features and symptoms in reported cases (n = 36). max, maximum; min, minimum SD, standard deviation; ND, not determined; m, male; f, female. (B) Distribution of used medications. PRED, prednisolone; MP, methylprednisolone; AZA, azathioprin; MMF, mycophenolate mofetil; MTX, methotrexate; CTX, cyclophosphamide. (C) Course of GFR in the reported cases. (D) Influence of initial presentation on GFR at the end of follow-up. GIN opposed to ngTIN and concentration impairment are strongest yet statistically insignificant predictors for a decline in GFR.\n\nDiscussion\n\nChildhood sarcoidosis is a granulomatous disease affecting multiple organs. More than 70% of children have 3.8–5.1 organs involved (1, 3). Surprisingly, reported cases of renal involvement in 116 cases of pediatric sarcoidosis are rare and only amount to 3 (1–3). We performed a literature review and found a total of 36 cases of renal involvement to be included into our analysis. We could show that AKI is a common feature (86%) in pediatric sarcoidosis with renal involvement. Other renal symptoms occur, but no single symptom occurs in all children and no specific sign for renal involvement exists. Our findings are consistent with patient characteristics from an adult cohort with 47 patients with renal sarcoidosis. In adults, 62% presented with renal failure with a GFR <30 ml/min/1.73 m2, 22% had hematuria (47% in our collection), 29% had leukocyturia (48% in our collection), and 66% had proteinuria (78% in our collection). Hypercalcemia was present in 34% of all cases (47% in our collection) (13). Overall, it appears that children with renal sarcoidosis tend to be more symptomatic than adults. GIN is the predominant histology in adults and children (66% in our collection and 79% in the adult series) (13). Although sarcoidosis in general is evenly distributed among the sexes (8), renal involvement seems to be slightly more prevalent in male patients: 62% in our collection and 60% of patients in the adult collection are male (13). Both the lack of systematic screening and the lack of specific clinical symptoms may account for underreporting of renal sarcoidosis. To improve detection, Bergner et al. suggest a kidney biopsy if AKI, proteinuria, leukocyturia, or hematuria is present. A renal biopsy should be considered in pediatric patients with sarcoidosis and renal symptoms. Presence of non-necrotizing granulomas are necessary to establish the diagnosis. Furthermore, as shown from this case collection, the histology may help to assess the prognosis and to choose the treatment. Nevertheless, in cases with mild renal involvement and an established diagnosis, a renal biopsy can be omitted. As reported in the present case, nephrocalcinosis should be evaluated with a kidney ultrasound and measurement of vitamin D metabolites, serum calcium, and urine calcium concentration (14). Indications for biopsy were AKI and polyuria with salt wasting and impaired concentration ability: hallmarks of TIN. The biopsy revealed the ngTIN.\n\nPrognosis of renal sarcoidosis is difficult to capture and highly variable. So far, no treatment studies exist, and reported case series were relatively small. Full recovery as well as end-stage renal disease are described (12). Predictive parameters would be a key component to adapt the therapy intensity and duration for each individual patient. Hence, we analyzed the predictive value of symptoms at presentation with linear regression. Because of the small number of cases, no clinical feature at presentation could significantly predict outcome, but clear trends exist. The predictors with the strongest trend for decline in GFR are presence of GIN (p = 0.14), concentration impairment (p = 0.06), and the intensity of GFR impairment at presentation (p = 0.06).\n\nBoth GIN and concentration impairment represent relevant tubulointerstitial damage; therefore, their positive correlation with a more severe clinical outcome seems reasonable. In contrast, less severely affected patients might not have enough tubulointerstitial damage for clinically apparent concentration impairment. Additionally, granuloma burden in lesser affected patients is probably low, and therefore, granulomas might be missed in the biopsy due to sampling error. This finding is supported by data from an adult case series, where the subgroup of patients with CKD 5 at end of follow-up was exclusively diagnosed with GIN, while that with CKD 1–2 predominantly had ngTIN (15). In contrast, the higher the GFR was at presentation and therefore the lesser the renal damage, the better was the renal outcome in pediatric renal sarcoidosis.\n\nInterestingly hypercalcemia also showed a trend toward a better prognosis. Hypercalcemia in sarcoidosis is caused by 1-α-hydroxylase production of macrophages (7) and may lead to nephrocalcinosis. One could argue that patients with nephrocalcinosis and not GIN might have a better prognosis, because under treatment, hypercalcemia is reversible and nephrocalcinosis may resolve, whereas the GIN may turn into fibrotic scars and therefore leave a permanent kidney damage.\n\nBecause of the small sample size and partially incomplete clinical data, the p-values for other symptoms were too large to translate them into statistically significant predictions; only the negative predictors GIN and concentration impairment were close to significance. Although all published cases of renal pediatric sarcoidosis were included, the major limitation of this analysis is the sample size, the estimation of the GFR as described in Methods and the lack of consistent definitions for the clinical symptoms in the cases. The sample size is responsible for the insignificant p-values and the tradeoff to choose univariate linear regression. From a statistical point of view, a multiple linear regression would have been the better choice, since it would take the influence between the initial clinical symptoms into account. Prospective registries for pediatric renal sarcoidosis with standardized data entry are needed and could verify the trends we found in this report.\n\nCurrently, no treatment protocol for pediatric renal sarcoidosis exists. In all reported cases, prednisolone was a major pillar of the treatment. Other immunosuppressants including mycophenolate mofetil, cyclophosphamide, and methotrexate were added in refractory cases or to spare steroids. Since treatment was only intensified in the severe cases, an analysis of the effect of different treatment regimens on end-of-follow-up GFR would be biased and was therefore not performed. While in the older cases only prednisolone and methylprednisolone were used, in newer cases, MTX and MMF became more important. To date, systematic evaluation of these substances in renal sarcoidosis is lacking in children as well as adults. However, in 2014, Hilderson et al. proposed a treatment protocol for renal sarcoidosis in adults (16). Similarly to what we observed in pediatric cases, prednisolone is used in induction therapy and methylprednisolone pulses are added in case of impaired renal function. If glucocorticoids fail to control the disease or cannot be tapered, other immunosuppressants are added for maintenance (14, 16). Therapeutic management remains challenging. The treatment itself has side effects and therefore is desired to be administered as short as possible, but relapses may occur during the tapering or after the end of the therapy (13). Because of multiorgan involvement in our case, interdisciplinary consensus was to start induction therapy with methylprednisolone pulse, high-dose prednisolone, and weekly oral methotrexate. Treatment was effective and remission was achieved 1 month after initiation. This is highly beneficial because studies in adults show that no significant changes in kidney function are to be expected 4–6 weeks after initiation, and therefore, early treatment success is considered a prognostic factor for a better outcome (13, 15).\n\nConclusion\n\nRenal involvement in pediatric sarcoidosis is rare but may be underreported due to variable clinical presentation and lack of systematic screening. AKI is the most common feature. Biopsy should be considered in patients with renal involvement. Presence of secondary nephrocalcinosis should be evaluated, and hypercalcemia has a trend toward a rather beneficial prognosis. In contrast, GIN in histology and concentration impairment show the strongest trend toward a decline in GFR, underscoring the importance of kidney biopsy in suspected renal sarcoidosis.\n\nPatient's Perspective (Translated From German)\n\nIn the beginning of the 2nd week of my stay in the children's hospital, I got the first diagnosis: cancer. Me and my whole family were shocked. The time until I was told that I had sarcoidosis and not a lymphoma was very difficult for me. By then, I had already accepted that I had cancer and was mentally prepared to repeatedly come to the hospital for a long time. Therefore, I was more than jubilant when I was told that I had sarcoidosis. Nevertheless, the following 2–3 weeks were challenging, because I still had to adapt to being sick and the whole new situation. My family, my friends, and the treating physicians supported me a lot during this difficult time.\n\nIn the beginning of the treatment, I had lots of side effects like weight gain. During that time, I did not feel comfortable, was unhappy with myself and my body. In the course of the treatment that changed to the better. Due to the dose reduction, the side effects have vanished almost completely, and I can live my life like I did before the onset of my disease.\n\nData Availability Statement\n\nThe original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author.\n\nEthics Statement\n\nWritten informed consent was obtained from the participant/next of kin for the publication of this case report.\n\nAuthor Contributions\n\nRK and BL-S did the outline for the review of literature and wrote the manuscript. Literature review and data analysis and interpretation was done by RK and BL-S. AJ, MG, TS, and KA contributed to the treatment of our patient and to the manuscript. KA assessed the histology and provided the image in Figure 1. All authors contributed to the article and approved the submitted version.\n\nFunding\n\nBL-S was funded by the Deutsche Forschungsgemeinschaft DFG LA1257/5-1.\n\nConflict of Interest\n\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n\nPublisher's Note\n\nAll claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.\n\nWe thank the patient and her parents for their consent to participate in this study. We thank Dr. Robert L. Chevalier for critically reading the manuscript.\n\nSupplementary Material\n\nThe Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fped.2021.724728/full#supplementary-material\n\nSupplementary Table 1 Clinical data of included and excluded patients. Patients written in italic were excluded: written in blue, exclusion occurred due to missing end-of-follow-up GFR; written in red, the patient is included in two of the collections and therefore excluded once; written in green, our criteria for renal sarcoidosis were not met. NS, not specified; ND, not determined.\n\nClick here for additional data file.\n\nSupplementary Table 2 Detailed results from univariate linear regressions. Bold printed lines are represented in Figure 2D or mentioned in the results.\n\nClick here for additional data file.\n\nAbbreviations\n\nAKI acute kidney injury\n\nAZA azathioprine\n\nBAL bronchoalveolar lavage\n\nCTX cyclophosphamide\n\nGIN granulomatous interstitial nephritis\n\nGFR glomerular filtration rate\n\nMMF mycophenolate mofetil\n\nMP methylprednisolone\n\nMTX methotrexate\n\nND not determined\n\nPRED prednisolone\n\nngTIN non-granulomatous tubulointerstitial nephritis\n\nTIN tubulointerstitial nephritis.\n==== Refs\nReferences\n\n1. Gedalia A Khan TA Shetty AK Dimitriades VR Espinoza LR . Childhood sarcoidosis: Louisiana experience. Clin Rheumatol. (2016) 35 :1879–84. 10.1007/s10067-015-2870-9 25616361\n2. Hoffmann AL Milman N Byg KE . Childhood sarcoidosis in Denmark 1979-1994: incidence, clinical features and laboratory results at presentation in 48 children. Acta Paediatr. (2004) 93 :30–6. 10.1111/j.1651-2227.2004.tb00670.x 14989436\n3. Nathan N Marcelo P Houdouin V Epaud R de Blic J Valeyre D . Lung sarcoidosis in children: update on disease expression and management. Thorax. (2015) 70 :537–42. 10.1136/thoraxjnl-2015-206825 25855608\n4. Mortaz E Adcock IM Barnes PJ . Sarcoidosis: role of non-tuberculosis mycobacteria and Mycobacterium tuberculosis. Int J Mycobacteriol. (2014) 3 :225–9. 10.1016/j.ijmyco.2014.10.008 26786620\n5. Newman KL Newman LS . Occupational causes of sarcoidosis. Curr Opin Allergy Clin Immunol. (2012) 12 :145–50. 10.1097/ACI.0b013e3283515173 22314258\n6. Chiu B Chan J Das S Alshamma Z Sergi C . Pediatric sarcoidosis: a review with emphasis on early onset and high-risk sarcoidosis and diagnostic challenges. Diagnostics (Basel). (2019) 9 :160. 10.3390/diagnostics9040160 31731423\n7. Inui N Murayama A Sasaki S Suda T Chida K Kato S . Correlation between 25-hydroxyvitamin D3 1 alpha-hydroxylase gene expression in alveolar macrophages and the activity of sarcoidosis. Am J Med. (2001) 110 :687–93. 10.1016/S0002-9343(01)00724-0 11403752\n8. Nathan N Sileo C Calender A Pacheco Y Rosental PA Cavalin C . Paediatric sarcoidosis. Paediatr Respir Rev. (2019) 29 :53–9. 10.1016/j.prrv.2018.05.003 30917882\n9. Schwartz GJ Work DF . Measurement and estimation of GFR in children and adolescents. Clin J Am Soc Nephrol. (2009) 4 :1832–43. 10.2215/CJN.01640309 19820136\n10. Wang C Liu H Zhang T Xu H Shen J Feng J . Acute kidney injury as a rare manifestation of pediatric sarcoidosis: a case report and systematic literature review. Clin Chim Acta. (2019) 489 :68–74. 10.1016/j.cca.2018.11.014 30414436\n11. Hobbs DJ Barletta GM Chung JY Bunchman TE . Isolated sarcoid granulomatous interstitial nephritis in pediatrics: a case report and review of literature. Clin Nephrol. (2009) 72 :410–3. 10.2379/CN106136 19863887\n12. Coutant R Leroy B Niaudet P Loirat C Dommergues JP Andre JL . Renal granulomatous sarcoidosis in childhood: a report of 11 cases and a review of the literature. Eur J Pediatr. (1999) 158 :154–9. 10.1007/s004310051038 10048615\n13. Mahevas M Lescure FX Boffa JJ Delastour V Belenfant X Chapelon C . Renal sarcoidosis: clinical, laboratory, and histologic presentation and outcome in 47 patients. Medicine (Baltimore). (2009) 88 :98–106. 10.1097/MD.0b013e31819de50f 19282700\n14. Bergner R Loffler C . Renal sarcoidosis: approach to diagnosis and management. Curr Opin Pulm Med. (2018) 24 :513–20. 10.1097/MCP.0000000000000504 29965860\n15. Loffler C Loffler U Tuleweit A Waldherr R Uppenkamp M Bergner R . Renal sarcoidosis: epidemiological and follow-up data in a cohort of 27 patients. Sarcoidosis Vasc Diffuse Lung Dis. (2014) 31 :306–15. 25591142\n16. Hilderson I Van Laecke S Wauters A Donck J . Treatment of renal sarcoidosis: is there a guideline? Overview of the different treatment options. Nephrol Dial Transplant. (2014) 29 :1841–7. 10.1093/ndt/gft442 24235078\n\n",
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"keywords": "acute kidney injury; case report; prognostic factor analysis; sarcoidosis; tubulointerstitial nephritis",
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"title": "Case Report: Pediatric Renal Sarcoidosis and Prognostic Factors in Reviewed Cases.",
"title_normalized": "case report pediatric renal sarcoidosis and prognostic factors in reviewed cases"
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"abstract": "Background. Mitoxantrone (MTX) and Rituximab (RTX) are successfully used for treatment of multiple sclerosis (MS) and can be combined to increase efficacy. Objective. We used MTX, RTX, and methylprednisolone in a single combined regiment and observed patients prospectively. Methods. We present results of observational pilot study of combined therapy of RTX and MTX in 28 patients with active MS. Therapeutic protocol consisted of two infusions within 14 days. First infusion was 1000 mg methylprednisolone (MP) IV, 1000 mg RTX IV, and 20 mg MTX IV. On day 14, 1000 mg MP IV and 1000 mg RTX IV were given. Patients were followed prospectively from 12 to 48 months. Results and Conclusion. There were no relapses among all 28 patients during the observation period. B-cell depletion of CD19+ and CD19+/CD27+ memory B-cell subpopulation in both compartments was confirmed in all patients at 6 months. We found a more rapid reconstitution of B cells in the CSF than in the peripheral blood and longstanding depression of CD19+CD27+ memory B-cell. Conclusion. Effectiveness of combined regimen of RTX and MTX could be related to longstanding depletion of CD19+CD27+ memory B-cell subset.",
"affiliations": "St. Petersburg's Center of MS and Autoimmune Diseases, City Hospital N31, Saint Petersburg, Russia.",
"authors": "Evdoshenko|Evgeniy|E|;Maslyanskiy|Alexey|A|;Lapin|Sergey|S|;Zaslavsky|Leonid|L|;Dobson|Ruth|R|;Totolian|Areg|A|;Skoromets|Alexander|A|;Bar-Or|Amit|A|",
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"fulltext": "\n==== Front\nISRN NeurolISRN NeurolISRN.NEUROLOGYISRN Neurology2090-55052090-5513Hindawi Publishing Corporation 10.1155/2013/748127Clinical StudyDynamics of B-Cell Populations in CSF and Blood in Patients Treated with a Combination of Rituximab and Mitoxantrone Evdoshenko Evgeniy \n1\n*http://orcid.org/0000-0003-2427-4148Maslyanskiy Alexey \n2\nLapin Sergey \n3\nZaslavsky Leonid \n4\nhttp://orcid.org/0000-0002-2993-585XDobson Ruth \n5\nTotolian Areg \n6\nSkoromets Alexander \n7\nBar-Or Amit \n8\n1St. Petersburg's Center of MS and Autoimmune Diseases, City Hospital N31, Saint Petersburg, Russia2Department of Rheumatology, Federal Clinical Center of Heart, Blood and Endocrinology, Saint Petersburg, Russia3Laboratory of Autoimmune Diagnostics, Saint-Petersburg Pavlov Medical University, Saint Petersburg, Russia4Department of Neurology, Leningrad Region Hospital, Saint Petersburg, Russia5Neuroimmunology Group, Blizard Institute, Great Britain, UK6Laboratory of Immunology, Pasteur Institute for Microbiology and Epidemiology, Saint Petersburg, Russia7Department of Neurology, Saint-Petersburg Pavlov Medical University, Saint Petersburg, Russia8Department of Neurology and Neurosurgery and Department of Microbiology and Immunology, McGill University, Montreal, QC, Canada*Evgeniy Evdoshenko: e.evdoshenko@gmail.comAcademic Editors: R. Beschorner and R. Saponara\n\n2013 10 9 2013 2013 74812716 7 2013 9 8 2013 Copyright © 2013 Evgeniy Evdoshenko et al.2013This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.\nBackground. Mitoxantrone (MTX) and Rituximab (RTX) are successfully used for treatment of multiple sclerosis (MS) and can be combined to increase efficacy. Objective. We used MTX, RTX, and methylprednisolone in a single combined regiment and observed patients prospectively. Methods. We present results of observational pilot study of combined therapy of RTX and MTX in 28 patients with active MS. Therapeutic protocol consisted of two infusions within 14 days. First infusion was 1000 mg methylprednisolone (MP) IV, 1000 mg RTX IV, and 20 mg MTX IV. On day 14, 1000 mg MP IV and 1000 mg RTX IV were given. Patients were followed prospectively from 12 to 48 months. Results and Conclusion. There were no relapses among all 28 patients during the observation period. B-cell depletion of CD19+ and CD19+/CD27+ memory B-cell subpopulation in both compartments was confirmed in all patients at 6 months. We found a more rapid reconstitution of B cells in the CSF than in the peripheral blood and longstanding depression of CD19+CD27+ memory B-cell. Conclusion. Effectiveness of combined regimen of RTX and MTX could be related to longstanding depletion of CD19+CD27+ memory B-cell subset.\n==== Body\n1. Introduction\nMultiple sclerosis (MS) is an autoimmune inflammatory disease of the CNS, characterized by focal demyelination, loss of axons, and gliosis that result in neurological symptoms. While our understanding of MS immunopathology continues to improve, the underlying etiology of the disorder remains unclear.\n\nThe overall efficacy of traditional MS treatments (beta-interferon, glatiramer acetate) is limited, and these drugs are widely accepted to have a relatively small effect on disease activity [1, 2]. More powerful approaches to disease modification in MS include the so-called “biological therapies” or monoclonal antibodies (natalizumab, alemtuzumab, daclizumab, rituximab, and ocrelizumab) and cytotoxic drugs (cladribine and mitoxantrone) [3–6]. The use of these therapies is limited by concerns regarding potential side effects, including an increased risk of infection and a theoretical increase in the lifetime risk of malignancy. It is thought that at least some of these risks increase as the cumulative dose of the drug increases [7].\n\nClinical trials of the anti-CD20 monoclonal antibody rituximab (RTX) in rheumatoid arthritis, systemic connective tissue diseases, and ANCA-associated vasculitides have reinforced its position as one of the leading potential therapeutic options in a range of autoimmune diseases [3, 8–11]. In MS, CD20+ B cells are rapidly becoming recognized as a valid therapeutic target, partly due to an increasing interest in their role in MS pathogenesis. The role of B cells in MS appears to be wide ranging and pervasive and includes the production of autoantibodies, antigen presentation to T cells, proinflammatory cytokine release, and tertiary lymphoid tissue formation in CNS of MS patients [12]. \n\nStudies examining the efficacy of RTX as a therapy in MS are limited. The largest and most important study to date is Helping to Evaluate Rituxan (rituximab) in Relapsing-Remitting Multiple Sclerosis (HERMES). Results demonstrated the ability of RTX to substantially control the focal inflammatory process in MS based on both MRI and clinical data. However, RTX did not completely suppress relapses—10 patients (14.5% of patients) experienced a clinical relapse during the first 24 weeks of the study [13]. Besides the inability of RTX to cross the blood-brain barrier, the limited efficacy of RTX monotherapy could also be explained by the capability of B cells to survive in certain tissues—referred to as “privileged sites.” This phenomenon has been seen in rheumatoid arthritis; pathological B cells found in the synovial lining of joints were decreased in number but not eliminated by RTX treatment [14, 15]. \n\nMitoxantrone (MTX) is a topoisomerase II inhibitor that is commonly used in the treatment of MS. Its clinical efficacy has been proven in a number of controlled studies [16, 17]. In animal models of MS, MTX was found to be tenfold more potent when compared to cyclophosphamide [18]. The effect of MTX may be partly due to its ability to induce B-cell apoptosis. It appears that the subpopulation that is most sensitive to this effect is the CD19+/CD27+ memory B cells. Additional clinical studies have shown correlations between CD19+CD27+ memory B-cell pool depletion and therapy effectiveness. [19–21]. \n\nThere are some lines of evidence that the combination of RTX and cytotoxic therapies could result in a more profound reduction in B-cell number. The combination of MTX and RTX forms part of the FCM-R regimen (fludarabine, cyclophosphamide, MTX, and RTX), which is used in the treatment of B-cell neoplasms with acceptable tolerability [22]. It appears that RTX and MTX could target B cells through different mechanisms. Therefore, we hypothesized that the combination of RTX with MTX may be effective in treatment of MS with high disease activity. \n\nIn this paper, we present the results of an observational pilot study of 28 MS patients who received a single course of combined therapy with RTX-MTX together with methylprednisolone (MP) and were followed clinically and immunologically with a maximal follow-up of 48 months. This study still provides an important insight into immunotherapy in MS.\n\n2. Material and Methods\n2.1. Patient Groups and Study Protocol\nWe assessed the efficacy of a single course of combined immunosuppressive therapy consisting of RTX and MTX together with methylprednisolone (MP) in MS. 28 patients with clinically definite MS (MacDonald 2005 criteria [23]) aged 18 to 55 who had at least one relapse in the 6 months prior to enrolment were recruited. All patients provided informed consent prior to study enrolment, and the study was approved by the local ethics committee.\n\nThe study group consisted of 8 patients resistant to standard therapy (beta-interferons, glatiramer acetate) and 8 patients who were resistant to different therapeutic approaches including bone marrow transplantation and 12 therapy naïve patients with very active MS. Disease modifying agents were withdrawn 1 month prior to any treatment in this study. The clinical details of the study participants are summarised in Table 1. \n\nThe therapeutic protocol consisted of two infusions 14 days apart and was performed as an inpatient during two separate hospital admissions to a specialised neurological department. On the first day, 1000 mg methylprednisolone (MP) IV was administered. On the second day, 1000 mg MP IV, 1000 mg RTX IV, and 20 mg MTX IV were given consecutively. Premedication with 1 g acetaminophen (paracetamol) and 20 mg diphenhydramine (piriton) IV was given 30 minutes prior to RTX infusion. On the third day, 1000 mg MP IV was administered. The patients were readmitted on day 14 when 1000 mg MP IV and 1000 mg RTX IV were administered. \n\nFor the initial three weeks, we checked complete blood counts and urinalysis every third day. Clinical and laboratory data as well as MRI examination were performed at several fixed time-points during the first year: 6 months, 9 months, and 12 months. After the first year of followup, patients were observed clinically at intervals of 6 months. At the date of paper preparation, the minimum duration of followup was 12 months and maximum observation period was 48 months. \n\nThe primary clinical endpoint was the tolerability of the combined regimen, and the primary imaging endpoint was the reduction in number of gadolinium-enhancing MRI lesions. \n\nAn aim of the study was to determine the changes in clinical disease measures, in the dynamics of B-cell populations cerebrospinal fluid (CSF), and in peripheral blood (PB). As there was no placebo arm, clinical examinations were unblinded and performed for safety rather than efficacy. \n\n2.2. Clinical and Magnetic Resonance Imaging Examinations\nBefore treatment, all patients underwent an extended neurological examination with formalised clinical scales (EDSS and MSFC) and an MRI. All patients were screened for viral hepatitis (B,C), HIV-1, and syphilis and had echocardiography and a chest X-ray performed. Blood and CSF were sampled 1 day prior to treatment. \n\nThe safety of the combination of RTX and MTX was determined by infusion-associated adverse events (AEs), drug-related AE, and infection-associated AE according to the National Cancer Institute (NCI) Common Toxicity Criteria (CTC) version 3.0 grading system over the study period [24, 25]. \n\nMRI examinations were performed with 1.5 T MRI apparatus (Siemens AG, Germany). Imaging endpoints were the change from baseline in the total number of gadolinium- (Gd-enhancing) T1 lesions, the total number of new T2 lesions, and the number of lesions changing from T2 to T1. MRI section thickness was 1 mm, and lesions greater than 3 mm in two dimensions were scored. \n\n2.3. Flow Cytometry and Other Immunological Tests\nPeripheral blood was taken on the day of lumbar puncture and examined using flow cytometry for the expression of lymphocyte markers CD3, 4, 8, 16, 56, 19, 27, HLADR, and CD4/25. Samples of CSF were taken by lumbar puncture. Aliquots of 5 mL CSF were sent for flow cytometry studies. The cells were spun down with careful centrifugation (1000 G), and 1 mL of cell pellet was taken for analysis. In all cases, samples were analysed within 4 hours of lumbar puncture.\n\nA 50 mL aliquot of CSF was sent for immunological studies including the detection of IgG oligoclonal bands by isoelectric focusing and immunoblotting in paired CSF and serum samples, according to established methods [26].\n\n3. Results\n3.1. Safety\nAEs were systematically examined during the study in all enrolled patients. An immediate infusion reaction of a urticarial rash and weakness developed in 1 patient and resolved spontaneously within 24 hours following the first infusion. This did not recur at the time of the second rituximab infusion (Table 2). \n\nA transient neutropenia of less than 1500 cells per microlitre was found in 100% (28/28) of patients but completely resolved in all patients by day 19 since the first infusion. This represents an AE that is recognized as grade 1–3 toxicity. In 46% (13/28) of patients, neutrophil counts were less than 500 cells per microlitre—that is, grade 4 toxicity. Detailed data on leukocyte and neutrophil counts is presented in Figure 1. This neutropenia was not complicated by infection or neutropenic fever, and spontaneous resolution was noted in all patients within 5–7 days. Malaise and fatigue were associated with neutropenia in all patients. Other noninfectious AEs are presented in Table 2.\n\nUpper respiratory tract infections including the common cold and nasopharyngitis were most frequent during the first year of observation and were seen in 13 (46%) patients. In all cases, infections were mild and resolved without antibiotic therapy. \n\n3.2. Clinical and Imaging Data\nThere were no relapses amongst patients receiving the combined therapy during the period of observation (Figure 2). \n\nWe found that treatment was associated with a significant decrease in the EDSS from 5.1 ± 1.7 to 3.5 ± 2.0 (P < 0.0001) in those patients followed up for 24 months (Figure 3). In 89% of patients, a persistent decrease in the EDSS score was seen, without any maintenance therapy. In 3/8 patients who were previously treated with bone marrow transplantation, a gradual increase of EDSS was seen (mean 0.5 point) by 6, 12, and 18 months of observation. \n\nThe baseline MRI examination was performed during the 3 months prior to the start of treatment. 89.3% (25/28) of patients had Gd-enhancing MRI lesions. The mean number of Gd-enhancing lesions was 4.43 ± 2.90 (range 0–10). All patients manifested new T2 lesions within the 3 months prior to therapy. The mean count of T2 lesions was 42 ± 31 (range 4–133), and the mean count of T1 lesions was 15 ± 12 (range 0–47). \n\nAfter 12 months of followup, the mean number of T2 lesions was 42 ± 32 (range 4–133) and T1 lesions 15 ± 12 (range 0–47) (Figure 4). During the study followup, no patients developed either Gd-enhancing or new T2 lesions. \n\nThere was a positive correlation between the number of Gd-enhancing lesions prior to treatment and the decrease in EDSS. A more pronounced decrease in EDSS at 6 months was seen in those patients who had more Gd-enhancing lesions at baseline (r = 0.42, P = 0.025). \n\n3.3. Immunology\nWe performed serial measurements of CD3-CD19+ B-cell and CD3-CD19+CD27+ memory B-cell subpopulations in peripheral blood and CSF. B-cell depletion (>95% reduction from baseline) in peripheral blood was confirmed in all patients at 6 months (Figure 5(a)). At 9 months, B cells reappeared in the peripheral blood (mean 0.018 ± 0.014× 10 ∗ 9 cells per liter) and expanded to 0.049 ± 0.080× 10 ∗ 9 cells per liter. In the majority of the patients, complete restoration of the number of B cells in peripheral blood occurred at 15 months after treatment. However, the number of CD27+ memory B cells was still significantly decreased compared to baseline (Figure 6(a)). \n\nThe number of B cells in peripheral blood fell over 150 times, while in the CSF the decrease was less pronounced and resulted in an approximate 5-fold reduction (Figure 5(b)). In the CSF, B cells dropped from 0.024 ± 0.028× 10 ∗ 6 cells per liter to 0.005 ± 0.008× 10 ∗ 6 cells per liter (P = 0.0034). By 12 months, B cells in the CSF had reached their initial levels of 0.022 ± 0.023× 10 ∗ 6 cells per liter (P = 0.687).\n\nWe found a more rapid reconstitution of B cells in the CSF than in the peripheral blood. By 9 months, B cells in the peripheral blood were still significantly lower (P = 0.001) than prior to therapy, whilst in the CSF, the number of B cells had returned to the levels observed prior to treatment (Figure 5). \n\nOligoclonal IgG bands in CSF samples were tested before therapy and at 12 months after therapy and were found in all patients. The frequency and intensity of oligoclonal IgG bands were unchanged at 12 months. \n\n4. Discussion\nThe rationale for our proposed treatment strategy is the general finding that “biologic” agents are more effective if used in combination with immunosuppressive or antiproliferative drugs. In the treatment of rheumatoid arthritis or system lupus erythematosis, RTX monotherapy is significantly less potent than RTX used in combination with another cytostatic drug such as cyclophosphamide or methotrexate [8]. \n\nWe treated 28 patients with a single therapeutic course of RTX-MTX-MP in combination and followed these patients for more than 1 year. All patients had very high MS activity at the time of enrolment in this study. \n\nThe treatment regimen was generally well tolerated and any immediate infusion reactions observed were mild. The unexpected finding in all patients treated with the combined therapy of RTX-MTX-MP was the high frequency of early neutropenia noticed by days 7–12. In over 40% of patients, the absolute neutrophil number was less than 500 cells per microliter. Neutropenia was characterized by fast recovery, taking less than 7 days, and the neutropaenia did not require treatment with colony-stimulating factors and/or antibiotics. There were no infection-related AEs associated with neutropaenia.\n\nNeutropenia is a recognised rare adverse effect of RTX therapy and is classified into early onset and late onset forms. The latter is more clinically relevant and typically occurs 2 to 4 months following RTX administration [27]. According to the data on hematological complications of RTX monotherapy, late onset RTX-induced neutropenia is seen in 6% of patients treated with a single course of the drug [28]. Cytotoxic drugs such as cyclophosphamide, which have been administered together with RTX in the treatment of systemic lupus erythematosis and other rheumatological diseases, have not been found to increase the frequency of either early or late onset RTX-induced neutropenia [20]. \n\nPublished data suggests that late onset neutropenia could be related to an excess of T-lymphocyte populations which express and secrete large amounts of Fas and Fas Ligand (FasL) leading to the apoptosis of mature neutrophils and the production of antineutrophil autoantibodies [29–31]. Another possible cause of neutropenia in RTX-treated patients is associated with the very high levels of BAFF, a strong stimulator of B-cell recovery, that can be seen in patients after B-cell depletion. These high levels could, in theory, promote B-cell lymphopoiesis in the bone marrow at the expense of normal granulopoiesis [32].\n\nThe dose of MTX typically recommended for monotherapy for MS (12 mg/m2) induces transient neutropenia in approximately one-third (27%) of patients [33]. When administered as a monotherapy, MTX-induced neutropenia usually peaks at 7–14 days and resolves by 21 days following treatment initiation. \n\nOur patients were followed clinically throughout the observation period which varied from 12 to 48 months. We confirmed suppression of MS activity and remission in 89% of patients that was sustained during followup. The absence of Gd-enhancing and new T2 lesions on repeated MRI suggests a profound decrease of inflammatory activity in these previously highly active MS patients. In most of the patients, clinical course of MS after single course of the combined therapy did not require any maintenance therapy during observation at the moment of the last data collection.\n\nWe noted B-cell depletion in peripheral blood which persisted for up to 15 months. In general, our data on the dynamics of B-cell counts is compatible with the results of the HERMES study. In the HERMES study, it was shown that RTX monotherapy induced a rapid depletion of CD19+ peripheral B lymphocytes from 2 weeks after treatment until 24 weeks. By week 48, CD19+ cells had returned to 30.7% of baseline values [13]. The number of CD27+ memory B cells in peripheral blood was still significantly decreased compared to baseline. We have also shown that in the CSF B cells reappeared at 9 months, and there was a preservation of oligoclonal IgG bands at 1 year that probably reflects propagation of intrathecal B cells.\n\nThe high frequency of neutropenia and long-term decrease in CD27+ memory B cells in our patients may reflect a biological synergism of the proposed combination of RTX and MTX with MP. Synergistic drug combinations of few relatively “strong” medications can potentially decrease the cumulative dose of any one medication and thus reduce some treatment associated risks. Such a combination could possibly be reserved as an escalation opportunity for patients with particularly active disease and poor prognostic factors [34], or as a preferable alternative to other induction approaches such as alemtuzumab [35], cladribine [4], high-dose cyclophosphamide (RevImmune) [36], and bone marrow transplantation.\n\nConflict of Interests\nThe authors declare that there is no conflict of interests.\n\nAcknowledgments\nThe authors wish to acknowledge Elena Babenko for flow-cytometry studies and Vladimir Fokin for imaging studies. Also, the authors appreciate Sergey Alekseev for clinical consultation and supervision hematological parameters. Tatyana Sidorenko spent much of her valuable time on finalizing the text and language of the paper.\n\nFigure 1 Dynamic of mean values of white blood cells (WBC), neutrophils (Neutroph), and lymphocytes (Lymph) after first infusion of rituximab with mitoxantrone and intravenous methylprednisolone. x-axis represents days after infusion.\n\nFigure 2 Number of relapses and period of observation before and after treatment. Month 0: start of the treatment; ▲: relapse.\n\nFigure 3 Dynamic of EDSS (mean) for a period observation of 30 months. Significant decrease in the EDSS score from 5.1 ± 1.7 before treatment to 3.5 ± 2.0 (P < 0.0001) at 12 months after treatment initiation in 28 patients and a decrease in the EDSS score from 5.1 ± 1.7 before treatment to 3.5 ± 2.0 (P < 0.0001) at 24 months after treatment in 15 patients. **P < 0.001; ***P < 0.0001. \n\nFigure 4 Dynamic of Gd-enhanced lesions after therapy with rituximab with mitoxantrone and intravenous methylprednisolone during observation period. Along the period of observation after combined therapy, there were neither Gd-enhancing MRI lesions nor new T2 lesions in any of the study patients.\n\nFigure 5 Dynamic of CD19+ cells in peripheral blood (a) and CSF (b) after treatment. *P < 0.05; **P < 0.001; ***P < 0.0001.\n\nFigure 6 Dynamic of CD19+CD27+ memory B cells in peripheral blood (a) and CSF (b) after treatment. ***P < 0.0001; **P = 0.0059.\n\nTable 1 Summary of clinical data of patients under study.\n\nPatient no./sex/age, yrs\tType of MS\tTime since initial symptoms, yrs\tTime since diagnosis, yrs\tMS therapy in previous 5 yrs\tEDSS at baseline\tRelapses in previous 2 yrs\tMRI findings \n(within 6 months before treatment)\nT2/T1/T1Gd\tOCB\t\n1/F/25\tRR\t3\t1\tNone\t3.0\t3\t34/22/5\t+\t\n2/F/21\tRR\t3\t2\tNone\t2.0\t2\t48/9/3\t+\t\n3/F/26\tSP\t4\t3\tINFβ-1b 250 μg\t6.0\t4\t35/11/3\t+\t\n4/M/23\tRR\t2\t2\tINFβ-1a 30 μg\t3.0\t3\t24/8/2\t+\t\n5/F/25\tRR\t2\t2\tINFβ-1b 250 μg\t4.0\t3\t53/18/3\t+\t\n6/M/38\tPP\t12\t10\tGA \nAuto-HSCT\t6.0\t4\t38/20/0\t+\t\n7/F/42\tRR\t6\t6\tAuto-HSCT\t2.0\t1\t38/15/5\t− \t\n8/M/28\tSP\t10\t10\tINFβ-1b 250 μg\t7.5\t4\t31/12/10\t+\t\n9/F/35\tSP\t12\t10\tAuto-HSCT\t6.0\t1\t38/23/0\t+\t\n10/F/20\tRR\t2\t2\tINFβ-1b 250 μg\t4.0\t2\t133/34/7\t+\t\n11/M/25\tRR\t3\t3\tNone\t4.5\t4\t23/6/4\t+\t\n12/F/28\tRR\t4\t3\tINFβ-1b 250 μg Mitoxantrone\t5.0\t4\t24/7/8\t+\t\n13/M/50\tRR\t10\t5\tNone\t4.0\t1\t40/21/5\t+\t\n14/M/53\tRR\t1\t0\tGA \t6.5\t2\t24/0/10\t+\t\n15/F/34\tRR\t6\t4\tGA \t4.0\t1\t30/10/4\t+\t\n16/F/29\tRR\t4\t2\tNone\t6.0\t3\t27/8/4\t+\t\n17/M/29\tRR\t15\t14\tNone\t6.0\t4\t92/47/6\t+\t\n18/F/28\tRR\t3\t2\tINFβ-1b 250 μg\t4.0\t2\t33/8/1\t+\t\n19/M/28\tSP\t4\t2\tNone\t6.0\t3\t24/8/9\t+\t\n20/M/30\tSP\t3\t3\tGA mitoxantrone\t9.0\t4\t22/13/7\t+\t\n21/M/51\tSP\t12\t10\tINFβ-1b 250 μg\t6.0\t1\t32/20/0\t+\t\n22/F/54\tSP\t13\t10\tGA mitoxantrone\t6.5\t3\t28/19/6\t+\t\n23/M/24\tRR\t1\t1\tNone\t3.0\t3\t130/40/2\t+\t\n24/F/44\tSP\t6\t5\tNone\t6.0\t2\t36/3/1\t+\t\n25/M/23\tRR\t \t \tNone\t4.0\t2\t12/0/4\t+\t\n26/F/36\tRR\t4\t4\tNone\t6.0\t3\t4/1/4\t+\t\n27/F/40\tRR\t4\t3\tNone\t5.5\t4\t89/23/3\t+\t\n28/F/55\tSP\t3\t3\tMitoxantrone\t8.0\t4\t22/2/8\t+\t\nRR: relapsing-remitting; PP: primary progressive; SP: secondary progressive; INFβ: interferon beta; GA: glatiramer acetate; Auto-HSCT: autohematopoietic stem cells transplantation; T2(PD): hyperintense lesions; T1: hypointense lesions; T1Gd: gadolinium-enhanced lesions; OCB: oligoclonal bands.\n\nTable 2 Adverse events in study population according to the common toxicity criteria, version 3.0.\n\nEvents\tPatients \n\nn (%)\t\nDrug-related events affecting\t \t\n Headache\t5 (17.8%)\t\n Nausea\t3 (10.7%)\t\n Fatigue\t10 (35.7%)\t\n Throat irritation\t1 (3.5%)\t\nInfusion-associated event—number of patients (%)***\t \t\n First infusion at w 0\t1 (3.5%)\t\n Second infusion at w 2\t0\t\nSpecific infection-associated event—number of patients (%)\t \t\n Nasopharyngitis\t11 (39.2%)\t\n Upper respiratory tract infection\t2 (15.3%)\t\n Urinary tract infection\t1 (3.5%)\t\n Sinusitis\t1 (3.5%)\t\nCommon toxicity criteria\t \t\n Grade 1\t28 (100%)\t\n Grade 2\t24 (86%)\t\n Grade 3\t16 (57%)\t\n Grade 4\t13 (46%*)\t\n Grade 5\t0\t\nSerious adverse event*\t0 (0%)\t\n*All cases presented with transient neutropenia (less than 500 cell/mL) which resolved spontaneously by day 19. \n\n**Serious adverse events were defined as life threatening, resulting in death, requiring prolonged inpatient hospitalization, resulting in a congenital anomaly or malignant condition, or requiring surgical intervention to prevent one of these outcomes.\n\n**Infusion-associated event included any adverse event occurring during or within 24 hours after rituximab and mitoxantrone infusion in all patients.\n==== Refs\n1 Jacobs LD Cookfair DL Rudick RA Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis Annals of Neurology 1996 39 3 285 294 2-s2.0-0029311748 8602746 \n2 Johnson KP Brooks BR Cohen JA Copolymer 1 reduces relapse rate and improves disability in relapsing- remitting multiple sclerosis: results of a phase III multicenter, double- blind, placebo-controlled trial Neurology 1995 45 7 1268 1276 2-s2.0-0029082566 7617181 \n3 Farrell RA Giovannoni G Current and future role of interferon beta in the therapy of multiple sclerosis Journal of Interferon and Cytokine Research 2010 30 10 715 726 2-s2.0-77957346546 20874249 \n4 Giovannoni G Comi G Cook S A placebo-controlled trial of oral cladribine for relapsing multiple sclerosis The New England Journal of Medicine 2010 362 5 416 426 2-s2.0-76149083915 20089960 \n5 Giovannoni G Kinkel RP Vartanian T Treating multiple sclerosis in the natalizumab era: risks, benefits, clinical decision making, and a comparison between North American and European Union practices Reviews in Neurological Diseases 2007 4 4 184 193 2-s2.0-37548998990 18195670 \n6 Rudick RA Miller D Hass S Health-related quality of life in multiple sclerosis: effects of natalizumab Annals of Neurology 2007 62 4 335 346 2-s2.0-36148945609 17696126 \n7 Kieseier BC Jeffery DR Chemotherapeutics in the treatment of multiple sclerosis Therapeutic Advances in Neurological Disorders 2010 3 5 277 291 2-s2.0-77957339494 21179618 \n8 Edwards JCW Szczepański L Szechiński J Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis The New England Journal of Medicine 2004 350 25 2572 2581 2-s2.0-2942537697 15201414 \n9 Fervenza FC Rituximab in ANCA-associated vasculitis: fad or fact? Nephron 2011 118 2 c182 c188 2-s2.0-78650072277 21160229 \n10 Garcia-Valladares I Espinoza LR Is rituximab superior to cyclophosphamide for ANCA-associated vasculitis for induction of remission, and with a better safety profile? Current Rheumatology Reports 2010 12 6 395 398 2-s2.0-77958105034 20844995 \n11 Schönermarck U de Groot K Vasculitis: rituximab: effective in ANCA-associated vasculitis? Nature Reviews Nephrology 2011 7 1 6 8 2-s2.0-78650475139 \n12 Holmøy T Immunopathogenesis of multiple sclerosis: concepts and controversies Acta Neurologica Scandinavica 2007 115 187 39 45 2-s2.0-34047240306 \n13 Hauser SL Waubant E Arnold DL B-cell depletion with rituximab in relapsing-remitting multiple sclerosis The New England Journal of Medicine 2008 358 7 676 688 2-s2.0-39049142995 18272891 \n14 Walsh CAE Fearon U FitzGerald O Veale DJ Bresnihan B Decreased CD20 expression in rheumatoid arthritis synovium following 8 weeks of rituximab therapy Clinical and Experimental Rheumatology 2008 26 4 656 658 2-s2.0-52649156563 18799100 \n15 Teng YK Levarht EW Toes RE Huizinga TW van Laar JM Residual inflammation after rituximab treatment is associated with sustained synovial plasma cell infiltration and enhanced B cell repopulation Annals of the Rheumatic Diseases 2009 68 6 1011 1016 2-s2.0-67449152722 18647852 \n16 Le Page E Leray E Taurin G Mitoxantrone as induction treatment in aggressive relapsing remitting multiple sclerosis: treatment response factors in a 5 year follow-up observational study of 100 consecutive patients Journal of Neurology, Neurosurgery and Psychiatry 2008 79 1 52 56 2-s2.0-37749016994 \n17 Komori M Kondo T Tanaka M Mitoxantrone for the treatment of patients with multiple sclerosis Brain and Nerve 2009 61 5 575 580 2-s2.0-68149089411 19514518 \n18 Ridge SC Sloboda AE McReynolds RA Suppression of experimental allergic encephalomyelitis by mitoxantrone Clinical Immunology and Immunopathology 1985 35 1 35 42 2-s2.0-0021923787 3873302 \n19 Bellosillo B Colomer D Pons G Gil J Mitoxantrone, a topoisomerase II inhibitor, induces apoptosis of B- chronic lymphocytic leukaemia cells British Journal of Haematology 1998 100 1 142 146 2-s2.0-0031982877 9450803 \n20 Duddy M Niino M Adatia F Distinct effector cytokine profiles of memory and naive human B cell subsets and implication in multiple sclerosis Journal of Immunology 2007 178 10 6092 6099 2-s2.0-34248230257 \n21 Duddy M Bar-Or A B-cells in multiple sclerosis International MS Journal 2006 13 3 84 90 2-s2.0-33845395095 17101076 \n22 Faderl S Wierda W O’Brien S Ferrajoli A Lerner S Keating MJ Fludarabine, cyclophosphamide, mitoxantrone plus rituximab (FCM-R) in frontline CLL <70 Years Leukemia Research 2010 34 3 284 288 2-s2.0-77649184591 19646755 \n23 Polman CH Reingold SC Edan G Diagnostic criteria for multiple sclerosis: 2005 revisions to the ‘McDonald Criteria’ Annals of Neurology 2005 58 6 840 846 2-s2.0-28544436950 16283615 \n24 Common Terminology Criteria for Adverse Events v3. 0 (CTCAE) http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev3.pdf \n25 Trotti A Colevas AD Setser A CTCAE v3.0: development of a comprehensive grading system for the adverse effects of cancer treatment Seminars in Radiation Oncology 2003 13 3 176 181 2-s2.0-10744228140 12903007 \n26 Hawkes CH Thompson EJ Keir G Iso-electric focusing of aqueous humour IgG in multiple sclerosis Journal of Neurology 1994 241 7 436 438 2-s2.0-0028233915 7931445 \n27 Martin P Furman RR Coleman M Leonard JP Phase I to III trials of anti-B cell therapy in non-Hodgkin’s lymphoma Clinical Cancer Research 2007 13 18 5636 5642 2-s2.0-34948866757 \n28 RITUXIMAB package insert. Biogen Idec Inc and Genentech, Inc. PI Revision Date 04, 2011 \n29 Papadaki T Stamatopoulos K Anagnostopoulos A Fassas A Rituximab-associated immune myelopathy Blood 2003 102 4 1557 1558 2-s2.0-0043240013 12900357 \n30 Papadaki T Stamatopoulos K Stavroyianni N Paterakis G Phisphis M Stefanoudaki-Sofianatou K Evidence for T-large granular lymphocyte-mediated neutropenia in Rituximab-treated lymphoma patients: report of two cases Leukemia Research 2002 26 6 597 600 2-s2.0-0036243335 12007508 \n31 Voog E Morschhauser F Solal-Céligny P Benyunes MC Multani PS Saunders A Neutropenia in patients treated with rituximab The New England Journal of Medicine 2003 348 26 2691 2694 2-s2.0-0038309769 12826650 \n32 Terrier B Ittah M Tourneur L Late-onset neutropenia following rituximab results from a hematopoietic lineage competition due to an excessive BAFF-induced B-cell recovery Haematologica 2007 92 2 e20 e23 2-s2.0-36249025353 17405749 \n33 Kingwell E Koch M Leung B Cardiotoxicity and other adverse events associated with mitoxantrone treatment for MS Neurology 2010 74 22 1822 1826 2-s2.0-77953206986 20427751 \n34 Comi G Induction versus escalating therapy in multiple sclerosis: practical implications Neurological Sciences 2008 29 supplement 2 S253 S255 2-s2.0-53649109121 18690509 \n35 Coles AJ Fox E Vladic A Alemtuzumab versus interferon beta-1a in early relapsing-remitting multiple sclerosis: post-hoc and subset analyses of clinical efficacy outcomes The Lancet Neurology 2011 10 4 338 348 2-s2.0-79952740129 21397567 \n36 Harrison DM Gladstone DE Hammond E Treatment of relapsing-remitting multiple sclerosis with high-dose cyclophosphamide induction followed by glatiramer acetate maintenance Multiple Sclerosis 2012 18 2 202 209 2-s2.0-84856700285 21865410\n\n",
"fulltext_license": "CC BY",
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"issue": "2013()",
"journal": "ISRN neurology",
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"medline_ta": "ISRN Neurol",
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"pmid": "24109519",
"pubdate": "2013",
"publication_types": "D016428:Journal Article",
"references": "20844995;16283615;21173754;17475834;19514518;9450803;17419827;7617181;21179618;15201414;19646755;20427751;17846110;12826650;3873302;12900357;21865410;17696126;18272891;18690509;21397567;7931445;17875800;20089960;18799100;17101076;8602746;18195670;17405749;12007508;20874249;12903007;18647852;21160229",
"title": "Dynamics of B-Cell Populations in CSF and Blood in Patients Treated with a Combination of Rituximab and Mitoxantrone.",
"title_normalized": "dynamics of b cell populations in csf and blood in patients treated with a combination of rituximab and mitoxantrone"
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"companynumb": "RU-MYLANLABS-2015M1007410",
"fulfillexpeditecriteria": "1",
"occurcountry": "RU",
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"activesubstancename": "RITUXIMAB"
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"abstract": "A 69-year-old man who had been hospitalized with acute coronary syndrome (ACS), underwent urgent percutaneous coronary intervention. In the subacute phase, he developed sudden chest pain and hemodynamic deterioration, and urgent coronary angiogram showed multiple coronary artery spasms. The discontinuation of beta-blocker treatment and the administration of a calcium antagonist helped prevent angina attacks. In Japanese patients who tend to have coronary artery spasm, the routine administration of beta-blockers for post-ACS patients with a preserved left ventricular systolic function should be considered carefully.",
"affiliations": "Department of Cardiology, Mie Prefectural General Medical Center, Japan.;Department of Cardiology, Mie Prefectural General Medical Center, Japan.;Department of Cardiology, Mie Prefectural General Medical Center, Japan.;Department of Cardiology, Mie Prefectural General Medical Center, Japan.;Department of Cardiology, Mie Prefectural General Medical Center, Japan.;Department of Cardiology, Mie Prefectural General Medical Center, Japan.;Department of Cardiology and Nephrology, Mie University Graduate School of Medicine, Japan.",
"authors": "Sawai|Toshiki|T|;Tajima|Yu|Y|;Hirota|Atsuya|A|;Yamamoto|Shigetada|S|;Nakajima|Hiroshi|H|;Makino|Katsutoshi|K|;Ito|Masaaki|M|",
"chemical_list": "D000319:Adrenergic beta-Antagonists; D002121:Calcium Channel Blockers",
"country": "Japan",
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"doi": "10.2169/internalmedicine.1208-18",
"fulltext": "\n==== Front\nIntern MedIntern. MedInternal Medicine0918-29181349-7235The Japanese Society of Internal Medicine 3014658110.2169/internalmedicine.1208-18Case ReportMultiple Life-threatening Coronary Artery Spasms after Percutaneous Coronary Intervention for Acute Coronary Syndrome Sawai Toshiki 12Tajima Yu 1Hirota Atsuya 1Yamamoto Shigetada 1Nakajima Hiroshi 1Makino Katsutoshi 1Ito Masaaki 3\n1 Department of Cardiology, Mie Prefectural General Medical Center, Japan\n2 Department of Cardiology, Mie Heart Center, Japan\n3 Department of Cardiology and Nephrology, Mie University Graduate School of Medicine, JapanCorrespondence to Dr. Toshiki Sawai, tsawai1974@yahoo.co.jp\n\n24 8 2018 15 1 2019 58 2 233 238 17 3 2018 28 4 2018 Copyright © 2019 by The Japanese Society of Internal Medicine2019The Internal Medicine is an Open Access journal distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (https://creativecommons.org/licenses/by-nc-nd/4.0/).A 69-year-old man who had been hospitalized with acute coronary syndrome (ACS), underwent urgent percutaneous coronary intervention. In the subacute phase, he developed sudden chest pain and hemodynamic deterioration, and urgent coronary angiogram showed multiple coronary artery spasms. The discontinuation of beta-blocker treatment and the administration of a calcium antagonist helped prevent angina attacks. In Japanese patients who tend to have coronary artery spasm, the routine administration of beta-blockers for post-ACS patients with a preserved left ventricular systolic function should be considered carefully. \n\nmultiple coronary artery spasmlife-threateningacute coronary syndromecalcium channel blockerbeta-blocker\n==== Body\nIntroduction\nCoronary artery spasms have been shown to cause life-threatening cardiac events (1-3). Beta-blockers have long been the standard treatment for prevention of cardiac events after acute coronary syndrome (ACS), however the administration of beta-blockers may induce coronary artery spasm. In this era of coronary revascularization for ACS, whether or not beta-blockers are associated with a reduced mortality in patients with a preserved left ventricular systolic function (LVSF) is unclear. We herein report the case of a 69-year-old man who developed beta-blocker induced multiple life-threatening coronary artery spasms after ACS.\n\nCase Report\nA 69-year-old man with no history of coronary artery disease was admitted to our hospital with acute chest pain. His coronary risk factors included hypertension, being a current smoker, and obesity, and he had been treated with antihypertensive drugs (amlodipine, valsartan, and eplerenone) for about nine years.\n\nHis electrocardiogram (ECG) showed ST-segment elevations in leads V1-V5 (Fig. 1A). He was diagnosed with ST-elevation anteroseptal myocardial infarction, and urgent coronary angiogram was performed. The initial angiogram revealed the culprit lesion in the proximal portion of the left anterior descending artery (LAD) and thrombolysis in myocardial infarction 2 flow of the LAD (Fig. 2A and B). There were no lesions in the right coronary artery (RCA) or left circumflex artery (LCx).\n\nFigure 1. (A) A 12-lead electrocardiogram showed ST-segment elevation in leads V1-V5, which was suggestive of left anterior descending coronary artery disease. (B) Electrocardiographic monitoring showed atrial fibrillation with bradycardia and an ST-elevation in lead II. (C) A 12-lead electrocardiogram obtained after cardiopulmonary resuscitation showed mild ST-segment elevation in leads V1-V5.\n\nFigure 2. Coronary angiogram at the first procedure. (A, B) Left coronary angiogram showed the culprit lesion in the proximal portion of the left anterior descending artery (LAD) (white arrows), whereas no significant stenosis was detected in the left circumflex artery. (C, D) The final coronary angiogram showed appropriate stent expansion (white broken lines).\n\nAspiration thrombectomy was performed, and small red thrombi were aspirated. Intravascular ultrasound (IVUS) showed a ruptured plaque containing a large necrotic core within the lesion (Fig. 3A). Left main coronary artery (LMCA)/LAD crossover stent implantation was conducted with a 3.0×28-mm everolimus-eluting stent (Xience Alpine, Abbott Vascular, Santa Clara, USA) at 18 atm, followed by kissing-balloon inflation (KBI). IVUS performed after KBI showed stent malapposition at the proximal edge of the stent; therefore, post-dilatation was conducted with a 3.25×13-mm non-compliant balloon (KUNAI, ASAHI Intecc, Nagoya, Japan) at 22 atm. The final angiogram showed good results (Fig. 2C and D).\n\nFigure 3. Intravascular ultrasound (IVUS). (A) IVUS after aspiration thrombectomy showed a ruptured plaque containing a large necrotic core within the lesion (white arrow). (B) IVUS showed mild in-stent plaque protrusion (white arrow).\n\nAfter the procedure, the patient's peak creatine phosphokinase (CPK) level was 1,158 IU/L, and echocardiography revealed an ejection fraction of 55% with hypokinesis of the anteroseptal wall. Aspirin (100 mg/day), prasugrel (3.75 mg/day), rosuvastatin (2.5 mg/day), eplerenone (50 mg/day), lisinopril (10 mg/day), and bisoprolol (2.5 mg/day) were orally administered. Amlodipine, which the patient had been taking before their admission, was discontinued because normotension was observed after the procedure. In the early morning on the second day after admission, the patient complained of sudden chest pain, and electrocardiographic monitoring showed brady atrial fibrillation with ST-elevation in lead II (Fig. 1B). He did not exhibit spontaneous respiration, and his carotid pulse could not be palpated; therefore, cardiopulmonary resuscitation (CPR) was started. After several minutes of CPR, he regained consciousness. After CPR, the patient’s ECG showed mild ST-segment elevation (Fig. 1C); therefore, urgent coronary angiogram was performed under a suspicion of subacute stent thrombosis. However, the coronary angiogram did not show significant stenosis (Fig. 4A and B).\n\nIVUS was carried out; however, only mild in-stent plaque protrusion was observed (Fig. 3B). When we were about to finish the procedure, the patient complained of sudden chest pain again. His ECG showed ST-segment elevation in leads II, III, and aVF. Angiogram of the RCA revealed severe spastic changes in the middle and distal portions of the RCA (Fig. 4C). The spastic changes and chest pain were improved by the intracoronary injection of isosorbide dinitrate (Fig. 4D). However, the patient soon complained of chest pain again, and angiogram of the left coronary artery (LCA) revealed spastic changes in the LAD and LCx, which were improved by the intracoronary injection of isosorbide dinitrate (Fig. 4E and F). We finished the angiogram after observing the patient's electrographic changes and symptoms for several minutes. After the angiogram, the beta-blocker treatment was discontinued, and low-dose calcium antagonist treatment (2.5 mg/day amlodipine) was administered. To this day, the patient's coronary spastic angina has not recurred.\n\nFigure 4. Coronary angiogram after cardiopulmonary resuscitation. (A, B) No significant stenosis or stent thrombosis was detected on left coronary angiogram. (C, D) Right coronary angiogram showed multiple severe coronary spasms in the middle and distal portions of the artery (white arrows), and the spasms improved after the intracoronary injection of isosorbide dinitrate. (E, F) Left coronary angiogram showed multiple severe coronary artery spasms in the proximal and middle portions of the left circumflex artery and the distal portion of the left anterior descending artery (LAD) (white arrows), and the spasms improved after the intracoronary injection of isosorbide dinitrate. A guidewire was passed into the LAD to allow the implanted stents to be observed on intravascular ultrasound (black arrows).\n\nDiscussion\nCoronary artery spasms have been shown to cause angina, myocardial infarctions, and arrhythmia (1-3). Multiple coronary artery spasms might cause more significant myocardial ischemia and be more life-threatening than a single coronary artery spasm (4-6). This report presents a case in which multiple life-threatening coronary artery spasms without organic stenosis occurred after percutaneous coronary intervention (PCI) for ACS. Repeated coronary angiogram showed severe coronary artery spasms in the RCA and LCA (at slightly different times), and these events resolved after the intracoronary injection of isosorbide dinitrate.\n\nThere have been several reports regarding severe coronary artery spasms associated with life-threatening events after the implantation of drug-eluting stents (DESs) (7, 8). Hypersensitivity reactions to stent components (e.g. coated polymers, drugs, and metal) and endothelial dysfunction have been recognized as important factors influencing the occurrence of coronary artery spasms (9-11). Most reports on this topic have described coronary artery spasms occurring in stent-implanted vessels or in proximal or distal stent segments (7, 12). In the current case, all spasm sites were located away from the stenting site (LMCA to the proximal LAD); therefore, we believe that the multiple coronary artery spasms encountered in this case were not associated with DES implantation.\n\nPristipino et al. evaluated the racial differences in coronary constrictor responses between Japanese and Caucasian patients who had recently suffered myocardial infarctions (13). They showed that, in the early phase of ACS, Japanese patients exhibited a three-fold greater incidence of coronary spastic responses (in both the infarct-affected and non-infarct-affected arteries) to the intracoronary acetylcholine provocation test than Caucasians, as well as a significantly higher incidence of multiple coronary artery spasms (13).\n\nIn the current case, after coronary artery spasms were detected, the discontinuation of beta-blocker treatment and the administration of a calcium antagonist helped prevent angina attacks. We consider that the multiple life-threatening coronary artery spasms encountered in our case were caused by the administration of a beta-blocker in addition to the coronary artery spastic tendency seen in Japanese people. There is also a possibility that the administration of a calcium antagonist as anti-hypertensive therapy before the patient's admission accidentally prevented coronary artery spasms.\n\nIn this case, the patient’s peak CPK level was mildly elevated, and echocardiography revealed that his LVSF had been preserved. In this era of coronary revascularization for ACS, whether or not beta-blockers are associated with a reduced mortality in patients with a preserved LVSF is unclear. Beta-blockers have long been the standard treatment for ACS; however, most studies evaluating the effects of beta-blockers on ACS were carried out several decades ago, at a time when coronary revascularization was not performed and when the currently used secondary prevention drugs, such as statins and renin angiotensin aldosterone system blockers, were not administered sufficiently often (14, 15). A recent cohort study, in which 52.8% of the included patients exhibited ST-elevation acute myocardial infarctions and 45.9% of the patients underwent coronary revascularization, evaluated the efficacy of beta-blocker treatment in patients with a preserved LVSF and showed that the use of beta-blockers was not associated with an improved survival (16). Furthermore, a meta-analysis that included patients with a preserved LVSF who underwent PCI did not obtain evidence to support the routine use of beta-blockers in ACS patients who undergo PCI (17).\n\nThe Japanese beta-blockers and calcium antagonists myocardial infarction (JBCMI) study compared the effects of beta-blockers on cardiovascular events with those of calcium antagonists in Japanese post-ACS patients who underwent coronary revascularization and showed that there was no significant difference in the incidence of cardiovascular mortality between the two groups (18). However, the incidence of coronary artery spasm was significantly higher in the beta-blocker group than in the calcium antagonist group (18). The current Japanese guideline shows the importance of beta-blocker for ischemic heart disease; however, the administration of beta-blockers to low-risk ACS patients who have undergone coronary revascularization remains controversial (19).\n\nIn daily clinical practice, we sometimes experience cases of coronary artery spasm caused by beta-blockers; however, there have been few reports about multiple life-threatening coronary artery spasms induced by beta-blocker treatment after PCI for ACS.\n\nBased on the abovementioned points, we consider that the routine administration of beta-blockers to post-ACS Japanese patients with a preserved LVSF who have undergone appropriate PCI should be considered carefully, and that the administration of calcium antagonists to Japanese ischemic heart disease patients is very important.\n\n\nAuthor's disclosure of potential Conflicts of Interest (COI).\n\nMasaaki Ito: Honoraria, Daiichi Sankyo, Takeda Pharmaceutical, and Bayer Yakuhin; Research funding, Bristol-Myers Squibb.\n==== Refs\n1. \nPrinzmetal M , Kennamer R , Merliss R , et al \nAngina pectoris. I. A variant form of angina pectoris; preliminary report . Am J Med \n27 : 375 -388 , 1959 .14434946 \n2. \nOng P , Athanasiadis A , Borgulya G , et al \n3-year follow-up of patients with coronary artery spasm as cause of acute coronary syndrome: the CASPAR (coronary artery spasm in patients with acute coronary syndrome) study follow-up . J Am Coll Cardiol \n57 : 147 -152 , 2011 .21211685 \n3. \nTakagi Y , Yasuda S , Takahashi J , et al \nImportance of dual induction tests for coronary vasospasm and ventricular fibrillation in patients surviving out-of-hospital cardiac arrest . Circ J \n73 : 767 -769 , 2009 .19261991 \n4. \nZhang H , Zhang WJ , Wu YJ , et al \nRecurrent multivessel coronary artery spasm presented as myocardial infarction . Chin Med J (Engl) \n129 : 2753 -2756 , 2016 .27824011 \n5. \nAhn JM , Lee KH , Yoo SY , et al \nPrognosis of variant angina manifesting as aborted sudden cardiac death . J Am Coll Cardiol \n68 : 137 -145 , 2016 .27386766 \n6. \nChuang YT , Ueng KC \nSpontaneous and simultaneous multivessel coronary spasm causing multisite myocardial infarction, cardiogenic shock, atrioventricular block, and ventricular fibrillation . Circ J \n73 : 1961 -1964 , 2009 .19179777 \n7. \nBhagwat A , Mukhedkar S \nSevere generalized resistant spasm of the right coronary artery causing hemodynamic collapse after stenting . JACC Cardiovasc Interv \n8 : e199 -e200 , 2015 .26493262 \n8. \nRhew SH , Ahn Y , Cho EA , et al \nA patient with repeated catastrophic multi-vessel coronary spasm after zotarolimus-eluting stent implantation . Korean Circ J \n43 : 48 -53 , 2013 .23407605 \n9. \nBrott BC , Anayiotos AS , Chapman GD , et al \nSevere, diffuse coronary artery spasm after drug-eluting stent placement . J Invasive Cardiol \n18 : 584 -592 , 2006 .17197707 \n10. \nTerashima M , Kaneda H , Nasu K , et al \nProtective effect of telmisartan against endothelial dysfunction after coronary drug-eluting stent implantation in hypertensive patients . JACC Cardiovasc Interv \n5 : 182 -190 , 2012 .22361603 \n11. \nKim JW , Seo HS , Park JH , et al \nA prospective, randomized, 6-month comparison of the coronary vasomotor response associated with a zotarolimus- versus a sirolimus-eluting stent: differential recovery of coronary endothelial dysfunction . J Am Coll Cardiol \n53 : 1653 -1659 , 2009 .19406340 \n12. \nSahin DY , Icen YK \nDiffuse coronary spasm mimicking acute thrombosis after stent implantation . Anadolu Kardiyol Derg \n11 : E29 -E30 , 2011 .21967797 \n13. \nPristipino C , Beltrame JF , Finocchiaro ML , et al \nMajor racial differences in coronary constrictor response between japanese and caucasians with recent myocardial infarction . Circulation \n101 : 1102 -1108 , 2000 .10715255 \n14. \nFreemantle N , Cleland J , Young P , et al \nbeta Blockade after myocardial infarction: systematic review and meta regression analysis . BMJ \n318 : 1730 -1737 , 1999 .10381708 \n15. \nCucherat M , Boissel JP , Leizorovicz A \nPersistent reduction of mortality for five years after one year of acebutolol treatment initiated during acute myocardial infarction. The APSI Investigators. Acebutolol et Prevention Secondaire de l'Infarctus . Am J Cardiol \n79 : 587 -589 , 1997 .9068513 \n16. \nDondo TB , Hall M , West RM , et al \nbeta-blockers and mortality after acute myocardial infarction in patients without heart failure or ventricular dysfunction . J Am Coll Cardiol \n69 : 2710 -2720 , 2017 .28571635 \n17. \nHuang BT , Huang FY , Zuo ZL , et al \nMeta-analysis of relation between oral beta-blocker therapy and outcomes in patients with acute myocardial infarction who underwent percutaneous coronary intervention . Am J Cardiol \n115 : 1529 -1538 , 2015 .25862157 \n18. \nJapanese beta-blockers calcium antagonists myocardial infarction, investigators. comparison of the effects of beta blockers and calcium antagonists on cardiovascular events after acute myocardial infarction in japanese subjects . Am J Cardiol \n93 : 969 -973 , 2004 .15081437 \n19. \nJapanese Circulation Society. 2013 Guidelines for the management of patients with ST-elevation acute myocardial infarction\n.\n[Internet]. [cited 2018 Apr. 4]. Available from: http://www.j-circ.or.jp/guideline/pdf/JCS2013_kimura_h.pdf\n(in Japanese)\n.\n\n",
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"title": "Multiple Life-threatening Coronary Artery Spasms after Percutaneous Coronary Intervention for Acute Coronary Syndrome.",
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"abstract": "Pisa syndrome (PS) is a state of dystonic muscle contraction with a marked truncal deviation to one side. It is an uncommon adverse effect of antipsychotic drugs, but is rarely reported in patients receiving acetylcholinesterase inhibitors, especially rivastigmine. We present a 57-year-old female patient with Alzheimer disease who began to develop symptoms of dementia at the age of 51 years. She was observed to have symptoms of PS after continuous use of rivastigmine (9 mg/d) for nearly 2 years. The PS symptoms improved after the dose of rivastigmine was reduced but recurred when the dose was added back to 9 mg/d. Finally, after we decreased the dose to 4.5 mg/d, her PS symptoms were remitted. This report reminds us that clinicians need to be cautious about the risk of PS when prescribing rivastigmine in a patient with early-onset Alzheimer disease.",
"affiliations": "Department of Psychiatry, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.",
"authors": "Hsu|Chih-Wei|CW|;Lee|Yu|Y|;Lee|Chun-Yi|CY|;Lin|Pao-Yen|PY|",
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"title": "Reversible Pisa Syndrome Induced by Rivastigmine in a Patient With Early-Onset Alzheimer Disease.",
"title_normalized": "reversible pisa syndrome induced by rivastigmine in a patient with early onset alzheimer disease"
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"abstract": "Impaired thermoregulation and heat intolerance may be intrinsic to autonomic dysfunction in Parkinson's disease due to disturbances in perspiration regulation. Thermoregulatory impairment leading to hyperthermia/heatstroke can be accentuated with the usage of anticholinergics, which block the ability to sweat. Oxybutynin chloride is one of the most used anticholinergic agents in clinical practice for the management of detrusor hyperreflexia secondary to neurogenic bladder dysfunction and is often used in the setting of Parkinson's disease. We present a rare instance of oxybutynin-induced heatstroke in an elderly patient with Parkinson's disease.",
"affiliations": "Internal Medicine, Icahn School of Medicine at Mount Sinai, Elmhurst Hospital Center, Elmhurst, USA.;Internal Medicine, Icahn School of Medicine at Mount Sinai, Elmhurst Hospital Center, Elmhurst, USA.;Internal Medicine/Nephrology, Mount Sinai Elmhurst Hospital, New York City, USA.",
"authors": "Ahmad|Saad|S|;Reyes|Jonathan Vincent M|JVM|;Lieber|Joseph|J|",
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"fulltext": "\n==== Front\nCureus\nCureus\n2168-8184\nCureus\n2168-8184\nCureus Palo Alto (CA)\n\n10.7759/cureus.14701\nInternal Medicine\nOxybutynin-Induced Hyperthermia in a Patient With Parkinson’s Disease\nMuacevic Alexander\nAdler John R\nAhmad Saad 1\nReyes Jonathan Vincent M 1\nLieber Joseph 2\n1 Internal Medicine, Icahn School of Medicine at Mount Sinai, Elmhurst Hospital Center, Elmhurst, USA\n2 Internal Medicine/Nephrology, Mount Sinai Elmhurst Hospital, New York City, USA\nSaad Ahmad sahmad9414@gmail.com\n26 4 2021\n4 2021\n13 4 e1470126 4 2021\nCopyright © 2021, Ahmad et al.\n2021\nAhmad et al.\nhttps://creativecommons.org/licenses/by/3.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.\nThis article is available from https://www.cureus.com/articles/56597-oxybutynin-induced-hyperthermia-in-a-patient-with-parkinsons-disease\nImpaired thermoregulation and heat intolerance may be intrinsic to autonomic dysfunction in Parkinson’s disease due to disturbances in perspiration regulation. Thermoregulatory impairment leading to hyperthermia/heatstroke can be accentuated with the usage of anticholinergics, which block the ability to sweat. Oxybutynin chloride is one of the most used anticholinergic agents in clinical practice for the management of detrusor hyperreflexia secondary to neurogenic bladder dysfunction and is often used in the setting of Parkinson’s disease. We present a rare instance of oxybutynin-induced heatstroke in an elderly patient with Parkinson’s disease.\n\nparkinson’s disease\nheat stroke\nanticholinergic\nhyperthermia\noxybutynin\nthermoregulation\nperspiration\nThe content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus.\n==== Body\nIntroduction\n\nThe presence of a wide array of non-motor symptoms indicates that Parkinson’s disease is not restricted to the substantia nigra or central dopaminergic system [1]. There are still debates on whether the disease originates peripherally or simply works in parallel peripherally. Morphological studies have demonstrated Lewy bodies in sympathetic trunk ganglia, cardiac nerve cells, intestinal plexus, and other areas of the peripheral nervous system [2]. Regardless of the origin of the pathology, there is no denying that the presence of autonomic failure causes a great impact on the patients’ daily function and quality of life [1]. Autonomic regulatory disorders were long considered to be a late manifestation of the disease process, however, this is no longer the case given significant evidence of autonomic dysfunction occurring prior to diagnosis [2]. Involvement of the autonomic nervous system contributes to dysfunctions in cardiovascular, urinary, sexual, gastric, and thermoregulatory systems.\n\nOver one-third of Parkinson’s disease patients can be assumed to have a thermoregulatory dysfunction with perspiration-related symptoms. Hyperhidrosis manifested as excessive sweating primarily affecting the axillae, face, palms, and soles of the feet, and hypohidrosis, a lack of sweating, have been described in current literature in patients with Parkinson's disease [3]. However, between the two perspiration-related symptoms, hyperhidrosis has been reported as a more common non-motor manifestation. Topical agents used to treat focal hyperhidrosis include aluminum chloride hexahydrate and anticholinergics [4]; oxybutynin has been proven effective in some trials, although not primarily used for this purpose [5]. The etiology behind hyperhidrosis in Parkinson’s disease is still in question as some studies suggest hyperhidrosis in axial body parts could be the expression of compensatory mechanisms for a defective submotor outflow, likely due to poor cholinergic activation in sweat glands [6].\n\nThe most used definition of heat stroke is Bouchama’s definition which defines heatstroke as a core body temperature that rises above 40 °C, often accompanied by dry skin and central nervous system abnormalities [7]. Bouchama has also stated that heatstroke is a form of hyperthermia associated with a systemic inflammatory response leading to multiorgan dysfunction. Individuals with impaired thermoregulatory sweating due to neurological disease states may be at greater risk of symptomatic anhidrosis from taking drugs with anticholinergic activity; this includes medications such as oxybutynin [8]. Peripheral blockade of muscarinic receptors in exocrine sweat glands would further contribute to impaired heat dissipation, potentially leading to the development of hyperthermia or heatstroke [9].\n\nCase presentation\n\nA 71-year-old female with a past medical history significant for Parkinson's disease presented to the emergency room with a fever and altered mental status. History of the patient was obtained from the daughter due to the patient's impairment on presentation. According to the daughter, the onset of the symptoms was first noted in the morning when the patient’s husband went to wake her up. The patient was warm and non-responsive to her family; the patient’s daughter took her oral temperature which read 107 °F, at which point the family contacted emergency medical services (EMS). As per the daughter, the patient started taking oxybutynin extended-release 5 mg oral, once daily, roughly five days prior to presentation to help with her overactive bladder. The daughter had reported that the mother had “doubled up” on some doses to alleviate her urinary symptoms. There were no reported alleviating or exacerbating factors to the patient’s condition. These symptoms never occurred prior. The patient did not complain of acute pain nor did the daughter state any knowledge of perceived pain. There was no reported history of recent travel for anyone in the family or a history of active tuberculosis. There was no prior history of hospitalizations or surgeries, drug allergies, or usage of tobacco, alcohol, or illicit substances. According to the daughter, at baseline, the patient requires assistance with basic activities due to tremors; however, the patient is generally alert and oriented with independent ambulation. The family had stated that the patient was not eating or drinking much lately. Aside from the oxybutynin, home medications included carbidopa/levodopa 192 mg, two capsules every four hours.\n\nUpon arrival to the emergency department, it was noted that the patient had an oral temperature of 106.5 °F (41.4 °C), heart rate of 145 beats/min, respiratory rate of 27 breaths/min, blood pressure of 133/87 mmHg, and oxygen saturation of 100%. The initial examination revealed that the patient was stuporous, and her skin was dry and warm to the touch. There were no signs of rigidity and her pupils were equal, round, and reactive to light bilaterally. Cardiac, respiratory, and abdominal examinations were unremarkable. Laboratory results demonstrated hyponatremia (128 mEq/L), hypokalemia (3.3 mEq/L), elevated creatine (1.32 mg/dL) with an unknown baseline, and slightly elevated lactate (2.4 mmol/L). Hematology, thyroid function, and liver function tests were normal. The blood gas demonstrated a pH of 7.482, carbon dioxide (CO2) of 17.6 mmol/L, and bicarbonate (HCO3) of 18 mmol/L. Serum creatine phosphokinase was elevated at 316 U/L, while initial magnesium and calcium concentrations were normal. Cerebrospinal fluid analysis and urinalysis were unremarkable. A portable chest X-ray and a CT head scan without contrast demonstrated no acute findings; however, imaging did demonstrate small, approximately 1 cm, bilateral frontal subdural hygromas (Figure 1). The patient’s bioreference test was negative, indicating no presence of COVID-19.\n\nFigure 1 Bilateral frontal subdural hygromas\n\n (A) Axial view and (B) sagittal view.\n\nThe patient was upgraded to the medical intensive care unit (MICU) where her temperature was decreased to normal levels using external whole-body cooling with a cooling blanket, room temperature intravenous NaCl 0.9% infusions, and acetaminophen. The patient remained in the MICU without demonstrating leukocytosis or growth in blood, urine, sputum, and cerebrospinal fluid cultures. The patient received three days of vancomycin and cefepime which were later discontinued due to no known source of infection. Throughout the course of the MICU, the patient’s electrolytes were replenished, her oxybutynin was held and she was placed on deep vein thrombosis (DVT) prophylaxis with heparin.\n\nOn the medical floors, the patient required multiple straight catheterizations due to urinary retention, as bladder scans showed 600 to 1200 mL of urine. A foley catheter was placed after urology consultation recommendation.\n\nUpon discharge, the patient was instructed to refrain from taking oxybutynin and to follow up with urology for possible alternative management.\n\nDiscussion\n\nHeatstroke is a common cause of hyperthermia and approximately 80% of deaths associated with heatstroke occur in individuals older than 50-years-old [10]. A normal body temperature is maintained at approximately 98.6 °F (37 °C) by the medial preoptic area/anterior hypothalamus through mechanisms of thermoregulation. The hypothalamic temperature-regulating center senses the temperature of the blood perfusing the brain and activates peripheral processes, predominately perspiration-related mechanisms [11]. These perspiration-related mechanisms, although effective at first, eventually cause further salt and water loss, impairing thermoregulation. Paired with shunting of blood from the central circulation to the skin and muscles, the reduced central volume leads to impaired visceral perfusion and subsequent organ failure [11]. It is important to note that most patients recover fully after a short period of hyperthermia, but patients exposed to higher temperatures for extended periods of time are more susceptible to progression to multi-organ failure and possible death. Hyperthermia, even if mild and occurring for a short period of time, may cause cognitive impairment and affect attention, memory, and information processing. Elevated temperatures have been linked to increased brain blood barrier permeability contributing to cerebral edema. Additionally, increased temperatures have been linked to decreased mitochondrial metabolism, and in the absence of elevated lactate levels, this may indicate a reduction in cerebral metabolic activity; this could manifest as cognitive and neurological symptoms [12].\n\nAs mentioned before, blood flow to central organs such as the gastrointestinal (GI) tract, is reduced in the setting of hyperthermia causing damage to cell membranes, protein denaturation, and increased production of free radicals. Overall, this loss of GI barrier integrity allows for the translocation of gut bacteria and/or endotoxins. This can lead to a systemic inflammatory cascade and multi-organ damage. Animal models have demonstrated improved survival with the initiation of antibiotics in the setting of heatstroke [12]. Although our patient did not demonstrate such, it is an important consideration for the treatment of other patients with a more septic-like picture.\n\nDysfunctions in the perspiration-related mechanisms can also predispose individuals to hypercoagulability as there is significant evidence demonstrating a link between hyperthermia and changes in coagulation. Coagulation activation was seen in human subjects with an exercise-induced elevation of the core body temperature and therapeutic hyperthermia; an increase in body temperature from 37.6 °C to 39.4 °C was associated with increased thrombin generation and impaired endogenous fibrinolysis [13]. There is accumulating evidence that extracellular DNA and DNA binding proteins, such as histones, released from nucleosomes of degraded cells may form a surface on which activated coagulation factor complexes can be assembled. Histones have been shown to activate platelets and stimulate thrombin generation. Activation and binding of neutrophils by DNA components have been shown to result in the formation of neutrophil extracellular traps which have been shown to further activate coagulation by proteolytic cleavage of physiological anticoagulants by abundant neutrophilic elastases [13]. The susceptibility to a hypercoagulable state further emphasizes the need for DVT prophylaxis in these patients.\n\nThe risk of heatstroke is increased when homeostatic mechanisms are compromised by drugs that impair perspiration or promote dehydration. These drugs include diuretics, neuroleptics, or medications with anticholinergic properties. Oxybutynin chloride is a tertiary amine compound with anticholinergic properties and is a commonly used drug known for its musculotropic relaxant activity [14]. Relative selectivity of the M3 and M1 parasympathetic muscarinic receptors allows for antispasmodic activity responsible for its relaxant effects on the detrusor muscle in many conditions such as Parkinson’s disease, allowing for increased bladder capacity and decreased frequency of uninhibited bladder contractions. Of the five types of muscarinic acetylcholine receptors, the M3 receptor is the predominant receptor subtype found in eccrine sweat glands [15]. This makes oxybutynin’s selectivity of the M3 receptor of particular importance when it comes to thermoregulation as the agent has demonstrated to be an effective alternative treatment for hyperhidrosis, which can be primary or secondary in origin [5]. Acetylcholine binds to G protein-coupled cholinergic muscarinic M3 receptors in the basolateral membrane of clear cells, activating a cascade of intracellular pathways that causes an influx of extracellular Ca+2 [8] which then leads to myoepithelial cell contraction and sweat production through subsequent efflux of K+ and Cl- ions and isotonic egress from the luminal side of the clear cell; isotonic fluid becomes hypotonic following active NaCl reabsorption in the sweat duct. A blockade of M3 receptors with the usage of oxybutynin would cause anti-perspiration effects leading to a predisposition for hyperthermia/heatstroke. This is of particular importance as some studies have demonstrated that hyperhidrosis secondary to peripheral or central nervous system abnormalities in axial body parts could lead to the expression of a compensatory mechanism for a defective submotor outflow in hands and feet. Noninvasive recordings of the galvanic potentials of the skin via the sympathetic sudomotor skin reflex response (SSR) demonstrated a lower prevalence of an N-type response waveform in Parkinson’s disease, pointing to a diminished cholinergic innervation of sweat glands [6]. This raises the question of safety when using anticholinergics in patients with Parkinson’s disease, especially individuals over the age of 50 years. The lack of acetylcholine release peripherally via an M3 blockade and poor submotor outflow puts patients at greater risk for hyperthermia and heatstroke. This was likely the mechanism that caused our patient to exhibit heatstroke.\n\nAs effective as oxybutynin, countless studies have demonstrated a significant increase in maximum plasma concentration in elderly patients with significant comorbidities, indicating a greater susceptibility for adverse events. Epidemiological studies have reported rates of 44-60% anticholinergic drug use in the elderly in an inpatient setting and 9-27% in an outpatient setting [8]. The elderly population is especially vulnerable to potential drug side effects as the elimination time of oxybutynin could be increased due to poly-pharmacy, resulting in drug interactions and/or competitions for the cytochrome P-450 CYP3A4 enzyme [8]. However, this was not the situation with our patient. It is important to know that the extended-release form allows for steady plasma concentrations by minimizing the peak and trough concentrations seen with twice-daily formulations. The difference between the two formulations is likely due to the lack of N-desethyl-oxybutynin metabolite formation in the extended-release form [14]. Most adverse events related to the administration of conventional oxybutynin have been attributed to this active metabolite which has demonstrated a high affinity for muscarinic receptors in animal models [14].\n\nDespite the anticholinergic adverse events, these “peripheral” anticholinergics are marketed as first-line treatment for overactive bladder; oxybutynin, administered orally or via a transdermal patch, is the most studied out of all these agents. Other effective agents include tolterodine, solifenacin, and darifenacin [1]. The efficacy of other agents, such as alpha-adrenoreceptor antagonists, is not supported by a high level of evidence [16]. Although oxybutynin is linked to adverse reactions (such as constipation, headaches, dry mouth, thermoregulatory dysfunction), the timing, dosage, and route of administration are key to the effective and optimal management of patients with avoidance of adverse effects.\n\nAs mentioned before, the medial preoptic area/anterior hypothalamus is responsible for controlling the core temperature at which sweating commences. This thermoregulatory set point is finely regulated and subject to the influence of numerous medications. Given the juxtaposition of the medial preoptic area to the suprachiasmatic nucleus of the hypothalamus, there is a circadian rhythm of body temperature in which the threshold for the onset of sweating is lowest around 2 am [17]. The timing of agents such as oxybutynin in relation to this circadian rhythm, as well as differences in bioavailability and pharmacodynamic half-life dependent on formulations, may result in variable alteration in an individual sweating response. In this case, the timing in which the patient had taken her medication may have predisposed her to heatstroke. As mentioned before, the extended-release allows for steady plasma concentrations by minimizing the peak and trough concentrations seen with twice-daily formulations. Usage of the extended-release formulation would be the safer option in elderly individuals and would less likely interfere with the circadian rhythm of temperature regulation if given at an appropriate time. However, it is important to note that the patient did double her medication dosage without proper medical advice. Timing along with increased dosage, even if it was the extended-release, could have been a contributing factor to the patient’s overall presentation.\n\nRegarding routes of administration, a large, randomized double-blinded study compared transdermal oxybutynin to a placebo. The transdermal route of oxybutynin was associated with reduced micturition frequency and increased voided volumes. Side effects of the transdermal form were primarily related to the site of administration. Dry mouth, and other common side effects associated with the oral formulation, were less common in the application of the transdermal formulation [18]. Although the oral route is the most thoroughly evaluated and commonly used form, this trial and others shed light on the possibility of using the transdermal route to reduce or avoid major adverse reactions.\n\nThe patient’s electrolyte abnormalities could have been contributed by thermal dysregulation, oxybutynin usage, and poor diet. The patient’s blood gas demonstrated the presence of a likely acute respiratory alkalosis in the setting of hyperventilation with metabolic compensation. A possible explanation for the abnormal blood gas could be hyperthermia-induced hyperventilation to help cool the elevated temperatures detected by the brain [19]. There was also a slight elevation of creatine phosphokinase noted upon initial lab draw, likely due to the elevated temperatures.\n\nIt is important to note that this case had occurred during the month of July on a particular day that was hot and humid. These weather conditions could have been a contributing factor to the patient’s overall presentation. In addition, patients older than 65 years are at an increased risk for a heat-related illness especially with insufficient fluids and anticholinergic usage.\n\nConclusions\n\nConditions that affect thermoregulation, such as Parkinson’s disease, are known to lead to a predisposition for hyperthermia and heatstroke. Heatstroke accounts for significant morbidity and mortality in those who have not been treated promptly. It is critical to initiate cooling and observe patients for end-organ damage. The risk of heatstroke is increased when homeostatic mechanisms are compromised by drugs that impair perspiration. Drugs with anticholinergic properties, such as oxybutynin, are among these medications. Clinicians should use caution and warn patients about the dangers of using drugs that could impair thermoregulation. Effective teaching can lead to proper usage of the medication and help prevent the adverse effects of hyperthermia and heatstroke. Different routes of administration, dosages, and timings of administration for the medication should be explored and adjusted to fit the needs of the patient.\n\nHuman Ethics\n\nThe authors have declared that no competing interests exist.\n\nConsent was obtained or waived by all participants in this study\n==== Refs\nReferences\n\n1 Treatment of dysautonomia associated with Parkinson’s disease Parkinsonism Relat Disord Mostile G Jankovic J 224 232 15 2009\n2 Autonomic dysfunction in Parkinson's disease: cardiovascular symptoms, thermoregulation, and urogenital symptoms Int Rev Neurobiol Jost WH 771 785 134 2017 28805582\n3 Sweating dysfunction in Parkinson's disease Mov Disord Swinn L Schrag A Viswanathan R Bloem BR Lees A Quinn N 1459 1463 18 2003 14673882\n4 Disease-oriented approach to botulinum toxin use Toxicon Jankovic J 614 623 54 2009 19073203\n5 Oxybutynin as an alternative treatment for hyperhidrosis An Bras Dermatol Delort S Marchi E Corrêa MA 217 220 92 2017 28538882\n6 Hyperhidrosis in Parkinson's disease Mov Disord Schestatsky P Valls-Solé J Ehlers JA Rieder CR Gomes I 1744 1748 21 2006 16773622\n7 Heat stroke N Engl J Med Bouchama A Knochel JP 1978 1988 346 2002 12075060\n8 Drug-induced hyperhidrosis and hypohidrosis: incidence, prevention and management Drug Saf Cheshire WP Fealey RD 109 126 31 2008 18217788\n9 Heat stroke during treatment with olanzapine, trihexyphenidyl, and trazodone in a patient with schizophrenia Acta Neuropsychiatr Lee CP Chen PJ Chang CM 380 385 27 2015 26503496\n10 Heat stroke N Engl J Med Clowes GH Jr O'Donnell TF Jr 564 567 291 1974 4604525\n11 Heat stroke J Intensive Care Hifumi T Kondo Y Shimizu K Miyake Y 30 6 2018 29850022\n12 The neurological and cognitive consequences of hyperthermia Crit Care Walter EJ Carraretto M 199 20 2016 27411704\n13 Hemostasis and thrombosis in extreme temperatures (hypo- and hyperthermia) Semin Thromb Hemost Levi M 651 655 44 2018 29920620\n14 Oxybutynin in detrusor overactivity Urol Clin North Am Diokno A Ingber M 439 0 439-45, vii 33 2006 17011379\n15 In vivo studies on receptor pharmacology of the human eccrine sweat gland Clin Auton Res Low PA Opfer-Gehrking TL Kihara M 29 34 2 1992 1638102\n16 Pharmacological treatment of overactive bladder: report from the International Consultation on Incontinence Curr Opin Urol Andersson KE Chapple CR Cardozo L 380 394 19 2009 19448545\n17 Circadian rhythm in sweating and cutaneous blood flow Am J Physiol Stephenson LA Wenger CB O'Donovan BH Nadel ER 0 4 246 1984\n18 Transdermal oxybutynin: for overactive bladder Drugs Aging Bang LM Easthope SE Perry CM 857 864 20 2003 12964892\n19 Characteristics of hyperthermia-induced hyperventilation in humans Temperature (Austin) Tsuji B Hayashi K Kondo N Nishiyasu T 146 160 3 2016 27227102\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2168-8184",
"issue": "13(4)",
"journal": "Cureus",
"keywords": "anticholinergic; heat stroke; hyperthermia; oxybutynin; parkinson’s disease; perspiration; thermoregulation",
"medline_ta": "Cureus",
"mesh_terms": null,
"nlm_unique_id": "101596737",
"other_id": null,
"pages": "e14701",
"pmc": null,
"pmid": "34055543",
"pubdate": "2021-04-26",
"publication_types": "D002363:Case Reports",
"references": "16773622;6703085;12075060;29920620;19448545;20082997;14673882;28538882;1638102;28805582;12964892;17011379;18217788;29850022;26503496;27227102;4604525;27411704;19073203",
"title": "Oxybutynin-Induced Hyperthermia in a Patient With Parkinson's Disease.",
"title_normalized": "oxybutynin induced hyperthermia in a patient with parkinson s disease"
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"companynumb": "US-BION-009832",
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"activesubstancename": "OXYBUTYNIN CHLORIDE"
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"abstract": "Remdesivir is the only antiviral approved for lower respiratory tract infection produced by SARS-CoV-2. The main objective of this study was to determine the mortality rate, readmissions, mean hospital stay, need for higher levels of oxygen support, and adverse effect-induced abandonment rate in hospitalized patients diagnosed with COVID-19 and treated with remdesivir (RDSV). The secondary objective was to determine mortality-related risk factors in these patients.The study included a prospective cohort of patients admitted to a third level Spanish hospital between July 5, 2020 and February 3, 2021 for COVID-19 diagnosed by SARS-CoV-2 polymerase chain reaction and/or antigen test and treated with RDSV.Remdesivir was received by 185 patients (69.7% males) with a mean age of 62.5 years, median Charlson index of 3 (interquartile range [IQR]: 1-4), and median ambient air oxygen saturation of 91% (IQR: 90-93); 61.6% of patients had hyper-inflammatory syndrome at admission. Median time with symptoms before RDSV treatment was 5 days (IQR: 3-6) and the median hospital stay was 10 days (IQR: 7-15); 19 patients (10.3%) died after a median stay of 13.5 days (IQR: 9.7-24 days), 58 patients (12.9%) were admitted to ICU, 58 (31.4%) needed higher levels of oxygen support, 0.5% abandoned the treatment due to adverse effects, and there were no readmissions. The only mortality-related factor was the need for higher levels of oxygen support (odds ratio 12.02; 95% confidence interval 2.25-64.2).All studied patients were admitted to hospital with a diagnosis of COVID-19 and in respiratory failure, needing initial low-flow oxygen support, and all received RDSV within 1 week of symptom onset. The percent mortality was lower in these patients than was observed in all patients with severe COVID-19 admitted to our center (10.3% vs 20.3%, respectively). Despite receiving RDSV, 1 in 3 patients needed higher levels of oxygen support, the sole mortality-related factor.",
"affiliations": "Unit of Infectious Diseases, Virgen de las Nieves University Hospital/Instituto de Investigación Biosanitario (IBS)-Granada, Spain.",
"authors": "Hidalgo-Tenorio|Carmen|C|;García-Vallecillos|Coral|C|;Sequera-Arquelladas|Sergio|S|;|||",
"chemical_list": "D000998:Antiviral Agents; C000606551:remdesivir; D000249:Adenosine Monophosphate; D000409:Alanine",
"country": "United States",
"delete": false,
"doi": "10.1097/MD.0000000000027228",
"fulltext": "\n==== Front\nMedicine (Baltimore)\nMedicine (Baltimore)\nMEDI\nMedicine\n0025-7974\n1536-5964\nLippincott Williams & Wilkins Hagerstown, MD\n\nMD-D-21-03827\n10.1097/MD.0000000000027228\n27228\n4900\nResearch Article\nObservational Study\nReal-world outcomes of COVID-19 treatment with remdesivir in a Spanish hospital\nHidalgo-Tenorio Carmen MD, PhD ∗\nGarcía-Vallecillos Coral Pharm\nSequera-Arquelladas Sergio Pharm\non behalf of COVID-19 Virgen de las Nieves TEAM\nElesela. Srikanth\nUnit of Infectious Diseases, Virgen de las Nieves University Hospital/Instituto de Investigación Biosanitario (IBS)-Granada, Spain.\n∗ Correspondence: Carmen Hidalgo-Tenorio, Unidad de Enfermedades Infecciosas, Hospital Universitario Virgen de las Nieves, Av. de las Fuerzas Armadas n2, 18014 Granada, España (e-mail: chidalgo72@gmail.com).\n17 9 2021\n17 9 2021\n17 9 2021\n100 37 e2722825 5 2021\n17 8 2021\n23 8 2021\nCopyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.\n2021\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0\nThis article is made available via the PMC Open Access Subset for unrestricted re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the COVID-19 pandemic or until permissions are revoked in writing. Upon expiration of these permissions, PMC is granted a perpetual license to make this article available via PMC and Europe PMC, consistent with existing copyright protections.\n\nAbstract\n\nRemdesivir is the only antiviral approved for lower respiratory tract infection produced by SARS-CoV-2. The main objective of this study was to determine the mortality rate, readmissions, mean hospital stay, need for higher levels of oxygen support, and adverse effect-induced abandonment rate in hospitalized patients diagnosed with COVID-19 and treated with remdesivir (RDSV). The secondary objective was to determine mortality-related risk factors in these patients.\n\nThe study included a prospective cohort of patients admitted to a third level Spanish hospital between July 5, 2020 and February 3, 2021 for COVID-19 diagnosed by SARS-CoV-2 polymerase chain reaction and/or antigen test and treated with RDSV.\n\nRemdesivir was received by 185 patients (69.7% males) with a mean age of 62.5 years, median Charlson index of 3 (interquartile range [IQR]: 1–4), and median ambient air oxygen saturation of 91% (IQR: 90–93); 61.6% of patients had hyper-inflammatory syndrome at admission. Median time with symptoms before RDSV treatment was 5 days (IQR: 3–6) and the median hospital stay was 10 days (IQR: 7–15); 19 patients (10.3%) died after a median stay of 13.5 days (IQR: 9.7–24 days), 58 patients (12.9%) were admitted to ICU, 58 (31.4%) needed higher levels of oxygen support, 0.5% abandoned the treatment due to adverse effects, and there were no readmissions. The only mortality-related factor was the need for higher levels of oxygen support (odds ratio 12.02; 95% confidence interval 2.25–64.2).\n\nAll studied patients were admitted to hospital with a diagnosis of COVID-19 and in respiratory failure, needing initial low-flow oxygen support, and all received RDSV within 1 week of symptom onset. The percent mortality was lower in these patients than was observed in all patients with severe COVID-19 admitted to our center (10.3% vs 20.3%, respectively). Despite receiving RDSV, 1 in 3 patients needed higher levels of oxygen support, the sole mortality-related factor.\n\nKeywords\n\nCOVID-19\nreal-world data\nRemdesivir\nSARS-CoV-2\nOPEN-ACCESSTRUE\n==== Body\npmc1 Introduction\n\nOn December 31, 2019, the World Health Organization (WHO) reported the first case of pneumonia produced by a beta coronavirus similar to Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) and Middle East Respiratory Syndrome (MERS-CoV), designated as SARS-CoV-2. After the global spread of this virus, initially detected in Wuhan (China), it was named “coronavirus disease 2019” (COVID-19) by the WHO on February 11, 2020.[1] The first case in Spain was reported on January 31, 2020 in the Mediterranean island of Gomera and the second on March 8 in the province of Granada (Southern Spain). In April 2021, it was estimated that the virus had been responsible for 136 million infections and almost 3 million deaths worldwide.[2] Spain has the 9th highest number of notified infections, with an infection prevalence of 2.5%, and around 2 million individuals have been infected to date and >75,000 have died.[2] More than 76,000 infections and 1632 deaths due to COVID-19 have been recorded in the province of Granada.[3]\n\nThe only antiviral so far approved to treat COVID-19 is the prodrug remdesivir (RDSV), an adenosine nucleoside analog (GS-5734) with broad activity against a wide range of RNA viruses, including those of the Paramyxoviridae, Coronaviridae, and Filoviridae families. It directly inhibits viral transcription and replication by acting on RNA polymerase.[4,5] The ACTT-1 trial run by the National Institute of Allergies and Infectious Diseases of North America found that treatment with RDSV versus placebo significantly shortened hospital stay, improved clinical status, diminished the need for higher levels of oxygen (O2) support, and reduced the mortality rate in patients requiring low-flow O2.[6]\n\nThe objectives of this study were: to determine outcomes in RDSV-treated patients with severe COVID-19, including hospital stay, ICU admission, need for further higher levels of O2 support, mortality, and readmission and to determine mortality-related factors in these patients.\n\n2 Patients and methods\n\n2.1 Study design and setting\n\nThis retrospective study included consecutive patients admitted for COVID-19 and treated with RDSV in a third-level Spanish hospital between July 5, 2020 and February 3, 2021. The pharmacy computer program of the center (PRISMA ATHOS) was used to enroll the patients.\n\nInclusion criteria were: age >18 years; hospital admission for polymerase chain reaction (PCR)-diagnosed SARS-CoV-2 after ≤7 days with symptoms; meeting at least 2 of the following criteria: respiratory rate ≥24 bpm, O2 saturation <94% in ambient air, and/or ratio of arterial O2 partial pressure to inspired O2 (PaO2/FiO2) <300 mmHg; receipt of at least 1 dose of RDSV during the study period after meeting the following Spanish Health Ministry criteria for its administration, that is, need for low-flow O2 therapy (via nasal cannula or simple face mask, with or without reservoir).[7]\n\nExclusion criteria were: severe disease requiring noninvasive ventilation or high-flow O2 therapy, invasive mechanical ventilation, or extracorporeal membrane O2, the presence of severe liver disease (alanine aminotransfresase or aspartate amonotransferase values ≥5-fold the upper limit of normality or severe renal failure (glomerular filtration <30 mL/min); treatment with hemodialysis or peritoneal dialysis; the need for 2 inotropic agents to maintain arterial blood pressure; pregnancy; breastfeeding status; positive pregnancy test; and evidence of multiple organ failure.\n\nThe study was approved by the ethics committee of the hospital, which waived the need for informed consent due to its retrospective and observational design. All information was treated in accordance with Spanish data protection legislation (Law 3/2018, December 5).\n\n2.2 Treatment\n\nRDSV was administered following a local protocol based on recommendations from scientific societies and the literature: day 1, bolus dose of 200 mg/iv; days 2 to 5, dose of 100 mg/iv/24 h. The treatment could be prolonged beyond 5 days if deemed appropriate by the attending clinician.\n\n2.3 Study variables\n\nPatient epidemiological, clinical, and analytical data were gathered from the DIRAYA computer program of the Public Health System of Andalusia. Information was gathered on age, sex, comorbidities, age-adjusted Charlson comorbidity index, days of hospital stay, days with symptoms before admission, symptomatology, ambient air O2 saturation, respiratory rate, SARS-CoV-2 diagnosis by PCR or antigen test, C-reactive protein (CRP) level (as qualitative variable [elevated vs normal] and quantitative variable [mg/dL]); lymphocytopenia (qualitative and quantitative [cells/mL]), thrombocytopenia (qualitative), anemia (qualitative), ferritin (qualitative [< vs ≥ 500 mg/dL] and quantitative [mg/dL]), and d-dimer (qualitative [< vs ≥ 0.5 ng/mL] and quantitative [ng/mL]). The following RDSV-related variables were also collected: days of administration, bolus, and total dose (in milligrams); treatment abandonment and reasons; days between symptom onset and RDSV administration; COVID-19 diagnosis by PCR and/or antigen test; need for higher levels of O2 support, need for ICU admission (whether or not actually admitted); mortality; and readmission within 30 days post-discharge.\n\nInformation was also collected from the daily report issued by the Department of Preventive Medicine of the hospital on all patients admitted with confirmed or suspected COVID-19 between July 5, 2020 and February 3, 2021, the hospital stay, mortality, discharge, and readmission by care area (normal ward or ICU) (https://www.huvn.es).\n\n2.4 Definition of variables\n\nCOVID-19: coronavirus infectious disease-2019 pneumonia produced by coronavirus SARS-CoV-2 with pulmonary infiltrates and microbiological confirmation by PCR and/or antigen test.\n\nHyperinflammatory syndrome or cytokine storm: the presence of pneumonia with SpO2 <93% accompanied by ≥2 of the following criteria: temperature >38°C, respiratory rate >24 bpm, PO2/FiO2 <300; and at least one of the following criteria: IL-6 >40 ng/L, d-dimer >1 mg/L, and ferritin >300 μg/L.[8]\n\nNeed for higher levels of O2 support: requirement for patient to move from support with low-flow O2 to high-flow nasal cannula (HFNC), noninvasive/invasive mechanical ventilation, or extracorporeal membrane oxygenation.[6]\n\n2.5 Sample size\n\nA sample size of at least 151 patients was estimated to obtain an accuracy of 5% in the estimation of a proportion by means of a normal 95% CI, assuming that the proportion was 91% (effectiveness reported in the previous study) and assuming possible losses of 20%.\n\n2.6 Statistical analysis\n\nFirst, means and standard deviations were calculated for quantitative variables. Student t test was then applied for independent variables when they were normally distributed (Kolmogorov-Smirnov test) and the Mann–Whitney U test when they were not. Absolute and relative frequencies were calculated for qualitative variables followed by application of Pearson χ2 test or Fisher χ2 test, as appropriate. Next, multivariate logistic regression analyses were conducted using Freeman formula [n = 10 × (k+1)],[9] entering variables that were significant in bivariate analyses by means of a stepwise approach, with significance levels of 0.05 for entry and 0.10 for exit. The Hosmer-Lemeshow test was used to analyze the goodness of fit of the models. A significance level of 0.05 was considered for all tests. SPSS 21.0 was used for the statistical analysis (SPSS Inc, Chicago, IL).\n\n3 Results\n\n3.1 Study population\n\nBetween July 5, 2020 and February 3, 2021, two thousand six hundred nineteen patients were admitted to our hospital for microbiologically confirmed COVID-19. The present sample comprised 185 (7.1%) of these patients who were treated with RDSV, with a mean age of 62.5 years: 69.7% were male, 84.9% had comorbidities, and their median Charlson index score was 3 (interquartile range [IQR]: 1–4). Table 1 displays results for the remaining variables. As shown in Table 2, the median number of days with symptoms before admission was 5 (IQR: 4–5) and the most frequent symptom was fever (81.6%), followed by cough (72.4%) and dyspnea (69.7%). SARS-CoV-2 diagnosis was by PCR alone in 84.3% and by antigen test subsequently confirmed by PCR in 28.6%. CRP was elevated in 96.2%, ferritin was >500 mg/dL in 60%, D-dimer was >1 ng/mL in 58.4%, lymphopenia was present in 55.7%, and hyperinflammatory syndrome in 61.6% (Table 2).\n\nTable 1 Baseline characteristics of the cohort.\n\nBaseline characteristics\tN = 185\t\nAge, y, median (±SD)\t62.5 (13.16)\t\nSex\t\n Female, n (%)\t56 (30.3)\t\n Male, n (%)\t129 (69.7)\t\nComorbidities, n (%)\t157 (84.9)\t\nCharlson index, median (p25–p75)\t3 (1–4)\t\nArterial hypertension, n (%)\t98 (53)\t\nDiabetes Mellitus, n (%)\t55 (29.7)\t\nBody mass index >25, n (%)\t34 (18.4)\t\nHeart failure, n (%)\t14 (7.6)\t\nCOPD, n (%)\t23 (12.4)\t\nRenal insufficiency grade 3–4, n (%)\t3 (1.6)\t\nSolid organ neoplasia, n (%)\t16 (8.6)\t\nHematological neoplasia, n (%)\t0\t\nHematological transplant\t0\t\nSolid organ transplant\t1 (0.5)\t\nCOPD = chronic obstruction pulmonary disease.\n\nTable 2 Clinical manifestations and analytical results.\n\n\tN = 185\t\nDays with symptoms, median (p25–p75)\t4 (3–6)\t\nSymptoms\t\t\nFever, n (%)\t151 (81.6)\t\nDyspnea, n (%)\t129 (69.7)\t\nAsthenia, n (%)\t114 (61.6)\t\nCough, n (%)\t134 (72.4)\t\nMyalgia, general discomfort, n (%)\t77 (41.6)\t\nDiarrhea, n (%)\t40 (21.6)\t\nAnosmia, n (%)\t14 (7.6)\t\nDysgeusia, n (%)\t15 (8.1)\t\nRespiratory rate, median (P25–P75)\t24 (24–26)\t\nRespiratory rate ≥22 bpm, n (%)\t102 (55.1)\t\nSO2 AA, median, (P25–P75)\t91 (90–93)\t\nSO2 < or = 93%, n (%)\t131 (70.8)\t\nCOVID-19 diagnosis\t\t\nSARS-CoV-2 PCR, n (%)\t156 (84.3)\t\nSARS-CoV-2 Ag and PCR, n (%)\t53 (28.6)\t\nAnalytical disorders\t\t\nElevated C-reactive protein, n (%)\t178 (96.2)\t\nC-Reactive protein, mg/dL, mean (±SD)\t106.9 (94.6)\t\nFerritin >500, n (%)\t111 (60)\t\nFerritin, mg/dL, mean (±SD)\t1033.9 (1044.9)\t\nd-dimer>1 mg/L, n (%)\t108 (58.4)\t\nd-dimer, mg/L, mean (±SD)\t1.2 (3.06)\t\nLymphopenia, n (%)\t103 (55.7)\t\nAnemia, n (%)\t85 (45.9)\t\nThrombopenia, n (%)\t15 (8.1)\t\nIL-6 >40, n (%)\t23/49 (46.9)\t\nHyperinflammatory syndrome, n (%)\t114 (61.6)\t\nIL-6 = interleukinn 6, SD = standard deviation.\n\nAmong the 3172 patients admitted to our center with COVID-19 between March 8, 2020 and February 3, 2021, the mean stay in normal ward was 10.6 days, with a crude mortality rate of 20.3%, and the mean stay in ICU was 18.3 days, with a mortality rate of 32.5%. Of these patients, 369 (10.2%) were admitted to the ICU, mainly to receive invasive or noninvasive mechanical ventilation or HFNC.\n\n3.2 Remdesivir treatment outcomes\n\nA median of 1 day (IQR: 1–2) elapsed between COVID-19 diagnosis and RDSV administration and a median of 5 days (4–7 days) between symptom onset and RDSV receipt. Nineteen (10.3%) patients died a median of 13.5 days (IQR: 9.7–24) after hospital admission, with 2 in septic shock. The attending physician requested ICU referral for 40 (21.6%) patients but only 24 (12.9%) were actually admitted, with admission being refused for 16 patients (8.6%) due to their present or previous clinical status. Higher levels of O2 support were required by 58 patients (31.4%). RDSV was suspended in 1 patient (0.5%) due to transaminase level 5-fold above normal value. No patient (0%) was readmitted (Table 3).\n\nTable 3 Remdesivir treatment and outcomes.\n\n\tN = 185\t\nDays between RDSV administration and positive diagnostic test, median (p25-p75)\t1 (1–2)\t\nDays between RDSV administration and symptom onset, median (p25–p75)\t5 (4–7)\t\nDays of RDSV administration, median (IQR)\t5 (5–5)\t\nTotal dose of RDSV administered, mg (±SD)\t524.3 (109.9)\t\nFive-day course of RDSV not completed, n (%)\t15 (8.1%)\t\nWithdrawn after admissionto ICU, n (%)\t8 (4.3%)\t\nDeath, n (%)\t2 (1.08)\t\nImprovement in <5 days, n (%)\t3 (1.6)\t\nALT >5-fold above normal value, n (%)\t1 (0.5)\t\nWithdrawn by attendingphysician due to respiratory overinfection, n (%)\t1 (0.5)\t\nDays of hospital stay, median (p25–p75)\t10 (7–15)\t\nDeath, n (%)\t19 (10.3)\t\nCOVID-19 with septic shock, n (%)\t2 (1.1)\t\nDays between first RDSV dose and death, median (p25–p75)\t12.5 (7–23.5)\t\nDays of hospital stay before death, median (p25–p75)\t13.5 (9.7–24)\t\nNeed for ICU admission despite RDSV, n (%)\t40 (21.6)\t\nAdmitted, n (%)\t24 (12.9)\t\nRequested admission not accepted due to clinical status of patient, n (%)\t16 (8.6)\t\nNeed for higher levels of oxygen support after receiving RDSV, n (%)\t58 (31.4)\t\nAdverse effects causing RDSV withdrawal, n (%)\t\t\nAST elevation\t1 (0.5)\t\nReadmissions, n (%)\t0\t\nALT = alanine aminotransfresase, AST = aspartate aminotransferase, ICU = intensive care unit, IQR = interquartile range, RDSV = Remdesivir.\n\n3.3 Mortality risk factors in the RDSV Cohort\n\nIn the bivariate analysis of results for the RDSV cohort (Table 4), mortality was significantly related to: older age (68.2 vs 61.9 years, P = .049); higher median Charlson index score (4 [IQR: 3.5–5] vs 2.5 [IQR: 1–4], P = .002); longer mean hospital stay (15 vs 10 days, P = .028); the presence of lymphopenia (89.5 vs 51.8%; P = .002), thrombopenia (21.1 vs 6.6%), or hyperinflammatory syndrome (89.5 vs 58.4%, P = .008); elevated CRP (154.3 vs 101 mg/dL); need for ICU admission (63 vs 16.9%, P = .0001); actual ICU admission (42.1 vs 7.8%, P = .0001); and need for higher levels of O2 support (84.2 vs 25.3%, P = .0001) (Table 4). In the multivariate analysis, the only variable significantly related to mortality was the need for higher levels of O2 support, that is, invasive or noninvasive mechanical ventilation or HFNC (odds ratio [OR] 12.02; 95% confidence interval [CI] 2.25–64.2) (Table 4).\n\nTable 4 Results of bivariate and multivariate analyses of mortality risk factors.\n\n\tSurvival, N = 166\tDeath, N = 19\tP ∗\tOR (95% CI)\t\nAge, mean (±SD)\t61.9 (12.9)\t68.2 (14.6)\t.049\t1.02 (0.95–1.09)\t\nSex\t\t\t\t\t\n Female, n (%)\t50 (30.1)\t6 (31.6)\t.89\t\t\n Male, n (%)\t116 (69.9)\t13 (68.4)\t\t\t\nComorbidities, n (%)\t138 (83.1)\t19 (100)\t.08\t\t\nCharlson index\t2.5 (1–4)\t4 (3.5–5)\t.002\t1.57 (0.96–2.57)\t\nBMI >25, n (%)\t29 (17.5)\t5 (26.3)\t.35\t\t\nDiabetes mellitus, n (%)\t48 (28.9)\t7 (36.8)\t.47\t\t\nArterial hypertension, n (%)\t88 (53)\t10 (52.6)\t.98\t\t\nHeart failure, n (%)\t11 (6.6)\t3 (15.8)\t.16\t\t\nCOPD, n (%)\t20 (12.1)\t3 (15.8)\t.71\t\t\nRenal insufficiency grade 3–4, n (%)\t3 (1.8)\t0\t1\t\t\nSolid neoplasia, n (%)\t13 (7.8)\t3 (15.8)\t.22\t\t\nSolid organ transplantation, n (%)\t1 (0.6)\t0\t1\t\t\nDays of hospital stay, median (P25–P75)\t10 (7–15)\t15 (9–24)\t.028\t0.97 (0.91–1.04)\t\nNeed for ICU admission, n (%)\t28 (16.9%)\t12 (63%)\t.0001\t3.81 (0.71–20.39)\t\nICU admission, n (%)\t13 (7.8)\t8 (42.1)\t.0001\t1.66 (0.22–12.64)\t\nLymphopenia, n (%)\t86 (51.8)\t17 (89.5)\t.002\t11.9 (0.79–181.3)\t\nLymphopenia, cells/mL, mean (±SD)\t1033 (488)\t806 (548)\t.062\t2.5 (0.32–18.4)\t\nAnemia, n (%)\t73 (44)\t12 (63.2)\t.11\t\t\nThrombopenia, n (%)\t11 (6.6)\t4 (21.1)\t.052\t0.5 (0.11–2.38)\t\nElevated CRP, n (%)\t159 (95.8)\t19 (100)\t1\t\t\nCRP, mg/dL, mean (±S),\t101.5 (90.2)\t154.3 (119.1)\t.023\t0.99 (0.99–1.005)\t\nd-dimer >1, n (%)\t97 (59.9)\t11 (57.9)\t.9\t\t\nFerritin >500, n (%)\t98 (59)\t13 (68.4)\t.43\t\t\nHyperinflammatory syndrome, n (%)\t97 (58.4)\t17 (89.5)\t.008\t1.35 (0.192–9.5)\t\nNeed for higher levels of O2 support, n (%)\t42 (25.3)\t16 (84.2)\t.0001\t12.02 (2.25–64.2)\t\nDays with symptoms before RDSV, median (p25–p75)\t5 (4–7)\t5 (5–6.5)\t.103\t\t\nDays between diagnosis and RDSV administration, median (p25–p75)\t1 (1–2)\t2 (1–5)\t.62\t\t\nDays of RDSV administration\t5 (5–5)\t5 (5–5)\t.62\t\t\nBolus dose not administered (n = 170), n (%)\t73 (47.1)\t9 (60)\t.34\t\t\nTotal milligrams of RDSV, mean (±SD)\t529.5 (105.7)\t478.9 (135.7)\t.057\t1 (0.99–1.005)\t\nBMI = body mass index, CI = confidence interval, CRP = C-reactive protein, OR = odds ratio, RDSV = Remdesivir.\n\n∗ P < .005.\n\n4 Discussion\n\nThis study in a Spanish hospital contributes evidence supporting the clinical benefit of the early administration of RDSV in patients admitted to hospital with COVID19 who require low-flow O2 support.\n\nThe COVID-19 patients treated with RDSV in our hospital were typically male sexagenarians with comorbidities, most frequently hypertension, diabetes, and overweight. A meta-analysis of 22 studies in patients with COVID-19 found that 40.8% of the patients with COVID-19 had comorbidities and that the mortality rate was 74.3% in this subpopulation; the most prevalent comorbidity was hypertension, followed by diabetes.[10] These conditions are known to upregulate expression of the ACE-2 receptor, increasing the release of proprotein convertase and thereby favoring entry of the virus into host cells.[11]\n\nAll of the present series of patients had experienced symptoms for less than one week, most frequently fever and cough, and more than three-fifths met the diagnostic criteria for hyperinflammatory syndrome. Almost all patients had elevated CRP levels, and more than half had ferritin levels above 500 mg/dL, d-dimer levels >1 ng/mL, and lymphocytopenia. The hyperinflammatory syndrome is attributable to a cytokine storm, most frequently observed within 1 week of symptom onset. It is associated with increased mortality in these patients through the excess production of proinflammatory cytokines. This leads to the aggravation of adult respiratory distress syndrome, which is present in around 15% of COVID-19 patients and responsible for generalized tissue damage, multiple organ failure, and death.[12] Poor prognostic factors identified in a study of 1449 hospitalized patients with COVID-19 included older age and elevated CRP, d-dimer, and lactate dehydrogenase levels, among others.[13]\n\n10% of the RDSV-treated patients in the present investigation did not complete the minimum five days of treatment recommended. Nevertheless, the mean hospital stay of treated patients was only 10 days, 1 patient alone abandoned the treatment, no patient was readmitted, and the mortality was around 10%, much lower than the mortality rate for all COVID-19 patients admitted to our center during the study period. The mortality of RDSV-treated patients was significantly related to the need for higher levels of O2 support. These findings are in line with the results of the double-blind, randomized, multicenter ACTT-1 trial, which compared 541 RDSV-treated patients with 521 placebo-treated patients. RDSV treatment was found to shorten the time to recovery by 5 to 7 days (according to the disease severity), reduce the need for mechanical ventilation by 43%; increase clinical improvement by 50%, and reduce mortality by 70% in patients needing only low-flow O2.[6] In contrast, the WHO-promoted Solidarity clinical trial reported that RDSV treatment did not reduce the mortality, need for mechanical ventilation, or hospital stay.[14] This discrepancy may be explained by the open and non–placebo-controlled design of the Solidarity trial and by the fact that they only compared between ventilated and nonventilated patients. The nonventilated group included not only patients who did not receive O2 support but also those requiring low-flow and high-flow support, associated with different degrees of severity and distinct prognoses. Importantly, the time interval between symptom onset and RDSV administration was not reported, and the drug is known to lose effectiveness from day 11 or 12. Finally, the hospital stay was only calculated indirectly and may have been overestimated, given that recovered patients had to remain hospitalized for 10 days to complete the RDSV schedule.\n\nThe present findings are in line with the results of another randomized open trial in hospitalized patients with moderate COVID-19 pneumonia (pulmonary infiltrates and SpO2 >94%), which observed a superior clinical status on day 11 after symptom onset in those administered with RDSV for 5 days than in those receiving standard care (OR, 1.65; 95% CI, 1.09–2.48; P = .02).[15] However, a randomized, double-blind, placebo-controlled, multicenter trial in China found no difference in mortality, recovery, or hospital stay between 158 COVID-19 patients treated with RDSV and 79 who received placebo, attributed by the authors to the late initiation of the RDSV treatment, which started on day 11 after symptom onset (IQR: 9–12).[16] The latter findings are not comparable with the present results, which were obtained in patients with severe COVID-19 who received RDSV within the first week (mean of 5 days). The early administration of RDSV appears essential to reduce viral replication, the progression of respiratory distress, and the risk of death. RDSV also demonstrated effectiveness when administered on a compassionate-use basis to 53 patients admitted to the ICU with severe COVID-19 (57% initially on mechanical ventilation and 8% on extracorporeal membrane oxygenation); during the 18-week follow-up period, 57% of the patients were extubated, 47% were discharged, and 13% died.[17]\n\nStudy limitations include the retrospective cohort design and the restriction of RDSV treatment to patients meeting Spanish Health Ministry criteria for its use, limiting the extrapolation of results to other types of patients with COVID-19. The strengths of our study include the large sample size, the standardized treatment protocol applied to all patients, and the reliability of the treatment information, being based on computerized systems that avoid the possibility of missing data.\n\n5 Conclusion\n\nRemdesivir was administered to our patients within 24 hours of a COVID-19 diagnosis and after a median of 5 days with symptoms. All patients initially required low-flow O2, and one-third needed high-flow O2 support. One-fifth of the patients required ICU admission and one-tenth of the patients died during the first 2 weeks of hospitalization, much lower than the global mortality rate for patients with COVID-19 admitted to our center. The sole factor related to mortality was the need for higher levels of O2 support.\n\nAcknowledgments\n\nThe authors thank all the staff and “COVID-19 Virgen de las Nieves TEAM” from the University Hospital “Virgen de las Nieves” in Granada, for their immense effort and job carried out in this pandemic; as well as patients and families for their patience and resistance, and especially to those who lost their lives due to SARS-COV2.\n\nAuthor contributions\n\nConceptualization: Carmen Hidalgo-Tenorio.\n\nData curation: Coral Garcia-Vallecillos, Sergio Sequera-Arquelladas.\n\nFormal analysis: Carmen Hidalgo-Tenorio, Sergio Sequera-Arquelladas.\n\nInvestigation: Carmen Hidalgo-Tenorio, Coral Garcia-Vallecillos, Sergio Sequera-Arquelladas.\n\nMethodology: Carmen Hidalgo-Tenorio, Coral Garcia-Vallecillos.\n\nProject administration: Carmen Hidalgo-Tenorio.\n\nSoftware: Coral Garcia-Vallecillos, Sergio Sequera-Arquelladas.\n\nSupervision: Coral Garcia-Vallecillos, Sergio Sequera-Arquelladas.\n\nValidation: Coral Garcia-Vallecillos, Sergio Sequera-Arquelladas.\n\nVisualization: Coral Garcia-Vallecillos, Sergio Sequera-Arquelladas.\n\nWriting – original draft: Carmen Hidalgo-Tenorio.\n\nWriting – review & editing: Coral Garcia-Vallecillos, Sergio Sequera-Arquelladas.\n\nAbbreviations: COVID-19 = severe coronavirus disease 2019, CPR = C-reactive protein, ECMO = extracorporeal membrane oxygenation, HFNC = high-flow nasal cannula, ICU = Intensive Care Unit, IMV = invasive mechanical ventilation, NIMV = noninvasive mechanical ventilation, RDSV = Remdesivir, SARS-CoV-2 = severe acute respiratory distress syndrome coronavirus 2, SpO2 = oxygen saturation, WHO = World Health Organization.\n\nHow to cite this article: Hidalgo-Tenorio C, García-Vallecillos C, Sequera-Arquelladas S. Real-world outcomes of COVID-19 treatment with remdesivir in a Spanish hospital. Medicine. 2021;100:37(e27228).\n\nEthics approval and consent to participate: This cohort of patients was established after obtaining approval from the ethical committee of the hospital.\n\nConsent for publication: All authors contributed significantly to the study and the preparation of the manuscript, and they have read and approved the final submitted version.\n\nAvailability of data and material: The researchers confirm the accuracy of the data provided for the study, as well as its availability.\n\nThe authors report no conflicts of interest.\n\nFunding: This study has not received any funding for its execution.\n\nTransparency declaration: None to declare.\n\nThe datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request. All data generated or analyzed during this study are included in this published article [and its supplementary information files].\n==== Refs\nReferences\n\n[1] World Health Organization Novel Coronavirus (2019-nCoV): situation report, 91. Geneva: World Health Organization; 2020.\n[2] Coronavirus Uptodate (Live). Available at: worldmeters.info/coronavirus/.\n[3] Coronavirus Covid-19. Comunicado Coronavirus 12 de abril 2021-Junta de Andalucía. Available at: www.juntadeandalucia.es.\n[4] Warren TK Jordan R Lo M . Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys. Nature 2016;531 :381–5.26934220\n[5] Lo MK Jordan R Arvey A . GS-5734 and its parent nucleoside analog inhibit Filo-, Pneumo-, and Paramyxoviruses. Sci Rep 2017;7 :43395.28262699\n[6] Beigel JH Tomashek KM Dodd LE . Remdesivir for the treatment of Covid-19—final report. New Engl J Med 2020;383 :1813–26.32445440\n[7] Protocolo farmacoclínico del uso de Remdesivir (veklury.®) en el tratamiento de la enfermedad por covid-19 en el sistema nacional de salud. Available at: https://www.mscbs.gob.es/profesionales/farmacia/valtermed/docs/20200908_Protocolo_farmacoclinico_remdesivir2.pdf).\n[8] Channappanavar R Perlman S . Pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology. Semin Immunopathol 2017;39 :529–39.28466096\n[9] Freeman DH . Applied Categorical Data Analysis. New York, USA: Marcel Dekker; 1987.\n[10] Ejaz H Alsrhani A Zafar A . COVID-19 and comorbidities: deleterious impact on infected patients. J Infect Public Health 2020;13 :1833–9.32788073\n[11] Gold MS Sehayek D Gabrielli S Zhang X McCusker C Ben-Shoshan M . COVID-19 and comorbidities: a systematic review and meta-analysis. Postgrad Med 2020;132 :749–55.32573311\n[12] Ragab D Salah Eldin H Taeimah M Khattab R Salem R . The COVID-19 cytokine storm; what we know so far. Front Immunol 2020;11 :1446.32612617\n[13] Li Q Cao Y Chen A-L . Hematological features of persons with COVID-19. Leukemia 2020;34 :2163–72.32528042\n[14] Pan H Peto R Restrepo-Henao A-M . WHO Solidarity Trial Consortium. Repurposed antiviral drugs for covid-19 interim WHO solidarity trial results. N Engl J Med 2012;384 :497–511.\n[15] Spinner CD Gottlieb RL Criner GJ . Effect of remdesivir vs standard care on clinical status at 11 days in patients with moderate COVID-19: a randomized clinical trial. JAMA 2020;324 :1048–57.32821939\n[16] Wang Y Zhou F Zhang D . Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial. Lancet 2020;395 :1569–78.32423584\n[17] Grein J Ohmagari N Shin D . Compassionate use of remdesivir for patients with severe Covid-19. N Engl J Med 2020;382 :2327–36.32275812\n\n",
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"mesh_terms": "D000249:Adenosine Monophosphate; D000368:Aged; D000409:Alanine; D000998:Antiviral Agents; D000086382:COVID-19; D005260:Female; D006760:Hospitalization; D006801:Humans; D008297:Male; D008875:Middle Aged; D017063:Outcome Assessment, Health Care; D012189:Retrospective Studies; D013030:Spain; D018709:Statistics, Nonparametric",
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"title": "Real-world outcomes of COVID-19 treatment with remdesivir in a Spanish hospital.",
"title_normalized": "real world outcomes of covid 19 treatment with remdesivir in a spanish hospital"
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"abstract": "Amiodarone-induced pulmonary toxicity (APT) is one of the most feared and underappreciated adverse effects of this commonly prescribed antiarrhythmic. APT has a variable presentation, among the rarest of these is amiodarone-induced diffuse alveolar hemorrhage with hemoptysis. Though previous cases confirmed with biopsy averaged a dose of 570 mg PO daily, APT can occur at any dose. Previous literature has suggested the importance of cumulative exposure to amiodarone rather than the patient's actual dose. The presented case describes amiodarone-induced hemoptysis occurring at a dose of 200 mg PO daily for five years. Additionally described is the treatment regimen which managed a patient with metabolic syndrome and elevated A1c while addressing the recommended treatment of extended high-dose steroids for APT with complicated respiratory status. To the best of the authors' knowledge, only two biopsied cases have been described at a dose this low. Furthermore, this case describes a more typical timeline for APT than those two cases.",
"affiliations": "Anesthesiology, University of South Dakota, Sanford School of Medicine, Sioux Falls, USA.;Radiology, University of South Dakota Sanford School of Medicine, Sioux Falls, USA.;Radiology, University of South Dakota Sanford School of Medicine, Sioux Falls, USA.;Interventional Radiology, Avera McKennan Hospital and University Health Center, Sioux Falls, USA.",
"authors": "Busch|Clayton D|CD|;Heiberger|Caleb J|CJ|;Mehta|Tej I|TI|;Yim|Douglas|D|",
"chemical_list": null,
"country": "United States",
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"doi": "10.7759/cureus.5289",
"fulltext": "\n==== Front\nCureusCureus2168-8184Cureus2168-8184Cureus Palo Alto (CA) 10.7759/cureus.5289Internal MedicinePulmonologyAmiodarone-induced Hemoptysis: A Rare Presentation of Amiodarone-induced Pulmonary Toxicity Occurs at a Low Dose Muacevic Alexander Adler John R Busch Clayton D 1Heiberger Caleb J 2Mehta Tej I 2Yim Douglas 3\n1 \nAnesthesiology, University of South Dakota, Sanford School of Medicine, Sioux Falls, USA \n2 \nRadiology, University of South Dakota Sanford School of Medicine, Sioux Falls, USA \n3 \nInterventional Radiology, Avera McKennan Hospital and University Health Center, Sioux Falls, USA \nClayton D. Busch clayton.busch@usd.edu31 7 2019 7 2019 11 7 e528916 7 2019 31 7 2019 Copyright © 2019, Busch et al.2019Busch et al.This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.This article is available from https://www.cureus.com/articles/21771-amiodarone-induced-hemoptysis-a-rare-presentation-of-amiodarone-induced-pulmonary-toxicity-occurs-at-a-low-doseAmiodarone-induced pulmonary toxicity (APT) is one of the most feared and underappreciated adverse effects of this commonly prescribed antiarrhythmic. APT has a variable presentation, among the rarest of these is amiodarone-induced diffuse alveolar hemorrhage with hemoptysis. Though previous cases confirmed with biopsy averaged a dose of 570 mg PO daily, APT can occur at any dose. Previous literature has suggested the importance of cumulative exposure to amiodarone rather than the patient’s actual dose. The presented case describes amiodarone-induced hemoptysis occurring at a dose of 200 mg PO daily for five years. Additionally described is the treatment regimen which managed a patient with metabolic syndrome and elevated A1c while addressing the recommended treatment of extended high-dose steroids for APT with complicated respiratory status. To the best of the authors’ knowledge, only two biopsied cases have been described at a dose this low. Furthermore, this case describes a more typical timeline for APT than those two cases.\n\namiodarone induced pulmonary toxicitydiffuse alveolar hemorrhagehemoptysishypoxemic respiratory failureThe content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus.\n==== Body\nIntroduction\nAmiodarone, one of the most frequently prescribed medications in the U.S., can cause amiodarone pulmonary toxicity (APT). APT is a potentially fatal and underrecognized drug complication [1, 2]. APT presenting with diffuse alveolar hemorrhage (DAH) and hemoptysis is a rare occurrence with only 10 biopsy proven events as of 2006 [3]. Borders et al. identified 15 cases as of 2012 regardless of biopsy status, and an additional case was described in 2018 [4, 5]. On average, biopsied patients had been on amiodarone for 5.6 months at a dose of 570 mg prior to experience alveolar hemorrhage and hemoptysis symptoms, and two of these cases reported at a dose of 200 mg which had been given for 14 and 200 days, respectively [3]. In comparison, Martin and Rosenow describe APT of any kind occurring in 5-7% of patients taking amiodarone, including doses as low as 200 mg, but these typically occur after “years of therapy” [6]. This case reports a patient on 200 mg of amiodarone for five years to treat paroxysmal atrial fibrillation that experienced DAH with hemoptysis.\n\nCase presentation\nA 73-year-old female with past medical history of hypothyroidism, class III obesity, myocardial infarction with four vessel coronary artery bypass grafting (CABG), and paroxysmal atrial fibrillation controlled with 200 mg amiodarone for five years presented to an outlying clinic with “vision trouble”. Symptoms began in one eye that morning and progressed to bilateral involvement over a few hours. Laboratory findings were significant for an erythrocyte sedimentation rate (ESR) of 115. Optometry diagnosed her with bilateral retinal artery occlusion. High dose IV steroids were promptly initiated for coverage of giant cell arteritis (GCA). She was admitted for further workup with temporal artery biopsy and echocardiogram. A carotid ultrasound, magnetic resonance imaging (MRI), and magnetic resonance angiogram (MRA) were also performed to evaluate for possible embolic etiology. The echocardiogram showed atrial fibrillation with moderate aortic stenosis and mild-moderate mitral stenosis. Carotid ultrasound showed extensive atherosclerosis without evidence of complete occlusion. MRI and MRA were unremarkable; temporal artery biopsy results were negative for any acute pathology.\n\nFour days after her initial presentation, the patient suddenly became hypoxemic with a cough productive of bloody expectorant. Seven liters (FiO2 of 44%) of supplemental oxygen were necessary to maintain saturations over 90%. A CT of her chest was performed, and it demonstrated extensive patchy bilateral areas of airspace opacity and consolidations and an enlarged heart with no interval change in heart size (Figure 1). These findings were suggested by radiology to be secondary to pneumonia vs. pulmonary hemorrhage. Empiric ceftriaxone and azithromycin were both started at this time. Amiodarone and warfarin therapies were stopped, but no reversal agents were given for warfarin since her international normalised ratio (INR) was 1.09 at that time. Baseline hemoglobin levels ranged from 10.7 to 11.5 g/dL (normal 12-16 g/dL), but hemoglobin in the acute setting was measured at 9.9 g/dL. She was promptly transferred to a tertiary care center ICU.\n\nFigure 1 Post-hemoptysis CT of chest\nRed arrows indicating bilateral opacities appreciated on CT scan consistent with diffuse alveolar hemorrhage vs. pneumonia. Diffuse alveolar hemorrhage was subsequently confirmed on bronchoalveolar lavage.\n\nThe following day in the ICU further workup was performed with a bronchoalveolar lavage (BAL) demonstrating frank blood in three consecutive aspirates consistent with DAH. Furthermore, a thick layer of blood was observed along the bronchi without evidence of laceration, mass, or damage that could be attributable to the pulmonary bleeding that appeared worse in more distal segments of the lungs where collections of blood were appreciated. ESR remained elevated above 80 mm/hr (normal 0-29 mm/hr) throughout her hospital stay despite a constant regimen of high dose steroids. White blood cells (WBC) remained elevated throughout most of her symptomatic period with a peak of 13.0 cells/mcL (normal 4.5-11.0 cells/mcL) eight days after her initial presentation. BAL samples were sent for microbiological testing with all results coming back negative including fungal cultures, respiratory syncytial virus (RSV), legionella, acid fast bacilli smear, and gram stain. Sputum sample and peripheral venous blood also produced negative gram stain and final cultures. An extensive rheumatologic workup was negative including antinuclear antibody (ANA), antineutrophil cytoplasmic antibody (ANCA), and anti-glomerular basement membrane (anti-GBM). Additionally, ultrasound of both legs was performed showing no evidence of deep vein thrombosis (DVT). Brain natriuretic peptide (BNP) was recorded at 672 (normal 0-100 pg/mL) which was elevated from her baseline of approximately 300 pg/mL. PT/INR was also unremarkable with constant values below 2 for the duration of her visit. Complete blood count (CBC) with differential was normal beyond the abnormalities previously described. Eosinophils were also within the normal reference range (0-0.45 cells x 109/L). Hemoglobin gradually dropped over the next week to a minimum of 8.1 g/dL at which time she received a transfusion. Her oxygen needs also increased along this timeframe.\n\nDuring her ICU stay oxygen needs increased to a peak of 65% FiO2 via mask delivery. Her oxygen needs diminished gradually, and she was transferred to a rehab unit adjacent to the ICU. In the rehab unit the patient was able to ambulate and function safely and independently on her decreasing supplemental oxygen needs. Fifteen days after her initial presentation she was discharged with stable vital signs on room air. There was no recurrence of dyspnea or related symptoms at three-month follow-up.\n\nDiscussion\nAmiodarone is an efficacious antiarrhythmic with activity against most arrhythmias, both ventricular and supraventricular [1]. It also carries a spectrum of side effects including corneal deposits, discoloration of skin, bone marrow suppression, and peripheral neuropathies. Its most severe side effect is APT [6, 7]. Meta-analysis suggests the rate of APT incidence is 1% per year on amiodarone [8]. Another source suggests approximately 5-7% of patients taking amiodarone will get APT and in 5-10% of these patients it will be fatal [6]. Risk factors for lung complications with amiodarone use include older age, duration of treatment, cumulative dose of medication and its metabolites, history of cardiothoracic surgery, high oxygen use, use of contrast, co-existing respiratory infections and pre-existing lung pathology [9]. Presentation of APT is non-specific, but it is typically classified as either acute or insidious onset. Acute onset is described in one-third of patients with APT, occurring after a couple weeks on amiodarone. These patients present with fever and an acute pneumonitis a couple weeks after taking amiodarone. Heart failure symptoms are also possible. The insidious onset is associated with at least two months of therapy and is typically characterized by progressive nonproductive cough, dyspnea, weight loss, and sometimes fever with interstitial infiltrates on chest x-ray [6].\n\nIt is important to note that toxicity is better correlated with total cumulative dose than either the patient’s daily dose or plasma level of amiodarone [7]. Toxicity can occur at any time, but Wolkove and Baltzan describe typical timelines as anticipated by dose: patients taking at least 400 mg for more than two months and patients taking 200 mg or less for more than two years. Oral amiodarone specifically has been observed to accumulate dramatically in lung and adipose tissue [7]. With class III obesity and a low dose of oral amiodarone, one would expect a later presentation of APT. As both lungs and adipocytes act as reservoirs for the drug, a larger adipocyte reservoir competing for accumulation could delay the onset of pathology in the lungs.\n\nDiagnosis of APT should include three or more of the following: new or worsening dyspnea or new findings on lung exam, abnormalities on imaging, abnormalities in total lung capacity or diffusion lung capacity (DLCO), CD8+ lymphocytes in BAL fluid, lung biopsy showing DAH, interstitial pneumonitis, pulmonary fibrosis or organizing pneumonia [10]. The presented case met diagnostic criteria as the patient had new dyspnea, bilateral patchy opacifications on chest CT, and diffuse crackles appreciated throughout all lung fields on physical exam. Further evaluation of the case using the Naranjo Adverse Effect Probability Scale indicated the diagnosis was probable [11].\n\nDLCO was not measured, but likely would have been altered as the carbon monoxide used to evaluate DLCO is sequestered by the blood occupying the lungs [12]. Furthermore, the clinical instability of our patient made performing DLCO testing impractical. Similar logic supported the decision to forego lung biopsy. Despite biopsy being the gold standard of diagnosis, it is rarely indicated as APT worsens with cardiothoracic surgery and patients typically are not optimal surgical candidates owing to their cardiopulmonary issues [7].\n\nImportant considerations for differential diagnosis in patients with APT with hemoptysis include pulmonary embolism, malignancy, pneumonia, eosinophilic pneumonitis, acute congestive heart failure (CHF), autoimmune disease, and warfarin-induced hemoptysis [3, 6]. The presented case did have unilateral leg edema, but she described this as her baseline since her saphenous vein was harvested for her CABG. Additionally, ultrasound of the lower-extremities showed no evidence of thrombosis. CT and BAL failed to demonstrate evidence of malignancy. BAL, sputum sample, and peripheral venous blood all came back negative for infection. CBC with differential demonstrated a normal eosinophil count making eosinophilic pneumonitis unlikely. A CHF exacerbation was considered as her BNP was 672 pg/mL with difficulty breathing. She did not, however, have leg edema more pronounced than her baseline, and her weight was also at baseline at the time of hemoptysis. Imaging of her heart showed borderline heart enlargement stable compared to previous radiographs. Given her new onset anemia, increased heart wall stress secondary to pulmonary pathology, and critical status it is reasonable to attribute her transiently elevated BNP to the stress imposed on the heart by her health status. An extensive auto-immune panel also came back negative, including Goodpasture disease.\n\nWarfarin-induced alveolar hemorrhage was also considered. There is a documented interaction with amiodarone inhibiting warfarin processing in the liver through CYP 2C9 and raising risk of pathologic hemorrhage. However, this patient’s INR was 1.09 at the time of hemoptysis making warfarin-induced hemoptysis unlikely as previous case reports emphasize elevated INR values [13, 14]. The current patient had a baseline hemoglobin of 10.7-11.5 g/dL, but it was 9.2 g/dL the day after her presentation with visual symptoms. She did not have hypoxemia or hemoptysis until four days after the initial presentation. Iskandar et al. questioned if subclinical alveolar hemorrhage may be occurring before the acute presentation [3]. The timeline of her hemoglobin dropping before she was started on warfarin and before her hypoxemic hemoptysis suggests warfarin was not the inciting factor and that a subclinical development of DAH was already in progression before clinical symptoms were apparent. Additionally, the patient’s warfarin was restarted by primary care for atrial fibrillation during follow-up. There was no return of pulmonary symptoms.\n\nThe most agreed upon therapy for APT is stopping amiodarone. There is less consensus on the use of steroids. Martin and Rosenow recommended two to six months of prednisone 40-60 mg daily. It is left to clinical judgement to decide the risk-benefit analysis of using steroids with respiratory status being a key consideration. Duello et al. elected to avoid steroids entirely as their patient only required a mild oxygen supplement [10]. There were reservations in maintaining such an extensive dose of steroids in a metabolic syndrome patient with questionable A1c. Initially, the patient in the present case report had symptoms of GCA so she was treated with an extensive course of steroids from the outset. Her oxygen needs were monitored inpatient until she was stable on room air both at rest and with activity. Steroids were tapered upon discharge giving her about a month of steroid treatment. This allowed a considerable course of steroids with tapered overlap after she was discharged with a stable respiratory status. Amiodarone was never re-started and no new anti-arrhythmics were started in its place, although her daily medications already included 200 mg of labetalol twice daily. At the point of three-month follow-up there were no complications with her atrial fibrillation management and no recurrence of pulmonary symptoms.\n\nConclusions\nHemoptysis is an extremely rare presentation of APT. The current case details a patient receiving 200 mg of amiodarone PO daily for five years. This presentation is similar to previously reported incidences of APT in regards to its presentation after years of therapy, but it is distinguished from the two reports with hemoptysis at 200 mg because those cases had less than a year of amiodarone therapy at their time of hemoptysis. Theoretically, the accumulation of amiodarone in lung tissue could be delayed by another amiodarone reservoir such as adipocytes in a morbidly obese patient. Although lung biopsy is the gold standard for diagnosis, consideration of patient’s health status prior to the workup is vital. Stopping amiodarone in APT-associated DAH is essential. Therapy with steroids should weigh the benefit on respiratory status against the adverse effects on metabolism and other body systems. Recovery of lung status with adequate saturation on room air is a reassuring response to therapy. Close follow-up is advised to monitor for recurrence. This case report described diffuse alveolar hemorrhage in association with amiodarone that was successfully treated by discontinuing amiodarone, giving high dose steroids, and managing respiratory status.\n\nThe authors have declared that no competing interests exist.\n\nHuman Ethics\nConsent was obtained by all participants in this study\n==== Refs\nReferences\n1 Is amiodarone an underrecognized cause of acute respiratory failure in the ICU? Chest Ashrafian H Davey P 275 282 120 2001 11451849 \n2 Amiodarone-induced pulmonary toxicity - A frequently missed complication Clin Med Insights Case Rep Sweidan AJ Singh NK Dang N Lam V Datta J 91 94 9 2016 27773995 \n3 Amiodarone-induced alveolar hemorrhage South Med J Iskandar SB Abi-Saleh B Keith RL Byrd RP Jr Roy TM 383 387 99 2006 16634249 \n4 A rare case of acute diffuse alveolar hemorrhage following initiation of amiodarone: a case report Mil Med Borders CW III Bennett S Mount C Claassen SL 118 120 177 2012 22338993 \n5 Am I drowning in blood? Or amio-daroning Chest Grewal H Singh A Thapa S 421 154 2018 \n6 Amiodarone pulmonary toxicity. Recognition and pathogenesis (Part I) Chest Martin WJ II Rosenow EC III 1067 1075 93 1988 3282816 \n7 Amiodarone pulmonary toxicity Can Respir J Wolkove N Baltzan M 43 48 16 2009 19399307 \n8 Bronchiolitis obliterans organizing pneumonia secondary to amiodarone: a rare aetiology Eur Respir J Valle JM Alvarez D Antunez J Valdes L 470 471 8 1995 7789497 \n9 Amiodarone: review of pulmonary effects and toxicity Drug Saf Papiris SA Triantafillidou C Kolilekas L Markoulaki D Manali ED 539 558 33 2010 20553056 \n10 48-Year-old woman with dyspnea, cough, and weight loss Mayo Clin Proc Duello KM Louh IK Burger CD 1124 1127 87 2012 23127737 \n11 A method for estimating the probability of adverse drug reactions Clin Pharmacol Ther Naranjo CA Busto U Sellers EM 239 245 30 1981 7249508 \n12 Diffuse alveolar hemorrhage: diagnosing it and finding the cause Cleve Clin J Med Ioachimescu OC Stoller JK 264 255 75 2008 https://www.ncbi.nlm.nih.gov/pubmed/18491433 \n13 Warfarin-amiodarone drug-drug interactions: determination of [I](u)/K(I,u) for amiodarone and its plasma metabolites Clin Pharmacol Ther McDonald MG Au NT Wittkowsky AK Rettie AE 709 717 91 2012 22398967 \n14 Diffuse alveolar hemorrhage associated with warfarin therapy Case Rep Med Kaya B Yildiz I Baha RM Zeytun NE Yetisgen A 3 2015 2015\n\n",
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"issue": "11(7)",
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"keywords": "amiodarone induced pulmonary toxicity; diffuse alveolar hemorrhage; hemoptysis; hypoxemic respiratory failure",
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"title": "Amiodarone-induced Hemoptysis: A Rare Presentation of Amiodarone-induced Pulmonary Toxicity Occurs at a Low Dose.",
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"abstract": "The management of multiple myeloma has evolved in the modern era, partially owing to the increasing number of biologic therapeutics. Nonetheless, radiation remains an important treatment in the management of painful lytic lesions from multiple myeloma. The goal of this study is to evaluate the side effect profile of radiation therapy (RT) while patients are concurrently treated with biologic agents.\nWe conducted a retrospective study based on data collected from patients receiving RT at our institute from 2007 to 2017. A total of 130 patients (279 treatment sites) were included in this study with a median follow-up time of 14 months. Patients were required to be receiving a biological agent at least within 1 month before starting and up to 1 month after RT. Generalized estimating equations with a log link function and binomial distribution were used to estimate the prevalence ratio (PR) and corresponding 95% confidence interval (CI) and compare the side effects between patients with RT alone and RT + biologic agent.\nThe median age of all patients in our cohort was 64 years, with 53 men (58.9%) and 37 women (41.1%). The mean Karnofsky performance status score of all cohorts was 80. No significant difference in incidence of acute (PR: 1.33; 95% CI, 0.80-2.22; P = .2660) or subacute (PR: 0.90; 95% CI, 0.49-1.67; P = .7464) toxicities was found between patients with or without biologic agents who were treated concurrently with RT. No significant difference was found in reduction in laboratory values between patients with or without biologic agents treated concurrently with RT for white blood cells (P = .6916), platelets (P = .7779), or hematocrit (P = .0858).\nOur study did not detect any significant toxicity rates from palliative radiation while patients were concurrently treated with biologic agents.",
"affiliations": "Department of Radiation Oncology, Mount Sinai Hospital, New York, New York.;Department of Radiation Oncology, Mount Sinai Hospital, New York, New York.;Department of Radiation Oncology, Mount Sinai Hospital, New York, New York.;Department of Radiation Oncology, Mount Sinai Hospital, New York, New York.;Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, New York.;Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, New York.;Department of Radiation Oncology, Mount Sinai Hospital, New York, New York.;Division of Hematology and Medical Oncology, Mount Sinai Hospital, New York, New York.;Department of Radiation Oncology, Mount Sinai Hospital, New York, New York.",
"authors": "Resende Salgado|Lucas|L|;Wang|Shutao|S|;Adler|Ava|A|;Chang|Sanders|S|;Ru|Meng|M|;Moshier|Erin|E|;Dharmarajan|Kavita|K|;Jay Cho|Hearn|H|;Bakst|Richard|R|",
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"doi": "10.1016/j.adro.2018.09.009",
"fulltext": "\n==== Front\nAdv Radiat OncolAdv Radiat OncolAdvances in Radiation Oncology2452-1094Elsevier S2452-1094(18)30219-710.1016/j.adro.2018.09.009Multiple MyelomaThe Safety Profile of Concurrent Therapy for Multiple Myeloma in the Modern Era Resende Salgado Lucas MD, MPALucas.resendesalgado@mountsinai.orga∗Wang Shutao PhDaAdler Ava aChang Sanders MDaRu Meng MSbMoshier Erin MSbDharmarajan Kavita MD, MSaJay Cho Hearn MD, PhDcBakst Richard MDaa Department of Radiation Oncology, Mount Sinai Hospital, New York, New Yorkb Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, New Yorkc Division of Hematology and Medical Oncology, Mount Sinai Hospital, New York, New York∗ Corresponding author. Mount Sinai Health System, One Gustave L. Levy Place, Box 1236, New York, NY 10029-6574. Lucas.resendesalgado@mountsinai.org27 9 2018 Jan-Mar 2019 27 9 2018 4 1 112 117 23 7 2018 23 8 2018 19 9 2018 © 2018 The Author(s)2018This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Purpose\nThe management of multiple myeloma has evolved in the modern era, partially owing to the increasing number of biologic therapeutics. Nonetheless, radiation remains an important treatment in the management of painful lytic lesions from multiple myeloma. The goal of this study is to evaluate the side effect profile of radiation therapy (RT) while patients are concurrently treated with biologic agents.\n\nMethods and Materials\nWe conducted a retrospective study based on data collected from patients receiving RT at our institute from 2007 to 2017. A total of 130 patients (279 treatment sites) were included in this study with a median follow-up time of 14 months. Patients were required to be receiving a biological agent at least within 1 month before starting and up to 1 month after RT. Generalized estimating equations with a log link function and binomial distribution were used to estimate the prevalence ratio (PR) and corresponding 95% confidence interval (CI) and compare the side effects between patients with RT alone and RT + biologic agent.\n\nResults\nThe median age of all patients in our cohort was 64 years, with 53 men (58.9%) and 37 women (41.1%). The mean Karnofsky performance status score of all cohorts was 80. No significant difference in incidence of acute (PR: 1.33; 95% CI, 0.80-2.22; P = .2660) or subacute (PR: 0.90; 95% CI, 0.49-1.67; P = .7464) toxicities was found between patients with or without biologic agents who were treated concurrently with RT. No significant difference was found in reduction in laboratory values between patients with or without biologic agents treated concurrently with RT for white blood cells (P = .6916), platelets (P = .7779), or hematocrit (P = .0858).\n\nConclusions\nOur study did not detect any significant toxicity rates from palliative radiation while patients were concurrently treated with biologic agents.\n==== Body\nSummary\nThe goal of this study is to evaluate the side effect profile of radiation therapy while patients are concurrently being treated with biological agents for multiple myeloma. Our study found that that patients can safely receive palliative radiation therapy while on biological agents.\n\n\n\nIntroduction\nMultiple myeloma (MM) is caused by the proliferation of a single clone of plasma cells that produce a monoclonal immunoglobulin. In turn, these plasma cell clones can cause extensive skeletal destruction with osteolytic lesions, osteopenia, or pathologic fractures. Additional disease-related complications include hypercalcemia, renal insufficiency, anemia, and infections. Some of the most common symptoms include fatigue, bone pain, and recurrent infections.1, 2\n\nThe mechanism through which MM causes bone damage is thought to be due to a host of different changes to the bone marrow microenvironment, including induction of angiogenesis, the suppression of cell-mediated immunity, and the development of paracrine signaling loops involving cytokines such as interleukin 6 and vascular endothelial growth factor.3 Discoveries such as these have led to the development of multiple targeted agents,4 including new applications of thalidomide and usage of bortezomib.5\n\nThere have been a number of new biologic agents introduced during the past decade that have improved the outcomes of this disease, including notably daratumumab, a monoclonal antibody to CD38, which myeloma cells have been shown to overexpress. Several studies have shown its efficacy as a monotherapy as well as in combination with pomalidomide and dexamethasone, which show overall survival (OS) rates of 18 months and progression-free survival (PFS) rates of 12 months, while maintaining a tolerable side effect profile.6, 7, 8, 9\n\nAs patients live longer, the development of pain metastatic lesions from MM becomes ever more prevalent. Radiation therapy (RT) has long been used for the management of painful bone lesions in patients with MM, with excellent response rates (as high as 89.6% complete or partial pain resolution in modern cohorts). Currently, RT remains a major therapeutic component for the management patients with MM because it provides pain relief but does not interfere with a potential stem cell transplant.10, 11, 12 Palliation of the lytic myeloma lesions can be accomplished using 20 Gy to 30 Gy in 5 to 10 fractions, and higher doses are often reserved for solitary plasmacytomas.13 In addition, different fractionation schemes have been employed with great success, including the utilization of a single 8-Gy fraction.14\n\nCurrently, lytic lesions that lead to bone pain are seen in as many as 60% of patients at the time of diagnosis, and as many as 40% of patients require RT to control the disease at some point during its course.15 Radiation in this setting is entirely palliative and therefore should ideally not interrupt ongoing systemic therapy.\n\nThe addition of daratumumab to other biologic agents, such as borterzomib, has shown a significant improvement in PFS compared with bortezomib and dexamethasone alone, for example. However, higher rates of thrombocytopenia, neutropenia, and infusion reactions were seen when daratumumab was added to bortezomib and dexamethasone.16 These increased rates of hematological toxicities were also seen when adding daratumumab to lenalidomide.17\n\nIn addition, a second-generation proteasome inhibitor, carfilzomib, has also been introduced for the management of refractory MM and has shown an improvement in PFS of as much as 26.3 months versus 17.6 months when added to dexamethasone and lenalidomide, with a safe toxicity profile.18, 19 This drug has also demonstrated an improvement of 8 months when added to dexamethasone and lenalidomide in median OS versus regimens without.20\n\nIn the modern era, patients often receive these biologic agents, but whether they should continue or end treatment while undergoing palliative RT owing to toxicity concerns by combining both treatments remains unclear. There are isolated reports of toxicity associated with concurrent RT, but there is a lack of systematic review of such toxicities.21 The current guidelines by the International Lymphoma Radiation Oncology Group raised the concern for lack of evidence pertaining to the safety of combining RT and chemotherapy agents, “specifically in terms of sensitization of normal tissue toxicity or depletion of the bone marrow reserve.”22 A retrospective review showed no differences in terms of hematologic toxicity between patients treated with RT alone and those receiving RT with concurrent, novel, agent-based chemotherapy.23\n\nGiven the important roles of both new biologic agents and RT in the management of MM, a presentation of a large modern series indicating the safety of the concurrent use of these 2 interventions was necessary, considering that many patients will require both at one point. Herein, we report on the largest modern, retrospective series to evaluate the safety and toxicity of concurrent biologic therapies including carfilzomib, bortezomib, and daratumumab.\n\nMethods and Materials\nWe conducted a retrospective study on the basis of data collected from patients receiving RT at our institute between 2007 and 2017, for which institutional review board approval was obtained. Patients were required to be receiving a biologic agent at least within 1 month before starting and up to 1 month after RT. The medical oncologists did not withhold therapy for these patients, and dosing was based on standard parameters as opposed to RT. A total of 130 patients and 279 treatment sites were included in this study with a median follow-up time of 14 months. A total of 91 patients received concurrent RT with at least 1 of the aforementioned biologic agents to 172 different sites. The remaining 39 patients received RT alone to 107 different sites. Toxicities were rated according to Common Terminology Criteria for Adverse Events, version 5.0. We reviewed the last complete blood count before starting RT and the first complete blood count after completion.\n\nContinuous variables were summarized by the median and range, and categorical variables were summarized by number and percentage. Demographic information and general treatment variables were described per patient, and radiation characteristics were summarized by RT. Generalized estimating equations with a log-link function and binomial distribution were used to estimate the prevalence ratio (PR) and corresponding 95% confidence interval (CI) and to compare the risk of onset of acute side effects (within 4 weeks of treatment), subacute side effects (during 4 weeks and 6 months of treatment), and hematological events (grade ≥3 anemia, need for platelet transfusion, and need for neupogen) between patients with RT alone and RT + biologic agents.\n\nA compound symmetrical covariance structure was assumed to control for intrasubject correlation. A mixed model analysis of covariance was used to estimate the changes in blood counts (white blood cells, platelets, and hematocrit) before and after treatment while adjusting for pretreatment values. All hypothesis testing was 2-sided, and conducted at the 5% level of significance. Statistical analyses were performed with the SAS, version 9.4 (SAS Institute Inc, Cary, NC) software package.\n\nResults\nThe median age of all patients in our cohort was 64 years (range, 28-85 years). A total of 91 patients received at least 1 biologic agent. Among the entire cohort, there were 81 men (62%) and 49 women (38%). Most patients had International Staging System for MM, stage 1 with 64 patients or 62% of the cohort. Fourteen patients (13%) and 26 patients (25%) were disease stage 2 and 3, respectively, and the remainder did not have staging information available. The median number of treatment sites per patient was 1 (range, 1-6 sites), and the median number of treatment courses per patient was 2 to different treatment sites. The mean Karnofsky performance status score of all cohorts was 80. By far, the most commonly treated site was the spine. Two hundred and seventy nine lesions were treated in total. The median dose was 20 Gy (range, 2-40 Gy). The median number of fractions was 10 (range, 1-20; Table 1).Table 1 Patient demographics (upper half of table) and by lesions treated (lower half of table)\n\n(Per patient)\tOverall N = 130\t\nAge at time of first RT, years\nMedian (range)\t64 (28-85)\t\nSex\t\n Male\t81 (62%)\t\n Female\t49 (38%)\t\nEthnicity\t\n White\t50 (40%)\t\n African American\t37 (30%)\t\n Hispanic/Latino\t19 (15%)\t\n Asian/other\t18 (15%)\t\nISS stage\t26 missing data\t\n 1\t64 (62%)\t\n 2\t14 (13%)\t\n 3\t26 (25%)\t\nKarnofsky performance status score (first on record)\nMedian (range)\t80 (30-100)\t\nTreatment sites per patient\nMedian (range)\t1 (1-6)\t\nCourses of RT per patient\nMedian (range)\t2 (1-13)\t\nPrior chemotherapy/cytotoxic agents (before first RT)\t\n Yes\t116 (89%)\t\n No\t14 (11%)\t\n(Per lesion)\tOverall RT N = 279\tRT + BA N = 172\tRT All N = 107\t\nRadiation dose group\t\n ≤20 Gy\t171 (61%)\t98 (57%)\t73 (68%)\t\n 20-30 Gy\t35 (13%)\t25 (15%)\t10 (9%)\t\n ≥30 Gy\t73 (26%)\t49 (28%)\t24 (22%)\t\nDose (Median, range)\t20 (2-40)\t20 (8-40)\t20 (2-40)\t\nRadiation fractions (Median, range)\t10 (1-20)\t10 (1-20)\t10 (1-20)\t\nRadiation technique\t\n 3-dimensional\t134 (48%)\t85 (49%)\t49 (46%)\t\n 2-dimensional\t102 (37%)\t61 (35%)\t41 (38%)\t\n Intensity modulated RT\t21 (8%)\t13 (8%)\t8 (7%)\t\n Stereotactic radiation surgery/Stereotactic RT/Stereotactic body RT\t17 (6%)\t8 (5%)\t9 (8%)\t\n En face/Electrons/Electron boost\t5 (2%)\t5 (3%)\t0 (0%)\t\nCommon sites (top 6 sites)\t\n Spine\t104 (37%)\t65 (38%)\t39 (36%)\t\n Pelvis\t38 (14%)\t27 (16%)\t11 (10%)\t\n Skull\t32 (11%)\t23 (13%)\t9 (8%)\t\n Shoulder\t25 (9%)\t10 (6%)\t15 (14%)\t\n Leg\t20 (7%)\t10 (6%)\t10 (9%)\t\n Arm\t19 (7%)\t8 (5%)\t11 (10%)\t\nBiologic agents\t\n Bortezomib\t/\t72 (42%)\t/\t\n Carfilzomib\t\t39 (23%)\t\t\n Daratumumab\t\t25 (15%)\t\t\n Other\t\t36 (20%)\t\t\nAbbreviations: BA = biologic agent; RT = radiation therapy.\n\n\n\nNo grade ≥3 toxicity was noted in the entire cohort. The most common acute toxicity that was documented in our entire cohort was fatigue, as reported by patients (42 events; 15.05%), followed by erythema (8 events, 2.86%), and cough (5 events, 1.79%). The most common subacute toxicities were fatigue (14 events; 5.01%), pain (10 events; 3.58%), and constipation (4 events; 1.43%; Table 2). Biologic agents had similar numbers of acute and subacute toxicities (Table 3; Fig 1).Table 2 Toxicity frequency data (Number of events of each toxicity noted, by lesion treated in the upper half and by patients in the lower half of the table).\n\nType\tEvent\tRT + BA N of Tx = 172\tRT alone N of Tx = 107\tTotal RT N of Tx = 279\t\nAcute\tFatigue\t29\t13\t42\t\nAcute\tErythema\t8\t0\t8\t\nAcute\tConstipation\t3\t1\t4\t\nAcute\tCough\t3\t2\t5\t\nAcute\tInsomnia\t3\t1\t4\t\nAcute\tNumbness\t3\t0\t3\t\nSubacute\tFatigue\t7\t7\t14\t\nSubacute\tPain\t9\t1\t10\t\nSubacute\tConstipation\t4\t0\t4\t\nSubacute\tAppetite loss\t1\t2\t3\t\nType\tEvent\tRT + BA\tRT al1\tNumber of Patients\t\nAcute\tFatigue\t17\t12\t25∗\t\nAcute\tErythema\t4\t0\t4\t\nAcute\tConstipation\t2\t1\t3\t\nAcute\tCough\t1\t2\t3\t\nAcute\tNumbness\t3\t0\t3\t\nAcute\tInsomnia\t2\t1\t3\t\nSubacute\tFatigue\t5\t5\t10\t\nSubacute\tPain\t4\t1\t5\t\nSubacute\tAppetite loss\t1\t2\t3\t\nAbbreviations: BA = biologic agent; RT = radiation therapy; Tx = toxicity.\n\n∗ Two patients who experienced fatigue had RT both with and without BA.\n\nToxicities <3 times in the database were not included in the table by lesion treated for simplification purposes. No Grade 3 toxicities noted in the cohort, only grades 1 and 2 reportedTable 3 Toxicities by drug combination (by lesion treated in the upper half of the table, and by patients in the lower half)\n\nType\tRT + bortezomib\tRT + carfizomib\tRT + daratumumab\tRT + other\tRT only\tTotal RT\t\nAcute\t13\t17\t14\t8\t20\t72\t\nSubacute\t4\t1\t6\t12\t14\t37\t\nType\tRT + bortezomib\tRT + carfizomib\tRT + daratumumab\tRT + other\tRT al1\t\nN (Patient)∗\t48\t24\t18\t23\t69\t\nAcute\t8 (17%)\t10 (42%)\t9 (50%)\t5 (22%)\t19\t\nSubacute\t3 (6%)\t1 (4%)\t4 (22%)\t6 (26%)\t11\t\nAbbreviation: RT = radiation therapy.\n\n∗ Total number of patient who received that particular type of treatment combination.\n\nFigure 1 Acuity of Toxicities vs. Toxicity Frequency with Different Drugs.\n\n\n\nNo significant difference in incidence of acute (PR: 1.33; 95% CI, 0.80-2.22; P = .2660) or subacute (PR: 0.90; 95% CI, 0.49-1.67, P = .7464) toxicities was found between patients with or without biologic agents concurrently with RT. Furthermore, no significant difference in anemia was observed. Similarly, neupogen requirements or rates of platelets transfusion were not different between the 2 groups (Table 4). No significant difference was found in reduction in laboratory values between patients with or without biologic agents concurrently with RT for white blood cells (P = .6916), platelets (P = .7779), or hematocrit (P = .0858). Therefore, receiving the biologic agents concurrently with RT did not predispose these patients to lower white blood cell, hematocrit, or platelet counts compared with patients receiving RT alone (Table 5).Table 4 Prevalence ratios for side effects and hematological events\n\n\tToxicity event by RT\tPrevalence ratios (95% CI)\tP-value\t\nAcute side effects (N = 157)\t\n RT alone\t20/52\tRef\t\t\n RT + BA\t52/105\t1.33 (0.80-2.22)\t.2660\t\nSubacute side effects (N = 121)\t\n RT alone\t14/42\tRef\t\t\n RT + BA\t23/79\t0.90 (0.49-1.67)\t.7464\t\nAnemia (N = 226)\t\n RT alone\t3/73\tRef\t\t\n RT + BA\t14/153\t2.49 (0.66-9.33)\t.1772\t\nPlatelet transfusion (N = 227)\t\n RT alone\t11/73\tRef\t\t\n RT + BA\t38/154\t1.35 (0.67-2.71)\t.3978\t\nNeupogen needed (N = 226)\t\n RT alone\t8/73\tRef\t\t\n RT + BA\t35/153\t1.58 (0.54-4.64)\t.4008\t\nAbbreviations: BA = biologic agent; CI = confidence interval; RT = radiation therapy.\n\nTable 5 Estimated means of reduction in laboratory values (white blood cells/platelets/hematocrit pre- and post-RT)\n\n\tEstimates (95% CI)\tDifference (RT + BA-RT alone)\tP-value\t\nWhite blood cells∗\t\n RT alone\t1.12 (0.54-1.69)\t0.13 (−0.52, 0.78)\t.6916\t\n RT + BA\t1.25 (0.79-1.71)\t\nPlatelets∗\t\n RT alone\t21.27 (6.10-36.44)\t2.63 (−15.81, 21.07)\t.7779\t\n RT + BA\t23.90 (12.77-35.03)\t\nHematocrit∗\t\n RT alone\t−0.12 (−1.05 to 0.82)\t0.94 (−0.13, 2.01)\t.0858\t\n RT + BA\t0.82 (0.08-1.55)\t\nAbbreviations: BA = biologic agent; CI = confidence interval; RT = radiation therapy.\n\n∗ Adjusted for baseline laboratory values.\n\n\n\nDiscussion\nOur data suggest that the concurrent use of biologic agents for the treatment of MM together with palliative RT does not portend upon these patients worse acute or subacute side effects compared with RT alone. In addition, these patients are not at a higher risk of having lower blood cell counts when receiving RT concurrently with the biologic drugs. As previously noted, daratumumab can increase risk of neutropenia, anemia, thrombocytopenia, and leukopenia in these patients, with as many as 50% of patient experiencing some degree of anemia from the drug.6, 17, 24 We noted, however, that combining this drug with RT did not increase the risk of hematological complications.\n\nComplications from RT, including risk of fractures, have always been a source of concern for patients.25 Historically, radiation has not been shown to worsen risk of fractures in patients with bony metastases and is a safe treatment for these patients.26, 27 In addition, in our study, patients were not at risk for further gastrointestinal or skin toxicities.\n\nThe toxicities of these biologic agents are well known, and current studies include gastrointestinal toxicities, upper airway/respiratory symptoms, and hematological toxicities.17, 28 Given that our studies show minimal amounts of these side effects (except for coughing in 1.79% of the cohort, no respiratory toxicities were noted), differences in toxicity between the different classes of biologic agents while undergoing RT are unlikely.\n\nOur study has some limitations, primarily its retrospective nature. In addition, the study is not randomized, which would be optimal when attempting to compare 2 groups (eg, patients who receive biologic agents vs those who do not). Nonetheless, based on the results of our large retrospective series, we can conclude that palliative RT can be safely administered concurrently with biologic agents without concern for major adverse effects. As these patients live longer the likelihood of RT being used in their care becomes more common; thus, this finding has important clinical implications for this patient population.\n\nConclusions\nTreatment with biologic agents does not need be held before, during, or after RT. Currently there are a number of new drugs being studied for MM, such as oral deacetylase inhibitor and panobinostat (not included in our study) for which the safety with concurrent RT should be studied in the future before widespread concurrent utilization.29, 30, 31 Maintenance systemic therapy and control is key to the management of MM, and we have shown that maintenance systemic therapy does not need to be stopped to treat MM.\n\nSources of support: This work did not have any specific funding. No financial disclosures.\n\nConflicts of interest: No conflicts of interest.\n==== Refs\nReferences\n1 Kyle R.A. Rajkumar S.V. Multiple myeloma N Engl J Med 351 2004 1860 1873 15509819 \n2 Kyle R.A. Gertz M.A. Witzig T.E. Review of 1027 patients with newly diagnosed multiple myeloma Mayo Clin Proc 78 2003 21 33 12528874 \n3 Hideshima T. Anderson K.C. Molecular mechanisms of novel therapeutic approaches for multiple myeloma Nat Rev Cancer 2 2002 927 937 12459731 \n4 Seidl S. Kaufmann H. Drach J. New insights into the pathophysiology of multiple myeloma Lancet Oncol 4 2003 557564 \n5 Anderson K.C. Multiple myeloma: How far have we come? Mayo Clin Proc 78 2003 15 17 12528872 \n6 Chari A. Suvannasankha A. Fay J.W. Daratumumab plus pomalidomide and dexamethasone in relapsed and/or refractory multiple myeloma Blood 130 2017 974 981 28637662 \n7 Lokhorst H.M. Plesner T. Laubach J.P. Targeting CD38 with daratumumab monotherapy in multiple myeloma N Engl J Med 373 2015 1207 1219 26308596 \n8 Lonial S. Weiss B.M. Usmani S.Z. Daratumumab monotherapy in patients with treatment-refractory multiple myeloma (SIRIUS): An open-label, randomized, phase 2 trial Lancet 387 2016 1551 1560 26778538 \n9 Usmani S.Z. Weiss B.M. Plesner T. Clinical efficacy of daratumumab monotherapy in patients with heavily pretreated relapsed or refractory multiple myeloma Blood 128 2016 37 44 27216216 \n10 Leigh B.R. Kurtts T.A. Mack C.F. Matzner M.B. Shimm D.S. Radiation therapy for the palliation of multiple myeloma Int J Radiat Oncol Biol Phys 25 1993 801 804 7683017 \n11 Talamo G. Dimaio C. Abbi K.K. Current role of radiation therapy for multiple myeloma Front Oncol 5 2015 40 25741475 \n12 Yaneva M.P. Goranova-Marinova V. Goranov S. Palliative radiation therapy in patients with multiple myeloma J BUON 11 2006 43 48 17318951 \n13 Terpos E. Morgan G. Dimopoulos M.A. International Myeloma Working Group recommendations for the treatment of multiple myeloma-related bone disease J Clin Oncol 31 2013 2347 2357 23690408 \n14 Rudzianskiene M. Inciura A. Juozaityte E. The impact of one fraction of 8 Gy radiation therapy in palliative treatment of multiple myeloma patients with painful bone destructions Turk J Med Sci 45 2015 364 371 26084129 \n15 Featherstone C. Delaney G. Jacob S. Barton M. Estimating the optimal utilization rates of radiation therapy for hematologic malignancies from a review of the evidence: Part II-leukemia and myeloma Cancer 103 2005 393 401 15593373 \n16 Palumbo A. Chanan-Khan A. Weisel K. Daratumumab, bortezomib, and dexamethasone for multiple myeloma N Engl J Med 375 2016 754 766 27557302 \n17 Dimopoulos M.A. Oriol A. Nahi H. Daratumumab, lenalidomide, and dexamethasone for multiple myeloma N Engl J Med 375 2016 1319 1331 27705267 \n18 Dimopoulos M.A. Stewart A.K. Masszi T. Carfilzomib, lenalidomide, and dexamethasone in patients with relapsed multiple myeloma categorised by age: Secondary analysis from the phase 3 ASPIRE study Br J Hematol 177 2017 404 413 \n19 Dimopoulos M.A. Stewart A.K. Masszi T. Carfilzomib-lenalidomide-dexamethasone vs lenalidomide-dexamethasone in relapsed multiple myeloma by previous treatment Blood Cancer J 7 2017 e554 28430175 \n20 Siegel D.S. Dimopoulos M.A. Ludwig H. Improvement in overall survival with carfilzomib, lenalidomide, and dexamethasone in patients with relapsed or refractory multiple myeloma J Clin Oncol 36 2018 728 734 29341834 \n21 Mohiuddin M.M. Harmon D.C. Delaney T.F. Severe acute enteritis in a multiple myeloma patient receiving bortezomib and spinal radiation therapy: Case report J Chemother 17 2005 343 346 16038531 \n22 Tsang R.W. Campbell B.A. Goda J.S. Radiation therapy for solitary plasmacytoma and multiple myeloma: Guidelines from the International Lymphoma Radiation Oncology Group Int J Radiat Oncol Biol Phys 101 2018 794 808 29976492 \n23 Shin S.M. Chouake R.J. Sanfilippo N.J. Feasibility and efficacy of local radiation therapy with concurrent novel agents in patients with multiple myeloma Clin Lymphoma Myeloma Leuk 14 2014 480 484 25176474 \n24 Plesner T. Arkenau H.T. Gimsing P. Phase 1/2 study of daratumumab, lenalidomide, and dexamethasone for relapsed multiple myeloma Blood 128 2016 1821 1828 27531679 \n25 Harada H. Katagiri H. Kamata M. Radiologic response and clinical outcome in patients with femoral bone metastases after radiation therapy J Radiat Res 51 2010 131 136 19934590 \n26 van der Linden Y.M. Kroon H.M. Dijkstra S.P. Simple radiographic parameter predicts fracturing in metastatic femoral bone lesions: Results from a randomized trial Radiat Ther Oncol 69 2003 21 31 \n27 Van der Linden Y.M. Dijkstra P.D. Kroon H.M. Comparative analysis of risk factors for pathologic fracture with femoral metastases J Bone Joint Surg Br 86 2004 566 573 15174555 \n28 Stewart A.K. Rajkumar S.V. Dimopoulos M.A. Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma N Engl J Med 372 2015 142 152 25482145 \n29 Bailey H. Stenehjem D.D. Sharma S. Panobinostat for the treatment of multiple myeloma: The evidence to date J Blood Med 6 2015 269 276 26504410 \n30 Andreu-Vieyra C.V. Berenson J.R. The potential of panobinostat as a treatment option in patients with relapsed and refractory multiple myeloma Ther Adv Hematol 5 2014 197 210 25469210 \n31 Majer I. van de Wetering G. Polanyi Z. Krishna A. Gray E. Roy A. Panobinostat plus bortezomib versus lenalidomide in patients with relapsed and/or refractory multiple myeloma: A matching-adjusted indirect treatment comparison of survival outcomes using patient-level data Appl Health Econ Health Policy 15 2017 45 55 27550239\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2452-1094",
"issue": "4(1)",
"journal": "Advances in radiation oncology",
"keywords": null,
"medline_ta": "Adv Radiat Oncol",
"mesh_terms": null,
"nlm_unique_id": "101677247",
"other_id": null,
"pages": "112-117",
"pmc": null,
"pmid": "30706018",
"pubdate": "2019",
"publication_types": "D016428:Journal Article",
"references": "12459731;12528872;12528874;12965277;14597353;15174555;15509819;15593373;16038531;17318951;19934590;23690408;25176474;25469210;25482145;25741475;26084129;26308596;26504410;26778538;27216216;27531679;27550239;27557302;27705267;28211560;28430175;28637662;29341834;29976492;7683017",
"title": "The Safety Profile of Concurrent Therapy for Multiple Myeloma in the Modern Era.",
"title_normalized": "the safety profile of concurrent therapy for multiple myeloma in the modern era"
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"companynumb": "US-JNJFOC-20190201429",
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"activesubstancename": "BORTEZOMIB"
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"abstract": "It remains unclear whether therapeutic drug monitoring (TDM) of pazopanib improves treatment outcomes in routine clinical practice. We did a prospective cohort study to evaluate the benefits of TDM for pazopanib therapy in real-world practice. Among 25 patients with pharmacokinetically guided dosing, only 5 (20%, 95% confidence interval 6.8-40.7%) discontinued treatment because of adverse events. However, 5 (41.7%, 95% confidence interval 15.2-72.3%) of historical controls including 12 patients not receiving such a strategy experienced adverse events leading to early termination. PK-guided dosing significantly increased median time-to-treatment discontinuation (252 vs 74 days, P = .012) with reduced toxicity and improved overall survival (not reached vs 313 days, P = .002) relative to conventional dosing in the control group. In conclusion, PK-guided dose adaptation through the use of TDM has the potential to improve treatment outcomes of pazopanib in routine clinical practice, warranting larger, randomized studies.",
"affiliations": "Department of Hospital Pharmacy and Pharmacology, Asahikawa Medical University, Asahikawa, Japan.;Department of Renal and Urologic Surgery, Asahikawa Medical University, Asahikawa, Japan.;Department of Renal and Urologic Surgery, Asahikawa Medical University, Asahikawa, Japan.;Department of Orthopedic Surgery, Asahikawa Medical University, Asahikawa, Japan.;Department of Orthopedic Surgery, Asahikawa Medical University, Asahikawa, Japan.",
"authors": "Fukudo|Masahide|M|0000-0002-7703-7827;Tamaki|Gaku|G|;Azumi|Makoto|M|;Shibata|Hiroaki|H|;Tandai|Susumu|S|",
"chemical_list": "D007191:Indazoles; D011743:Pyrimidines; D013449:Sulfonamides; C516667:pazopanib",
"country": "England",
"delete": false,
"doi": "10.1111/bcp.14580",
"fulltext": null,
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"issn_linking": "0306-5251",
"issue": "87(4)",
"journal": "British journal of clinical pharmacology",
"keywords": "individualized dosing; pazopanib, pharmacokinetics; therapeutic drug monitoring",
"medline_ta": "Br J Clin Pharmacol",
"mesh_terms": "D016903:Drug Monitoring; D006801:Humans; D007191:Indazoles; D011446:Prospective Studies; D011743:Pyrimidines; D013449:Sulfonamides",
"nlm_unique_id": "7503323",
"other_id": null,
"pages": "2132-2139",
"pmc": null,
"pmid": "33010046",
"pubdate": "2021-04",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Pharmacokinetically guided dosing has the potential to improve real-world outcomes of pazopanib.",
"title_normalized": "pharmacokinetically guided dosing has the potential to improve real world outcomes of pazopanib"
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"activesubstancename": "PAZOPANIB"
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"abstract": "Nalbuphine and fentanyl were compared as analgesic components of intravenous conscious sedation with diazepam in a double-blind, prospective trial of 50 patients undergoing elective oral surgery. Subjects were evaluated for intensity of pain, pain relief, sedation, anxiety, recall, and vital signs at systematic observation points intraoperatively and postoperatively. At the conclusion of surgery, 88% who received nalbuphine and 87% treated with fentanyl indicated complete pain relief. One observed adverse reaction was attributed to the combination of fentanyl and the sedative component diazepam. No statistically significant differences were observed between nalbuphine and fentanyl treatments.",
"affiliations": "Division of Oral and Maxillofacial Surgery, Duke University Medical Center, Durham, North Carolina 27710.",
"authors": "Dolan|E A|EA|;Murray|W J|WJ|;Immediata|A R|AR|;Gleason|N|N|",
"chemical_list": "D009019:Morphinans; D009266:Nalbuphine; D003975:Diazepam; D005283:Fentanyl",
"country": "United States",
"delete": false,
"doi": "10.1016/0278-2391(88)90414-4",
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"issue": "46(6)",
"journal": "Journal of oral and maxillofacial surgery : official journal of the American Association of Oral and Maxillofacial Surgeons",
"keywords": null,
"medline_ta": "J Oral Maxillofac Surg",
"mesh_terms": "D000328:Adult; D000766:Anesthesia, Dental; D003975:Diazepam; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005069:Evaluation Studies as Topic; D005260:Female; D005283:Fentanyl; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D009019:Morphinans; D009266:Nalbuphine; D010147:Pain Measurement; D010149:Pain, Postoperative; D011229:Preanesthetic Medication; D011446:Prospective Studies",
"nlm_unique_id": "8206428",
"other_id": null,
"pages": "471-3",
"pmc": null,
"pmid": "3164051",
"pubdate": "1988-06",
"publication_types": "D016430:Clinical Trial; D003160:Comparative Study; D018848:Controlled Clinical Trial; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Comparison of nalbuphine and fentanyl in combination with diazepam for outpatient oral surgery.",
"title_normalized": "comparison of nalbuphine and fentanyl in combination with diazepam for outpatient oral surgery"
} | [
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"companynumb": "US-ROCHE-2402339",
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"abstract": "Supraventricular tachycardia are common dysrhythmias seen in hospitalized patients. Electrolyte derangements and cardiomyopathy are among the most common causes. Rarely, blood culture negative endocarditis can lead to unexplained recurrentsupraventricular tachycardia. Herein, we present a case of recurrent atrioventricular nodal reentrant tachycardia in a patient with no previous history of cardiovascular disease.",
"affiliations": "Division of General Internal Medicine, Department of Medicine, University of Tennessee Health Science Center, Memphis, TN, USA. Electronic address: bsaadat@uthsc.edu.;Division of General Internal Medicine, Department of Medicine, University of Tennessee Health Science Center, Memphis, TN, USA.;Division of General Internal Medicine, Department of Medicine, University of Tennessee Health Science Center, Memphis, TN, USA.;Division of General Internal Medicine, Department of Medicine, University of Tennessee Health Science Center, Memphis, TN, USA.",
"authors": "Saadat|Brianna N|BN|;Haltom|Matthew B|MB|;Burroughs-Ray|Desiree C|DC|;Jackson|Christopher D|CD|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.jnma.2020.11.010",
"fulltext": null,
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"issn_linking": "0027-9684",
"issue": "113(3)",
"journal": "Journal of the National Medical Association",
"keywords": "AVNRT; Infective endocarditis; Supraventricular tachycardia",
"medline_ta": "J Natl Med Assoc",
"mesh_terms": "D002318:Cardiovascular Diseases; D004696:Endocarditis; D006801:Humans; D008487:Medical History Taking; D013611:Tachycardia, Atrioventricular Nodal Reentry; D013617:Tachycardia, Supraventricular",
"nlm_unique_id": "7503090",
"other_id": null,
"pages": "307-309",
"pmc": null,
"pmid": "33358633",
"pubdate": "2021-06",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Culture Negative Endocarditis Masquerading as Recurrent Supraventricular Tachycardia.",
"title_normalized": "culture negative endocarditis masquerading as recurrent supraventricular tachycardia"
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"abstract": "BACKGROUND\nPancreatic mucinous cystadenocarcinoma (MCAC) is a rare malignancy with a poor prognosis when it presents metastases at diagnosis. Due to its very low incidence, there are no clear recommendations for the treatment of advanced disease. Olaparib (an oral PARP inhibitor) has been approved for the maintenance treatment of patients with metastatic pancreatic adenocarcinoma harbouring germline BRCA1/2 mutations. Herein, we report the first case of a germline BRCA1 mutated unresectable MCAC which was effectively treated with olaparib.\n\n\nMETHODS\nA 41-year-old woman, without personal or family history of cancer, was diagnosed with ovarian and peritoneal metastases of MCAC. She underwent 12 cycles of gemcitabine plus oxaliplatin (GEMOX) obtaining a partial response and allowing radical surgery. One year later, local recurrence was documented, and other 12 cycles of GEMOX were administered obtaining a complete response. Seven years later, another local recurrence, not amenable to surgical resection, was diagnosed. She started FOLFIRINOX (oxaliplatin, irinotecan, leucovorin and fluorouracil), obtaining a partial response after 8 cycles. Given the excellent response to platinum-based chemotherapy, BRCA testing was performed, and a BRCA1 germline mutation was detected. She was switched to maintenance olaparib due to chemotherapy-related toxicities and achieved an almost complete metabolic response, with a reduction in the diameter of the lesion, after three months of therapy.\n\n\nCONCLUSIONS\nThe current case suggests the beneficial effect of olaparib in BRCA mutated MCAC. However, further studies are required.",
"affiliations": "Department of Experimental, Diagnostic, and Specialty Medicine-DIMES, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna 40138, Italy.;Department of Experimental, Diagnostic, and Specialty Medicine-DIMES, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna 40138, Italy. riccardo.carloni2@studio.unibo.it.;Division of Oncology, Azienda Ospedaliero-Universitaria di Bologna, Bologna 40138, Italy.;Radiology Unit, Department of Diagnostic Medicine and Prevention, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna 40138, Italy.;Department of Experimental, Diagnostic, and Specialty Medicine-DIMES, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna 40138, Italy.;Medical Oncology, Ospedale Degli Infermi, Faenza 48018, Italy.;Department of Experimental, Diagnostic, and Specialty Medicine-DIMES, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna 40138, Italy.;Department of Experimental, Diagnostic, and Specialty Medicine-DIMES, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna 40138, Italy.;Department of Experimental, Diagnostic, and Specialty Medicine-DIMES, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna 40138, Italy.;Department of Experimental, Diagnostic, and Specialty Medicine-DIMES, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna 40138, Italy.;Pathology Unit, Sant'Orsola-Malpighi Hospital, Bologna 40138, Italy.;Unit of Medical Genetics, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna 40138, Italy.;Division of Pancreatic Surgery, Azienda Ospedaliero-Universitaria Di Bologna, Bologna 40138, Italy.;Division of Pancreatic Surgery, Azienda Ospedaliero-Universitaria Di Bologna, Bologna 40138, Italy.;Division of Pancreatic Surgery, Azienda Ospedaliero-Universitaria Di Bologna, Bologna 40138, Italy.;Division of Pancreatic Surgery, Azienda Ospedaliero-Universitaria Di Bologna, Bologna 40138, Italy.;Radiology Unit, Department of Diagnostic Medicine and Prevention, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna 40138, Italy.;Department of Experimental, Diagnostic, and Specialty Medicine-DIMES, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna 40138, Italy.;Division of Pancreatic Surgery, Azienda Ospedaliero-Universitaria Di Bologna, Bologna 40138, Italy.",
"authors": "Di Marco|Mariacristina|M|;Carloni|Riccardo|R|;De Lorenzo|Stefania|S|;Mosconi|Cristina|C|;Palloni|Andrea|A|;Grassi|Elisa|E|;Filippini|Daria Maria|DM|;Ricci|Angela Dalia|AD|;Rizzo|Alessandro|A|;Di Federico|Alessandro|A|;Santini|Donatella|D|;Turchetti|Daniela|D|;Ricci|Claudio|C|;Ingaldi|Carlo|C|;Alberici|Laura|L|;Minni|Francesco|F|;Golfieri|Rita|R|;Brandi|Giovanni|G|;Casadei|Riccardo|R|",
"chemical_list": null,
"country": "China",
"delete": false,
"doi": "10.4251/wjgo.v12.i12.1456",
"fulltext": "\n==== Front\nWorld J Gastrointest Oncol\nWJGO\nWorld Journal of Gastrointestinal Oncology\n1948-5204 Baishideng Publishing Group Inc \n\njWJGO.v12.i12.pg1456\n10.4251/wjgo.v12.i12.1456\nCase Report\nPancreatic mucinous cystadenocarcinoma in a patient harbouring BRCA1 germline mutation effectively treated with olaparib: A case report\nDi Marco M et al. Pancreatic mucinous cystadenocarcinoma treated with olaparibDi Marco Mariacristina Department of Experimental, Diagnostic, and Specialty Medicine-DIMES, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna 40138, Italy\nDivision of Oncology, Azienda Ospedaliero-Universitaria di Bologna, Bologna 40138, Italy\n Carloni Riccardo Department of Experimental, Diagnostic, and Specialty Medicine-DIMES, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna 40138, Italy. riccardo.carloni2@studio.unibo.it\n De Lorenzo Stefania Division of Oncology, Azienda Ospedaliero-Universitaria di Bologna, Bologna 40138, Italy\n Mosconi Cristina Radiology Unit, Department of Diagnostic Medicine and Prevention, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna 40138, Italy\n Palloni Andrea Department of Experimental, Diagnostic, and Specialty Medicine-DIMES, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna 40138, Italy\n Grassi Elisa Medical Oncology, Ospedale Degli Infermi, Faenza 48018, Italy\n Filippini Daria Maria Department of Experimental, Diagnostic, and Specialty Medicine-DIMES, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna 40138, Italy\n Ricci Angela Dalia Department of Experimental, Diagnostic, and Specialty Medicine-DIMES, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna 40138, Italy\n Rizzo Alessandro Department of Experimental, Diagnostic, and Specialty Medicine-DIMES, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna 40138, Italy\n Di Federico Alessandro Department of Experimental, Diagnostic, and Specialty Medicine-DIMES, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna 40138, Italy\n Santini Donatella Pathology Unit, Sant'Orsola-Malpighi Hospital, Bologna 40138, Italy\n Turchetti Daniela Unit of Medical Genetics, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna 40138, Italy\n Ricci Claudio Division of Pancreatic Surgery, Azienda Ospedaliero-Universitaria Di Bologna, Bologna 40138, Italy\nDepartment of Internal Medicine and Surgery, Alma Mater Studiorum, University of Bologna, Bologna 40138, Italy\n Ingaldi Carlo Division of Pancreatic Surgery, Azienda Ospedaliero-Universitaria Di Bologna, Bologna 40138, Italy\nDepartment of Internal Medicine and Surgery, Alma Mater Studiorum, University of Bologna, Bologna 40138, Italy\n Alberici Laura Division of Pancreatic Surgery, Azienda Ospedaliero-Universitaria Di Bologna, Bologna 40138, Italy\nDepartment of Internal Medicine and Surgery, Alma Mater Studiorum, University of Bologna, Bologna 40138, Italy\n Minni Francesco Division of Pancreatic Surgery, Azienda Ospedaliero-Universitaria Di Bologna, Bologna 40138, Italy\nDepartment of Internal Medicine and Surgery, Alma Mater Studiorum, University of Bologna, Bologna 40138, Italy\n Golfieri Rita Radiology Unit, Department of Diagnostic Medicine and Prevention, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna 40138, Italy\n Brandi Giovanni Department of Experimental, Diagnostic, and Specialty Medicine-DIMES, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna 40138, Italy\nDivision of Oncology, Azienda Ospedaliero-Universitaria di Bologna, Bologna 40138, Italy\n Casadei Riccardo Division of Pancreatic Surgery, Azienda Ospedaliero-Universitaria Di Bologna, Bologna 40138, Italy\nDepartment of Internal Medicine and Surgery, Alma Mater Studiorum, University of Bologna, Bologna 40138, Italy\n Author contributions: Di Marco M, Carloni R and De Lorenzo S reviewed the literature and contributed to manuscript drafting; Brandi G, Grassi E, Di Federico A and Palloni A were the patient’s attending physicians and contributed to manuscript drafting; Golfieri R and Mosconi C reviewed the MRI findings and selected the figures; Filippini DM, Ricci AD and Rizzo A reviewed the literature; Ricci C, Ingaldi C, Alberici L, Minni F and Casadei R were the patient’s surgeons and reviewed the literature; Santini D and Turchetti D performed pathological examinations and BRCA testing, respectively, and reviewed the literature; Di Marco M was responsible for revision of the manuscript for important intellectual content; all authors issued final approval for the version to be submitted.\n\nCorresponding author: Riccardo Carloni, MD, Doctor, Department of Experimental, Diagnostic, and Specialty Medicine-DIMES, Sant'Orsola-Malpighi Hospital, University of Bologna, Via Massarenti 9, Bologna 40138, Italy. riccardo.carloni2@studio.unibo.it\n\n\n15 12 2020 \n15 12 2020 \n12 12 1456 1463\n13 10 2020 1 11 2020 10 11 2020 ©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.2020This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/Licenses/by-nc/4.0/BACKGROUND\nPancreatic mucinous cystadenocarcinoma (MCAC) is a rare malignancy with a poor prognosis when it presents metastases at diagnosis. Due to its very low incidence, there are no clear recommendations for the treatment of advanced disease. Olaparib (an oral PARP inhibitor) has been approved for the maintenance treatment of patients with metastatic pancreatic adenocarcinoma harbouring germline BRCA1/2 mutations. Herein, we report the first case of a germline BRCA1 mutated unresectable MCAC which was effectively treated with olaparib.\n\nCASE SUMMARY\nA 41-year-old woman, without personal or family history of cancer, was diagnosed with ovarian and peritoneal metastases of MCAC. She underwent 12 cycles of gemcitabine plus oxaliplatin (GEMOX) obtaining a partial response and allowing radical surgery. One year later, local recurrence was documented, and other 12 cycles of GEMOX were administered obtaining a complete response. Seven years later, another local recurrence, not amenable to surgical resection, was diagnosed. She started FOLFIRINOX (oxaliplatin, irinotecan, leucovorin and fluorouracil), obtaining a partial response after 8 cycles. Given the excellent response to platinum-based chemotherapy, BRCA testing was performed, and a BRCA1 germline mutation was detected. She was switched to maintenance olaparib due to chemotherapy-related toxicities and achieved an almost complete metabolic response, with a reduction in the diameter of the lesion, after three months of therapy. \n\nCONCLUSION\nThe current case suggests the beneficial effect of olaparib in BRCA mutated MCAC. However, further studies are required. \n\nMucinous cystadenocarcinomaPancreatic cancerBRCA1 geneOlaparibCase report\n==== Body\nCore Tip: Pancreatic mucinous cystadenocarcinoma (MCAC) is a rare malignancy with a poor prognosis when it presents metastases at diagnosis. Due to its very low incidence, there are no clear recommendations for the treatment of advanced disease. Olaparib (an oral PARP inhibitor) has remarkable curative effects in BRCA mutated pancreatic ductal adenocarcinoma, breast and ovarian cancers. However, there are few data on its efficacy in the treatment of other types of pancreatic malignancies. Herein, we report the first case of a germline BRCA1 mutated MCAC which was effectively treated with olaparib. We also provide a brief overview of the most relevant clinical features of MCAC.\n\nINTRODUCTION\nMucinous cystic neoplasms (MCNs) of the pancreas range from benign mucinous cystadenoma to malignant cystadenocarcinoma, and they represent 23% of all resected pancreatic cysts[1]. Lou et al[2] estimated that pancreatic mucinous cystadenocarcinoma (MCAC) accounts for approximately 0.5% of all pancreatic malignancies, using the Surveillance, Epidemiology and End Results program database. Surgery represents the first choice of treatment for patients with resectable disease. The prognosis of resectable MCAC seems to be significantly more favourable compared to that of pancreatic ductal adenocarcinoma (PDAC)[3]. However, locally advanced and metastatic MCACs have a poor prognosis. Due to the very low incidence of MCAC, both controlled prospective studies and clear recommendations for the treatment of advanced disease are lacking[4].\n\n\nBRCA1 and BRCA2 genes code for proteins that are involved in homologous recombination repair of double-strand DNA breaks, and their mutations are associated with an increased risk of several types of cancer[5]. In pancreatic adenocarcinoma, the prevalence of germline BRCA1/2 mutations among patients with apparently sporadic forms of the disease ranges from 1.8% to 4.6%[6,7]. Recently, maintenance olaparib (an oral PARP inhibitor) has been approved for the treatment of patients with metastatic pancreatic adenocarcinoma harbouring germline BRCA1/2 mutations based on the results of the POLO trial[8]. Nevertheless, the prevalence of germline BRCA1/2 mutations in pancreatic MCAC is unclear, and there are no data on the efficacy of PARP inhibitors in the treatment of BRCA1/2 mutated MCAC. \n\nCASE PRESENTATION\nChief complaints\nA 41-year-old Caucasian woman was referred to our centre. She had a history of nausea, constipation and epigastric pain for several months.\n\nHistory of present illness\nThe patient had no relevant events in her medical history.\n\nHistory of past illness\nThe patient had no relevant events in her medical history.\n\nPersonal and family history\nNo significant personal or family history. \n\nPhysical examination\nUnremarkable.\n\nLaboratory examinations\nThe serum cancer antigen (CA) 125 level was 150 IU/mL (reference range 0.00–35.00 IU/mL), while serum CA19-9 level was 354 IU/mL (reference range 0.00–37.00 IU/mL) and serum carcinoembryonic antigen (CEA) level was 13.4 ng/mL (reference range 0.00–5.00 ng/mL for non-smokers).\n\nImaging examinations\nShe underwent computed tomography (CT) which revealed two bilateral ovarian masses 145 mm and 71 mm in diameter, respectively, and a lesion measuring 40 mm in the body of the pancreas. \n\nFINAL DIAGNOSIS\nPathology revealed ovarian and peritoneal metastases of pancreatic MCAC.\n\nTREATMENT\nSuspecting two different tumours, she underwent surgery with radical intent in November 2008. The surgeons immediately detected a previously unrecognized peritoneal carcinosis during the exploratory laparotomy. Nonetheless, they still performed a hysterectomy and a bilateral salpingo-oophorectomy to resolve the associated symptoms caused by these masses. The surgical specimen included the uterus and ovaries, which were macroscopically infiltrated by two cystic lesions measuring 65 mm × 60 mm × 40 mm and 100 mm × 90 mm × 50 mm, respectively. Pathology revealed ovarian and peritoneal metastases of pancreatic MCAC (Figure 1). One month later, she started chemotherapy with gemcitabine plus oxaliplatin (GEMOX, gemcitabine 1000 mg/sm/d1 and oxaliplatin 100 mg/sm/d2 every two weeks) obtaining a partial response after 12 cycles. Given the excellent response to chemotherapy, we performed a second exploratory laparotomy in October 2009 during which no peritoneal carcinosis was found. She underwent distal pan-createctomy and pathological examination confirmed the initial diagnosis of pancreatic MCAC. The patient remained disease-free until September 2011, when both CT and 18F-fluoro-D-glucose positron emission tomography/X-ray computed tomography (18F-FDG PET-CT) showed a local recurrence and GEMOX was restarted obtaining a complete response after 12 cycles (confirmed both by CT and 18-FDG PET-CT). In June 2019, during the follow-up program, laboratory tests documented an increase of serum CEA (14.2 ng/mL), while serum CA125 and CA19-9 were normal. We performed magnetic resonance imaging and 18F-FDG PET-CT (Figure 2) which showed a local recurrence not amenable to surgical resection (invasion of the hepatic artery and superior mesenteric vein). The diagnosis was confirmed with an endoscopic ultrasound-guided biopsy. She started FOLFIRINOX (oxaliplatin 85 mg/sm, irinotecan 180 mg/sm, leucovorin 400 mg/sm and fluorouracil 400 mg/sm given as a bolus followed by 2400 mg/sm as a 46 h continuous infusion, every two weeks) obtaining a significant response, with a decrease of 18F-FDG uptake (SUV = 3.9 vs 6) and reduction in CEA level (2.78 ng/mL) after 8 cycles (Figure 3). However, toxicities were observed and included febrile neutropenia and grade 3 vomiting. Considering the excellent radiological response to platinum-based chemotherapy, we performed BRCA testing. Constitutional DNA of the patient was analyzed for BRCA1 and BRCA2 variants using Next Generation Sequencing (ION Torrent S5) and the variant c.4117G>T (p.Glu1373Ter) was detected in the BRCA1 gene. In January 2020 she was switched to maintenance olaparib tablets (300 mg twice daily) with good tolerance, except for anaemia G2 and fatigue G1. \n\nFigure 1 \nHistological examination of the ovarian metastases. A: Hematoxylin-eosin staining (× 10) of the resected specimen showing glandular areas (arrows) next to cystic spaces (stars); B: Higher-power view (× 20) of the glands shown before displaying malignant cytology and an infiltrating pattern. \n\nFigure 2 \nMagnetic resonance imaging and 18F-fluoro-D-glucose positron emission tomography/X-ray computed tomography. June 2019, Magnetic resonance imaging (MRI) shows the presence of a lesion approximately 4.4 cm × 3.2 cm in the cephalopancreatic area, with MRI characteristics compatible with local recurrence of the basic neoplastic pathology; A: Arterial phase; B: Portal phase; C and D: 18F-fluoro-D-glucose (FDG) positron emission tomography/X-ray computed tomography confirms the diagnostic suspicion of disease recurrence showing a pathological 18F-FDG uptake. \n\nFigure 3 \n18F-fluoro-D-glucose positron emission tomography/X-ray computed tomography performed after eight courses of FOLFIRINOX. A and B: 18F-fluoro-D-glucose positron emission tomography/X-ray computed tomography shows a metabolic reduction in cephalopancreatic disease.\n\nOUTCOME AND FOLLOW-UP\nAn 18F-FDG PET-CT performed in May 2020 documented an almost complete metabolic response (SUV = 2.1) with a reduction in the diameter of the lesion (Figure 4). Over the next three weeks, treatment was discontinued due to drug shortage related to the COVID-19 pandemic. In June 2020, treatment was restarted and another 18F-FDG PET-CT performed in September 2020 revealed 18F-FDG uptake similar to that shown in May 2020 (SUV = 2.3), while CEA level was 1.45 ng/mL. The patient is still well and receiving olaparib.\n\nFigure 4 18F-fluoro-D-glucose positron emission tomography/X-ray computed tomography performed after three months of maintenance olaparib. A and B: 18F-fluoro-D-glucose positron emission tomography/X-ray computed tomography shows complete metabolic normalization of the pancreatic lesion, which is also reduced in size.\n\nDISCUSSION\nMucin-producing cystic tumours of the pancreas are classified into two different entities: Intraductal papillary mucinous neoplasms (IPMNs) and MCNs, which are defined by the presence of ovarian-type stroma and do not communicate with the ductal system, unlike IPMNs[9-13]. MCNs represent 23% of all resected pancreatic cysts with a mean age at diagnosis of 51 years[1], whereas the mean age at diagnosis for MCAC is higher with a difference of more than ten years (mean 64 years)[2]. MCAC represents the malignant form of a mucinous cystic neoplasm; approximately 70% of all patients are female presenting with a relatively large tumour (median size 5.5 cm) which is mainly located in the body/tail of the pancreas[14]. MCAC is usually symptomatic at the time of diagnosis with pain (59%) and jaundice (32%) being the two most frequent symptoms. Also, serum CA19-9 level is often increased[15]. The prognosis of resectable MCAC seems to be significantly more favourable compared to pancreatic ductal adenocarcinoma[2,3]. In a retrospective study involving 507 patients with MCAC, the median observed survival for patients with resectable disease was 111.0 mo vs 14.0 mo and 4.0 mo for those with regional and metastatic disease, respectively[14]. Interestingly, the performance of curative-intent surgery and the tumour stage were independent predictors of survival. Instead, tumour size seemed to have an insignificant impact on the disease-specific survival of patients with localized MCAC, different to pancreatic ductal adenocarcinoma[16]. Due to the very low incidence of this malignancy, there are no prospective studies focusing on chemotherapy for MCAC, and data are available from only case series and case reports. Thus, it is unclear what is the most appropriate therapeutic approach for advanced disease[4,17,18]. This fact is reflected in the poor prognosis of advanced MCAC, especially when compared with that of resectable disease.\n\nBRCA1 and BRCA2 proteins play a crucial role in repairing double-strand DNA breaks via the homologous DNA repair mechanism. Deleterious mutations within these genes are associated with an increased risk of breast, ovarian and prostate cancer[19,20]. In addition, germline BRCA1 and BRCA2 mutations are associated with a relative risk of 2.26 and 3.51 for developing pancreatic adenocarcinoma, respectively[21,22]. PARP inhibitors interfere with base excision repair, a crucial pathway in the repair of DNA single-strand breaks, causing an accumulation of single-strand DNA breaks which result into DNA double-strand breaks. Inactivation of BRCA1 or BRCA2 genes sensitizes cells to the inhibition of PARP, causing cell cycle arrest and apoptosis when cells are exposed to PARP inhibitors[23]. Olaparib (an oral PARP inhibitor) has recently been approved for the maintenance treatment of patients with metastatic pancreatic adenocarcinoma that had not progressed during first-line platinum-based chemotherapy[8]. To date, there are no reports of BRCA-mutated MCAC treated with PARP inhibitors.\n\nAt the time of diagnosis, our patient had metastatic disease, but an aggressive surgical approach associated with a marked response to platinum-based chemotherapy allowed a complete response. Although her family history was negative for cancer, given the impressive response to platinum-based chemotherapy, we investigated and detected a BRCA1 germline mutation. Historically, screening for BRCA mutations was offered only to those patients with a family history highly suspicious for a genetic predisposition syndrome[24]. However, this strategy fails to identify a relevant proportion of patients with germline BRCA1/2 mutations[24]. Given the results of the POLO trial, and emerging evidence on the efficacy of platinum-based chemotherapy in BRCA mutated PDAC, National Comprehensive Cancer Network guidelines now recommend germline testing for all patients with PDAC[25-27]. \n\nTo our knowledge, this is the first report on the efficacy of a PARP inhibitor in a MCAC patient harbouring a germline BRCA mutation. After three months of treatment with maintenance olaparib, we documented a deep metabolic response with a reduction in the diameter of the lesion and after seven months of therapy 18F-FDG PET-CT still shows an almost complete metabolic response. Treatment was well tolerated except for anaemia G2 and fatigue G1, and it was discontinued for only one week due to fatigue. Reported toxicities in our case are in line with previous studies, with fatigue (60%), nausea (45%) and anaemia (27%) being the three most common adverse events reported in the POLO trial[8].\n\nCONCLUSION\nIncreased use of BRCA testing, not based only on personal or family history of cancer, may help to identify a higher number of patients which could benefit from target therapies. As previously demonstrated in the treatment of patients with other types of cancers harbouring a germline BRCA mutation, we suggest that maintenance olaparib should also be considered for MCAC patients as it is safe and effective. However, further studies are needed to confirm our results. \n\nACKNOWLEDGEMENTS\nWe would like to thank the Centro Interdipartimentale di Ricerca sul Cancro “Giorgio Prodi” for the support.\n\nInformed consent statement: The patient provided informed consent for the publication of her case.\n\nConflict-of-interest statement: The authors declare that they have no conflicts of interest.\n\nCARE Checklist (2016) statement: The authors have read the CARE Checklist (2016), and the manuscript was prepared and revised according to the CARE Checklist (2016).\n\nManuscript source: Unsolicited manuscript\n\nPeer-review started: October 13, 2020\n\nFirst decision: October 23, 2020\n\nArticle in press: November 10, 2020\n\nSpecialty type: Oncology \n\nCountry/Territory of origin: Italy\n\nPeer-review report’s scientific quality classification\n\nGrade A (Excellent): A\n\nGrade B (Very good): B\n\nGrade C (Good): 0\n\nGrade D (Fair): 0\n\nGrade E (Poor): 0\n\nP-Reviewer: Tanabe H S-Editor: Zhang H L-Editor: Webster JR P-Editor: Ma YJ\n==== Refs\n1 Valsangkar NP Morales-Oyarvide V Thayer SP Ferrone CR Wargo JA Warshaw AL Fernández-del Castillo C 851 resected cystic tumors of the pancreas: a 33-year experience at the Massachusetts General Hospital Surgery 2012 152 S4 12 22770958 \n2 Luo G Fan Z Gong Y Jin K Yang C Cheng H Huang D Ni Q Liu C Yu X Characteristics and Outcomes of Pancreatic Cancer by Histological Subtypes Pancreas 2019 48 817 822 31210663 \n3 Ridder GJ Maschek H Klempnauer J Favourable prognosis of cystadeno- over adenocarcinoma of the pancreas after curative resection Eur J Surg Oncol 1996 22 232 236 8654602 \n4 Brunetti O Aprile G Marchetti P Vasile E Casadei Gardini A Scartozzi M Barni S Delfanti S De Vita F Di Costanzo F Milella M Cella CA Berardi R Cataldo I Scarpa A Basile D Mazzuca F Graziano G Argentiero A Santini D Reni M Cascinu S Silvestris N Systemic Chemotherapy for Advanced Rare Pancreatic Histotype Tumors: A Retrospective Multicenter Analysis Pancreas 2018 47 759 771 29771769 \n5 Walsh CS Two decades beyond BRCA1/2: Homologous recombination, hereditary cancer risk and a target for ovarian cancer therapy Gynecol Oncol 2015 137 343 350 25725131 \n6 Shindo K Yu J Suenaga M Fesharakizadeh S Cho C Macgregor-Das A Siddiqui A Witmer PD Tamura K Song TJ Navarro Almario JA Brant A Borges M Ford M Barkley T He J Weiss MJ Wolfgang CL Roberts NJ Hruban RH Klein AP Goggins M Deleterious Germline Mutations in Patients With Apparently Sporadic Pancreatic Adenocarcinoma J Clin Oncol 2017 35 3382 3390 28767289 \n7 Holter S Borgida A Dodd A Grant R Semotiuk K Hedley D Dhani N Narod S Akbari M Moore M Gallinger S Germline BRCA Mutations in a Large Clinic-Based Cohort of Patients With Pancreatic Adenocarcinoma J Clin Oncol 2015 33 3124 3129 25940717 \n8 Golan T Hammel P Reni M Van Cutsem E Macarulla T Hall MJ Park JO Hochhauser D Arnold D Oh DY Reinacher-Schick A Tortora G Algül H O'Reilly EM McGuinness D Cui KY Schlienger K Locker GY Kindler HL Maintenance Olaparib for Germline BRCA -Mutated Metastatic Pancreatic Cancer N Engl J Med 2019 381 317 327 31157963 \n9 Klöppel G Solcia E Longnecker DS Capella C SOBIN L Histological typing of tumors of the exocrine pancreas. World Health Organization. Geneva, Switzerland: Springer; 1996. Available from: https://www.springer.com/gp/book/9783540602804 \n10 Stark A Donahue TR Reber HA Hines OJ Pancreatic Cyst Disease: A Review JAMA 2016 315 1882 1893 27139061 \n11 Tanaka M Fernández-del Castillo C Adsay V Chari S Falconi M Jang JY Kimura W Levy P Pitman MB Schmidt CM Shimizu M Wolfgang CL Yamaguchi K Yamao K International Association of Pancreatology International consensus guidelines 2012 for the management of IPMN and MCN of the pancreas Pancreatology 2012 12 183 197 22687371 \n12 Tanaka M Chari S Adsay V Fernandez-del Castillo C Falconi M Shimizu M Yamaguchi K Yamao K Matsuno S International Association of Pancreatology International consensus guidelines for management of intraductal papillary mucinous neoplasms and mucinous cystic neoplasms of the pancreas Pancreatology 2006 6 17 32 16327281 \n13 Reddy RP Smyrk TC Zapiach M Levy MJ Pearson RK Clain JE Farnell MB Sarr MG Chari ST Pancreatic mucinous cystic neoplasm defined by ovarian stroma: demographics, clinical features, and prevalence of cancer Clin Gastroenterol Hepatol 2004 2 1026 1031 15551256 \n14 Doulamis IP Mylonas KS Kalfountzos CE Mou D Haj-Ibrahim H Nasioudis D Pancreatic mucinous cystadenocarcinoma: Epidemiology and outcomes Int J Surg 2016 35 76 82 27638187 \n15 Le Borgne J de Calan L Partensky C Cystadenomas and cystadenocarcinomas of the pancreas: a multiinstitutional retrospective study of 398 cases. French Surgical Association Ann Surg 1999 230 152 161 10450728 \n16 Park H An S Eo SH Song KB Park JH Kim KP Lee SS Cho H Seo DW Kim SC Yu E Hong SM Survival effect of tumor size and extrapancreatic extension in surgically resected pancreatic cancer: proposal for improved T classification Hum Pathol 2014 45 2341 2346 25248573 \n17 Björk Werner J Sturesson C Dawiskiba S Andersson R Mucinous cystadenocarcinoma of the pancreas - outcome following different modes of treatment Ann Gastroenterol 2011 24 213 217 24713784 \n18 Shimada K Iwase K Aono T Takeda S Yoshida H Koma M Nomura M Nishikawa K Tamagawa H Matsuda C Fushimi H Tanaka Y A case of advanced mucinous cystadenocarcinoma of the pancreas with peritoneal dissemination responding to gemcitabine Gan To Kagaku Ryoho 2009 36 995 998 19542723 \n19 Wooster R Weber BL Breast and ovarian cancer N Engl J Med 2003 348 2339 2347 12788999 \n20 Castro E Eeles R The role of BRCA1 and BRCA2 in prostate cancer Asian J Androl 2012 14 409 414 22522501 \n21 Breast Cancer Linkage Consortium Cancer risks in BRCA2 mutation carriers J Natl Cancer Inst 1999 91 1310 1316 10433620 \n22 Thompson D Easton DF Breast Cancer Linkage Consortium Cancer Incidence in BRCA1 mutation carriers J Natl Cancer Inst 2002 94 1358 1365 12237281 \n23 Farmer H McCabe N Lord CJ Tutt AN Johnson DA Richardson TB Santarosa M Dillon KJ Hickson I Knights C Martin NM Jackson SP Smith GC Ashworth A Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy Nature 2005 434 917 921 15829967 \n24 Wong W Raufi AG Safyan RA Bates SE Manji GA BRCA Mutations in Pancreas Cancer: Spectrum, Current Management, Challenges and Future Prospects Cancer Manag Res 2020 12 2731 2742 32368150 \n25 Wattenberg MM Asch D Yu S O'Dwyer PJ Domchek SM Nathanson KL Rosen MA Beatty GL Siegelman ES Reiss KA Platinum response characteristics of patients with pancreatic ductal adenocarcinoma and a germline BRCA1, BRCA2 or PALB2 mutation Br J Cancer 2020 122 333 339 31787751 \n26 Golan T Kanji ZS Epelbaum R Devaud N Dagan E Holter S Aderka D Paluch-Shimon S Kaufman B Gershoni-Baruch R Hedley D Moore MJ Friedman E Gallinger S Overall survival and clinical characteristics of pancreatic cancer in BRCA mutation carriers Br J Cancer 2014 111 1132 1138 25072261 \n27 National Comprehensive Cancer Network Pancreatic Adenocarcinoma (Version 3. 2019). Available from: https://www.nccn.org/\n\n",
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"title": "Pancreatic mucinous cystadenocarcinoma in a patient harbouring BRCA1 germline mutation effectively treated with olaparib: A case report.",
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"abstract": "We describe a case of unilateral renal lymphangiectasia (RLM) in a 30-year-old male with severe, refractory hypertension (HTN) and end-organ effects despite five anti-hypertensives. After diagnostic testing, the patient ultimately underwent a successful right laparoscopic nephrectomy with significant improvement of HTN. We review the literature regarding the pathophysiology and management strategies of HTN in patients with renal lymphangiectasia.",
"affiliations": "Department of Surgery, Division of Urology, Fox Chase Cancer Center - Temple University Health System, USA.;Department of Surgery, Division of Urology, Fox Chase Cancer Center - Temple University Health System, USA.;Division of Cardiology, Heart and Vascular Institute - Temple University Health System, USA.;Department of Anatomic Pathology, Fox Chase Cancer Center - Temple University Health System, USA.;Department of Surgery, Division of Urology, Fox Chase Cancer Center - Temple University Health System, USA.;Department of Surgery, Division of Urology, Fox Chase Cancer Center - Temple University Health System, USA.",
"authors": "Uzzo|Robert N|RN|;Bloom|Evan|E|;Peters|Andrew|A|;Parab|Meena|M|;Masic|Selma|S|;Kutikov|Alexander|A|",
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"fulltext": "\n==== Front\nUrol Case Rep\nUrol Case Rep\nUrology Case Reports\n2214-4420 Elsevier \n\nS2214-4420(20)30065-6\n10.1016/j.eucr.2020.101177\n101177\nOncology\nRefractory hypertension due to unilateral renal lymphangiectasia: An uncommon case with a surgical solution\nUzzo Robert N. a Bloom Evan a Peters Andrew b Parab Meena c Masic Selma a Kutikov Alexander Alexander.Kutikov@fccc.edua∗ a From the Department of Surgery, Division of Urology, Fox Chase Cancer Center – Temple University Health System, USA\nb From the Division of Cardiology, Heart and Vascular Institute – Temple University Health System, USA\nc From the Department of Anatomic Pathology, Fox Chase Cancer Center – Temple University Health System, USA\n∗ Corresponding author. Division of Urologic Oncology, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA, 19111, USA. Alexander.Kutikov@fccc.edu\n08 4 2020 \n9 2020 \n08 4 2020 \n32 1011773 3 2020 26 3 2020 © 2020 The Authors. Published by Elsevier Inc.2020This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).We describe a case of unilateral renal lymphangiectasia (RLM) in a 30-year-old male with severe, refractory hypertension (HTN) and end-organ effects despite five anti-hypertensives. After diagnostic testing, the patient ultimately underwent a successful right laparoscopic nephrectomy with significant improvement of HTN. We review the literature regarding the pathophysiology and management strategies of HTN in patients with renal lymphangiectasia.\n\nHighlights\n• Renal lymphangiectasia (RLM) is an uncommon cause of secondary hypertension.\n\n• RLM is diagnosed using conventional imaging which notes dilated perinephric and/or peri-pelvic lymphatic channels.\n\n• RLM is believed to be an uncommon benign and congenital developmental malformation of the renal sinus lymphatics.\n\n• Clinically the condition is most often asymptomatic, but symptoms may include flank pain, hematuria, ascites, weight loss, HTN, or other vague constitutional symptoms.\n\n• Antihypertensive therapy is the mainstay of treatment, but refractory drainage and/or nephrectomy may improve BP control.\n\n\n\nKeywords\nLymphangiectasiaPage kidneyHypertension\n==== Body\n1 Introduction\nWhile primary hypertension (HTN) accounts for most cases of sustained HTN, secondary HTN, due to a remediable cause, accounts for 5-10% of additional cases. Other than sleep apnea, secondary HTN is most commonly due to renovascular pathophysiology.1\n\nWe present an unusual case of secondary HTN and end-organ effects due to unilateral renal lymphangiectasia (RLM). We review the presentation, evaluation, treatment with laparoscopic nephrectomy, and subsequent course. To our knowledge, this represents the first case of severe, refractory HTN due to unilateral RLM, and improvement following nephrectomy.\n\n2 Case presentation\nA 30-year-old male presented with severe, refractory HTN (>160/110 mmHg) despite five anti-hypertensive agents (lisinopril, amlodipine, clonidine, carvedilol, hydrochlorothiazide which was replaced with chlorthalidone). He was first diagnosed with HTN at age eight and started on lisinopril at age 19. He developed hypertensive retinopathy in his twenties with retinal hemorrhage and partial vision loss requiring multiple bilateral eye surgeries. His past medical history was remarkable for mild diabetes mellitus (NIDDM), chronic kidney disease (CKD) stage 2 (eGFR = 86), and obesity (BMI 31.4). Physical exam was unremarkable. Serum creatinine was 1.14 mg/dl, hemoglobin 13.5 g/dl, resting peripheral renin 21.7 ng/dl (ref = 0.167–5.38) on lisinopril, aldosterone 4.9 ng/ml/hr (ref = 0-30), and aldosterone/renin ratio 0.23 ng/dl per ng/ml/hr.\n\nRenal artery duplex ultrasound revealed no arterial stenosis and normal resistive indices. Abdominal computerized tomography noted multiple right parapelvic cysts with pelvic calyceal system distortion and perinephric fluid suggestive of intrarenal and retroperitoneal lymphangiectasia (Fig. 1).Fig. 1 Axial CT angiogram.CT scan of the abdomen with contreast demonstrates right-sided RLM and dilated retropertoneal iymphatics as indicated by the arrow.A delayed right nephorgram is suggestive of impaired circulation.\n\nFig. 1\n\nThe patient underwent aspiration of the paranephric fluid to assess for lymphatic content given clinical suspicion for lymphangiectasia. The fluid noted a neutrophil-predominant (74%) leukocytosis with elevated white cell count (31 cells/mm3), absent chylomicrons, total protein content (<3.0 g/dl), and normal creatinine (0.9 mg/dl). These findings are consistent with prior descriptions of renal lymphangiectasia with the exception of his leukocytosis, which was neutrophil-predominant compared to previous small published series, which were lymphocyte predominant.2\n\nFollowing aspiration of all the paranephric fluid, the patient's blood pressure (BP) remained unchanged. Further review of imaging revealed a diminutive versus absent main renal vein, and dilated perirenal and pararenal lymphatics. The lymphangiectasia appeared predominantly intrarenal and not amenable to additional percutaneous drainage or sclerosis. Given the patient's refractory HTN with hypertensive retinopathy and adverse sequela, a right laparoscopic nephrectomy was recommended and subsequently performed (Fig. 2). Microscopic evaluation demonstrated endothelial-lined cysts containing lymph fluid and surrounding focal inflammation (Fig. 3).Fig. 2 Right nephrectomy specimen.Gross anatomy of the right kidney specimen demonstrates server peri-pelvic and intrarenal lymphatic dilatation and diminished parenchymal volume.\n\nFig. 2Fig. 3 Microscopic examination with hematoxylin and eosin (H&E) stains.(a)2x magnification showing lymphangioma (center) in relation to renal parenchyma (top) and sinus fat (bottom).(b)10x magnification showing cystic spaces lined by endothelial cells with focal inflammation as demonstrated by a lymphocytic infiltrate.\n\nFig. 3\n\nAfter surgery, the patient's BP regimen was reduced to two medications (lisinopril and carvedilol). At his 3-week follow-up, he reported systolic BPs between 140 and 150 mmHg at home. Two months postoperatively, his BP was 140/90 mmHg, and his carvedilol was increased slightly with a BP goal of <130/80 mmHg. Four months postoperatively, his BP was 135/100 mmHg on the same regimen. The patient recovered well surgically with a stable creatinine of 1.4–1.5 mg/dl. He was referred to nephrology given his complex comorbidity profile and solitary kidney.\n\n3 Discussion\nRenal lymphangiectasia is a rare clinical entity. Diagnosis is based primarily on radiological features of dilated perinephric and/or peri-pelvic lymphatic channels. It is believed to be a benign developmental malformation that results from noncommunication of perirenal and peri-pelvic lymphatic channels with the main lymphatic system.3 The resulting cystic lesions may be intrarenal and involving the renal sinus or parenchyma, or extrarenal and involving the perirenal fascia.4 Familial associations have been made in some cases arguing for a congenital etiology.3\n\nThe nomenclature for the disorder is varied in the literature and includes renal lymphangiomatosis, renal lymphangioma, and renal peri-pelvic multi-cystic lymphangiectasia.4 Clinically the condition is most often asymptomatic but may present with variable manifestations including flank pain, hematuria, ascites, weight loss, HTN, or other vague constitutional symptoms. While overall renal function is usually preserved, cases of renal insufficiency with anemia or polycythemia have been reported, particularly when bilateral.4 Radiographically, the lesions may present as diffuse renal enlargement and/or dilated cystic lesions affecting various parts of the renal parenchyma and collecting system. Pathology can be unilateral or bilateral as well as focal or diffuse.3 Occasionally, patients present with retroperitoneal fluid in the subcapsular, perirenal or pararenal spaces.4\n\nIn a series by Schwarz et al. examining 42 cases of symptomatic RLM, nearly 60% were associated with HTN. Of these, nearly 2/3 reported that HTN was reversible or markedly improved by drainage or resection of the cysts or nephrectomy.5 Several authors presume the mechanism of HTN is related to a Goldblatt-like effect on the renal parenchyma causing pressure-related ischemia and renin release. This compression effect is known as Page Kidney and has been described under a number of clinical conditions. The diagnosis is usually based on clinical suspicion and radiographic findings on ultrasound and/or CT. In typical cases, renal compression leads to ischemia and triggers release of vasoactive hormones by the renin-angiotensin-aldosterone system (RAAS). This in turn results in arterial HTN. Multiple pharmacological therapies targeting RAAS may improve BP control but fail to completely overcome the effects of renal compression on systemic BP. Interventions to reduce parenchymal compression such as cyst decortication or paranephric fluid aspiration may diminish the compressive effects on the kidney and improve BP.5 Unfortunately, in cases of predominantly intrarenal RLM as described in our patient, the compressive effects on renal parenchyma are intrarenal and diffuse and therefore less amenable to such interventions. While RLM may respond to medical therapy or even spontaneously regress in rare patients, the condition usually persists and necessitates escalation of therapy as was the case for our patient.\n\n4 Conclusion\nWe present an unusual case of unilateral intrarenal RLM in a young man with refractory HTN and end-organ disease. Despite aggressive pharmacologic therapy with five antihypertensives, the HTN persisted. Given the diffuse and predominantly intrarenal distribution of lymphangiectasia, aspiration did not improve BP control and the patient ultimately underwent laparoscopic nephrectomy. He recovered well postoperatively and had significant BP improvement with a reduced antihypertensive regimen.\n\nSupport\nNone.\n\nFinancial disclosure\nThe authors declare that they have no relevant financial interests.\n\nDeclaration of competing interest\nThe authors have no conflicts of interest to disclose.\n\nThis work was supported by the National Cancer Institute [grant number P30 CA006972]. Its contents are solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health.\n\nAcknowledgements\nThe authors would like to thank Drs. Ziho Lee, David Becker, and Arthur Patchefsky for their care and thoughtful review of this manuscript.\n==== Refs\nReferences\n1 Rimoldi S.F. Scherrer U. Messerli F.H. Secondary arterial hypertension: when, who, and how to screen? Eur Heart J 35 19 2014 1245 1254 24366917 \n2 Meredith W.T. Levine E. Ahlstrom N.G. Exacerbation of familial renal lymphangiomatosis during pregnancy AJR Am J Roentgenol 151 5 1988 965 966 3263029 \n3 Pandya V.K. Shah M.K. Ghandi S.P. Bilateral renal lymphangiectasia J Clin Diagn Res 10 9 2016 TD01 TD02 \n4 Upreti L. Dev A. Kumar Puri S. Imaging in renal lymphangiectasia: report of two cases and review of literature Clin Radiol 63 9 2008 1057 1062 18718237 \n5 Schwarz A. Lenz T. Klaen R. Hygroma renale: pararenal lymphatic cysts associated with renin-dependent hypertension (Page kidney). Case report on bilateral cysts and successful therapy by marsupialization J Urol 150 3 1993 953 957 8345618\n\n",
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"mesh_terms": "D000230:Adenocarcinoma; D000368:Aged; D000970:Antineoplastic Agents; D003131:Combined Modality Therapy; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D008175:Lung Neoplasms; D010190:Pancreatic Neoplasms; D011013:Pneumonectomy; D012086:Reoperation",
"nlm_unique_id": "7810034",
"other_id": null,
"pages": "2199-2201",
"pmc": null,
"pmid": "28133268",
"pubdate": "2016-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Long-Term Survival after Reoperation for Lung Metastasis of Resected Pancreatic Adenocarcinoma - A Case Report.",
"title_normalized": "long term survival after reoperation for lung metastasis of resected pancreatic adenocarcinoma a case report"
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"abstract": "High rates of liver enzyme elevation (LEE) in women receiving antiretroviral treatment (ART) during pregnancy have been reported, but causes remain unclear. We estimated the prevalence and risk factors of LEE in a national prospective multicenter cohort.\n\n\n\nWe studied 5748 pregnant women living with HIV enrolled in the French Perinatal Cohort 2005-2014, treated with ART, with no active hepatitis B or C coinfection. Adjusted hazard ratio (aHR) was estimated using Cox models with ART as time-dependent variable, separately for women on ART at conception and those initiating ART during pregnancy.\n\n\n\nLEE (grade ≥ 1) was observed in 16.7%, grade 3-4 in 2%. Among women with LEE, 6.7% had pre-eclampsia, 9.8% intrahepatic cholestasis of pregnancy, and 1.4% other identified medical causes. Most LEEs (82.2%) were unexplained. In women with unexplained LEE, LEE was the reason for hospitalization in 51 (6%) women, cesarean section in 13 (2%), induction of labor in 3 (0.4%), and change in ART regimen in 49 (6%) women. Unexplained LEE was associated with higher risk of preterm births, P < 0.001. Among women on ART at conception, the risk of unexplained LEE was lower with NNRTI-based regimens than with PI-based regimens: aHR = 0.5 (0.3-0.7), with no difference among the PI drugs. Most women initiating ART during pregnancy were on a PI-based regimen (89%). Among them, LEE was less frequent for women on nelfinavir vs. lopinavir/r [aHR = 0.4 (0.2-0.8)].\n\n\n\nRates of LEE among pregnant women living with HIV are high and impact obstetrical care management. The possible role of PIs needs further investigation.",
"affiliations": "Department of Obstetrics and Gynecology, APHP-Hôpital Louis Mourier, Colombes, France.;Department of Epidemiology, Centre de Recherche en Épidémiologie et Santé des Populations, Institut National de la Santé et de la Recherche Médicale (INSERM) U1018, Le Kremlin-Bicêtre, France.;Department of Infectiology, APHP-GH Pitié Salpétrière, Paris, France.;Department of Epidemiology, Centre de Recherche en Épidémiologie et Santé des Populations, Institut National de la Santé et de la Recherche Médicale (INSERM) U1018, Le Kremlin-Bicêtre, France.;Department of Infectiology, APHP-Hôpital Louis Mourier, Colombes, France.;Department of Pediatrics, AP-HP Hôpital Robert Debré, Paris, France.;Professor, Department of Pediatrics, Hôpital Necker, Paris, 75015 France.;Department of Epidemiology, Centre de Recherche en Épidémiologie et Santé des Populations, Institut National de la Santé et de la Recherche Médicale (INSERM) U1018, Le Kremlin-Bicêtre, France.",
"authors": "Sibiude|Jeanne|J|;Warszawski|Josiane|J|;Tubiana|Roland|R|;Le Chenadec|Jérôme|J|;Meier|Françoise|F|;Faye|Albert|A|;Blanche|Stéphane|S|;Mandelbrot|Laurent|L|;|||",
"chemical_list": "D019380:Anti-HIV Agents; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase",
"country": "United States",
"delete": false,
"doi": "10.1097/QAI.0000000000001963",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1525-4135",
"issue": "81(1)",
"journal": "Journal of acquired immune deficiency syndromes (1999)",
"keywords": null,
"medline_ta": "J Acquir Immune Defic Syndr",
"mesh_terms": "D000328:Adult; D000410:Alanine Transaminase; D019380:Anti-HIV Agents; D001219:Aspartate Aminotransferases; D005260:Female; D005602:France; D015658:HIV Infections; D006801:Humans; D008099:Liver; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious; D055815:Young Adult",
"nlm_unique_id": "100892005",
"other_id": null,
"pages": "83-94",
"pmc": null,
"pmid": "30702449",
"pubdate": "2019-05-01",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Liver Enzyme Elevation in Pregnant Women Receiving Antiretroviral Therapy in the ANRS-French Perinatal Cohort.",
"title_normalized": "liver enzyme elevation in pregnant women receiving antiretroviral therapy in the anrs french perinatal cohort"
} | [
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"companynumb": "FR-GILEAD-2016-0248130",
"fulfillexpeditecriteria": "1",
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"actiondrug": "6",
"activesubstance": {
"activesubstancename": "RITONAVIR"
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"drugadditional": null,
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"abstract": "Because pregnant women are often excluded from clinical trials, there is still very limited information about the risk and safety of prescription drugs during pregnancy.\nWe aimed to determine the prevalence of Adverse Drug Reactions (ADRs) in high-risk pregnant women after hospital admission. A prospective study was carried out in a teaching maternity hospital in Brazil during six months. Causality of ADRs was assessed through the Naranjo Algorithm and Korean Algorithm for ADR Causality Assessment. Severity of ADRs was assessed using Hartwig's Severity Assessment Scale.\nThe prevalence of ADRs among the 294 inpatients studied was 8.8%. The mean age was 27.14 (±7.5) y.o. Patient's age was related to the presence of ADRs, while the manifestation of these events was not associated with any adverse pregnancy outcome. 75.9% of the ADRs reported in the study were of mild severity and 24.1% were of moderate severity. No ADR was caused by drug-drug interaction; however, a significant increase in blood pressure was observed in all patients using concurrent methyldopa and ferrous sulfate.\nOverall, ADRs were not common events among high-risk pregnant women and no adverse pregnancy outcomes following these events were observed.",
"affiliations": "Núcleo de Estudos em Farmacoterapia (NEF), School of Nursing and Pharmacy (ESENFAR), Federal University of Alagoas, Brazil.;Núcleo de Estudos em Farmacoterapia (NEF), School of Nursing and Pharmacy (ESENFAR), Federal University of Alagoas, Brazil.;Department of Medicine, Federal University of Sergipe, Brazil.;Núcleo de Estudos em Farmacoterapia (NEF), School of Nursing and Pharmacy (ESENFAR), Federal University of Alagoas, Brazil.;Department of Medicine, Federal University of Sergipe, Brazil.;Department of Medicine, Federal University of Sergipe, Brazil.;Department of Medicine, Federal University of Sergipe, Brazil.;Department of Medicine, Federal University of Sergipe, Brazil.",
"authors": "de Oliveira-Filho|Alfredo Dias|AD|;Vieira|Antonio Emanuel Soares|AES|;da Silva|Roberta Cruz|RC|;Neves|Sabrina Joany Felizardo|SJF|;Gama|Thiago Antonio Barros|TAB|;Lima|Ryane Vieira|RV|;Oliveira|Wlisses Ramon|WR|;de Gonçalves Dias|Júlia Maria|JM|",
"chemical_list": null,
"country": "Saudi Arabia",
"delete": false,
"doi": "10.1016/j.jsps.2017.01.005",
"fulltext": "\n==== Front\nSaudi Pharm JSaudi Pharm JSaudi Pharmaceutical Journal : SPJ1319-01642213-7475Elsevier S1319-0164(17)30019-110.1016/j.jsps.2017.01.005ArticleAdverse drug reactions in high-risk pregnant women: A prospective study de Oliveira-Filho Alfredo Dias alfredo.dias@pq.cnpq.bra⁎Vieira Antonio Emanuel Soares ada Silva Roberta Cruz bNeves Sabrina Joany Felizardo aGama Thiago Antonio Barros bLima Ryane Vieira bOliveira Wlisses Ramon bde Gonçalves Dias Júlia Maria ba Núcleo de Estudos em Farmacoterapia (NEF), School of Nursing and Pharmacy (ESENFAR), Federal University of Alagoas, Brazilb Department of Medicine, Federal University of Sergipe, Brazil⁎ Corresponding author at: Escola de Enfermagem e Farmácia – ESENFAR, Universidade Federal de Alagoas – UFAL, Campus A. C. Simões, Av. Lourival Melo Mota, s/n, Tabuleiro do Martins, Maceió, AL CEP: 57072-970, Brazil. Fax: +55 (82) 32141154.Escola de Enfermagem e Farmácia – ESENFARUniversidade Federal de Alagoas – UFALCampus A. C. SimõesAv. Lourival Melo Motas/nTabuleiro do MartinsMaceióALCEP: 57072-970Brazil alfredo.dias@pq.cnpq.br02 2 2017 11 2017 02 2 2017 25 7 1073 1077 3 3 2016 25 1 2017 © 2017 The Authors2017This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Background\nBecause pregnant women are often excluded from clinical trials, there is still very limited information about the risk and safety of prescription drugs during pregnancy.\n\nObjective\nWe aimed to determine the prevalence of Adverse Drug Reactions (ADRs) in high-risk pregnant women after hospital admission. A prospective study was carried out in a teaching maternity hospital in Brazil during six months. Causality of ADRs was assessed through the Naranjo Algorithm and Korean Algorithm for ADR Causality Assessment. Severity of ADRs was assessed using Hartwig’s Severity Assessment Scale.\n\nResults\nThe prevalence of ADRs among the 294 inpatients studied was 8.8%. The mean age was 27.14 (±7.5) y.o. Patient's age was related to the presence of ADRs, while the manifestation of these events was not associated with any adverse pregnancy outcome. 75.9% of the ADRs reported in the study were of mild severity and 24.1% were of moderate severity. No ADR was caused by drug-drug interaction; however, a significant increase in blood pressure was observed in all patients using concurrent methyldopa and ferrous sulfate.\n\nConclusion\nOverall, ADRs were not common events among high-risk pregnant women and no adverse pregnancy outcomes following these events were observed.\n\nKeywords\nAdverse drug reactionsHigh-risk pregnancyPrevalenceMaternal ageMethyldopaFerrous sulfateDrug-drug interactions\n==== Body\n1 Introduction\nAdverse Drug Reactions (ADR) – one of the most frequent complications during hospitalization, reaching up to 30% of inpatients – can be defined as a response to a drug which is noxious and unintended and which occurs at doses normally used in humans for prophylaxis, diagnosis, or therapy of disease or for the modification of physiologic function (de Vries et al., 2008, Hakkarainen et al., 2012, Miguel et al., 2012). Consequences of ADRs include drug-related hospital admission, prolongation of hospital stay, increased risk of mortality and health problems that occur after hospitalization (Sultana et al., 2013, Pedrós et al., 2014, Nivya et al., 2015). ADRs previously reported in pregnancy include those associated with fetal disorders (e.g. malformations after use of thalidomide or antiepileptic drugs during pregnancy) and ADRs that affect the mother (e.g. gastrointestinal reactions after the use of antiretroviral drugs or iron preparations) (Dhanani et al., 2012, Wettach et al., 2013, Santini-Oliveira et al., 2014).\n\nBecause pregnant women are often excluded from clinical trials, which are the main premarketing methods used to detect and quantify ADRs, information about the safety of medications during pregnancy is limited, and epidemiological studies to assess the prevalence of these events in pregnant women are still needed, especially among patients at high risk for pregnancy complications (van Gelder et al., 2010, Sinclair et al., 2016). On the other hand, the use of prescription drugs is common during pregnancy, ranging from 23% to 96% of pregnant women worldwide (Mitchell et al., 2011, Daw et al., 2011, Matsui, 2012) and 90–95% in Brazil (Fonseca et al., 2002; Brum et al., 2011, Osorio-de-Castro et al., 2004). Furthermore, adverse drug reactions are more frequently observed among inpatients compared with outpatients and can be minimized if appropriate precautions - driven by increasing knowledge about the manifestations of these events - are taken by healthcare professionals (Hakkarainen et al., 2012; Alshammari, 2016). This study was designed to determine the prevalence of ADRs in hospitalized patients at high risk antepartum and their associated factors.\n\n2 Materials and methods\nA prospective study was carried out in a teaching maternity hospital in Aracaju, Brazil, from August 2012 to January 2015. All pregnant female patients admitted for labor with living fetus and diagnosed as having high-risk pregnancy during the study period were invited to participate in the study. High-risk pregnancy was defined as any pregnancy that threatens the health or life of the mother or her fetus due to a disorder or situation coincidental with or unique to pregnancy (Gray, 2006). Patients who left the ward before 24 h of admission were excluded. All patients were informed of the objective of the study and gave written consent before inclusion in the study, which was approved by the Ethics Committee of the Federal University of Sergipe, Brazil. Those under 18 years were required to have parental consent to participate in the study. The age of consent to sex in Brazil is 18 (16 with parental or guardian consent).\n\n2.1 Data collection\nData were collected by six trained medical students using a pre-tested questionnaire that was applied to 30 patients who were not included in the final analysis. The medical records of all patients included in the study were reviewed in a daily basis until the end of the follow-up period, in order to update clinical information, focusing on ADR, potential predictive factors and related outcomes: age, previous pregnancies, previous abortions, previous deliveries, gestational age at birth, medication use during hospitalization, diagnosis, patients complaints during hospitalization and adverse clinical findings (e.g. vital signs and complementary diagnosis examinations).\n\n2.2 Identification of ADRs - causality and severity assessments\nAdverse drug reactions were identified through the correlation between drug intake and the onset of the ADR. Two clinical pharmacists and an obstetrician physician determined causality assessment using the Naranjo Algorithm and Korean Algorithm for ADR Causality Assessment - version 2.0 (Naranjo et al., 1981, Son et al., 2011). Causality assessment of ADRs obtained with Naranjo criteria was categorized into definitely (scores from 9 to 13), probable (scores from 5 to 8), possible (1 to 4) and doubtful (less than 1). The Korean algorithm scores were categorized as follows: certain (score greater than 9), probable/likely (score from 6 to 8), possible (3–5), unlikely (1–2) and contradictory (score less than 0). To be considered an Adverse Drug Reaction, the event must be categorized as probable, at least in both scales. The identification of drug-drug interactions was based on the database DRUGDEX®, Micromedex base, considering only the interactions clinically manifested. Severity of the reactions was assessed using Hartwig’s Severity Assessment Scale – which classifies ADRs into mild, moderate and severe (Hartwig et al., 1992).\n\n2.3 Sample size and statistical analysis\nConsidering previous prevalence studies in which ADR in pregnant inpatients ranged from 0.3% to 12.1%, as well as absolute accuracy of 5% and confidence interval of 95%, a minimum sample of 162 individuals was determined (Lacroix et al., 2007, Hernández-Hernández et al., 2002). Data analysis was performed using SPSS software, release 12. Statistical analyzes involved descriptive analyzes, chi-square and Kruskal–Wallis test to test the relationship between ADR manifestation and other independent variables (age, diagnosis, previous pregnancies, previous abortions, gestational age at birth, drugs).\n\n3 Results\nWe selected 308 patients, 14 of whom declined to participate in the study (refusal rate = 4.6%). The age of patients varied from 14 to 48 years, with a mean age of 27.14 (±7.5) years. 44.9% of patients were aged from 20 to 30 years old. All patients had previous pregnancies, 79.6% were admitted during the third trimester of pregnancy, and 31.3% had at least one previous spontaneous abortion. In 98.0% of cases, fetal heart rate on admission was >130 beats/min (Table 1).Table 1 Sociodemographic and pregnancy characteristics.\n\nCharacteristic\tPatients\t\nN\t%\t\nMaternal age at delivery (years)\t\n<20\t81\t25.5\t\n20–30\t132\t44.90\t\n30–40\t67\t22.79\t\n40+\t14\t4.76\t\n\n\n\t\nGestational age\t\nNon-informed\t18\t6.12\t\nFirst trimester\t1\t0.34\t\nSecond trimester\t41\t13.95\t\nThird trimester\t234\t79.59\t\n\n\n\t\nFetal heart rate (bpm)\t\nNon-informed\t1\t0.34\t\n110–120\t2\t0.68\t\n120–130\t2\t0.68\t\n130–140\t121\t41.16\t\n140–150\t138\t46.94\t\n150–160\t30\t10.20\t\n\n\n\t\nNumber of previous pregnancies\t\nNon-informed\t4\t1.36\t\n1–4\t169\t57.49\t\n5–8\t99\t33.67\t\n9–13\t22\t7.48\t\n\n\n\t\nPrevious labor\t\nNon-informed\t4\t1.36\t\n1–4\t240\t81.63\t\n5–8\t45\t15.30\t\n9–12\t5\t1.71\t\n\n\n\t\nPrevious abortion\t\nNon-informed\t4\t1.36\t\nNone\t202\t68.70\t\n1–3\t87\t29.59\t\n4–6\t1\t0.35\t\nCI = 95%.\n\n\n\n3.1 Prescribed drugs\nThe average number of prescribed drugs per patient was 5.32 (SD 2.13). The most prescribed drugs were scopolamine (72.1%), metamizole (60.9%), betamethasone (56.5%), cefalotin (54.1%), ferrous sulfate (44.2%), nifedipine (32.3%), methyldopa (25.2%), cefalexin (26.2%), hydralazine (23.1%) and paracetamol (20.1%). Magnesium sulfate - the drug of choice for prevention of seizures in the pre-eclamptic women, or prevention of recurrence of seizures in the eclamptic women (Duley et al., 2010) - was prescribed to 3 patients (0.1%).\n\n3.2 Adverse drug reactions\nSuspect events were assessed for causality in 211 of 294 patients (71.8%) and at least one adverse drug reaction reached 26 (8.8%) patients. Overall, 29 ADRs (1.1 per patient with ADR) were identified through the double screening method. With the exception of the patients' age, other characteristics such as diagnosis, number of previous pregnancies and previous abortions, gestational age at birth, prescribed drugs and number of drugs per patient (p = 0.239, Kruskal-Wallis Test) were not related to ADRs (Table 2, Table 3).Table 2 Adverse drug reactions and patients' characteristics.\n\n\tADR\tp\t\n\tYes\tNo\t\nMean age\t28.6 ± 7.7, y.o.\t25.7 ± 7.3, y.o.\t0.026a\t\n\n\n\t\nDiagnosis\tn (%)\tn (%)\t0.104b\t\nPreterm labor\t16 (17.8)\t74 (82.2)\t\nPremature rupture of the membranes\t2 (3.3)\t58 (96.7)\t\nPreeclampsia\t9 (17.6)\t42 (82.4)\t\nUrinary infection\t6 (1.82)\t27 (81.8)\t\nGestational diabetes\t4 (20.0)\t16 (80.0)\t\nOther\t0 (0)\t27 (100)\t\n\n\n\t\n\tMean (SD)\tMean (SD)\t\t\nPrevious pregnancy\t3.08 (2.352)\t2.69 (2.007)\t0.470a\t\nPrevious childbirth\t1.63 (1.909)\t1.28 (1.673)\t0.509a\t\nPrevious abortion\t0.42 (0.722)\t0.41 (0.765)\t0.991a\t\nGestational age\t29.05 (6.913)\t27.91 (9.187)\t0.964a\t\na Kruskal-Wallis.\n\nb Pearson’s Chi-square.\n\nTable 3 Drugs used during hospitalization and clinical manifestation of adverse drug reactions.\n\nDrug\tFDA pregnancy risk classification\tPatients with clinically manifested ADR (26)\tPatients without clinically manifested ADR (268)\tTotal\tPa\tOR\tC\t\nN\t%\tN\t%\t\nCefalexin\tB\t5\t19.2\t72\t26.9\t77\t0.441\t0.65\t0.28–1.49\t\nCefalotin\tB\t14\t53.8\t145\t54.1\t159\t0.865\t0.99\t0.46–1.78\t\nBetamethasone\tC\t15\t57.7\t151\t56.3\t166\t0.865\t1.05\t0.57–1.97\t\nHydralazine\tC\t9\t34.6\t57\t21.3\t68\t0.072\t1.96\t0.95–3.98\t\nMethyldopa\tC\t8\t30.8\t66\t24.2\t74\t0.311\t1.36\t1.25–4.99\t\nNifedipine\tC\t9\t34.6\t86\t32.1\t95\t0.720\t1.12\t0.56–2.2\t\nParacetamol\tC\t5\t19.2\t54\t20.1\t59\t0.906\t0.94\t0.42–2.93\t\nScopolamine\tC\t16\t61.5\t196\t73.1\t212\t0.085\t0.59\t0.25–1.03\t\nMetamizole\tD\t18\t69.2\t161\t60.1\t179\t0.485\t1.49\t0.67–2.78\t\nFerrous sulfateb\t–\t13\t50.0\t117\t43.7\t130\t0.734\t1.29\t0.58–2.23\t\nTotal sample: 294.\n\na Chi-square test; OR = odds ratio; CI = confidence interval.\n\nb Ferrous sulfate has not been formally assigned to a pregnancy category by the FDA.\n\n\n\nManifestation of ADRs was not associated with any adverse pregnancy outcome, and it may be due to the low severity of ADRs: 22 (75.9%) of the ADRs reported in the study were of mild severity and 7 (24.1%) were of moderate severity, and none of them were significantly associated (p > 0.05) with any specific drug or class of drugs (Table 3), although moderate ADRs were caused mainly by betamethasone (4 cases of BP arising) and cefalotin (3 cases of tachycardia).\n\nNo ADR was caused by drug-drug interactions. However, we identified a recurrent clinically manifested drug-drug interaction in which one drug makes another less effective: an increase in systolic blood pressure was observed in all 14 patients using methyldopa and ferrous sulfate as well as an increase in both systolic and diastolic blood pressures in 7 patients. A decrease in blood pressure was observed in all patients after ferrous sulfate was discontinued.\n\n4 Discussion\nAlthough several studies have assessed the presence of adverse drug reactions among hospitalized patients, very few studies with hospitalized pregnant women have been performed and none of them included any high-risk pregnant women. A prospective study to estimate the incidence of ADRs related to the use of antiretroviral therapy in hospitalized pregnant women in southeast of Brazil observed that 20.2% of the patients without previous experiences with antiretroviral therapy presented an ADR (Miguel et al., 2012). In another prospective study, ADRs and allergy discrepancies were identified among 59 of 300 of women admitted to either the antenatal or the postnatal ward at an Australian tertiary-level maternity hospital (Cano and Rozenfeld, 2009). Among non-hospitalized pregnant women, a prospective pharmacovigilance survey of adverse drug reactions performed in southwest France found an incidence of ADRs of 0.3% (Lacroix et al., 2007). In our study, ADRs were identified in a prospective manner, using patient charts (medical and nursing records), laboratory data and drug prescriptions as sources of information combined with the causality assessment of each ADR; thus, although we assessed several suspect events, only a small but significant part of them were considered adverse drug reactions.\n\nIn our study, patient's aging was the only variable related to the manifestation of ADRs. In the literature, higher maternal age is associated with a range of adverse pregnancy outcomes and it usually implies in high-risk pregnancies, which leads to a higher number of prescribed medicines (Santini-Oliveira et al., 2014, Nash et al., 2015). However, we observed that the number of prescribed medicines did not influence the manifestation of ADRs. The presence of multimorbidities and related polypharmacy is associated with a higher risk for ADRs via age-related changes in pharmacokinetics and pharmacodynamics that influence drug elimination and response (Wacker et al., 2015, Kenny et al., 2013). Our findings seem to indicate that the age-related changes play a more important role than polypharmacy in the manifestation of ADRs in high-risk pregnant women.\n\nWe did not observe any association between ADRs and adverse pregnant outcomes. We believe this may be due to the fact that no ADR reported in our study was of high severity and most of the drugs prescribed during hospitalization have been assigned to Food and Drug Administration (FDA) pregnancy categories B and C. Although the FDA updated the pregnancy risk letter categories in 2015 with new information to make them more meaningful to both patients and healthcare providers, this new approach did not guide prescribers in our study.\n\nWe also believe that the lack of adverse pregnant outcomes in our study may be due to the relatively short duration of treatment to which pregnant inpatients are exposed when compared to pregnant outpatients. However, Wacker et al. (2015), in a cohort study of prospectively observed pregnant women who spontaneously contacted a teratology information service in Berlin for drug risk consultation, did not find evidence for an increased risk of adverse pregnancy outcomes after average drug exposure during pregnancy, compared with non-exposed or insignificantly exposed pregnancies.\n\nAs for the clinically manifested drug interactions involving methyldopa, Orbach and colleagues (2013) state that the effects of hypertension have not been separated appropriately from the effects of the medications that are used in pregnant women. In our study, we were able to identify the adverse effect of medications through causality assessment and we also did not find any association between the use of antihypertensive drug and adverse effects. Nevertheless, the concurrent use of methyldopa and ferrous sulfate proved to be largely ineffective to control blood pressure in pregnant women. The absorption of methyldopa is significantly reduced when taken with a dose of ferrous sulfate, increasing both systolic and diastolic blood pressures in hypertensive patients (Campbell et al., 1988). In general, methyldopa is the first choice for antihypertensive therapy in pregnant women and its safety has been shown in several studies (Al Khaja et al., 2014). The present findings recommend caution in the concurrent use of these drugs, a potential problem which may be circumvented if scheduling adjustments are made.\n\nOur study had limitations. The assessment of causality through the Naranjo Algorithm and Korean Algorithm for ADR Causality Assessment required that patients who remained at the service less than 24 consecutive hours were excluded from the final sample. This may have introduced some bias in the study once ADRs that have manifested and disappeared in a short period of time were not identified. In addition, ADR probability scales have inherent limitations, especially in the distinction between probability categories. Nevertheless, Naidu (2013) states that grades of causality (e.g., “possible,” “probable,” “definite”) offer little practical advantage and recommend binary yes/no causality (i.e., related/not related) for study investigators or regulatory reporting requirements, an approach adopted in our study.\n\n5 Conclusion\nIn conclusion, Adverse drug reactions were not highly prevalent among high-risk pregnant women admitted for labor in a teaching maternity hospital and no adverse pregnancy outcomes following these events were observed. Although this may be due to the safety profile of drugs commonly used in the management of at-risk pregnancies, larger studies are still needed to confirm these findings. Our results also suggest that the age-related changes play a more important role in pregnant women than polypharmacy in the manifestation of ADRs. Moreover, all patients using methyldopa and ferrous sulfate had an increase in blood pressure, and we recommend caution in the concurrent use of these drugs.\n\nConflict of interest\nThe authors report no conflict of interests.\n\nPeer review under responsibility of King Saud University.\n==== Refs\nReferences\nAl Khaja K.A. Sequeira R.P. Alkhaja A.K. Damanhori A.H. Drug treatment of hypertension in pregnancy: a critical review of adult guideline recommendations J. Hypertens. 32 3 2014 454 463 24384846 \nAlshammari T.M. Drug safety: the concept, inception and its importance in patients' health Saudi Pharm. J. 24 4 2016 405 412 27330371 \nBrum L.F. Pereira P. Felicetti L.L. da Silveira R.D. Prescribed and unprescribeddrug use among pregnant patients attended by the Unified Health System in SantaRosa (State of Rio Grande do Sul, Brazil) Cien Saude Colet. 16 5 2011 2435 2442 21655716 \nCampbell N. Paddock V. Sundaram R. Alteration of methyldopa absorption metabolism, and blood pressure control caused by ferrous sulfate and ferrous gluconate Clin. Pharmacol. Ther. 43 4 1988 381 386 3356082 \nCano F.G. Rozenfeld S. Adverse drug events in hospitals: a systematic review Cad Saude Publica 25 Suppl 3 2009 S360 72 20027385 \nDhanani J.V. Ganguly B.P. Chauhan L.N. Comparison of efficacy and safety of two parenteral iron preparations in pregnant women J. Pharmacol. Pharmacother. 3 4 2012 314 319 23326102 \nDaw J.R. Hanley G.E. Greyson D.L. Morgan S.G. Prescription drug use during pregnancy in developed countries: a systematic review Pharmacoepidemiol. Drug Saf. 20 9 2011 895 902 21774029 \nde Vries E.N. Ramrattan M.A. Smorenburg S.M. Gouma D.J. Boermeester M.A. The incidence and nature of in-hospital adverse events: a systematic review Qual. Saf. Health Care 17 3 2008 216 223 18519629 \nDuley L. Matar H.E. Almerie M.Q. Hall D.R. Alternative magnesium sulphate regimens for women with pre-eclampsia and eclampsia Cochrane Database Syst. Rev. 4 8 2010 CD007388 \nFonseca M.R.C.C. Fonseca E. Bergsten-Mendes G. Prevalência do uso de medicamentos na gravidez: uma abordagem farmacoepidemiológica Rev. Saúde Pública 36 2 2002 \nGray B.A. Hospitalization history and differences in self-rated pregnancy risk West J. Nurs. Res. 28 2006 216 229 16513920 \nHakkarainen K.M. Hedna K. Petzold M. Hägg S. Percentage of patients with preventable adverse drug reactions and preventability of adverse drug reactions – a meta-analysis PLoS ONE 7 3 2012 e33236 22438900 \nHartwig S.C. Siegel J. Schneider P.J. Preventability and severity assessment in reporting adverse drug reactions Am. J. Hosp. Pharm. 49 9 1992 Sep 2229 2232 1524068 \nHernández-Hernández D. Vargas-Rivera M. Nava-Ocampo A.A. Palma-Aguirre J. Sumano-López H. Drug therapy and adverse drug reactions to terbutaline in obstetric patients: a prospective cohort study in hospitalized women BMC Pregnancy Childbirth 2 1 2002 3 11934352 \nKenny L.C. Lavender T. McNamee R. O'Neill S.M. Mills T. Khashan A.S. Advanced maternal age and adverse pregnancy outcome: evidence from a large contemporary cohort PLoS ONE 8 2 2013 e56583 23437176 \nLacroix I. Cabou C. Montastruc J.L. Damase-Michel C. Adverse drug reactions in pregnant women Therapie 62 5 2007 455 460 18206108 \nMatsui D.M. Therapeutic drug monitoring in pregnancy Ther. Drug Monit. 34 5 2012 507 511 22846897 \nMiguel A. Azevedo L.F. Araújo M. Pereira A.C. Frequency of adverse drug reactions in hospitalized patients: a systematic review and meta-analysis Pharmacoepidemiol. Drug Saf. 21 11 2012 1139 1154 22761169 \nMitchell A.A. Gilboa S.M. Werler M.M. Kelley K.E. Louik C. Hernández-Díaz S. National birth defects prevention study. Medication use during pregnancy, with particular focus on prescription drugs: 1976–2008 Am. J. Obstet. Gynecol. 205 1 2011 51.e1-8 21514558 \nNaidu R.P. Causality assessment: a brief insight into practices in pharmaceutical industry Perspect. Clin. Res. 4 4 2013 233 236 24312892 \nNaranjo C.A. Busto U. Sellers E.M. Sandor P. Ruiz I. Roberts E.A. Janecek E. Domecq C. Greenblatt D.J. A method for estimating the probability of adverse drug reactions Clin. Pharmacol. Ther. 30 2 1981 239 245 7249508 \nNash L. Dixon R. Eaton V. Grzeskowiak L.E. Accuracy of information on medication use and adverse drug reactions recorded in pregnancy hand-held records Aust. N Z J Obstet. Gynaecol. 55 6 2015 547 551 26122265 \nNivya K. Sri Sai Kiran V. Ragoo N. Jayaprakash B. Sonal Sekhar M. Systemic review on drug related hospital admissions – a pubmed based search Saudi Pharm. J. 23 1 2015 1 8 25685036 \nOrbach H. Matok I. Gorodischer R. Sheiner E. Daniel S. Wiznitzer A. Koren G. Levy A. Hypertension and antihypertensive drugs in pregnancy and perinatal outcomes Am. J. Obstet. Gynecol. 208 4 2013 301.e1-6 23159698 \nOsorio-de-Castro C.G. Pepe V.L. Luiza V.L. Cosendey M.A. Freitas A.M. Miranda F.F. Bermudez J.A. Leal Mdo C. Prescribed and reported drug use during pregnancy Cad Saude Publica 20 Suppl 1 2004 S73 S82 16636737 \nPedrós C. Quintana B. Rebolledo M. Porta N. Vallano A. Arnau J.M. Prevalence, risk factors and main features of adverse drug reactions leading to hospital admission Eur. J. Clin. Pharmacol. 70 3 2014 361 367 24362489 \nSantini-Oliveira M. Friedman R.K. Veloso V.G. Cunha C.B. Pilotto J.H. Marins L.M. João E.C. Torres T.S. Grinsztejn B. Incidence of antiretroviral adverse drug reactions in pregnant women in two referral centers for HIV prevention of mother-to-child-transmission care and research in Rio de Janeiro, Brazil Braz. J. Infect. Dis. 18 4 2014 372 378 24662139 \nSinclair S.M. Miller R.K. Chambers C. Cooper E.M. Medication safety during pregnancy: improving evidence-based practice J. Midwifery Women’s Health 61 1 2016 52 67 26771055 \nSon Y.M. Lee J.R. Roh J.Y. Causality assessment of cutaneous adverse drug reactions Ann. Dermatol. 23 4 2011 432 438 22148009 \nSultana J. Cutroneo P. Trifirò G. Clinical and economic burden of adverse drug reactions J. Pharmacol. Pharmacother. 4 Suppl 1 2013 S73 7 24347988 \nvan Gelder M.M. van Rooij I.A. Miller R.K. Zielhuis G.A. de Jong-van den Berg L.T. Roeleveld N. Teratogenic mechanisms of medical drugs Hum. Reprod. Update 16 4 2010 378 394 20061329 \nWacker E. Navarro A. Meister R. Padberg S. Weber-Schoendorfer C. Schaefer C. Does the average drug exposure in pregnant women affect pregnancy outcome? A comparison of two approaches to estimate the baseline risks of adverse pregnancy outcome Pharmacoepidemiol. Drug Saf. 24 4 2015 353 360 25644395 \nWettach C. Thomann J. Lambrigger-Steiner C. Buclin T. Desmeules J. von Mandach U. Pharmacovigilance in pregnancy: adverse drug reactions associated with fetal disorders J. Perinat. Med. 41 3 2013 301 307 23027583\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "1319-0164",
"issue": "25(7)",
"journal": "Saudi pharmaceutical journal : SPJ : the official publication of the Saudi Pharmaceutical Society",
"keywords": "Adverse drug reactions; Drug-drug interactions; Ferrous sulfate; High-risk pregnancy; Maternal age; Methyldopa; Prevalence",
"medline_ta": "Saudi Pharm J",
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"pages": "1073-1077",
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"pubdate": "2017-11",
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"title": "Adverse drug reactions in high-risk pregnant women: A prospective study.",
"title_normalized": "adverse drug reactions in high risk pregnant women a prospective study"
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"abstract": "Mixed states are common and severe manifestations of bipolar disorder, with limited data on the differential efficacy of treatments on depressive and manic symptoms. This study assessed the effectiveness of open-label adjunctive risperidone in achieving sustained effectiveness in patients with mixed mania, with a specific focus on the differential benefits on manic and depressive symptomatology. Forty patients with bipolar disorder I, currently in a mixed manic episode, were treated with adjunctive risperidone. Behavioral measures at baseline and weeks 1, 2, 4, 8, 12, 16, and 20 were assessed using the following scales: the Young Mania Rating Scale, the Montgomery Asberg Depression Rating Scale (MADRS), and the Global Assessment Scale. The primary outcome measure was the proportion of patients who attained a sustained response on either depressive or manic symptomatology, defined as at least 50% reduction from the baseline on the Montgomery Asberg Depression Rating Scale or the Young Mania Rating Scale, maintained over at least 8 weeks without subsequent relapse during the 20-week trial. A significantly higher proportion of patients achieved a sustained response for mania than depression, 16/40 versus 6/40, respectively (McNemar's χ² 8.33, P=0.004). Higher elevated mood at baseline and lower apparent sadness (P<0.016) each predicted a sustained response for mania (P<0.0001). Mixed manic patients who were treated with risperidone adjunctive to mood stabilizer/s for 20 weeks were significantly more likely to achieve a sustained response for manic than for depressive symptomatology.",
"affiliations": "Department of Psychiatry, University of Texas Health Science Center at San Antonio, Texas 78229-3900, USA. singhv@uthscsa.edu",
"authors": "Singh|Vivek|V|;Bowden|Charles L|CL|;Mintz|Jim|J|",
"chemical_list": "D000928:Antidepressive Agents; D018692:Antimanic Agents; D018020:Lithium Compounds; D014227:Triazines; D014635:Valproic Acid; D018967:Risperidone; D000077213:Lamotrigine",
"country": "England",
"delete": false,
"doi": "10.1097/YIC.0b013e32835c7590",
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"issn_linking": "0268-1315",
"issue": "28(2)",
"journal": "International clinical psychopharmacology",
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"medline_ta": "Int Clin Psychopharmacol",
"mesh_terms": "D000328:Adult; D000928:Antidepressive Agents; D018692:Antimanic Agents; D001714:Bipolar Disorder; D003866:Depressive Disorder; D039721:Diagnostic and Statistical Manual of Mental Disorders; D004351:Drug Resistance; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D000077213:Lamotrigine; D018020:Lithium Compounds; D059012:Lost to Follow-Up; D008297:Male; D008875:Middle Aged; D011569:Psychiatric Status Rating Scales; D018967:Risperidone; D055502:Secondary Prevention; D013997:Time Factors; D014227:Triazines; D014635:Valproic Acid",
"nlm_unique_id": "8609061",
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"pages": "91-5",
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"pmid": "23238761",
"pubdate": "2013-03",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Relative effectiveness of adjunctive risperidone on manic and depressive symptoms in mixed mania.",
"title_normalized": "relative effectiveness of adjunctive risperidone on manic and depressive symptoms in mixed mania"
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"abstract": "Corticosteroids are potent anti-inflammatory and anti-allergic agents used in the treatment of various inflammatory diseases, including allergic disease. They are frequently considered the therapy-of-choice for many skin diseases. However, allergic reactions caused by corticosteroids have been reported. Among these, delayed reactions to topical steroids are more common, whereas immediate reactions to systemic steroids are rare. Herein, we report the case of a 32-year-old woman with triamcinolone-induced immediate hypersensitivity reaction, in which the patient had a positive prick test result with triamcinolone. She has had atopic dermatitis (AD) for three years. She had used systemic steroid, cyclosporine, and antihistamine with topical steroids for AD. In clinic, approximately 10 minutes after intralesional injection of triamcinolone, she complained of erythematous patches with slight elevation and itching on the face, trunk, and both hands. After intravenous injection of dexamethasone, her symptoms got worse. After treatment with epinephrine, all symptoms resolved within two hours. We performed an open test and skin prick test. She had a positive result only from the prick test with triamcinolone; all other steroids showed negative results from the open tests. Dermatologists should be aware of the possibility of anaphylaxis or other allergic hypersensitivity in response to corticosteroids.",
"affiliations": "Department of Dermatology, Hallym University Kangnam Sacred Heart Hospital, College of Medicine, Hallym University, Seoul, Korea.;Department of Dermatology, Hallym University Kangnam Sacred Heart Hospital, College of Medicine, Hallym University, Seoul, Korea.;Department of Dermatology, Hallym University Kangnam Sacred Heart Hospital, College of Medicine, Hallym University, Seoul, Korea.;Department of Dermatology, Hallym University Kangnam Sacred Heart Hospital, College of Medicine, Hallym University, Seoul, Korea.;Department of Dermatology, Hallym University Kangnam Sacred Heart Hospital, College of Medicine, Hallym University, Seoul, Korea.;Department of Dermatology, Hallym University Kangnam Sacred Heart Hospital, College of Medicine, Hallym University, Seoul, Korea. dermap@hanmail.net.",
"authors": "Son|Jee Hee|JH|https://orcid.org/0000-0002-7816-1942;Park|Sook Young|SY|https://orcid.org/0000-0002-3703-5456;Cho|Yong Se|YS|https://orcid.org/0000-0001-7280-118X;Chung|Bo Young|BY|https://orcid.org/0000-0002-2795-0140;Kim|Hye One|HO|https://orcid.org/0000-0001-5846-0008;Park|Chun Wook|CW|https://orcid.org/0000-0003-4512-8668",
"chemical_list": "D000893:Anti-Inflammatory Agents; D005938:Glucocorticoids; D006633:Histamine Antagonists; D014221:Triamcinolone; D003907:Dexamethasone; D016572:Cyclosporine; D004837:Epinephrine",
"country": "Korea (South)",
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"doi": "10.3346/jkms.2018.33.e87",
"fulltext": "\n==== Front\nJ Korean Med Sci\nJ Korean Med Sci\nJKMS\nJournal of Korean Medical Science\n1011-8934\n1598-6357\nThe Korean Academy of Medical Sciences\n\n29542298\n10.3346/jkms.2018.33.e87\nCase Report\nImmunology, Allergic Disorders & Rheumatology\nImmediate Hypersensitivity Reactions Induced by Triamcinolone in a Patient with Atopic Dermatitis\nhttps://orcid.org/0000-0002-7816-1942\nSon Jee Hee\nhttps://orcid.org/0000-0002-3703-5456\nPark Sook Young\nhttps://orcid.org/0000-0001-7280-118X\nCho Yong Se\nhttps://orcid.org/0000-0002-2795-0140\nChung Bo Young\nhttps://orcid.org/0000-0001-5846-0008\nKim Hye One\nhttps://orcid.org/0000-0003-4512-8668\nPark Chun Wook\nDepartment of Dermatology, Hallym University Kangnam Sacred Heart Hospital, College of Medicine, Hallym University, Seoul, Korea.\nAddress for Correspondence: Chun Wook Park, MD. Department of Dermatology, Hallym University Kangnam Sacred Heart Hospital, College of Medicine, Hallym University, 1 Singil-ro, Yeongdeungpo-gu, Seoul 07441, Korea. dermap@hanmail.net\n13 2 2018\n19 3 2018\n33 12 e8726 9 2016\n03 2 2017\n© 2018 The Korean Academy of Medical Sciences.\n2018\nThe Korean Academy of Medical Sciences\nhttps://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.\nCorticosteroids are potent anti-inflammatory and anti-allergic agents used in the treatment of various inflammatory diseases, including allergic disease. They are frequently considered the therapy-of-choice for many skin diseases. However, allergic reactions caused by corticosteroids have been reported. Among these, delayed reactions to topical steroids are more common, whereas immediate reactions to systemic steroids are rare. Herein, we report the case of a 32-year-old woman with triamcinolone-induced immediate hypersensitivity reaction, in which the patient had a positive prick test result with triamcinolone. She has had atopic dermatitis (AD) for three years. She had used systemic steroid, cyclosporine, and antihistamine with topical steroids for AD. In clinic, approximately 10 minutes after intralesional injection of triamcinolone, she complained of erythematous patches with slight elevation and itching on the face, trunk, and both hands. After intravenous injection of dexamethasone, her symptoms got worse. After treatment with epinephrine, all symptoms resolved within two hours. We performed an open test and skin prick test. She had a positive result only from the prick test with triamcinolone; all other steroids showed negative results from the open tests. Dermatologists should be aware of the possibility of anaphylaxis or other allergic hypersensitivity in response to corticosteroids.\n\nGraphical Abstract\n\nSteroid\nHypersensitivity\nSkin Prick Test\nOpen Test\nNational Research Foundation of Korea http://dx.doi.org/10.13039/501100003725 NRF-2017R1A2B4006252 Ministry of Health and Welfare http://dx.doi.org/10.13039/501100003625 HURF-2017-35 HURF-2017-52\n==== Body\npmcINTRODUCTION\n\nCorticosteroids have immunosuppressive, anti-proliferative, anti-inflammatory, and anti-allergic effects, and are used in the management of numerous conditions, including malignancy, transplantation, autoimmune, and allergic disease.12 Corticosteroids have a wide range of adverse effects, but considering the frequent use of corticosteroids, hypersensitivity reactions are rare.3 It may be paradoxical that corticosteroids, potent anti-inflammatory agents and immunomodulators used in the treatment of allergic manifestations, can produce immediate or delayed allergic hypersensitivity reactions.1 Among these, delayed reactions to topical steroids are more common (0.5%–5%), whereas immediate reactions to systemic steroids are rare (0.1%–0.3%).34 Herein, we report the case of a 32-year-old, female patient with atopic dermatitis (AD) exhibiting a triamcinolone-induced immediate hypersensitivity reaction.\n\nCASE DESCRIPTION\n\nA 32-year-old woman presented to the dermatology department for treatment for AD one year ago (in January 2015). She had had AD for three years. Measurement of serum food-specific immunoglobulin E levels (MAST) was negative and total immunoglobulin E (IgE) level was normal. She had no history of food or drug allergy, no suggestive family history, and no other systemic diseases. She typically used oral antihistamine and intermittent oral corticosteroid (methylprednisolone) and cyclosporine with topical steroids for the AD.\n\nShe was given intermittent intramuscular injections with antihistamine and dexamethasone, and intralesional injections with triamcinolone. During previous intermittent treatment with methylprednisolone tablets (4 mg Methylon; Albogen Korea, Seoul, Korea), dexamethasone injection 5 mg/mL (Dexa-S; Ilsung Pharmaceuticals, Seoul, Korea), and triamcinolone acetonide injection 2.5 mg/mL (TRIAM®; Shin Poong Pharmaceuticals, Seoul, Korea), there had been no adverse reaction. We used triamcinolone solution, made of only triamcinolone and normal saline, which the concentration is 2.5 mg/mL. In her case, no other agents, including lidocaine, were inserted.\n\nIn clinic (in December 2015), approximately 10 minutes after intralesional injection of triamcinolone on her dorsum of both hands, she complained of erythematous patches with slight elevation and itching on the face, trunk, and both hands (Fig. 1). Totally, 0.7 mL of triamcinolone solution, which the concentration was 2.5 mg/mL, was injected divided into two severe sites of her hands. Intravenous injection of dexamethasone was done 5 minutes after her symptoms occurred. Even after intravenous injection of dexamethasone, her symptoms got worse. After treatment with epinephrine, all symptoms resolved within two hours.\n\nFig. 1 Clinical images of the 32-year-old patient with atopic disease. Well-demarcated erythematous wheals on the (A) face, (B) both hands, and (C, D) trunk, 30 and 20 minutes after intralesional triamcinolone injection and intramuscular dexamethasone injection, respectively.\n\nTo confirm the causal relationship between the symptoms and corticosteroid, four weeks after the hypersensitivity reaction, we performed an open test and skin prick test (SPT). We performed these tests for hydrocortisone, mometasone furoate, prednicarbate, desonide, desoxymethasone, prednisolone valerate, triamcinolone acetonide, clobetasol propionate, methylprednisolone, and prednisolone. A positive response was only observed after the prick test with triamcinolone, 20 × 23 mm at 15 minutes and at 45 minutes, maximum reaction was observed, 20 × 25 mm; no other steroid prick tests gave positive results, including dexamethasone (Fig. 2). In SPT with steroid, it is known that the reactions might be a maximum after around 30 minutes and the reactions reduce with time after that, at around 60 minutes. We observe time-course results every 15 minutes.15 All steroids showed negative open test results after 30 minutes (Fig. 2). For definitive diagnosis, an intravenous or oral provocation test was planned. She refused permission for these tests because she had become pregnant four months after the skin tests.\n\nFig. 2 Skin prick tests (SPTs) and topical provocation test were done and we observed the results every 15 minutes. (A) SPTs showed positive reaction to triamcinolone, but not to other steroids, after 30 minutes. (B) All steroids showed negative results for an open test after 30 minutes.\n\n1 = hydrocortisone, 2 = mometasone furoate, 3 = prednicarbate, 4 = desonide, 5 = desoxymethasone, 6 = prednisolone valerate, 7 = triamcinolone acetonide, 8 = clobetasol propionate, 9 = methylprednisolone, 10 = prednisolone, TCN = triamcinolone acetonide, DX = dexamethasone, PIP = piprinhydrinate.\n\nFinally, we diagnosed the patient with immediate hypersensitivity reactions induced by triamcinolone and recommended avoidance of this drug. During the next six months, she did not experience any recurrence.\n\nDISCUSSION\n\nIt is possible to identify hypersensitivity reactions to corticosteroids with skin prick and intradermal tests, but many cases will only be diagnosed correctly by intravenous or oral challenge tests.3 There are several invasive/non-invasive epicutaneous tests to diagnose immediate skin responses.26 We chose the invasive SPT and non-invasive open test for diagnosis.\n\nIn our patient, the SPT with triamcinolone showed positive. The SPT was done to evaluate type I IgE-mediated allergy by confirming allergen-specific IgE.5 It was done on the volar aspect of the forearm, using commercially available topical steroids.57 A 1-mm single-peak lancet with shoulder was used. This test breaks the skin barrier and changes skin permeability so haptens of high molecular weight can penetrate and induce hypersensitivity reactions. Histamine was assumed to be released from mast cells in response to exposure to an eliciting substance. Meanwhile, the open test showed a negative result. An open test is usually done to diagnose contact urticaria.8 Contact urticaria is classified as non-immunological/irritant or immunological/allergic, according to the underlying mechanism, which is incompletely understood.9 It has been assumed non-immunologic urticaria is the commonest form, which might be mediated by prostaglandins. Release of prostaglandin D2 without concomitant histamine release has been demonstrated.9 However, immunological contact urticaria is due to immediate-type hypersensitivity, medicated primarily by histamine and confirmed by simple investigations such as skin prick testing or measurement of specific IgE.9 The mechanism following skin challenge involves allergen penetration through the epidermis, then binding to IgE on mast cells, causing degranulation and release of histamine and other vasoactive substances.9 When a hypersensitivity reaction simply occurs by epicutaneous absorption, which means haptens might be small enough to penetrate the skin, the open test can be helpful. However, in a case of haptens related to systemic absorption, the agents producing the hypersensitivity reaction have comparatively higher molecular weight. An open test could also be helpful, but may be negative unless the substance is applied against broken or eczematous skin.9 Skin permeability may be increased because of AD with abnormal skin barrier function.10 The open test can be negative when the skin has healed.10 Our case might also show a negative result for the open test after the skin has healed. Due to these differences between mechanisms, our patient might show different results in the SPT and open test. According to the patient's history and the results of tests, there appears to be a high probability of systemic hypersensitivity reaction due to intravenous or intralesional injections, not contact urticaria. Further testing (intravenous or oral provocation) is needed for a definitive diagnosis.\n\nDue to anti-inflammatory properties of corticosteroids, the clinical signs of allergy may be masked and the results of skin tests are difficult to interpret. It often mimics the symptoms of the underlying disease so that it often likely remains undiagnosed.\n\nEarly studies did not identify significant host factors associated with corticosteroid allergy, but more recent work has found several risk factors, which include renal transplant or history of asthmatic disease (especially for those who are aspirin sensitive),111213 hypersensitivity to nonsteroidal drugs,4 a history of nephritis, and high percutaneous absorption caused by sweat, cutaneous infections, and AD. However, this impression might be related more to the frequent use of corticosteroids, than to the disease itself.411 The factors associated with individual characteristics include the immune system's ability to identify the antigen, the enzymatic ranges and activity producing metabolites that may exert a different sensitizing capacity, as well as genetic predisposition.114 It has also become clear the allergen that triggers an immune reaction may be a by-product of corticosteroid metabolism, not by corticosteroid itself.115\n\nOur patient was at high risk of corticosteroid allergy, having AD with frequent corticosteroid use and repeated intralesional triamcinolone injections.16 High percutaneous absorption caused by AD could be another risk factor.\n\nOur patient's symptoms got worse even after the dexamethasone injection. She had no cross-reaction to other steroids, which was confirmed by results from open test and SPT. So, we thought the dose of dexamethasone was not enough for relieving her symptoms and the improvement of symptoms might take some time. The courses of cutaneous reactions due to systemic corticosteroid have been variable in previous cases, from rapid improvement to requiring several months.17\n\nAlthough the Coopman classification (the cross-reactivity spectrum of topical corticosteroids based on molecular structure) does not apply to systemic corticosteroids and is not necessarily pertinent in immediate hypersensitivity reactions,18 it could provide guidance to doctors for how to choose a replacement corticosteroid. However, cases of cross-reactivity have shown that hypersensitivity to a corticosteroid in one group does not rule out the safe use of other corticosteroids in the same group.19 Therefore, such loose guidance cannot replace a systematic evaluation of the individual patient's sensitivity and tolerability.3 Graded challenge is recommended to ensure tolerance of the alternative preparation4; our patient refused the challenge by intravenous or oral provocation test, so we could not determine a replacement corticosteroid. Finally, we recommended that she avoid steroids, and we have not prescribed any steroids for her to date.\n\nWe report a unique case of triamcinolone-induced hypersensitivity with a positive SPT result. Immediate hypersensitivity reactions are possibly underdiagnosed, particularly because corticosteroids are common therapy for hypersensitivity disorders. Physicians should be aware of the possibility of anaphylaxis or other allergic hypersensitivity in response to corticosteroids. It should be taken into consideration in the differential diagnosis of patients receiving corticosteroid.\n\nFunding: This study was supported by grants of the National Research Foundation of Korea (NRF), funded by the Ministry of Science, ICT & Future Planning (NRF-2017R1A2B4006252), Korea Healthcare Technology R & D project, funded by Ministry of Health & Welfare, Republic of Korea (HI17C0597), and the Hallym University Research Fund (HURF-2017-35, HURF-2017-52).\n\nDisclosure: The authors have no potential conflicts of interest to disclose.\n\nAuthor Contributions: Conceptualization: Park CW.\n\nData curation: Son JH, Park SY.\n\nInvestigation: Cho YS, Son JH.\n\nWriting - original draft: Son JH, Chung BY.\n\nWriting - review & editing: Son JH, Park SY, Cho YS, Chung BY, Kim HO, Park CW.\n==== Refs\n1 Baeck M Marot L Nicolas JF Pilette C Tennstedt D Goossens A Allergic hypersensitivity to topical and systemic corticosteroids: a review Allergy 2009 64 7 978 994 19416135\n2 Rietschel RL Contact dermatitis and diagnostic techniques Allergy Proc 1989 10 6 403 411 2534095\n3 Knarborg M Bendstrup E Hilberg O Increasing awareness of corticosteroid hypersensitivity reactions is important Respirol Case Rep 2013 1 2 43 45 25473540\n4 Patel A Bahna SL Immediate hypersensitivity reactions to corticosteroids Ann Allergy Asthma Immunol 2015 115 3 178 182.e3 26211812\n5 Ahn YH Koh YI Kim JH Ban GY Lee YK Hong GN The potential utility of iodinated contrast media (ICM) skin testing in patients with ICM hypersensitivity J Korean Med Sci 2015 30 3 245 251 25729245\n6 Hannuksela M Epicutaneous testing Allergy 1979 34 1 5 10 378015\n7 Kekki OM Turjanmaa K Isolauri E Differences in skin-prick and patch-test reactivity are related to the heterogeneity of atopic eczema in infants Allergy 1997 52 7 755 759 9265992\n8 Lahti A Nonimmunologic contact urticaria Amins S Lahti A Maibach HI Contact Urticaria Syndrome Boca Raton, FL CRC Press 1997 Chapter 3\n9 Wakelin SH Contact urticaria Clin Exp Dermatol 2001 26 2 132 136 11298101\n10 Helaskoski E Kuuliala O Aalto-Korte K Occupational contact urticaria caused by cyclic acid anhydrides Contact Dermat 2009 60 4 214 221\n11 Vatti RR Ali F Teuber S Chang C Gershwin ME Hypersensitivity reactions to corticosteroids Clin Rev Allergy Immunol 2014 47 1 26 37 23567983\n12 Dajani BM Sliman NA Shubair KS Hamzeh YS Bronchospasm caused by intravenous hydrocortisone sodium succinate (Solu-Cortef) in aspirin-sensitive asthmatics J Allergy Clin Immunol 1981 68 3 201 204 7264102\n13 Partridge MR Gibson GJ Adverse bronchial reactions to intravenous hydrocortisone in two aspirin-sensitive asthmatic patients BMJ 1978 1 6126 1521 1522 656781\n14 Wilkinson SM Morrey K Hollowood K Heagerty AH English JS HLA-A, -B and -DR antigens in hydrocortisone contact hypersensitivity Contact Dermat 1993 28 5 295 297\n15 Bundgaard H The possible implication of steroid-glyoxal degradation products in allergic reactions to corticosteroids Arch Pharm Chem Sci Ed 1980 8 83 90\n16 Kim JE Kim HJ Lew BL Lee KH Hong SP Jang YH Consensus guidelines for the treatment of atopic dermatitis in Korea (part II): systemic treatment Ann Dermatol 2015 27 5 578 592 26512172\n17 Whitmore SE Delayed systemic allergic reactions to corticosteroids Contact Dermat 1995 32 4 193 198\n18 Coopman S Degreef H Dooms-Goossens A Identification of cross-reaction patterns in allergic contact dermatitis from topical corticosteroids Br J Dermatol 1989 121 1 27 34 2757954\n19 Aranda A Mayorga C Ariza A Doña I Blanca-Lopez N Canto G IgE-mediated hypersensitivity reactions to methylprednisolone Allergy 2010 65 11 1376 1380 20486918\n\n",
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"issn_linking": "1011-8934",
"issue": "33(12)",
"journal": "Journal of Korean medical science",
"keywords": "Hypersensitivity; Open Test; Skin Prick Test; Steroid",
"medline_ta": "J Korean Med Sci",
"mesh_terms": "D000328:Adult; D000893:Anti-Inflammatory Agents; D016572:Cyclosporine; D003876:Dermatitis, Atopic; D003907:Dexamethasone; D004342:Drug Hypersensitivity; D004837:Epinephrine; D005260:Female; D005938:Glucocorticoids; D006633:Histamine Antagonists; D006801:Humans; D012882:Skin Tests; D014221:Triamcinolone",
"nlm_unique_id": "8703518",
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"pmid": "29542298",
"pubdate": "2018-03-19",
"publication_types": "D002363:Case Reports",
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"title": "Immediate Hypersensitivity Reactions Induced by Triamcinolone in a Patient with Atopic Dermatitis.",
"title_normalized": "immediate hypersensitivity reactions induced by triamcinolone in a patient with atopic dermatitis"
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"abstract": "The renin-angiotensin-aldosterone system (RAAS) is a key component of blood pressure regulation. Patients who take RAAS antagonists on the morning of surgery are at risk of developing hypotension under anesthesia that is refractory to treatment with fluid boluses and conventional vasopressors. This case report describes a unique case of refractory hypotension in a patient with a history of anabolic steroid abuse taking an angiotensin II receptor blocker. An understanding of the role of the RAAS in blood pressure regulation is essential for managing refractory hypotension in the patient under general anesthesia. A scarcity of data on the anesthetic implications of anabolic steroid abuse exists, but an understanding of the physiologic implications of anabolic steroid abuse can help guide management for these patients.",
"affiliations": "is a staff anesthetist at Virginia Commonwealth University Medical Center in Richmond, Virginia.;is the former program director of York College of Pennsylvania/WellSpan Health Nurse Anesthetist Program, York, Pennsylvania.",
"authors": "Jensen|Alyssa B|AB|;Haas|Richard E|RE|",
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"keywords": "Anabolic steroid abuse; anesthesia; angiotensin-receptor blockers; refractory hypotension",
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"pages": "340-344",
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"title": "Refractory Hypotension in a Patient with a History of Anabolic Steroid Abuse Taking an Angiotensin-II Receptor Blocker: A Case Report.",
"title_normalized": "refractory hypotension in a patient with a history of anabolic steroid abuse taking an angiotensin ii receptor blocker a case report"
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"abstract": "OBJECTIVE\nCD3/CD19 depletion may improve engraftment and immune reconstitution after haploidentical hematopoietic cell transplantation (HHCT) as grafts not only contain CD34+ stem cells but also CD34- progenitors and natural killer, dendritic, and facilitating cells.\n\n\nMETHODS\nTen consecutive patients received HHCT with CD3/CD19-depleted grafts. Reduced-intensity conditioning was performed with fludarabine (150-200 mg/m2), thiotepa (10 mg/kg), melphalan (120 mg/m2), and OKT-3 (5 mg/day, day -5 to +14) without additional posttransplant immunosuppression. Diagnoses were AML (n = 4), ALL (n = 3), NHL (n = 2), and multiple myeloma (n = 1). All patients were \"high risk\" with refractory disease or relapse after preceding HCT. The CD3/CD19-depleted haploidentical grafts contained a median of 7.8 x 10(6) (range, 5.2-17 x 10(6)) CD34+ cells/kg, 5.5 x 10(7) (range, 0.02-8.6 x 10(7)) CD56+ cells/kg, and 2.0 x 10(4) (range, 0.006-44 x 10(4)) CD3+ T cells/kg. Engraftment was rapid with median time to greater than 500 granulocytes/microL of 13 (range, 11-17) days, greater than 20,000 platelets/microL of 11 (range, 8-16) days, and full donor chimerism after 2 weeks in all patients. Six cases of grade II GVHD occurred. One patient, who received the highest T cell dose, developed lethal grade IV GVHD. Treatment-related mortality in the first 100 days was 3/10 (30%) with one death each due to idiopathic pneumonia syndrome, GVHD, and CMV disease. Two patients died after day 100, one due to relapse and one with systemic adenoviral infection. Overall survival is 5/10 patients (50%) with a median follow-up of 435 (range, 229-814) days.\n\n\nCONCLUSIONS\nThis regimen is promising in high-risk patients lacking a suitable donor, and a prospective phase I/II study is ongoing.",
"affiliations": "Medical Center, University of Tuebingen, Tuebingen, Germany. wolfgang.bethge@med.uni-tuebingen.de",
"authors": "Bethge|Wolfgang A|WA|;Haegele|Matthias|M|;Faul|Christoph|C|;Lang|Peter|P|;Schumm|Michael|M|;Bornhauser|Martin|M|;Handgretinger|Rupert|R|;Kanz|Lothar|L|",
"chemical_list": "D018941:Antigens, CD19; D017252:CD3 Complex",
"country": "Netherlands",
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"journal": "Experimental hematology",
"keywords": null,
"medline_ta": "Exp Hematol",
"mesh_terms": "D000328:Adult; D018941:Antigens, CD19; D017252:CD3 Complex; D005260:Female; D005500:Follow-Up Studies; D006086:Graft vs Host Disease; D006239:Haplotypes; D019337:Hematologic Neoplasms; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008212:Lymphocyte Depletion; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D015996:Survival Rate; D019172:Transplantation Conditioning; D014184:Transplantation, Homologous; D016896:Treatment Outcome",
"nlm_unique_id": "0402313",
"other_id": null,
"pages": "1746-52",
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"pubdate": "2006-12",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article",
"references": null,
"title": "Haploidentical allogeneic hematopoietic cell transplantation in adults with reduced-intensity conditioning and CD3/CD19 depletion: fast engraftment and low toxicity.",
"title_normalized": "haploidentical allogeneic hematopoietic cell transplantation in adults with reduced intensity conditioning and cd3 cd19 depletion fast engraftment and low toxicity"
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"abstract": "Christianson syndrome (CS) is an X-linked intellectual disorder caused by mutations in the SLC9A6 gene. Clinical features of CS include an inability to speak, truncal ataxia, postnatal microcephaly, hyperkinesis, and epilepsy. Almost all patients with CS develop drug-resistant epilepsy-its most serious complication. We report two cases of CS with drug-resistant epilpesy associated with the Lennox-Gastaut syndrome (LGS). One patient experienced generalized tonic seizures since 9 months of age with cognitive regression, which evolved to include atonic seizures at the age of 7 years. Electroencephalography (EEG) showed generalized slow spike-wave complexes and generalized paroxysmal fast activity. Seizures remained drug-resistant despite multiple anti-seizure drugs. The second patient experienced generalized tonic seizures since the age of 17 months and arrested development. EEG showed generalized slow spike-wave complexes, with frequent atonic seizures since the age of 6 years. Electrical status epilepticus during slow-wave sleep (ESES) developed at the age of 7 years. Our cases illustrate that CS may cause LGS in addition to other developmental and epileptic encephalopathies of the neonatal and infantile period. We suggest that generalized tonic or tonic-clonic seizures and generalized slow spike-wave complexes in interictal EEG be included as potential electroclinical features of epilepsy in CS.",
"affiliations": "Department of Neurology, Kanagawa Children's Medical Center, Yokohama, Japan.;Department of Neurology, Kanagawa Children's Medical Center, Yokohama, Japan.;Department of Neurology, Kanagawa Children's Medical Center, Yokohama, Japan.;Department of Neurology, Kanagawa Children's Medical Center, Yokohama, Japan.;Department of Neurology, Kanagawa Children's Medical Center, Yokohama, Japan.;Department of Neurology, Kanagawa Children's Medical Center, Yokohama, Japan.;Clinical Research Institute, Kanagawa Children's Medical Center, Yokohama, Japan.;Division of Medical Genetics, Kanagawa Children's Medical Center, Yokohama, Japan.;Division of Medical Genetics, Kanagawa Children's Medical Center, Yokohama, Japan.;Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.;Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.;Department of Neurology, Kanagawa Children's Medical Center, Yokohama, Japan.",
"authors": "Ikeda|Azusa|A|;Yamamoto|Ayako|A|;Ichikawa|Kazushi|K|;Tsuyusaki|Yu|Y|;Tsuji|Megumi|M|;Iai|Mizue|M|;Enomoto|Yumi|Y|;Murakami|Hiroaki|H|;Kurosawa|Kenji|K|;Miyatake|Satoko|S|;Matsumoto|Naomichi|N|;Goto|Tomohide|T|",
"chemical_list": null,
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"doi": "10.1016/j.ebr.2019.100349",
"fulltext": "\n==== Front\nEpilepsy Behav RepEpilepsy Behav RepEpilepsy & Behavior Reports2589-9864Elsevier S2589-9864(19)30145-510.1016/j.ebr.2019.100349100349ArticleEpilepsy in Christianson syndrome: Two cases of Lennox–Gastaut syndrome and a review of literature Ikeda Azusa azusaikeda39@gmail.coma⁎Yamamoto Ayako aIchikawa Kazushi k-ichi@sky.plala.or.jpaTsuyusaki Yu aTsuji Megumi mtsuji@kcmc.jpaIai Mizue miai@kcmc.jpaEnomoto Yumi yenomoto@kcmc.jpbMurakami Hiroaki hmurakami@kcmc.jpcKurosawa Kenji kkurosawa@kcmc.jpcMiyatake Satoko miyatake@yokohama-cu.ac.jpdMatsumoto Naomichi naomat@yokohama-cu.ac.jpdGoto Tomohide tgoto@kcmc.jpaa Department of Neurology, Kanagawa Children's Medical Center, Yokohama, Japanb Clinical Research Institute, Kanagawa Children's Medical Center, Yokohama, Japanc Division of Medical Genetics, Kanagawa Children's Medical Center, Yokohama, Japand Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan⁎ Corresponding author at: Department of Neurology, Kanagawa Children's Medical Center, 2-138-4, Mutsukawa, Minami-ku, Yokohama, Kanagawa 232-8555, Japan. azusaikeda39@gmail.com05 12 2019 2020 05 12 2019 13 10034926 9 2019 19 11 2019 1 12 2019 © 2019 The Authors2019This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Christianson syndrome (CS) is an X-linked intellectual disorder caused by mutations in the SLC9A6 gene. Clinical features of CS include an inability to speak, truncal ataxia, postnatal microcephaly, hyperkinesis, and epilepsy. Almost all patients with CS develop drug-resistant epilepsy—its most serious complication. We report two cases of CS with drug-resistant epilpesy associated with the Lennox–Gastaut syndrome (LGS). One patient experienced generalized tonic seizures since 9 months of age with cognitive regression, which evolved to include atonic seizures at the age of 7 years. Electroencephalography (EEG) showed generalized slow spike–wave complexes and generalized paroxysmal fast activity. Seizures remained drug-resistant despite multiple anti-seizure drugs. The second patient experienced generalized tonic seizures since the age of 17 months and arrested development. EEG showed generalized slow spike–wave complexes, with frequent atonic seizures since the age of 6 years. Electrical status epilepticus during slow-wave sleep (ESES) developed at the age of 7 years. Our cases illustrate that CS may cause LGS in addition to other developmental and epileptic encephalopathies of the neonatal and infantile period. We suggest that generalized tonic or tonic–clonic seizures and generalized slow spike–wave complexes in interictal EEG be included as potential electroclinical features of epilepsy in CS.\n\nHighlights\n• Christianson syndrome (CS) is rare and difficult to diagnose from clinical symptoms.\n\n• Epilepsy, the most serious complication of CS, is drug-resistant.\n\n• CS epilepsy involves generalized tonic or tonic–clonic seizures.\n\n• CS epilepsy is characterized by generalized slow spike–wave complexes in EEG.\n\n\n\nAbbreviations\nCS, Christianson syndromeDEE, developmental and epileptic encephalopathyEEG, electroencephalographyESES, electrical status epilepticus during slow-wave sleepLGS, Lennox–Gastaut syndromeKeywords\nEpilepsyChristianson syndromeSLC9A6Lennox–Gastaut syndromeElectrical status epilepticus in slow-wave sleep\n==== Body\n1 Introduction\nChristianson syndrome (CS) is an X-linked condition that was first reported by Christianson et al. in South African families who displayed severe intellectual disability, epilepsy, mild craniofacial dysmorphology, ophthalmoplegia, speech absence, acquired microcephaly, and cerebellar and brainstem atrophy [1]. Later, patients were also reported from other regions in Europe [2]. SLC9A6 was identified as the causative gene; moreover, clinical features in patients with CS may overlap with those seen in Angelman syndrome [2]. Pescosolido et al., based on a study on 12 families note the characteristic symptoms of CS include an inability to speak, moderate to severe intellectual disability, epilepsy in 100% of patients, truncal ataxia, postnatal microcephaly or growth arrest of head circumference, and hyperkinesis [3]. Female carriers are known to manifest mild to moderate intellectual disabilities, behavioral issues, and psychiatric illnesses [4].\n\nEpilepsy in CS is often drug-resistant and is a leading concern for family members [3]. While there have been several reports of electrical status epilepticus during slow-wave sleep (ESES) [[5], [6], [7]], few reports provide detailed description regarding the long-term course of epilepsy in CS.\n\nWe describe two cases of CS presenting with Lennox–Gastaut syndrome (LGS) and the progression of epilepsy in CS along with a review of the relevant literature.\n\n2 Patient description\n2.1 Patient 1\nThe patient was born via normal vaginal delivery at a gestational age of 40 weeks with a birth weight of 3134 g. His development was normal during early infancy; he could sit at 9 months and subsequently crawled appropriately. However, generalized tonic seizures developed several times a day from the age of 9 months, and he was referred to our hospital at the age of 11 months. At presentation, he had microcephaly (43.4 cm, 1.8 SD) and mild developmental delay. Blood tests and brain MRI revealed no abnormal findings. However, a sleep electroencephalography (EEG) showed frontal and occipital spike–wave complexes and generalized slow spike–wave complexes. Seizure occurrence temporarily decreased following treatment with valproate and clonazepam. However, weekly seizures persisted, and they became drug-resistant at the age of 3 years when psychomotor regression was also observed. Until the age of 3 years, the child had an ataxic gait but gradually progressed to the point of being unable to walk with severe intellectual disability and without the ability to speak. Topiramate was included in the drug regimen at the age of 5 years but seizures were not controlled. By the age of 7 years, he experienced weekly atonic seizures in addition to weekly tonic seizures and he was diagnosed with LGS. Sleep EEG showed frequent generalized slow spike–wave complexes (Fig. 1A), followed by generalized paroxysmal fast activity by the age of 12 years. Seizures spontaneously decreased at the age of 14 years but weekly tonic seizures during sleep persisted. Brain MRI at 16 years of age showed mild atrophy in the cerebrum and cerebellum.Fig. 1 A. EEG of patient 1.\n\nSleep EEG at 7 years of age shows frequent 2.0–2.5 Hz generalized slow spike–wave complexes.\n\nB. EEG of patient 2.\n\nSleep EEG at 6 years of age shows frequent 1.5–2.0 Hz generalized slow spike–wave complexes.\n\nC. EEG of patient 2.\n\nSleep EEG at 7 years of age shows continuous generalized spike–waves forming more than 85% of the sleep recording, which is consistent with electrical status epilepticus during slow-wave sleep (ESES).\n\nFig. 1\n\nExome analysis using the TruSight One Sequencing Panel and the MiSeq platform (Illumina, Inc., San Diego, CA, USA) for the patient's leukocyte DNA identified an SLC9A6 mutation (NM_006359.3:c.1402C > T:p.Arg468*). His younger sister was found to be a carrier for the same mutation and suffered from mild intellectual disability and epilepsy that was well-controlled with valproate. This mutation was not detected in their mother's peripheral blood sample and the patient was considered to be a mosaic carrier.\n\n2.2 Patient 2\nThe patient was born via a normal vaginal delivery at a gestational age of 37 weeks with a birth weight of 2945 g. At the age of 4 months, he could hold his head and roll over; at the age of 14 months, he could sit. At the age of 17 months, he started experiencing generalized tonic seizures, for which valproate was administered. Seizure frequency increased to daily, and hence, clobazam was included in the drug regimen. At that time, he showed arrested motor and intellectual development and he was referred to our hospital at the age of 3 years. At presentation, he had microcephaly (46.7 cm, − 1.9 SD), severe intellectual impairment without speech, ataxic gait, truncal hypotonia, and hyperkinesis. Daily generalized tonic seizures continued despite adding topiramate, lamotrigine, levetiracetam, and carbamazepine to his antiseizure drug therapy. EEG showed frequent generalized slow spike–wave complexes (Fig. 1B). At the age of 6 years, falling due to atonic seizures became frequent and he was diagnosed with LGS. Brain MRI at this age (6 years) showed T2 hyperintensity and atrophy of the lower cerebellum. At the age of 7 years, his daytime level of consciousness declined and EEG demonstrated ESES (Fig. 1C). At the age of 8 years, atonic seizures disappeared with rufinamide; however, daily generalized tonic seizures during sleep persisted.\n\nWhole-exome sequencing of the patient's leukocyte DNA revealed a novel SLC9A6 mutation (NM_006359.3:c.477_481del:p.Ile160Leufs*5), which is considered pathogenic according to the American College of Medical Genetics and Genomics guidelines [8]. This mutation was not detected in their parents' peripheral blood sample and therefore was considered de novo.\n\n3 Review of the literature\nTable 1 summarizes the findings from previous reports of epilepsy in CS. All known CS patients with information about epilepsy to date were included. Onset of epilepsy ranges from infancy to 26 months of age. Seizure types seen are generalized tonic–clonic seizures or tonic seizures in most cases, atonic seizures or drop attacks in several cases, and partial seizures in only a few patients.Table 1 Previous reports of epilepsy in CS.\n\nTable 1\tn\tAge at onset\tSeizure type (n)\tEEG findings\tEpilepsy classification (n)\tSLC9A6 mutation (NM_006359.3)\t\nMathieu et al. [7]\t5\t< 2 y\tMyoclonic (2)\nGTC (4)\nTonic–clonic (1)\nAtonic (1)\nGelastic seizure (1)\tDiffuse spike and Polyspike–waves (4)\nESES (3)\nFast background activity (3)\nDiffuse alpha (1)\tND\t40-Mb deletion in Xq26.3\np.Trp491*\np.Gly351Asp\t\nMasurel-Paulet et al. [9]\t2\tND\tGTC (1)\tNormal (1)\tND\tc.430-9_430-5delTTTTA\t\nCoorg and Weisenberg [6]\t1\t1 y\tGeneralized seizure\tDiffuse generalized discharges\nESES\tND\tp.Trp538*\t\nZanni et al. [5]\t1\t< 2 y\tTonic–clonic\tESES\tND\tc.1255-1G > A\t\nPescosolido et al. [3]\t14\t4 m to 3 y\tInfantile spasms\nTonic\nTonic–clonic\nMyoclonic\nDrop seizure\nStaring spells\tFrequent generalized spike–wave complexes\nIrregular generalized spike–wave pattern\nMultifocal spikes\tLGS (3)\nInfantile spasms (1)\tp.Gly351Asp\np.Arg440Lysfs*4\np.Trp538*\np.Trp491*\nc.512_519dupAGAAGTAT (p.Phe151fs*1)\nc.498-1G > A\np.Glu64*\np.Arg468*\nc.1237-557_UTRdel\np.Glu515*\t\nMingot et al. [13]\t1\t2 y\tGTC\tBilateral frontal slow-waves\nSpike–waves\nGeneralized bursts of spikes\tND\tc.820C > T (p.Gln274*)\t\nTzschach et al. [10]\t1\t11 m\tND\tND\tND\t314 kb deletion in Xq26.3\t\nTakahashi et al. [14]\t1\t4 y\tMultiple types\t5–6 Hz theta\n3 Hz diffuse high voltage slow waves\tND\tc.441delG (p.Ser147fs) (NM_001042537)\t\nSchroer et al. [15]\t7\t< 2 y\tGTC (5)\nTonic–clonic (2)\nPartial seizure (1)\nAtypical absence (1)\nAtonic seizure (1)\tND\tLGS (1)\tp.Arg468*\np.Gln375*\t\nGilfillan et al. [2]\t8\t9 to 26 m\tMultiple seizure types (1)\tEpileptiform discharges (8)\nAbnormal fast activity (3)\nSlow frequency of 1.5–3 Hz with high voltage (1)\tND\tc.764_769delAAAGTG (p.Glu255_Ser256del)\nc.1402C > T (p.Arg468*)\nc.507 + 3_507 + 6delAAGT (p.Val144_Arg169 del)\t\nChristianson et al. [1]\t16\t< 1 y\tTonic and Tonic-clonic (1)\tND\tND\tc.512_513delAT (p.His171Lysfs*60)\t\nEEG = electroencephalography, ESES = electrical status epilepticus during slow-wave sleep, GTC = generalized tonic–clonic seizure, ND = no data.\n\n\n\nEEG findings have been predominantly described as generalized slow spike–wave complexes. Several cases of high-voltage slow waves or abnormal fast activity were reported. Three reports corresponded to five cases of ESES. The age when ESES was first observed varied from 4 to 8 years, and all seizures were refractory except in one case where felbamate was effective in a patient reported by Coorg and Weisenberg [6].\n\nOnly two reports to date have classified epilepsy and both included LGS. Only one case of epileptic spasms was reported. Although most cases are resistant to antiseizure drug therapy, there are reports of milder cases [9] and patients whose seizures responded to antiseizure medication such as diazepam [10].\n\n4 Discussion\nWe have described the course and progression of two cases of CS subsequently developing LGS with both patients showing similar generalized slow spike–wave complexes in EEG and one child also exhibiting ESES. We propose that LGS may be relatively common in patients with CS in addition to ESES. When taken together with the previous reports, generalized tonic or tonic–clonic seizures and generalized slow spike–wave complexes in interictal EEG tests are common in CS, although other seizure types and EEG results may occur. Even though epilepsy in CS has often been reported as drug-resistant, there is limited information on the course of epilepsy in CS. Therefore, this report provides additional information on patients with epilepsy and CS.\n\nInterictal EEG in both our patients showed frequent generalized slow spike–wave complexes that were very similar to those reported by Pescosolido et al. [3], Zanni et al. [5], and Mathieu et al. [7]. Although the precise details of the EEG including spike–wave complexes (whether “slow” spike–wave or not) cannot be determined from previous reports, we note generalized spike–wave complexes are a characteristic feature of interictal EEG in CS. Interestingly, a few previous reports have described high-voltage slow waves similar to those seen in Angelman syndrome [2], and although it has been reported that CS symptoms are similar those of Angelman syndrome, it has now become clear that neither such wave forms nor symptoms are frequently encountered [3].\n\nOur literature survey identified five cases of ESES at ages between 4 and 8 years, and our second patient developed drug-resistant ESES at the age of 7 years. ESES that develops in early childhood is considered to be one of the features of epilepsy in CS.\n\nOnly two reports to date have classified epilepsy and both included LGS; therefore we suspect the frequency of LGS may be higher based on the limited amount of information on epilepsy classification in available reports. Mutations in GABRB3, ALG13, SCN8A, STXBP1, DNM1, FOXG1, and CHD2 have been reported to result in LGS [11]. All of these genetic mutations may be associated with epilepsy or developmental delays and are known to cause other developmental and epileptic encephalopathies as phenotypes apart from LGS. SLC9A6 encodes the endosomal Na+-H+ exchanger 6 (NHE6) [2], and NHE6 has been reported to be required for neuronal arborization and synapse development [12]. There is also a case report of spasms and CS in a patient with a developmental and epileptic encephalopathy though there is very little information on how developmental processes are affected. The onset of epilepsy in CS occurs in late infancy, and so it may tend to present with LGS phenotypes rather than as early infantile epileptic encephalopathy or West syndrome.\n\nOur first patient had drug-resistant seizures and developed severe intellectual disability; however, the seizures decreased by age 14 years, which is similar to the disease course reported by Mathieu et al. [7]. Therefore, it appears that seizures may decrease spontaneously in some patients during adolescence.\n\nIn summary, CS may be associated with LGS rather than manifesting as other forms of developmental and epileptic encephalopathies in the neonatal and infantile period, along with ESES. The presentation and progression of the two cases described here and those of previous reports suggest that generalized tonic or tonic–clonic seizures and generalized slow spike–wave complexes in interictal EEG may be characteristic features in patients with epilepsy and CS.\n\nEthical statement\nThe work described has been carried out in accordance with the Code of Ethics of the World Medical Association (Declaration of Helsinki) for experiments involving humans.\n\nInformed consent was obtained from the parents of the patients.\n\nFunding\nThis work was supported by Grants-in-Aid for Scientific Research (N. Matsumoto: JP17H01539) from the Japan Society for the Promotion of Science; Grants-in-Aid for Young Scientists (S. Miyatake: JP17K10080) from the Japan Society for the Promotion of Science; the Japan Agency for Medical Research and Development under grant numbers JP18kk02050 (K. Kurosawa), JP19ek0109280, JP19dm0107090, JP19ek0109301, JP19ek0109348, JP18am0101108, JP18kk020501 (N. Matsumoto) and; the Takeda Science Foundation (N. Matsumoto).\n\nDeclaration of competing interest\nThe authors have no financial or personal relations that could pose a conflict of interest.\n==== Refs\nReferences\n1 Christianson AL Stevenson RE van der Meyden CH Pelser J Theron FW van Rensburg PL X linked severe mental retardation, craniofacial dysmorphology, epilepsy, ophthalmoplegia, and cerebellar atrophy in a large South African kindredindred is localised to Xq24–q27 J Med Genet 36 1999 759 766 10528855 \n2 Gilfillan GD Selmer KK Roxrud I Smith R Kyllerman M Eiklid K SLC9A6 cause X-linked mental retardation, microcephaly, epilepsy, and ataxia, a phenotype mimicking Angelman syndrome Am J Hum Genet 82 2008 1003 1010 18342287 \n3 Pescosolido MF Stein DM Schmidt M El Achkar CM Sabbagh M Rogg JM Genetic and phenotypic diversity of NHE6 mutations in Christianson syndrome Ann Neurol 76 2014 581 593 25044251 \n4 Sinajon P Verbaan D So J The expanding phenotypic spectrum of female SLC9A6 mutation carriers: a case series and review of the literature Hum Genet 135 2016 841 850 27142213 \n5 Zanni G Barresi S Cohen R Specchio N Basel-Vanagaite L Valente EM A novel mutation in the endosomal Na +/H + exchanger NHE6 (SLC9A6) causes Christianson syndrome with electrical status epilepticus during slow-wave sleep (ESES) Epilepsy Res 108 2014 811 815 24630051 \n6 Coorg R Weisenberg JL Successful treatment of electrographic status epilepticus of sleep with felbamate in a patient with SLC9A6 mutation Pediatr Neurol 53 2015 527 531 26421989 \n7 Mathieu ML de Bellescize J Till M Flurin V Labalme A Chatron N Electrical status epilepticus in sleep, a constitutive feature of Christianson syndrome? Eur J Paediatr Neurol 22 2018 1124 1132 30126759 \n8 Richards S Aziz N Bale S Bick D Das S Gastier-Foster J Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology Genet Med 17 2015 405 424 25741868 \n9 Masurel-Paulet A Piton A Chancenotte S Redin C Thauvin-Robinet C Henrenger Y A new family with an SLC9A6 mutation expanding the phenotypic spectrum of Christianson syndrome Am J Med Genet A 170 2016 2103 2110 27256868 \n10 Tzschach A Ullmann R Ahmed A Martin T Weber G Decker-Schwering O Christianson syndrome in a patient with an interstitial Xq26.3 deletion Am J Med Genet A 155A 2011 2771 2774 21932316 \n11 Mastrangelo M Lennox–Gastaut syndrome: a state of the art review Neuropediatrics 48 2017 143 151 28346953 \n12 Ouyang Q Lizarraga SB Schmidt M Yang U Gong J Ellisor D Christianson syndrome protein NHE6 modulates TrkB endosomal signaling required for neuronal circuit development Neuron 80 2013 97 112 24035762 \n13 Mignot C Héron D Bursztyn J Momtchilova M Mayer M Whalen S Novel mutation in SLC9A6 gene in a patient with Christianson syndrome and retinitis pigmentosum Brain Dev 35 2013 172 176 22541666 \n14 Takahashi Y Hosoki K Matsushita M Funatsuka M Saito K Kanazawa H A loss-of-function mutation in the SLC9A6 gene causes X-linked mental retardation resembling Angelman syndrome Am J Med Genet B Neuropsychiatr Genet 156B 2011 799 807 21812100 \n15 Schroer RJ Holden KR Tarpey PS Matheus MG Griesemer DA Friez MJ Natural history of Christianson syndrome Am J Med Genet A 152A 2010 2775 2783 20949524\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2589-9864",
"issue": "13()",
"journal": "Epilepsy & behavior reports",
"keywords": "CS, Christianson syndrome; Christianson syndrome; DEE, developmental and epileptic encephalopathy; EEG, electroencephalography; ESES, electrical status epilepticus during slow-wave sleep; Electrical status epilepticus in slow-wave sleep; Epilepsy; LGS, Lennox–Gastaut syndrome; Lennox–Gastaut syndrome; SLC9A6",
"medline_ta": "Epilepsy Behav Rep",
"mesh_terms": null,
"nlm_unique_id": "101750909",
"other_id": null,
"pages": "100349",
"pmc": null,
"pmid": "31879735",
"pubdate": "2020",
"publication_types": "D016428:Journal Article",
"references": "20949524;24630051;18342287;24035762;21812100;28346953;25741868;26421989;25044251;22541666;27142213;21932316;27256868;30126759;10528855",
"title": "Epilepsy in Christianson syndrome: Two cases of Lennox-Gastaut syndrome and a review of literature.",
"title_normalized": "epilepsy in christianson syndrome two cases of lennox gastaut syndrome and a review of literature"
} | [
{
"companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2020R1-233549",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TOPIRAMATE"
},
"drug... |
{
"abstract": "OBJECTIVE\nInterferon-free therapies have an improved safety and efficacy profile. However, data in elderly patients, who have frequently advanced liver disease, associated comorbidities, and use concomitant medications are scarce. The im of this study was to assess the effectiveness and tolerability of all-oral regimens in elderly patients in real-life clinical practice.\n\n\nMETHODS\nRetrospective analysis of hepatitis C virus (HCV) patients aged ≥65 years receiving interferon-free regimens within the Spanish National Registry (Hepa-C).\n\n\nRESULTS\nData of 1,252 patients were recorded. Of these, 955 (76%) were aged 65-74 years, 211 (17%) were aged 75-79 years, and 86 (7%) were aged ≥80 years at the start of antiviral therapy. HCV genotype-1b was predominant (88%) and 48% were previous non-responders. A significant proportion of patients had cirrhosis (922; 74%), of whom 11% presented decompensated liver disease. The most used regimens were SOF/LDV (33%), 3D (28%), and SOF/SMV (26%). Ribavirin was added in 49% of patients. Overall, the sustained virological response (SVR12) rate was 94% without differences among the three age categories. Albumin ≤3.5 g/dl was the only independent negative predictor of response (0.25 (0.15-0.41); P<0.01). Regarding tolerability, the rate of severe adverse events increased with age category (8.8, 13, and 14%; P=0.04). In addition, the main predictors of mortality (2.3%) were age ≥75 years (2.59 (1.16-5.83); P =0.02) and albumin ≤3.5 (17 (6.3-47); P <0.01).\n\n\nCONCLUSIONS\nSVR rates with interferon-free regimens in elderly patients are high and comparable to the general population. Baseline low albumin levels (≤3.5 g/dl) was the only predictor of treatment failure. Importantly, the rate of severe adverse events and death increased with age. Elderly patients (≥75 years) or those with advanced liver disease (albumin ≤3.5) presented higher mortality. Thus a careful selection of patients for antiviral treatment is recommended.",
"affiliations": "Liver Unit, Hospital Clínic, University of Barcelona, IDIBAPS, CIBERehd, Barcelona, Spain.;Digestive Disease Service, Hospital Universitario 12 de Octubre, Madrid, Spain.;Liver Unit, Hospital Clínic, University of Barcelona, IDIBAPS, CIBERehd, Barcelona, Spain.;Liver Unit, Hospital La Fe de Valencia, Valencia, Spain.;Liver Unit, Parc Tauli Sabadell, Hospital Universitari Sabadell, Universitat Autonoma Barcelona, Barcelona, Spain.;Digestive Department, Hospital Universitario Mutua Terrassa, Terrassa, Spain.;Liver Unit, Hospital Universitario Puerta de Hierro, Madrid, Spain.;Liver Unit, Hospital General Universitario Valencia, Valencia, Spain.;Liver Unit, Internal Medicine, Hospital Vall d'Hebron, Barcelona, Spain.;Gastroenterology and Hepatology Department, Marqués de Valdecilla University Hospital, Santander, Spain.;Liver Unit, Hospital Santa Creu i Sant Pau, CIBERehd, Barcelona, Spain.;Gastroenterology and Hepatology Department, Hospital San Pedro, Logroño, Spain.;Liver Unit, Consorci Sanitari de Terrassa, Terrassa, Spain.;Gastroenterology and Hepatology Department, Hospital Universitario Fundacion Alcorcon Universidad Rey Juan Carlos, Madrid, Spain.;Liver Unit, Gastroenterology Division, Hospital Central de Asturias, Oviedo, Spain.;Gastroenterology and Hepatology Department, Hospital Universitario Miguel Servet, Zaragoza, Spain.;Gastroenterology and Hepatology Department, Hospital Universitario de Toledo, Toledo, Spain.;Gastroenterology and Hepatology Department, Clinico Universitario Zaragoza, Zaragoza, Spain.;Gastroenterology and Hepatology Department, Hospital Universitario de Burgos, Burgos, Spain.;Liver Unit, Hospital Bellvitge, Barcelona, Spain.;Liver Unit, Hospital Germans Trias i Pujol, Badalona, Spain.;Liver Unit, Hospital Clínic, University of Barcelona, IDIBAPS, CIBERehd, Barcelona, Spain.",
"authors": "Lens|Sabela|S|;Fernández|Inmaculada|I|;Rodríguez-Tajes|Sergio|S|;Hontangas|Vanessa|V|;Vergara|Mercedes|M|;Forné|Montserrat|M|;Calleja|Jose Luis|JL|;Diago|Moisés|M|;Llaneras|Jordi|J|;Llerena|Susana|S|;Torras|Xavier|X|;Sacristán|Begoña|B|;Roget|Merce|M|;Fernández-Rodríguez|Conrado Manuel|CM|;Navascués|Mari Carmen|MC|;Fuentes|Javier|J|;Sánchez-Ruano|Juan-José|JJ|;Simón|Miguel-Ángel|MÁ|;Sáez-Royuela|Federico|F|;Baliellas|Carmen|C|;Morillas|Rosa|R|;Forns|Xavier|X|;|||",
"chemical_list": "D000998:Antiviral Agents; D007372:Interferons",
"country": "United States",
"delete": false,
"doi": "10.1038/ajg.2017.157",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0002-9270",
"issue": "112(9)",
"journal": "The American journal of gastroenterology",
"keywords": null,
"medline_ta": "Am J Gastroenterol",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000998:Antiviral Agents; D005260:Female; D006299:Health Services for the Aged; D016174:Hepacivirus; D019698:Hepatitis C, Chronic; D006801:Humans; D007372:Interferons; D008297:Male; D012189:Retrospective Studies; D012720:Severity of Illness Index; D013030:Spain; D011795:Surveys and Questionnaires; D019562:Viral Load",
"nlm_unique_id": "0421030",
"other_id": null,
"pages": "1400-1409",
"pmc": null,
"pmid": "28585554",
"pubdate": "2017-09",
"publication_types": "D016428:Journal Article",
"references": "24725238;26155891;26825683;27549000;27667367;24795200;24428467;25911336;26008618;15346240;25837829;26704693;24713005;19523048;27410963;27256744;23121150;27890790;25846144;21827733;17403072",
"title": "Interferon-Free Therapy in Elderly Patients With Advanced Liver Disease.",
"title_normalized": "interferon free therapy in elderly patients with advanced liver disease"
} | [
{
"companynumb": "ES-JNJFOC-20170919944",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "SIMEPREVIR"
},
"drugadditional": null,
... |
{
"abstract": "Hyponatraemia is a well-known side effect of desmopressin therapy. Nocturia in elderly patients can be treated with desmopressin, which usually induces mild and reversible hyponatraemia. This case report is about two patients, in which severe hyponatriaemia, at least partly induced by desmopressin, was observed. The patients were affected by nausea, vomiting and confusion. These symptoms are caused by brain swelling, which can result in coma and death. The case reports illustrate the importance in measuring baseline P-sodium concentration during therapy and examining current medication before prescribing desmopressin.",
"affiliations": "suvazen@hotmail.com.",
"authors": "Sivalingam|Suvanjaa|S|;Sonne|Mette Paulli|MP|;Eldrup|Ebbe|E|",
"chemical_list": "D050034:Antidiuretic Agents; D012964:Sodium; D003894:Deamino Arginine Vasopressin",
"country": "Denmark",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-5782",
"issue": "180(30)",
"journal": "Ugeskrift for laeger",
"keywords": null,
"medline_ta": "Ugeskr Laeger",
"mesh_terms": "D000369:Aged, 80 and over; D050034:Antidiuretic Agents; D003894:Deamino Arginine Vasopressin; D005260:Female; D006801:Humans; D007010:Hyponatremia; D053158:Nocturia; D012964:Sodium",
"nlm_unique_id": "0141730",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "30037383",
"pubdate": "2018-07-23",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Desmopressin therapy of nocturia in elderly patients may contribute to severe hyponatraemia.",
"title_normalized": "desmopressin therapy of nocturia in elderly patients may contribute to severe hyponatraemia"
} | [
{
"companynumb": "DK-SUN PHARMACEUTICAL INDUSTRIES LTD-2019R1-229410",
"fulfillexpeditecriteria": "1",
"occurcountry": "DK",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "DESMOPRESSIN"
},
"dr... |
{
"abstract": "Checkpoint inhibitors enhance T-lymphocyte-mediated antitumor responses, resulting in increased survival for patients with neoplastic disease. However, a subset of patients receiving checkpoint inhibitor therapy may experience adverse complications that include the development of autoimmune conditions, such as thrombotic thrombocytopenic purpura (TTP). Given the potential etiologic differences of checkpoint inhibitor-related autoimmunity, TTP that develops in the presence of checkpoint inhibitors may be refractory to current treatment methods and therefore may require additional treatment and prognostic consideration.\n\n\n\nHerein, we describe the unique clinical course of a patient who was treated with the combined checkpoint inhibitors nivolumab and ipilimumab for Stage IV malignant melanoma, who subsequently developed TTP. Unlike many patients with TTP, this patient failed to develop a sustained response to therapeutic plasma exchange. Additional use of steroids, anti-CD20, and plasma cell-targeting therapy (bortezomib) also failed to substantially reverse thrombocytopenia in a sustainable fashion. During this time, her melanoma progressed, and she ultimately succumbed.\n\n\n\nThis case illustrates not only that TTP may be a potential complication of checkpoint inhibitor therapy, but also that TTP developing in this setting may result in an unpredictable response to commonly employed TTP treatment modalities. Ultimately, checkpoint inhibitor-related TTP may require distinct management approaches and prognostic considerations.",
"affiliations": "Center for Transfusion and Cellular Therapy, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia, USA.;Center for Transfusion and Cellular Therapy, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia, USA.;Center for Transfusion and Cellular Therapy, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia, USA.;Center for Transfusion and Cellular Therapy, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia, USA.",
"authors": "Lancelot|Moira|M|;Miller|Maureen J|MJ|;Roback|John|J|;Stowell|Sean R|SR|0000-0002-1130-9551",
"chemical_list": "D000082082:Immune Checkpoint Inhibitors",
"country": "United States",
"delete": false,
"doi": "10.1111/trf.16117",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1132",
"issue": "61(1)",
"journal": "Transfusion",
"keywords": "immune checkpoint inhibitors; immunotherapy; thrombotic thrombocytopenic purpura (TTP)",
"medline_ta": "Transfusion",
"mesh_terms": "D015551:Autoimmunity; D018450:Disease Progression; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D000082082:Immune Checkpoint Inhibitors; D007167:Immunotherapy; D008545:Melanoma; D008875:Middle Aged; D009367:Neoplasm Staging; D010951:Plasma Exchange; D011697:Purpura, Thrombotic Thrombocytopenic; D012878:Skin Neoplasms",
"nlm_unique_id": "0417360",
"other_id": null,
"pages": "322-328",
"pmc": null,
"pmid": "33119913",
"pubdate": "2021-01",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Refractory thrombotic thrombocytopenic purpura related to checkpoint inhibitor immunotherapy.",
"title_normalized": "refractory thrombotic thrombocytopenic purpura related to checkpoint inhibitor immunotherapy"
} | [
{
"companynumb": "US-BRISTOL-MYERS SQUIBB COMPANY-BMS-2020-096651",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "NIVOLUMAB"
},
"drugaddi... |
{
"abstract": "In patients with chronic heart failure, spironolactone added to conventional treatment may lead to serious and, occasionally, fatal hyperkalaemia. In some cases this seems to happen because spironolactone causes diarrhoea. Four cases involving men with New York Heart Association functional class III heart failure are presented. As these cases revealed, close monitoring of blood chemistry is mandatory after starting spironolactone, and patients should be advised to stop spironolactone immediately if diarrhoea develops.",
"affiliations": "Department of Cardiology, Western Infirmary, Dumbarton Road, Glasgow G11 6NT, UK. colin.berry@clinmed.gla.ac.uk",
"authors": "Berry|C|C|;McMurray|J J|JJ|",
"chemical_list": "D004232:Diuretics; D000451:Mineralocorticoid Receptor Antagonists; D013148:Spironolactone",
"country": "England",
"delete": false,
"doi": "10.1136/heart.85.4.e8",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1355-6037",
"issue": "85(4)",
"journal": "Heart (British Cardiac Society)",
"keywords": null,
"medline_ta": "Heart",
"mesh_terms": "D000368:Aged; D003967:Diarrhea; D004232:Diuretics; D017809:Fatal Outcome; D006323:Heart Arrest; D006333:Heart Failure; D006801:Humans; D006947:Hyperkalemia; D008297:Male; D008875:Middle Aged; D000451:Mineralocorticoid Receptor Antagonists; D013148:Spironolactone",
"nlm_unique_id": "9602087",
"other_id": null,
"pages": "E8",
"pmc": null,
"pmid": "11250985",
"pubdate": "2001-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "6990088;10471456;2823245",
"title": "Serious adverse events experienced by patients with chronic heart failure taking spironolactone.",
"title_normalized": "serious adverse events experienced by patients with chronic heart failure taking spironolactone"
} | [
{
"companynumb": "GB-PFIZER INC-2021432210",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ENALAPRIL"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nCentral Diabetes Insipidus (CDI) results from decreased production of antidiuretic hormone (ADH) leading to an inability to concentrate urine. CDI is treated with desmopressin (DDAVP). Rarely reported in the literature, opioids and non-steroidal anti-inflammatories (NSAIDs) can induce hyponatremia in individuals treated for CDI.\n\n\nMETHODS\nA 10-year-old boy with septo-optic dysplasia and CDI was treated with DDAVP 1.6 mg orally TID maintaining normal sodium levels. Post admission for a femur fracture, he was discharged on ibuprofen and hydromorphone. Sodium was 136 mmol/l two days before discharge. He returned to the ED after having a seizure at home. He was euvolemic and mildly lethargic. Sodium was low at 108 mmol/l. DDAVP and hydromorphone were held and he was fluid restricted, but the sodium remained low. Sodium began to rise when Ibuprofen was stopped. Intermittent small doses of DDAVP were given to facilitate gradual correction of hyponatremia. At discharge, sodium had normalized.\n\n\nCONCLUSIONS\nHyponatremia has occasionally been described as a side effect of opioids and rarely of NSAIDs in patients with CDI. Stimulation of the thirst centre may play a role with opioids while a decrease in urine output may be the mechanism with NSAIDs.",
"affiliations": "Division of Endocrinology and Metabolism, Department of Pediatrics, Dalhousie University and IWK Health Centre, 5850/5980 University Avenue, Halifax, NS, B3K6R8, Canada. Teresa.pinto@iwk.nshealth.ca.;Division of Endocrinology and Metabolism, Department of Pediatrics, Dalhousie University and IWK Health Centre, 5850/5980 University Avenue, Halifax, NS, B3K6R8, Canada.;Division of Endocrinology and Metabolism, Department of Pediatrics, Dalhousie University and IWK Health Centre, 5850/5980 University Avenue, Halifax, NS, B3K6R8, Canada.",
"authors": "Pinto|Teresa E|TE|;Mokashi|Arati|A|;Cummings|Elizabeth A|EA|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/s40842-021-00124-9",
"fulltext": "\n==== Front\nClin Diabetes Endocrinol\nClin Diabetes Endocrinol\nClinical Diabetes and Endocrinology\n2055-8260\nBioMed Central London\n\n124\n10.1186/s40842-021-00124-9\nCase Report\nCentral diabetes insipidus and pain medications – a risky combination\nPinto Teresa E. Teresa.pinto@iwk.nshealth.ca\n\nMokashi Arati\nCummings Elizabeth A.\ngrid.414870.e 0000 0001 0351 6983 Division of Endocrinology and Metabolism, Department of Pediatrics, Dalhousie University and IWK Health Centre, 5850/5980 University Avenue, Halifax, NS B3K6R8 Canada\n16 6 2021\n16 6 2021\n2021\n7 1110 12 2020\n21 5 2021\n© The Author(s) 2021\nhttps://creativecommons.org/licenses/by/4.0/ Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.\nBackground\n\nCentral Diabetes Insipidus (CDI) results from decreased production of antidiuretic hormone (ADH) leading to an inability to concentrate urine. CDI is treated with desmopressin (DDAVP). Rarely reported in the literature, opioids and non-steroidal anti-inflammatories (NSAIDs) can induce hyponatremia in individuals treated for CDI.\n\nCase presentation\n\nA 10-year-old boy with septo-optic dysplasia and CDI was treated with DDAVP 1.6 mg orally TID maintaining normal sodium levels. Post admission for a femur fracture, he was discharged on ibuprofen and hydromorphone. Sodium was 136 mmol/l two days before discharge.\n\nHe returned to the ED after having a seizure at home. He was euvolemic and mildly lethargic. Sodium was low at 108 mmol/l. DDAVP and hydromorphone were held and he was fluid restricted, but the sodium remained low. Sodium began to rise when Ibuprofen was stopped. Intermittent small doses of DDAVP were given to facilitate gradual correction of hyponatremia. At discharge, sodium had normalized.\n\nConclusion\n\nHyponatremia has occasionally been described as a side effect of opioids and rarely of NSAIDs in patients with CDI. Stimulation of the thirst centre may play a role with opioids while a decrease in urine output may be the mechanism with NSAIDs.\n\nSupplementary Information\n\nThe online version contains supplementary material available at 10.1186/s40842-021-00124-9.\n\nKeywords\n\nDiabetes insipidus\nOpioid\nNon-steroidal anti-inflammatory (NSAID)\nHyponatremia\nissue-copyright-statement© The Author(s) 2021\n==== Body\nBackground\n\nCentral Diabetes Insipidus (CDI) is due to decreased or absent production of antidiuretic hormone (ADH). This results in an inability to concentrate urine and hypernatremia if access to sufficient free water is not possible. Desmopressin (DDAVP) is the mainstay of treatment. The Syndrome of Inappropriate ADH Secretion (SIADH), on the contrary, is the result of excessive ADH secretion. Clinically the patients are euvolemic with low serum sodium and osmolality and high urine sodium and osmolality with low urine output.\n\nOpioids and non-steroidal anti-inflammatory drugs (NSAIDS) have both been reported individually, to cause hyponatremia, typically secondary to SIADH [1–3]. Rarely, have they been reported to cause hyponatremia in an individual with CDI [4, 5]. The mechanism for the hyponatremia would have to be different in this situation given that patients with DI do not produce ADH. To the best of our knowledge, hyponatremia with the use of NSAIDS or opioids in CDI has not been reported in the pediatric population nor has it been reported in patients treated with both concomitantly.\n\nHere we report the case of a boy with CDI who presented with severe hyponatremia in the context of both opioid and NSAID treatment following a femur fracture. The patient’s mother provided written informed consent for the publication of this case.\n\nCase presentation\n\nA 10-year-old boy with septo-optic dysplasia, adrenocorticotropic hormone (ACTH) and growth hormone (GH) deficiency, and CDI was treated with DDAVP 1.6 mg (tablets) orally four times daily maintaining normal sodium levels. CDI was diagnosed 3 years prior, when he presented with polyuria and polydipsia. A water depravation test showed high urine output after 20.5 h of fasting, a urine osmolality of only 462 mmol/kg, and a serum osmolality of 317 mmol/kg. He responded promptly to 10 µg of intranasal DDAVP with urine osmolality of 804 mmol/kg and a drop in urine output to less than 1 ml/kg/hour, confirming the diagnosis of CDI. He was also treated with hydrocortisone 6 mg orally twice daily (6.3 mg/m2/day) and growth hormone 1.3 mg by subcutaneous injection daily. Free T4 levels, monitored routinely, were normal with values of 10 pmol/l (8-22 pmol/l) 4 months prior to admission and 5 months post-admission. In addition, he was developmentally delayed with visual impairment and poor mobility and a body mass index of 34 kg/m2. Post-admission for a femur fracture, he was discharged on ibuprofen 600 mg q6hr prn and hydromorphone 1 mg q4hr prn which he was taking regularly. Sodium was 136 mmol/l (133–148) two days before discharge.\n\nLess than 24 h later, he returned to the Emergency Department after having a seizure at home. His mother described it as an episode of increased tone in his arms, teeth grinding, and rocking after which he was unresponsive and apneic. She reported performing cardio-pulmonary resuscitation for 1 min before he started breathing again. Approximately 3 min later he regained alertness. In hospital, he was euvolemic and mildly lethargic. Blood pressure was 121/93 with a heart rate of 90–100. The patient had a brisk capillary refill, normal skin turgor and mucous membranes were noted to be moist. His glucose was 5.6 mmol/l however sodium was very low at 108 mmol/l. His mother denied any potential error in DDAVP administration and given his limited mobility he did not have free access to water outside of what his mother provided. She denied any additional water than his normal daily intake. She reported that the only change in his medications was the regular dosing of both ibuprofen and hydromorphone.\n\nHe was admitted to hospital and stress doses of hydrocortisone (15 mg three times daily) were initiated and continued for 3 days and double maintenance for 2 additional days until returning to maintenance doses. His hydromorphone was held and he was fluid restricted. Intermittent small doses of DDAVP were given initially to facilitate gradual correction of hyponatremia.\n\nSodium rose somewhat but remained below the normal range. Sodium normalized and remained stable when Ibuprofen was stopped (Table 1). At discharge, sodium had normalized on DDAVP 0.5 mg BID but he soon required higher doses again.Table 1 Sodium Trend in Hospital\n\nDay\tSodium (mmol/L)\tPain med (name/dose)\tDDAVP (mg)\t\nPrior to initial discharge\t136\tHydromorphone 1 mg q4hr\n\nIbuprofen 600 mg q4hrs\n\n\t1.6 mg q6hr\t\n1 of admission\t108\tHydromorphone held\tHeld\t\n2\t110–118\tNo change\t0.6 mg Prn\t\n3\t120–128\tNo change\t0.6 mg Prn\t\n4\t127–137\tNo change\t0.6 mg Prn\t\n5\t135–137\tIbuprofen held\t0.6 mg Prn\t\n6–14\t137–141\tNone\t0.5 mg BID, 0.1 mg prn\t\n5 months post\t139\tNone\t1.4 mg qam, 0.6 mg qpm, 1.4 mg qhs\t\nPrn: as needed\n\nDiscussion\n\nSIADH has been described as a potential side effect of opioids. Multiple potential mechanisms likely exist. Opioids may increase ADH secretion independently [6]. In addition, opioids block the reuptake of certain neurotransmitters, namely norepinephrine and serotonin. This in turn increases serotonin centrally. Serotonin increases ADH release centrally [7]. Finally, opioids work through opioid receptors (μ, ĸ, δ). Morphine binds to the μ receptor and has an inhibitory effect on the release of the neurotransmitter ƴ-aminobutyric acid (GABA) in the hypothalamic axis. Inhibition of GABA may result in an increase in ADH release [8], though the effects of GABA on vasopressin release show conflicting findings. Grossman suggests that opioids suppress ADH release suggesting that this mechanism is not the cause of hyponatremia [9]. Regardless, all potential mechanisms suggest an increase in ADH production or release as a cause of hyponatremia.\n\nNSAIDs on the other hand, are felt to induce hyponatremia secondary to their potentiating effect on ADH action and resultant water retention. Renal prostaglandins typically inhibit ADH. Through decreasing renal prostaglandins, NSAIDs in turn result in increased ADH effect at the level of the kidney causing increased water retention and hyponatremia [6, 10]. Some have suggested that this occurs through prostaglandin E2’s (PGE2) inhibition of ADH-induced translocation of the aquaporin 2 receptor (AQP2) to the apical cell membrane of the collecting duct cells [11]. Ren and colleagues report that inhibition of PGE2 may actually increase ADH dependent translocation of the AQP2 receptor. Therefore the mechanism is unclear [12].\n\nThe current case is unique, however, as the patient had minimal endogenous ADH production. Bhat and colleagues reported on a 19-year-old woman with panhypopituitarism who developed hyponatremia after receiving hydrocodone for a wisdom tooth extraction. Interestingly, she experienced polydipsia postoperatively and then presented with hyponatremia. Subsequently, desmopressin was held after receiving morphine for an ambulatory ankle arthroscopic debridement and sodium remained in the normal range suggesting the cause of the original episode of hyponatremia was the use of opioids in association with DDAVP. No mention of increased thirst was made after the second surgery. The authors suggest that hydrocodone stimulated the patient’s thirst centre resulting in the hyponatremia [5]. Their hypothesis is supported by mouse models that show an increase in water intake with opiate agonists. It is proposed that the centre of action is the paraventricular nucleus of the hypothalamus which is rich in opioid receptors [13]. Our patient did not experience polydipsia post-operatively however, or at any time in the days following the surgery and water intake was closely monitored given his developmental delay, suggesting an alternative mechanism of action.\n\nTo our knowledge, there are only 2 cases in the literature that report hyponatremia in NSAID treated patients with DI. Bergoglio et al. described a 46-year-old man, taking desmopressin for CDI, who was admitted for symptomatic hyponatremia with a sodium of 113 mEq/L (113 mmol/L). The only change in his usual medication regime had been the addition of 200 mg/day of aceclofen for back pain [4]. The patient was reported to be euvolemic and had documented normal sodium levels prior to aceclofen. DDAVP was held and the patient was treated with hypertonic saline with resolution of the hyponatremia. Verrua et al. describe a 50-year-old man with known CDI who presented with a hyponatremic seizure and coma following 3 days of ketoprofen for cervical pain secondary to spondylosis. He was treated with 3% saline, and eventually, DDAVP was re-introduced. While he had likely taken NSAIDs before without symptomatic hyponatremia, the authors conclude that there may have been increased sensitivity to the effect due to age [14].\n\nThe current case is unique for several reasons. Firstly, it is the first case to our knowledge, that reports on a patient with CDI receiving both an opioid and an NSAID. It was noted that although the sodium improved with holding the opioid and fluid restriction, full recovery was not obtained until the NSAID was also held, suggesting a synergistic effect of both medications to cause hyponatremia. Secondly, the opioid effect would have to be mostly independent of ADH release given that this patient was known to have CDI requiring relatively high doses of DDAVP both before and after the event suggesting minimal endogenous ADH production. Thirdly, there was no evidence of increased water intake since his fluid intake was measured out due to his developmental delay and poor mobility and he was euvolemic at the time of presentation. The hyponatremia cannot, therefore, be explained by increased fluid intake. Finally, this is the first described case occurring in a pediatric patient. Adolescent brains have been shown to have a higher number of opioid μ-receptors than adult brains [15]. This might suggest a higher sensitivity to opioids in adolescents than adults which would suggest this may occur more commonly in youth. It may be under-recognized however, as the cause of hyponatremia in CDI may be misdiagnosed as DDAVP excess or excess fluid intake during times of illness.\n\nThis case brings to attention the importance of careful prescribing and monitoring when a patient with CDI requires pain medication. Review of this case led to quality improvement/patient initiatives at our centre. A complex care plan is filled out for such patients in order to bring awareness to other health care providers of potential risks associated with their condition (Additional file 1).\n\nConclusion\n\nOpioids and NSAIDs can both result in hyponatremia independently and together. This case suggests a synergistic effect that can be life-threatening. Cautious monitoring of sodium levels should take place whenever prescribing opioids or NSAIDs in this population with consideration of reducing or even temporarily discontinuing DDAVP while taking these medications. In addition, pharmacies should be aware and alert prescribers of this potential interaction while families and patients need to be educated in order to avoid potentially harmful outcomes.\n\nSupplementary Information\n\nAdditional file 1: Complex Care Plan.\n\nAbbreviations\n\nCDI Central Diabetes Insipidus\n\nADH Anti-diuretic hormone\n\nDDAVP Desmopressin\n\nNSAID Non-steroidal anti-inflammatory\n\nSIADH Syndrome of inappropriate anti-diuretic hormone Secretion\n\nACTH Adrenocorticotropic hormone\n\nGH Growth hormone\n\nGABA ƴ-Aminobutyric acid\n\nPGE2 Prostaglandin E2\n\nAQP2 Aquaporin 2\n\nAcknowledgements\n\nNot applicable.\n\nAuthors’ contributions\n\nTP wrote, edited and reviewed the case report. BC and AM reviewed and edited the report. The authors read and approved the final manuscript.\n\nFunding\n\nnone.\n\nAvailability of data and materials\n\nNot applicable.\n\nDeclarations\n\nEthics approval and consent to participate\n\nEthics committee approval is not required at our centre for case reports.\n\nThe patient’s mother provided written informed consent for the publication of this case.\n\nConsent for publication\n\nConsent for publication was provided by the patient’s mother.\n\nCompeting interests\n\nThe authors declare that they have no competing interests.\n\nPublisher's Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Kokko H Hall PD Afrin LB Fentanyl-associated syndrome of inappropriateantidiuretic hormone secretion Pharmacotherapy 2002 22 9 1188 1192 10.1592/phco.22.13.1188.33526 12222557\n2. Yong TY Khow KSF Hyponatraemia associated with tramadol use: a case report Curr Drug Saf 2018 13 3 217 220 10.2174/1574886313666180508123232 29745338\n3. Fournier JP Yin H Nessim SJ Montastruc JL Azoulay L Tramadol for noncancer pain and the risk of hyponatremia Am J Med 2015 128 4 418 25.e5 10.1016/j.amjmed.2014.10.046 25460534\n4. Bergoglio MT Sola Izquierdo E Veses Martin S Hernandez Mijares A Acute severe hyponatremia induced by aceclofen in a male patient with central diabetes insipidus Endocrinol Nutr 2013 60 6 338 340 10.1016/j.endonu.2012.06.012 23022363\n5. Bhat N Balliu E Osipoff J Lane A Wilson T Opioid-induced hyponatremia in a patient with central diabetes insipidus: independence from ADH J Pediatr Endocrinol Metab 2017 30 6 693 696 10.1515/jpem-2017-0001 28593907\n6. Liamis G Milionis H Elisaf M A review of drug-induced hyponatremia Am J Kidney Dis 2008 52 1 144 153 10.1053/j.ajkd.2008.03.004 18468754\n7. Udy A Deacy N Barnes D Sigston P Tramadol-induced hyponatraemia following unicompartmental knee replacement surgery Anaesthesia 2005 60 8 814 816 10.1111/j.1365-2044.2005.04260.x 16029233\n8. Karahan S Karagoz H Erden A Avci D Esmeray K Codeine-induced syndrome of inappropriate antidiuretic hormone: case report Balkan Med J 2014 31 1 107 109 10.5152/balkanmedj.2013.9424 25207179\n9. Grossman A Brain Opiates and Neuroendocrine Function Clin Endocrinol Metab 1983 12 3 725 10.1016/S0300-595X(83)80062-0 6323067\n10. Demir ME Horoz M Ulas T Eren MA Ercan Z Nonsteroidal anti-inflammatory drug-induced severe hyponatremia Medicina (Kaunas) 2012 48 12 619 621 23652618\n11. Zelenina M Christensen BM Palmer J Nairn AC Nielsen S Aperia A Prostaglandin E(2) interaction with AVP: effects on AQP2 phosphorylation and distribution Am J Physiol Renal Physiol 2000 278 3 F388 F394 10.1152/ajprenal.2000.278.3.F388 10710543\n12. Ren H Yang B Molina PA Sands JM Klein JD NSAIDs Alter Phosphorylated Forms of AQP2 in the Inner Medullary Tip PLoS ONE 2015 10 10 e0141714 10.1371/journal.pone.0141714 26517129\n13. Nagatomo I Katafuchi T Koizumi K Effects of the opiates on the paraventricular nucleus in genetically polydipsic mice Brain Res 1992 598 1–2 23 32 10.1016/0006-8993(92)90163-4 1362519\n14. Verrua E Mantovani G Ferrante E Noto A Sala E Malchiodi E Severe water intoxication secondary to the concomitant intake of non-steroidal anti-inflammatory drugs and desmopressin: a case report and review of the literature Hormones (Athens) 2013 12 1 135 141 10.1007/BF03401295 23624139\n15. Smith CJW Ratnaseelan AM Veenema AH Robust age, but limited sex, differences in mu-opioid receptors in the rat brain: relevance for reward and drug-seeking behaviors in juveniles Brain Struct Funct 2018 223 1 475 488 10.1007/s00429-017-1498-8 28871491\n\n",
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"keywords": "Diabetes insipidus; Hyponatremia; Non-steroidal anti-inflammatory (NSAID); Opioid",
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"title": "Central diabetes insipidus and pain medications - a risky combination.",
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"abstract": "Toxic epidermal necrolysis (TEN), also known as Lyell's syndrome, is a severe cutaneous drug reaction with a high mortality. Immune response is the possible cause in its pathogenesis. Levofloxacin is one of the most commonly used quinolones and has been reported to cause of TEN. On the other hand, furazolidone was proposed to augment the action of immediate hypersensitivity of levofloxacin by its cytotoxic effect and by the generation of free radicals. Here, we present a case of TEN where, levofloxacin and furazolidone were the probable cause of these adverse drug reactions.",
"affiliations": "Department of Pharmacology, Mahatma Gandhi Institute of Medical Sciences, Sewagram, Wardha, Maharashtra, India.;Department of Pharmacology, Mahatma Gandhi Institute of Medical Sciences, Sewagram, Wardha, Maharashtra, India.;Department of Pharmacology, Mahatma Gandhi Institute of Medical Sciences, Sewagram, Wardha, Maharashtra, India.",
"authors": "Varma|Sushil Kumar|SK|;Sutradhar|Shanta|S|;Misra|Arup Kumar|AK|",
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"fulltext": "\n==== Front\nIndian J PharmacolIndian J PharmacolIJPharmIndian Journal of Pharmacology0253-76131998-3751Medknow Publications & Media Pvt Ltd India IJPharm-45-62510.4103/0253-7613.121380Drug WatchLevofloxacin and furazolidone induced toxic epidermal necrosis Varma Sushil Kumar Sutradhar Shanta Misra Arup Kumar Department of Pharmacology, Mahatma Gandhi Institute of Medical Sciences, Sewagram, Wardha, Maharashtra, IndiaCorrespondence to: Dr. Shanta Sutradhar, E-mail: shanta@mgims.ac.inNov-Dec 2013 45 6 625 626 17 6 2013 09 7 2013 12 9 2013 Copyright: © Indian Journal of Pharmacology2013This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Toxic epidermal necrolysis (TEN), also known as Lyell's syndrome, is a severe cutaneous drug reaction with a high mortality. Immune response is the possible cause in its pathogenesis. Levofloxacin is one of the most commonly used quinolones and has been reported to cause of TEN. On the other hand, furazolidone was proposed to augment the action of immediate hypersensitivity of levofloxacin by its cytotoxic effect and by the generation of free radicals. Here, we present a case of TEN where, levofloxacin and furazolidone were the probable cause of these adverse drug reactions.\n\nKEY WORDS\nCytotoxicityfurazolidonehypersensitivity reactionlevofloxacintoxic epidermal necrolysis\n==== Body\nIntroduction\nStevens-Johnson syndrome and toxic epidermal necrolysis (TEN, Lyell's syndrome) are severe life-threatening cutaneous adverse drug reactions (ADR). TEN is characterized by the involvement of more than 30% skin detachment and causes mortality in 25-35% cases.[1] Fluoroquinolones are the most widely used drugs which have broad coverage and low adverse effect profile. Levofloxacin has a high incidence of this ADR among all the drugs in this class.[2] Furazolidone is a synthetic nitrofuran widely used in the treatment of gastrointestinal infections. Levofloxacin has been implicated as an offending agent in TEN in literature,[3] whereas furazolidone induces the skin condition by affecting the immune system. We present a case of TEN probably caused by levofloxacin and furazolidone.\n\nCase Report\nA 69-year-old male patient with the complaints of fever of mild to moderate grade and loose motions, 4-6 times a day consulted a private practitioner and was prescribed tablet levofloxacin 500 mg twice daily, tablet furazolidone 100 mg thrice a day and tablet rabeprazole 20 mg once a day. After taking medications for 2 days, he complained of rashes all over his body associated with pain, which later developed into erosions and peeling of the skin. He also complained the difficulty in swallowing food due to oral ulcers.\n\nOn examination, the patient was alert and his pulse and blood pressure were within normal limits. He had no pallor, icterus, lymphadenopathy, clubbing and pedal edema. His respiratory, cardiovascular and central nervous systems were within normal limits. On examination, oral erosions, dusky red skin over the chest, abdomen, back, face, upper and lower limbs with epidermal peeling involving more than 40% of the total body surface area was observed. The Nikolsky's sign was positive. Ocular inflammation was also present [Figure 1].\n\nFigure 1 Toxic epidermal necrolysis before treatment Access\n\nOn the day of admission, his serum urea and serum creatinine was 78 mg/dl and 1.4 mg/dl, respectively. The red blood cell counter was 19.7 cell/μl (mcL) and peripheral blood smear showed neutrophils with toxic granules and band form. Nuclei and platelets were adequate. His erythrocyte sedimentation rate was 60 mm/h. The liver function tests were within the normal limit. Blood culture report done at the time of admission was negative after 24 h incubation. His Scorten Score was 2. Following the abnormal reports, levofloxacin and furazolidone were stopped and he was prescribed injection dexamethasone 8 mg intravenous (i.v.) 4 times a day for 5 days, later tapered for the next 4 days. Injection of combination of amoxicillin with clavulunic acid 1.2 g i.v. thrice a day for 15 days, calamine lotion locally twice a day, betadine gargles 4 times a day for oral ulcers and injection pantoprazole 40 mg i.v once a day were also prescribed. At 10 days later, the symptoms improved, he was able to take food orally and the epidermal peeling also subsided. Laboratory investigations were repeated after 10 days were normal.\n\nDiscussion\nTEN is a rare disease that usually follows drug-exposure. It is predominantly induced by medications such as allopurinol, anticonvulsants, quinolones and non-steroidal anti-inflammatory drugs.[1] The pathogenesis of TEN is complicated but believed to be immune-mediated. TEN is a specific drug hypersensitivity reaction in which T lymphocytes play a role in the pathogenesis of the disease. In literature, it was found that in early stage of the disease, the blister fluid contains cytotoxic CD8+ T lymphocytes, which may suggest a major histocompatibility class-I restricted drug presentation, which may lead to clonal expansion of CD8 and cytotoxic lymphocytes.[4] The increase in the leucocytes counts in the case may correlate with finding in the literature. The cytotoxic proteins and cells implicated in the pathogenesis of TEN are not fully understood and is a key subject of ongoing research. There is a cross-link which suggest that disseminated keratinocyte apoptosis in TEN is mostly due to cytotoxic molecules FasL and granulysin.[5]\n\nFurazolidone is an antimicrobial used in Gram negative bacterial infections, giardiasis and trichomoniasis. It up-regulates the production of intracellular reactive oxygen species which bind with mitochondrial deoxyribonucleic acid and causes oxidation of the cell. Due to oxidative stress, it may cause abnormal progression of cell cycle, which may result in cell cytotoxicity and cell death. Thus, it has been known to cause agranulocytosis, hemolysis and rash.[6] On the other hand, levofloxacin has already been reported as an offending agent in TEN.[3] The probable cause of the ADR in this case may be immediate hypersensitivity reaction due to levofloxacin which is a rare adverse reaction of this drug. The mechanism of underlying immediate reaction is not clearly defined. However, it may be postulated that the drug may bind with basal keratinocytes and stimulate the inflammatory process by causing the release of lymphokines, mast cell and antibodies, which in turn causes damage to basal cell. CD8+ on activation causes the release of interferon and cytotoxic granules which may add to further damage to basal cell.[7] This may up-regulate the immune response and cause TEN. Thus, we can assume that the combination of levofloxacin induces immediate hypersensitivity reaction and furazolidone induced oxidative stress and cell toxicity may be the contributing factor in the pathogenesis of TEN.\n\nIn this case, patient had improved gradually after offending drugs were withdrawn. Causality assessment using Naranjo algorithm shows that a probable relationship exists between levofloxacin and furazolidine and TEN.[8] Hence, caution is advised while co-administering these drugs, particularly in patients with a known history of hypersensitivity to these drugs.\n\nSource of Support: Nil\n\nConflict of Interest: No\n==== Refs\n1 French LE Toxic epidermal necrolysis and Stevens Johnson syndrome: Our current understanding Allergol Int 2006 55 9 16 17075281 \n2 Carbon C Comparison of side effects of levofloxacin versus other fluoroquinolones Chemotherapy 2001 47 Suppl 3 9 14 44 11549784 \n3 Davila G Ruiz-Hornillos J Rojas P De Castro F Zubeldia JM Toxic epidermal necrolysis induced by levofloxacin Ann Allergy Asthma Immunol 2009 102 441 2 19492670 \n4 Correia O Delgado L Ramos JP Resende C Torrinha JA Cutaneous T-cell recruitment in toxic epidermal necrolysis. Further evidence of CD8+ lymphocyte involvement Arch Dermatol 1993 129 466 8 8466217 \n5 Chung WH Hung SI Yang JY Su SC Huang SP Wei CY Granulysin is a key mediator for disseminated keratinocyte death in Stevens-Johnson syndrome and toxic epidermal necrolysis Nat Med 2008 14 1343 50 19029983 \n6 Jin X Tang S Chen Q Zou J Zhang T Liu F Furazolidone induced oxidative DNA damage via up-regulating ROS that caused cell cycle arrest in human hepatoma G2 cells Toxicol Lett 2011 201 205 12 21195149 \n7 Shiohara T Fixed drug eruption: Pathogenesis and diagnostic tests Curr Opin Allergy Clin Immunol 2009 9 316 21 19474709 \n8 Naranjo CA Busto U Sellers EM Sandor P Ruiz I Roberts EA A method for estimating the probability of adverse drug reactions Clin Pharmacol Ther 1981 30 239 45 7249508\n\n",
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"keywords": "Cytotoxicity; furazolidone; hypersensitivity reaction; levofloxacin; toxic epidermal necrolysis",
"medline_ta": "Indian J Pharmacol",
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"title": "Levofloxacin and furazolidone induced toxic epidermal necrosis.",
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"abstract": "A 42-year-old male presented with diplopia, headache, and nausea. Magnetic resonance imaging (MRI) of the brain showed pineal tumor, and chest computed tomography (CT) demonstrated a lung tumor. Disorientation developed, with occurrence of hydrocephalus, and we performed neuroendoscopic surgery for biopsy of the pineal tumor and third ventriculostomy. The lung tumor was biopsied under bronchoscopic and CT guidance, and based on the pathological results, we diagnosed pineal metastasis of pulmonary sarcomatoid carcinoma (cT3N1M1b Stage IVA). Stereotactic radiotherapy for the metastatic pineal tumor and systemic chemotherapy (carboplatin + pemetrexed) were pursued, but hemorrhage of the tumor occurred, hydrocephalus worsened, and neoplastic meningitis was diagnosed by MRI. Therapy was switched to nivolumab, but without effect, and the patient succumbed. Even among lung tumors, sarcomatoid carcinoma is rare. There are also few reports of lung tumors metastasized to the pineal gland. Our case report of pineal tumor regarded as metastasis of pulmonary sarcomatoid carcinoma also includes a discussion of the literature.",
"affiliations": "Department of Neurosurgery, Fujita Health University, Toyoake, Aichi, Japan.;Department of Neurosurgery, Fujita Health University, Toyoake, Aichi, Japan.;Department of Neurosurgery, Fujita Health University, Toyoake, Aichi, Japan.;Department of Neurosurgery, Fujita Health University, Toyoake, Aichi, Japan.;Department of Neurosurgery, Fujita Health University, Toyoake, Aichi, Japan.",
"authors": "Mitsumasa|Akiyama|A|;Shinya|Nagahisa|N|;Motoki|Oeda|O|;Hirotaka|Kougame|K|;Tadashi|Kumai|K|",
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"doi": "10.4103/ajns.AJNS_60_20",
"fulltext": "\n==== Front\nAsian J Neurosurg\nAsian J Neurosurg\nAJNS\nAsian Journal of Neurosurgery\n1793-5482 2248-9614 Wolters Kluwer - Medknow India \n\n32656152\nAJNS-15-449\n10.4103/ajns.AJNS_60_20\nCase Report\nDiplopia Presenting in a Case of Pineal Metastasis of Pulmonary Sarcomatoid Carcinoma Refractory to Treatment\nMitsumasa Akiyama Shinya Nagahisa Motoki Oeda Hirotaka Kougame Tadashi Kumai Department of Neurosurgery, Fujita Health University, Toyoake, Aichi, Japan\nAddress for correspondence: Dr. Akiyama Mitsumasa, Department of Neurosurgery, Fujita Health University, Toyoake, Aichi, Japan. E-mail: trafalgarlaw4oku@gmail.com\nApr-Jun 2020 \n04 4 2020 \n15 2 449 454\n20 2 2020 06 3 2020 30 3 2020 Copyright: © 2020 Asian Journal of Neurosurgery2020This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.A 42-year-old male presented with diplopia, headache, and nausea. Magnetic resonance imaging (MRI) of the brain showed pineal tumor, and chest computed tomography (CT) demonstrated a lung tumor. Disorientation developed, with occurrence of hydrocephalus, and we performed neuroendoscopic surgery for biopsy of the pineal tumor and third ventriculostomy. The lung tumor was biopsied under bronchoscopic and CT guidance, and based on the pathological results, we diagnosed pineal metastasis of pulmonary sarcomatoid carcinoma (cT3N1M1b Stage IVA). Stereotactic radiotherapy for the metastatic pineal tumor and systemic chemotherapy (carboplatin + pemetrexed) were pursued, but hemorrhage of the tumor occurred, hydrocephalus worsened, and neoplastic meningitis was diagnosed by MRI. Therapy was switched to nivolumab, but without effect, and the patient succumbed. Even among lung tumors, sarcomatoid carcinoma is rare. There are also few reports of lung tumors metastasized to the pineal gland. Our case report of pineal tumor regarded as metastasis of pulmonary sarcomatoid carcinoma also includes a discussion of the literature.\n\nEndoscopic biopsymetastasispineal glandsarcomatoid carcinomathird ventriculostomy\n==== Body\nIntroduction\nIn the WHO Classification of Tumors of the Lung, Pleura, Thymus, and Heart (2015 edition), sarcomatoid carcinoma of the pulmonary origin is a generalized term for pleomorphic carcinoma, spindle cell carcinoma, giant cell carcinoma, carcinosarcoma, and pulmonary blastoma, representing minimally differentiated, nonsmall cell carcinomas including sarcoma or sarcomatoid component. Pineal metastasis is a rarity as a metastatic site for lung cancer. We report the clinical course from our experience of a case of pineal tumor regarded as metastasized, sarcomatoid carcinoma of the pulmonary origin.\n\nCase Report\nMale, age 42 years\n\nChief complaints: Diplopia, headache, and nausea.\n\nPrior history/familial history: None noteworthy.\n\nSmoking history: 30 cigarettes/day, 22 years.\n\nPresent illness history\nEmergency outpatient treatment was received for complaints of sudden diplopia, headache, and nausea in the late February 2019. Parinaud's syndrome was observed, but additional, distinct, atypical findings of neurological nature were not observed. In computed tomography (CT) brain, a 1.9 cm × 1.5 cm × 1.9 cm neoplastic lesion was observed in the pineal gland. In contrast magnetic resonance imaging (MRI), the entire tumor demonstrated an enhancement; gradient recalled echo imaging showed intratumoral hemorrhage. Chest CT also demonstrated a 5 cm × 4.5 cm × 3.5 cm pulmonary lesion at D1/2 level on the right [Figure 1a]. Laboratory findings on admission included tumor markers CEA (13.8 ng/ml), CYFRA (1.4 ng/ml), and ProGRP (23.1 pg/ml). The cerebrospinal fluid (CSF) cytology was Class I, and CSF testing showed levels of 3.6 ng/ml ACTH, 15.4 ng/ml CEA, and less than 1 HCGβ [Frpm April to September for 6 months].\n\nFigure 1a (i) Head computed tomography demonstrated a 1.9 cm × 1.5 cm × 1.9 cm pineal lesion. (ii and vi) Contrast magnetic resonance imaging demonstrated a contrast enhancement in the pineal lesion. (iii) Gradient recalled echo imaging showed intratumoral microhemorrhage. (iv and v) Chest computed tomography demonstrated a 5 cm × 4.5 cm × 3.5 cm pulmonary lesion at D1/2 level on the right\n\nAfter admission, disorientation and urinary incontinence developed gradually, and head CT demonstrated hydrocephalus with aqueduct stenosis [Figure 1b]. In order to confirm pathological findings of both pineal and pulmonary lesions in deciding the treatment strategy, first, we performed surgery that Releasing of hydrocephalus which is a cause of Consciousness disorder and pathological diagnosis of pineal lesions. In the surgery, an 11-Fr transparent sheath was inserted into the anterior horn of the lateral ventricle with neuronavigational assistance; a flexible scope (Visera ventricular videoscope, VEF Type V) was inserted through the foramen of Monro to the point of the third ventricle; and after the tuber cinereum was punctured by forceps, an expanding balloon catheter was inflated to confirm CSF interchange. Next, we ascertained a tumor occluding the aqueduct entrance at the posterior end of the third ventricle and collected a portion with biopsy forceps [Figure 1c]. The tumor was hemorrhagic, but hemostasis was achieved by the recirculation of artificial CSF. After biopsy, the surgery was completed by visualized confirmation of hemostasis and placement of a ventricular drain to evaluate intracranial pressure (ICP). After surgery, ICP was monitored in our intensive care unit. Postoperative neurological observations showed residual disturbance of ocular motility but improvement in headache, nausea, and disorientation.\n\nFigure 1b Head computed tomography demonstrated hydrocephalus with attendant aqueduct stenosis\n\nFigure 1c (i and iii) Neuroendoscopic findings included tumor with gross hemorrhage and bleeding when grasped with forceps. (ii) The tuber cinereum was fenestrated, and cerebrospinal fluid interchange was observed\n\nThe pineal tumor biopsy demonstrated a mass of atypical cells and was positive for AE1/AE3 and CAM5.2. No mucicarmine-positive mucous was observed, and in immunostaining, the majority of cells were positive for Ki67 and P53. Results were negative for CK5/6, CK7, CK20, CEA, TTF1, napsin-A, P40, S100, GFAP, chromogranin, synapsin, and CD56. No papillary structures were observed, and the specimen was deemed a minimally differentiated epithelial tumor. No disposition was noted toward differentiation into glands, squamous epithelium, or other such tissues [Figure 2a]. The specimen was deemed a minimally differentiated epithelial tumor not consistent with a pineal primary tumor.\n\nFigure 2a (i-iii) Pineal tumor pathological findings (H and E stain): Atypical cells form a nearly solid cellular nest. No apparent disposition toward differentiation into glandular cavities/papillary structures. (iv) Immunostaining: AE1/AE3-positive (D). Regarded as minimally differentiated epithelial tumor not consistent with pineal primary tumor\n\nPositron emission tomography-CT demonstrated FDG accumulation in the right upper lobe lesion and hilar lymph nodes [Figure 3]. The lung tumor was difficult to approach by bronchofiberscope and was therefore biopsied with CT guidance. Biopsy of the lung tumor demonstrated a mass of spindle cells. Mucicarmine-positive mucous was not observed, and the specimen was positive for AE1/AE3 and P53 and negative for TTF1, P40, EGFR, ALK, and ROS1. PD-L1 expression showed tumor proportion score (TPS) <1%. No disposition was noted toward differentiation into glands, squamous epithelium, or other such tissues, and the specimen was regarded as a carcinoma derived from sarcomatoid pyramidal cells [Figure 2b].\n\nFigure 2b (i-iii) Lung tumor pathology findings (H and E stain): Spindle cells replicating densely into bundled/figured mat form. One area showing notable cylindroid and multiform cells. No apparent disposition toward differentiation into glandular cavity/papillary structures. (iv) Immunostaining: AE1/AE3-positive\n\nFigure 3 Positron emission tomography-computed tomography: FDG accumulation observed in right upper lobe lesion and hilar lymph nodes\n\nAccording to the JLCS Rules for Lung Cancer Management, 8th edition,[1] confirmative diagnosis is possible only through a biopsied partial histology specimen or cytology, but pineal metastasis of sarcomatoid carcinoma regarded as spindle cell carcinoma was diagnosed by additional imaging studies and clinical observations. Approximately 1 month after the head surgery, stereotactic radiotherapy was pursued for the pineal tumor at a dosage of 35 Gy/5 Fr.\n\nAt the same time, chemotherapy was also initiated by the case pulmonologist. The lung cancer stage was cT3N1M1b Stage IVA, and the first-line treatment implemented was six courses of carboplatin + pemetrexed (PEM). During the first-line treatment, tumor hemorrhage occurred two times [Figure 4a]. MRI after the second incident of tumor hemorrhage showed slight growth of the pineal tumor and enlargement of the lateral ventricle, but selective inversión recovery (IR) pulsing in MRI demonstrated CSF interchange at the fenestration in the third ventricular base [Figure 4b], and because nausea was also improved by dexamethasone treatment, continuation of chemotherapy was prioritized. In chest CT 1 month after the first-line treatment, the lung tumor showed a growth trend, but even at such time, CSF cytology detected no tumor cells. Nonetheless, MRI demonstrated aggravation of hydrocephalus and contrast enhancement of areas including the ventricular wall proximal to the left hypothalamus and the cerebellar fissure, suggesting meningeal dissemination.\n\nFigure 4a (i and ii) Intratumoral hemorrhage occurring on 6/2 and 7/20. Notable ventricular enlargement and periventricular lucency due to hydrocephalus\n\nFigure 4b (i and ii) 3T-magnetic resonance imaging: Cine-imaging of cerebrospinal fluid using selective IR pulsing demonstrated cerebrospinal fluid interchange at fenestration\n\nThe pineal metastatic focus was also refractory to radiotherapy, and additional whole-brain irradiation was not performed [Figure 5a]. Due to apparent resistance to the first-line chemotherapy, treatment was switched to nivolumab as the second-line option. On MRI 1 month after initiation of the second-line treatment, hydrocephalus had not progressed, but a contrast-enhancement effect was noted in the hypothalamus walls bilaterally and within the left-sided hypothalamus, and the basal portion of the tumor had progressed to the fourth ventricle [Figure 5b].\n\nFigure 4c (i and ii) Head computed tomography on 9/4: Increased hydrocephalus and hemorrhage extending inside/outside tumor to pons and cerebellum\n\nFigure 5a (i and ii) Contrast-enhanced magnetic resonance imaging of head after tumor hemorrhage on 7/20: Notable aggravation of hydrocephalus and contrast enhancement of areas including ventricular wall of left hypothalamus and cerebellar fissure. (iii and iv) Chest computed tomography: Pattern of enlargement in lung tumor\n\nFigure 5b (i) Contrast-enhanced head magnetic resonance imaging on 8/13: No progression of hydrocephalus, but notable contrast-enhancement effect in hypothalamus walls bilaterally and within left-sided hypothalamus. (ii) Tumor progression to fourth ventricle\n\nDue to the lack of deterioration in higher cognitive function testing from the time of initial admission, and to avoid interruption of chemotherapy, we elected to observe progress without additional efforts to manage hydrocephalus, such as ventriculoperitoneal (VP) shunt or Ommaya reservoir.\n\nAfter this 3-week period, bodily movement became impaired, nausea and diminished consciousness level, and head CT demonstrated increased hydrocephalus and hemorrhage from the tumor to the pons and cerebellum [Figure 4c]. Given the reduction in performance status and a lack of desire for treatment on the part of the family, nivolumab was also discontinued after three courses. Consciousness level declined gradually after admission, resulting in an outcome of death 2 weeks after the repeat hemorrhage. The family did not provide consent for autopsy.\n\nDiscussion\nMetastases of cancer to the pineal region are rare. From 1984 to 2000, there were 37 cases of metastasis to the pineal region among 10,489 reported cases of metastatic brain tumor, a mere 0.4% rate of metastatic brain tumor.[2] Reports state that the most frequent primary focus of tumors which metastasize to the pineal body is lung cancer, and among these, the most frequent by histological type is small cell cancer.[3] The majority of metastatic pineal tumor cases are asymptomatic and are often diagnosed by autopsy.[45] When accompanied by symptoms, reports cite frequent headache or nausea accompanied by increased ICP.[6] Intervention for pineal tumors is considered on a case-by-case basis. Pyramidal cell cancer is another rare tumor,[1] comprising only spindle cells. According to the report of Mainwaring et al., this cancer is extremely rare, occurring in only 0.2%–0.3% of primary lung cancers, and its prognosis is reportedly poor, with a 2-year survival rate of 10%.[7] However, these statistics also include tumors demonstrating squamous epithelium, and there are additional reports of pleomorphic cancer and reports which categorize cancer type.[8] The specimen tissue in our case report also represented only a portion of the entire tumor, which may have been a pleomorphic cancer, but we believe that it lay in the category of sarcomatoid carcinoma.\n\nTreatments such as chemotherapy and radiotherapy also have little effect on spindle cell, pleomorphic, and other such cancers.[910] Even when treated with cisplatin + PEM,[11] which has a high reported response rate of 42% against brain metastasis of solid cancers, the effect of chemotherapy or radiotherapy was poor not only on the primary focus but also on metastatic foci in the pineal region, where there is no blood–brain barrier.\n\nEven when a pineal tumor is detected, investigation is needed to determine whether it is metastatic or primary to the pineal body, since treatment must conform to its histological type. The localization of these tumors often poses difficulties for complication-free removal, and opinions also diverge as to timing and necessity.\n\nNeoplastic meningitis occurs in approximately 5% of solid cancers, and the median survival is reportedly 6–8 weeks.[12] For solid cancers, positive rates in CSF cytology are reportedly 50% in the first test and approximately 80% in the second test and are barely increased at all in the third and subsequent tests.[13] When CSF cytology is negative, means such as CEA or other such biological markers can provide adjunct diagnosis, but there is no consensus as to cutoff values. Contrast-enhanced T1 or FLAIR diagnostic imaging is known to provide a high signal in the cerebellum or occipital lobe in 25%–35% of CSF cytology-positive patients,[14] while impaired absorption is known to represent occurrence of hydrocephalus. In the current case, CSF cytology was negative, but selective IR-pulsed MRI allowed diagnosis of meningeal dissemination after demonstrated CSF interchange at the third ventriculostomy, concomitant with aggravated hydrocephalus, and contrast enhancement of areas, including the ventricular wall of the left hypothalamus and the cerebellar fissure. VP shunt was also considered; however, given the possibility of peritoneal dissemination and the fact that chemotherapy would have been delayed until healing of the wound, we prioritized chemotherapy. For hydrocephalus, ICP can be monitored,[15] symptoms of elevated ICP can be controlled by external drainage,[16] and in the event of observations suggesting dissemination, intraventricular CSF cytology allows simple follow-up. In this light, and once time frames are considered, we believe that the placement of an Ommaya reservoir is another alternative.\n\nConclusion\nWe reported the clinical course of a pineal tumor representing a suspected metastasis of primary pulmonary sarcomatoid carcinoma. We also discussed intervention through placement of an Ommaya reservoir when aggravation of hydrocephalus is observed despite third ventriculostomy, and neoplastic meningitis is suspected. Although control of metastatic brain tumors is a challenging issue in the development of cancer drug therapy, including development of molecular-targeted drugs, these drugs had little effect in the case of sarcomatoid carcinoma that we report. Further case collection is needed.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n==== Refs\n1 Japan Lung Cancer Society General Rules for Clinical and Pathological Registry of Lung Cancer 2017 8th ed Tokyo Kanehara Shuppan \n2 Report of the Brain Tumor Registry of Japan (1984-2000), Part I- General Features of Brain Tumors; Part II- Individual Analysis of Brain Tumors (1984-2000) 2019 49 12th ed S26 S34 \n3 Samanci Y Iplikcioglu C Ozek E Ozcan D Marangozoglu B Lung carcinoma metastasis presenting as a pineal region tumor Neurocirugia (Astur) 2011 22 579 82 22167289 \n4 Kakita A Kobayashi K Aoki N Eguchi I Morita T Takahashi H Lung carcinoma metastasis presenting as a pineal region tumor Neuropathology 2003 23 57 60 12722927 \n5 Ortega P Malamud N Shimkin MB Metastasis to the pineal body AMA Arch Pathol 1951 52 518 28 14877387 \n6 Hanada T Oyoshi T Hirano H Arita K Metastatic pineal tumors treated by neuroendoscopic surgery—two case reports Neurol Med Chir (Tokyo) 2010 50 232 6 20339275 \n7 Mainwaring MG Poor C Zander DS Harman E Complete remission of pulmonary spindle cell carcinoma after treatment with oral germanium sesquioxide Chest 2000 117 591 3 10669709 \n8 Hamanaka K Toishi M Nishimura H A case of rapidly progressing pulmonary spindle cell carcinoma Jap J Lung Cancer 2005 45 363 6 \n9 Rossi G Marchioni A Romagnani E Bertolini F Longo L Cavazza A Primary lung cancer presenting with gastrointestinal tract involvement: Clinicopathologic and immunohistochemical features in a series of 18 consecutive cases J Thorac Oncol 2007 2 115 20 17410025 \n10 Rossi G Cavazza A Sturm N Migaldi M Facciolongo N Longo L Pulmonary carcinomas with pleomorphic, sarcomatoid, or sarcomatous elements: A clinicopathologic and immunohistochemical study of 75 cases Am J Surg Pathol 2003 27 311 24 12604887 \n11 Barlesi F Gervais R Lena H Hureaux J Berard H Paillotin D Pemetrexed and cisplatin as first-line chemotherapy for advanced non-small-cell lung cancer (NSCLC) with asymptomatic inoperable brain metastases: A multicenter phase II trial (GFPC 07-01) Ann Oncol 2011 22 2466 70 21321089 \n12 Le Rhun E Taillibert S Chamberlain MC Carcinomatous meningitis: Leptomeningeal metastases in solid tumors Surg Neurol Int 2013 4 S265 88 23717798 \n13 Clarke JL Perez HR Jacks LM Panageas KS Deangelis LM Leptomeningeal metastases in the MRI era Neurology 2010 74 1449 54 20439847 \n14 Debnam JM Mayer RR Chi TL Ketonen L Weinberg JS Wei W Most common sites on MRI of intracranial neoplastic leptomeningeal disease J Clin Neurosci 2017 45 252 6 28802798 \n15 Aquilina K Edwards RJ Pople IK Routine placement of a ventricular reservoir at endoscopic third ventriculostomy Neurosurgery 2003 53 91 6 12823877 \n16 Iuchi T Shingyoji M Hara R Treatment strategies for brain metastases in the era of molecular targeted therapy Jpn J Neurosurg 2019 28 715 23\n\n",
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"keywords": "Endoscopic biopsy; metastasis; pineal gland; sarcomatoid carcinoma; third ventriculostomy",
"medline_ta": "Asian J Neurosurg",
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"pages": "449-454",
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"title": "Diplopia Presenting in a Case of Pineal Metastasis of Pulmonary Sarcomatoid Carcinoma Refractory to Treatment.",
"title_normalized": "diplopia presenting in a case of pineal metastasis of pulmonary sarcomatoid carcinoma refractory to treatment"
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"abstract": "Anti-glutamic acid decarboxylase directed antibodies are a rare cause of autoimmune limbic encephalitis that is relatively resistant to immunotherapy. Here we report a 15-year-old boy with nonparaneoplastic, anti-glutamic acid decarboxylase limbic encephalitis presenting with subacute headache, memory disturbance, psychiatric symptoms, and seizures. At onset, his memory disturbance manifested as transient global amnesia-like episodes. Clinical remission was achieved with rituximab, intravenous immunoglobulin, and corticosteroids.",
"affiliations": "1Division of Neurology, Department of Paediatrics, The Hospital for Sick Children, Toronto, Canada.",
"authors": "Mishra|Navin|N|;Rodan|Lance H|LH|;Nita|Dragos A|DA|;Gresa-Arribas|Nuria|N|;Kobayashi|Jeff|J|;Benseler|Susanne M|SM|",
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"keywords": "anti-GAD; autoimmune; glutamic acid decarboxylase; limbic encephalitis; rituximab; transient global amnesia",
"medline_ta": "J Child Neurol",
"mesh_terms": "D000293:Adolescent; D000906:Antibodies; D001327:Autoimmune Diseases; D004569:Electroencephalography; D005968:Glutamate Decarboxylase; D006801:Humans; D020363:Limbic Encephalitis; D008279:Magnetic Resonance Imaging; D008297:Male",
"nlm_unique_id": "8606714",
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"title": "Anti-glutamic Acid decarboxylase antibody associated limbic encephalitis in a child: expanding the spectrum of pediatric inflammatory brain diseases.",
"title_normalized": "anti glutamic acid decarboxylase antibody associated limbic encephalitis in a child expanding the spectrum of pediatric inflammatory brain diseases"
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"abstract": "Thymic atypical carcinoid (TAC) is a rare thymic neuroendocrine tumor that originates in the neuroendocrine system and lacks a standardized treatment. The combination of capecitabine (CAP) and temozolomide (TEM) is associated with an extremely high and long-lasting response rate in patients with metastatic pancreatic neuroendocrine tumors. However, there is little evidence showing that the CAPTEM regimen is effective for TAC. For patients with unresectable or metastatic atypical carcinoid of the thymus, few treatment options are available, and the treatment efficacy is not satisfactory. To explore the efficacy and safety of the CAPTEM regimen against TAC, we conducted a retrospective review.\n\n\n\nA total of nine patients with advanced atypical carcinoid of the thymus in the China-Japan Friendship Hospital were treated with capecitabine (750 mg/m2 twice daily, days 1-14) and temozolomide (200 mg/m2 once daily, days 10-14) every 28 days between 2014 and 2018. The disease control rate (DCR), progression-free survival (PFS), and adverse effects after treatment were analyzed. The DCR was calculated by RECIST version 1.1. Progression-free survival was calculated by the Kaplan-Meier survival method.\n\n\n\nA total of nine patients (six male and three female) were included. The median age at CAPTEM initiation was 50 years (range, 26-58). The median number of CAPTEM cycles was 8 (range, 3-23). The DCR was 89% (8/9), with eight patients achieving stable disease. Only one patient (11%) showed progressive disease. The median PFS was 8 months. Because we applied vitamin B6 and ondansetron before administering the drugs, the side effects of this regimen were very small. Adverse reactions were all below grade 3 and included myelosuppression and digestive tract reaction.\n\n\n\nOur results suggest that the CAPTEM regimen may be effective and well tolerated for the treatment of TAC. More evidence is needed to validate the effectiveness of this regimen.\n\n\n\nCapecitabine and temozolomide regimen is effective and well tolerated in patients with advanced thymic atypical carcinoid.",
"affiliations": "Department of Integrative Oncology, China-Japan Friendship Hospital, Beijing, People's Republic of China.;Department of Integrative Oncology, China-Japan Friendship Hospital, Beijing, People's Republic of China.;Department of Radiology, China-Japan Friendship Hospital, Beijing, People's Republic of China.;Department of Integrative Oncology, China-Japan Friendship Hospital, Beijing, People's Republic of China.;Department of Integrative Oncology, China-Japan Friendship Hospital, Beijing, People's Republic of China.;Department of Integrative Oncology, China-Japan Friendship Hospital, Beijing, People's Republic of China.;Department of Integrative Oncology, China-Japan Friendship Hospital, Beijing, People's Republic of China tanhuangying@263.net.",
"authors": "Wang|Xin|X|;Li|Yuanliang|Y|;Duan|Jianghui|J|;Chen|Yingying|Y|;Yuan|Bing|B|;Qi|Zhirong|Z|;Tan|Huangying|H|",
"chemical_list": "D000069287:Capecitabine; D000077204:Temozolomide",
"country": "United States",
"delete": false,
"doi": "10.1634/theoncologist.2018-0291",
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"issue": "24(6)",
"journal": "The oncologist",
"keywords": "Capecitabine; Neuroendocrine tumor; Temozolomide; Thymic atypical carcinoid",
"medline_ta": "Oncologist",
"mesh_terms": "D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D000069287:Capecitabine; D002276:Carcinoid Tumor; D004066:Digestive System Diseases; D004334:Drug Administration Schedule; D005260:Female; D006410:Hematopoiesis; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D000077982:Progression-Free Survival; D066066:Response Evaluation Criteria in Solid Tumors; D012189:Retrospective Studies; D000077204:Temozolomide; D013950:Thymus Gland; D013953:Thymus Neoplasms",
"nlm_unique_id": "9607837",
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"title": "Capecitabine and Temozolomide as a Promising Therapy for Advanced Thymic Atypical Carcinoid.",
"title_normalized": "capecitabine and temozolomide as a promising therapy for advanced thymic atypical carcinoid"
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"abstract": "Page 3, Table 2, 'Renal function indexes at different dates after admission': The cell entry in column 2, detailing the patient's urea concentration (μmol/L) on Day 1.",
"affiliations": "Department of Pharmacy, The Affiliated Hospital of Medical College, Ningbo University, No.247, Renmin Road, Jiangbei District, Ningbo, 315020, Zhejiang, China.;Department of Pharmacy, The Affiliated Hospital of Medical College, Ningbo University, No.247, Renmin Road, Jiangbei District, Ningbo, 315020, Zhejiang, China.;Department of Respiratory Medicine, The Affiliated Hospital of Medical College, Ningbo University, No.247, Renmin Road, Jiangbei District, Ningbo, 315020, Zhejiang, China.;Department of Pharmacy, The Affiliated Hospital of Medical College, Ningbo University, No.247, Renmin Road, Jiangbei District, Ningbo, 315020, Zhejiang, China.;Department of Pharmacy, The Affiliated Hospital of Medical College, Ningbo University, No.247, Renmin Road, Jiangbei District, Ningbo, 315020, Zhejiang, China.;Department of Pharmacy, The Affiliated Hospital of Medical College, Ningbo University, No.247, Renmin Road, Jiangbei District, Ningbo, 315020, Zhejiang, China.;Department of Respiratory Medicine, The Affiliated Hospital of Medical College, Ningbo University, No.247, Renmin Road, Jiangbei District, Ningbo, 315020, Zhejiang, China.;Department of Respiratory Medicine, The Affiliated Hospital of Medical College, Ningbo University, No.247, Renmin Road, Jiangbei District, Ningbo, 315020, Zhejiang, China. ccding2005@163.com.",
"authors": "Huang|Jing|J|;Lin|Wei|W|;Lv|Dan|D|;Yu|Li|L|;Wu|Lun|L|;Jin|Haiying|H|;Deng|Zaichun|Z|;Ding|Qunli|Q|",
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"fulltext": "\n==== Front\nDrug Saf Case RepDrug Saf Case RepDrug Safety - Case Reports2199-11622198-977XSpringer International Publishing Cham 290942175610.1007/s40800-017-0056-xCorrectionCorrection to: Dabigatran-Induced Massive Spontaneous Hemothorax Huang Jing 1Lin Wei 1Lv Dan 2Yu Li 1Wu Lun 1Jin Haiying 1Deng Zaichun 2Ding Qunli 86-13757412042ccding2005@163.com 21 0000 0000 8950 5267grid.203507.3Department of Pharmacy, The Affiliated Hospital of Medical College, Ningbo University, No.247, Renmin Road, Jiangbei District, Ningbo, 315020 Zhejiang China 2 0000 0000 8950 5267grid.203507.3Department of Respiratory Medicine, The Affiliated Hospital of Medical College, Ningbo University, No.247, Renmin Road, Jiangbei District, Ningbo, 315020 Zhejiang China 1 11 2017 1 11 2017 12 2017 4 16© The Author(s) 2017\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommercial use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.issue-copyright-statement© The Author(s) 2017\n==== Body\nCorrection to: Drug Saf - Case Rep (2017)4:12 DOI 10.1007/s40800-017-0054-z\nPage 3, Table 2, ‘Renal function indexes at different dates after admission’: The cell entry in column 2, detailing the patient’s urea concentration (μmol/L) on Day 1,\n\nwhich previously read\n\n“5970”,\n\nshould read\n\n“597.00”.\n\n\nThe online version of the original article can be found under doi:10.1007/s40800-017-0054-z.\n\n",
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"issue": "4(1)",
"journal": "Drug safety - case reports",
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"pubdate": "2017-11-01",
"publication_types": "D016428:Journal Article; D016425:Published Erratum",
"references": null,
"title": "Correction to: Dabigatran-Induced Massive Spontaneous Hemothorax.",
"title_normalized": "correction to dabigatran induced massive spontaneous hemothorax"
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"abstract": "OBJECTIVE\nSteroids are used to induce remission in autoimmune pancreatitis (AIP). Low-dosage steroid therapy or immunosuppressant (IMs) has been proposed as maintenance therapy to prevent AIP relapse. Few and conflicting data have been published on the efficacy of azathioprine (AZA) in preventing AIP relapse. The aim of this study was to evaluate the indication and efficacy of AZA as maintenance therapy to prevent disease relapse in AIP.\n\n\nMETHODS\nPatients suffering from AIP diagnosed according to the ICDC in type 1, type 2, and not otherwise specified (NOS) were divided in those treated with AZA (AZA+ group) as maintenance therapy and not treated with maintenance therapy (AZA- group). Exclusion criteria were: previous pancreatic surgery, other autoimmune diseases as indication for AZA treatment, and use of IMs different from AZA. Drug safety, clinical and instrumental outcome of AZA+ patients were evaluated.\n\n\nRESULTS\nA total of 23 patients (18 Males and 5 Females, mean age 54±11 years) in AZA+ group and 97 (58 Males and 39 Females, mean age 45±18 years) in AZA- group were compared. In AZA+ group, patients were significantly older (P=0.043), type 1 AIP was more frequently diagnosed (87 vs. 51%, P=0.006), sIgG4 higher (758±625 vs. 311±409 mg/dl, P<0.001), other organ involvement (OOI) more frequently observed (83 vs. 48%, P=0.002), with higher frequency of relapse before AZA treatment (78 vs. 14%, P<0.001). Three patients in AZA+ group required drug discontinuation because of adverse events. Twenty patients were therefore evaluated for outcome. Six out of 20 patients (30%) relapsed after 24±15 months (5 in pancreas and 1 on biliary tract). They were retreated with steroids and continued AZA. Two out of 6 patients (33%) had a second relapse,after respectively 11 months (in pancreas and kidney) and 22 months (in kidney).\n\n\nCONCLUSIONS\nAZA is an effective and safe treatment to prevent AIP relapses.",
"affiliations": "Gastroenterology Unit, Department of Medicine, Pancreas Center, University of Verona, Verona, Italy.;Gastroenterology Unit, Department of Medicine, Pancreas Center, University of Verona, Verona, Italy.;Gastroenterology Unit, Department of Medicine, Pancreas Center, University of Verona, Verona, Italy.;Gastroenterology Unit, Department of Medicine, Pancreas Center, University of Verona, Verona, Italy.;Gastroenterology Unit, Department of Medicine, Pancreas Center, University of Verona, Verona, Italy.;Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA.;Gastroenterology Unit, Department of Medicine, Pancreas Center, University of Verona, Verona, Italy.;Gastroenterology Unit, Department of Medicine, Pancreas Center, University of Verona, Verona, Italy.;Gastroenterology Unit, Department of Medicine, Pancreas Center, University of Verona, Verona, Italy.;Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA.;Gastroenterology Unit, Department of Medicine, Pancreas Center, University of Verona, Verona, Italy.",
"authors": "de Pretis|Nicolò|N|;Amodio|Antonio|A|;Bernardoni|Laura|L|;Campagnola|Pietro|P|;Capuano|Fabiana|F|;Chari|Suresh T|ST|;Crinò|Stefano|S|;Gabbrielli|Armando|A|;Massella|Arianna|A|;Topazian|Mark|M|;Frulloni|Luca|L|",
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"country": "United States",
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"doi": "10.1038/ctg.2017.17",
"fulltext": "\n==== Front\nClin Transl GastroenterolClin Transl GastroenterolClinical and Translational Gastroenterology2155-384XNature Publishing Group ctg20171710.1038/ctg.2017.1728448071Original ContributionsAzathioprine Maintenance Therapy to Prevent Relapses in Autoimmune\nPancreatitis Azathioprine Maintenance Therapy in AIPde Pretis Nicolò 1Amodio Antonio 1Bernardoni Laura 1Campagnola Pietro 1Capuano Fabiana 1Chari Suresh T 2Crinò Stefano 1Gabbrielli Armando 1Massella Arianna 1Topazian Mark 2Frulloni Luca 1*1 Gastroenterology Unit, Department of\nMedicine, Pancreas Center, University of Verona, Verona,\nItaly2 Division of Gastroenterology and\nHepatology, Mayo Clinic, Rochester, Minnesota,\nUSA* Department of Medicine, Pancreas Center, University of\nVerona, Policlinico GB Rossi, p.le LA Scuro, 10,\nVerona\n37134, Italy. E-mail: luca.frulloni@univr.it04 2017 27 04 2017 1 4 2017 8 4 e90 06 12 2016 11 02 2017 Copyright © 2017 the American College of Gastroenterology2017the American College of GastroenterologyClinical and Translational Gastroenterology is an open-access journal\npublished by Nature Publishing Group. This work is licensed under a Creative\nCommons Attribution-NonCommercial-NoDerivs 4.0 International License. The images or\nother third party material in this article are included in the article’s\nCreative Commons license, unless indicated otherwise in the credit line; if the\nmaterial is not included under the Creative Commons license, users will need to\nobtain permission from the license holder to reproduce the material. To view a copy\nof this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/Objectives:\nSteroids are used to induce remission in autoimmune pancreatitis (AIP). Low-dosage\nsteroid therapy or immunosuppressant (IMs) has been proposed as maintenance\ntherapy to prevent AIP relapse. Few and conflicting data have been published on\nthe efficacy of azathioprine (AZA) in preventing AIP relapse. The aim of this\nstudy was to evaluate the indication and efficacy of AZA as maintenance therapy to\nprevent disease relapse in AIP.\n\nMethods:\nPatients suffering from AIP diagnosed according to the ICDC in type 1, type 2, and\nnot otherwise specified (NOS) were divided in those treated with AZA\n(AZA+ group) as maintenance therapy and not treated with\nmaintenance therapy (AZA− group). Exclusion criteria were:\nprevious pancreatic surgery, other autoimmune diseases as indication for AZA\ntreatment, and use of IMs different from AZA. Drug safety, clinical and\ninstrumental outcome of AZA+ patients were evaluated.\n\nResults:\nA total of 23 patients (18 Males and 5 Females, mean age 54±11 years) in\nAZA+ group and 97 (58 Males and 39 Females, mean age\n45±18 years) in AZA− group were compared. In\nAZA+ group, patients were significantly older\n(P=0.043), type 1 AIP was more frequently diagnosed (87 vs.\n51%, P=0.006), sIgG4 higher (758±625 vs.\n311±409 mg/dl, P<0.001), other organ involvement\n(OOI) more frequently observed (83 vs. 48%, P=0.002), with\nhigher frequency of relapse before AZA treatment (78 vs. 14%,\nP<0.001). Three patients in AZA+ group required drug\ndiscontinuation because of adverse events. Twenty patients were therefore\nevaluated for outcome. Six out of 20 patients (30%) relapsed after\n24±15 months (5 in pancreas and 1 on biliary tract). They were retreated\nwith steroids and continued AZA. Two out of 6 patients (33%) had a second\nrelapse,after respectively 11 months (in pancreas and kidney) and 22 months (in\nkidney).\n\nConclusions:\nAZA is an effective and safe treatment to prevent AIP relapses.\n==== Body\nIntroduction\nAutoimmune pancreatitis (AIP) is a particular form of pancreatitis with unique\nhistological features.1, 2 Two histological subtypes in AIP have been recognized with\ndifferent clinical profiles.2, 3, 4, 5 Type 1 AIP is characterized by periductal infiltration of\nlymphocytes, abundant IgG4-positive plasma cells in pancreatic parenchyma, storiform\nfibrosis and obliterative phlebitis. Patients suffering from type 1 AIP are elderly,\nwith a prevalence of male sex, with high IgG4 serum levels, extra pancreatic\ninvolvement (biliary tree, salivary glands, kidney, retroperitoneum), and frequent\nrelapses. Type 2 AIP is characterized by the presence of granulocytic epithelial\nlesions, whereas IgG4-positive plasma cells are rare or absent in pancreatic\nparenchyma. Patients suffering from type 2 AIP are younger, inflammatory bowel\ndisease is commonly observed, and relapses after steroids are rare.\n\nThe International Association of Pancreatology in 2011 defined the International\nConsensus Diagnostic Criteria (ICDC) based on five cardinal features (parenchymal and\npancreatic duct imaging, serology, other organ involvement, histology, and response\nto steroid) categorized as level 1 and 2 of evidence according to their reliability\nto diagnose AIP.6 These criteria are able to\ndiagnose AIP subtypes also in the absence of histology, and introduced criteria for\nAIP not otherwise specified (NOS), if type 1 and type 2 AIP cannot be diagnosed.\n\nA dramatic response to steroid therapy has been reported in AIP, independently from\nthe subtype.7, 8,\n9 However, a significant proportion of\npatients (15–60%) develop disease relapse after steroids, more\nfrequently those suffering from type 1 and NOS AIP compared to type 2\nAIP.7, 8,\n9, 10 There\nis no consensus on indications, type and duration of maintenance therapy because no\nprospective randomized controlled trials have been published yet. To prevent\nrecurrences low-dosage long-term steroid therapy (that is, prednisone\n2.5–10 mg up to 3 years) after induction of remission has been proposed\nmainly by Japanese authors,11 whereas\nimmunosuppressant drugs (azathioprine [AZA], 6-mercaptopurine,\nmycophenolate mofetil) have been suggested in Western countries to avoid the side\neffects of steroids.12, 13 Few studies report the efficacy of immunosuppressants as\nmaintenance therapy for AIP.8, 14, 15, 16, 17 A study from\nMayo Clinic shows no differences in relapse-free survival in patients treated with\nimmunosuppressants and steroids compared to steroids alone.17 In the same study, rituximab (RTX), an anti-CD20 antibody,\nseems to be effective in 12 patients in steroid-dependent or intolerant, and\nresistant to immunosuppressants. A recent UK multicenter study in patients suffering\nfrom IgG4-related disease involving the pancreas (92%) shows that in 41\npatients treated by AZA, 13 were intolerant and only eight of the remaining\n(28%) had a disease relapse.18\nFurthermore, none of AZA treated patients need to be retreated with steroids or\nRTX.\n\nThe aim of this study was therefore to evaluate indication, efficacy and safety of\nAZA as maintenance therapy in patients suffering from AIP.\n\nMethods\nWe retrospectively reviewed the AIP database in our Department on January 2014. We\nincluded patients with a diagnosis of AIP based on ICDC6 and patients were therefore classified in type 1, 2, and\nNOS. Exclusion criteria were: (1) pancreatic surgery; (2) use of an immunosuppressant\ndifferent from azathioprine; (3) indication for the use of azathioprine different\nfrom AIP. Patients were then divided into those treated with AZA as maintenance\ntherapy (AZA+ group) and those not treated (AZA−\ngroup).\n\nThe demographic data (sex, age at presentation, alcoholic consumption, smoking\nhabits), symptoms and signs at clinical onset (weight loss, pancreatitis, jaundice,\nsteatorrhea, diabetes), radiological (CT, MRI) findings (focal and diffuse\ninvolvement of the pancreas, abdominal extra pancreatic involvement), serum IgG4\n(sIgG4) levels, fecal elastase 1, steroid treatment were evaluated. Salivary gland\ninvolvement was based on clinical examination.\n\nThe upper normal limit of sIgG4 levels was considered 135 mg/dl, as\npreviously reported by Hamano et al.19\n\nPrednisone was administered at initial dose of 1 mg/kg of body weight per\nday for 2–4 weeks and then tapered by 5 mg every week up to\nsuspension.\n\nRelapsing AIP was defined as development of pancreatic and/or extra pancreatic\nalterations at imaging.20, 21 In particular, sIgG4 elevation alone was not considered\ndisease relapse.\n\nAZA is generally used in our Department after a first or second relapse in AIP\npatients or in AIP patients with a high risk of relapse (other organ’s\ninvolvement and/or high IgG4 levels). After recurrence, patients were re-treated\nwith another course of prednisone. In those treated with AZA, the immunosuppressant\nwas added after starting the steroid course, and maintained after steroids\nwithdrawal.\n\nTuberculosis, cytomegalovirus, Epstein–Barr, hepatitis B and C screening prior\nto treatment with AZA was evaluated in all patients. AZA was started at\n25–50 mg per day and increased by 25 mg every 3–7 days\nafter regular monitoring the biochemical data (peripheral blood counts, pancreatic,\nkidney, and liver serum tests). The target dose was 2–2.5 mg/kg per\nday, and monthly laboratory test were routinely performed. AZA withdrawal was decided\nby physician when adverse drug reactions occurred, or in the presence of altered\nlaboratory tests after an attempt of dose reduction. All patients underwent CT or MRI\nimaging 3–6 months after steroid and AZA introduction and then yearly, as\nprotocol in our Institution. Further imaging assessments were performed depending on\nclinical and biochemical evaluation.\n\nOutcome of patients treated with AZA was then assessed. Pancreatic exocrine function\nwas also evaluated in AZA+ group before AZA initiation and after at\nleast 6 months of immunosuppressant therapy by fecal elastase 1.\n\nPatients without a radiological detection in the last 3 years were considered\ndrop-out. The end of follow-up was January 2014.\n\nKruskal–Wallis test and Mann–Whitney U-test were used to analyze\nthe non parametric data.\n\nFisher’s exact test and χ2 test were used for discrete\nvariables as appropriate. Survival curve was used to evaluate relapses during AZA\ntherapy.\n\nSpearman’s rank-order correlation was used to measure the strength of\nassociation between serum IgG4 levels before and after steroids, and after steroids\nand after AZA.\n\nA P-value <0.05 was considered significant. Mean and s.d. are reported.\nStatistic was processed using the SPSS 17 statistical program (SPSS Inc., Chicago,\nIL, USA).\n\nResults\nA total of 165 patients were in our database of AIP on January 2014. Forty-five\npatients were excluded from this study (13 could not be classified according to the\nICDC, 21 underwent pancreatic surgery, eight had other autoimmune diseases as\nindication for AZA treatment and three were treated with other immunosuppressants). A\ntotal of 120 patients were therefore included in the present study and divided in\nthose treated with AZA (AZA+ group) as maintenance therapy and those\nnot treated (AZA− group). Twenty-three patients in\nAZA+ group (18 Males and 5 Females, mean age 54±11 years,\n20 type 1 AIP and 3 AIP-NOS) and 97 in AZA− group (58 Males and 39\nFemales, mean age 45±18 years, 50 type 1 AIP, 19 type 2 AIP and 28 AIP-NOS)\nwere compared. The characteristics of these two groups are summarized in Table 1.\n\nIn AZA+ group, patients were significantly older\n(P=0.043), type 1 AIP was more frequently diagnosed (87 vs.\n51%, P=0.006), sIgG4 higher (758±625 vs.\n311±409 mg/dl, P<0.001), other organ involvement (OOI)\nmore frequently observed (83 vs. 48%, P=0.002). AIP relapse\nwas observed in 18 patients (78%) before AZA treatment in AZA+\ngroup and in 14 patients (14%) in AZA− group\n(P<0.001).\n\nThe indications for the maintenance therapy with AZA were relapse of AIP in 18\npatients (78%), extra pancreatic involvement in 3 (13%, 1 proximal bile\nduct stricture and 2 renal lesions) and markedly increase of serum IgG4 after steroid\ntreatment in 2 (9%).\n\nThree patients (13%) required AZA discontinuation within two months after\nstarting because of adverse events: hepatitis (1 patient, then treated with RTX),\nanaphylactic shock (1 patient, then treated with maintenance dose of 5 mg per\nday of oral prednisone), nausea and body weight loss (1 patient who then refused AZA\ndose reduction and re-challenge).\n\nTwenty patients were therefore evaluated for outcome (15 Males and 5 Females mean age\n53±10.8 years, 18 type 1 AIP and 2 AIP-NOS). Mean duration of treatment was\n35.6±21.3 months and AZA dose was between 2 and 2.27 mg/kg per day.\nFigure 1 summarized the results of AZA treatment.\n\nFourteen out of 20 patients (70%) reached and maintained complete disease\nremission during follow-up (30±20.2months), while 6 out of 20 (30%)\nrelapsed after 24±15.4 months. Five patients had disease relapse in pancreas\nand 1 in biliary tract. Relapse-free survival from the beginning of AZA treatment to\nthe first relapse under immunosuppressant therapy is shown in Figure 2. Median relapse-free survival time was 47 months.\n\nThe proportion of subjects having a relapse was similar in those with and without\nbiliary involvement (22 vs. 36%, respectively, P=ns). Disease\nrelapse was not correlated with focal or diffuse pancreatic involvement at diagnosis\n(33 vs. 27%, respectively, P=ns). None of the four patients\nwith only pancreatic involvement had a relapse during AZA treatment compared with 6\nout of 16 with other organ involvement (38%), but this difference did not\nreach the statistical significance. Moreover, none of the four patients with normal\nserum IgG4 at onset but 6 out of 14 (43%) with abnormal serum IgG4 levels at\nonset had a relapse, but also this difference was not significant.\n\nPatients who presented recurrences were all retreated with another course of steroids\nfollowed by complete tapering and continued AZA therapy. Two out of six patients\n(33%) had a second relapse after respectively 11 months (in pancreas and\nkidney) and 22 months (in kidney) and are in screening for RTX treatment. The other\nfour patients did not have a second relapse after a mean follow-up time of\n19±10 months. Serum IgG4 levels in AZA+ group were higher at\nonset compared with those detected after steroids and before the AZA treatment\n(764±675 mg/dl vs. 435±272 mg/dl, respectively,\nP=0.006). We found a correlation between sIgG4 measured at onset\nand before AZA treatment (R=0.797, P<0.0001) (Figure 3). Serum IgG4 levels were significantly higher in\npatients before AZA treatment compared with those detected almost 6 months after AZA\ntreatment (435±272 vs. 225±155 mg/dl, respectively,\nP=0.003). sIgG4 measured before and after AZA treatment were\nsignificantly correlated (R=0.684, P=0.002) (Figure 4).\n\nSixteen out of 20 patients underwent determination of fecal elastase 1 before AZA\ntreatment and after almost 6 months later. Fecal elastase 1 was significantly lower\nin these 16 patients before AZA treatment (109.2±98.8 mg/dl) than\nafter (270.8±156.7 mg/dl) (P=0.002). No\nmodification on diabetic status was observed before and after AZA treatment.\n\nNo malignancy has been observed in AZA treated patients.\n\nAmong the 97 AZA- patients, 14 experienced a relapse of the disease. Among these, 5\n(including 3 patients with >1 relapse) refused AZA, one had a recent breast cancer\ntreated with chemo- and radio-therapy, and eight were retreated with steroids after\nthe first relapse without experiencing additional relapses.\n\nDiscussion\nThe results of this study seem to show the efficacy and safety of AZA maintenance\ntherapy in AIP.\n\nThe conflicting and retrospective data have been published on the efficacy of AZA in\nthe treatment of AIP14, 15, 16, 17 depending on limited number of patients, indications,\ninclusion/exclusion criteria, dose and duration of therapy, definition of disease\nrelapse.\n\nIn the current study, we excluded patients who underwent pancreatic surgery because\npartial pancreatectomy has been suggested as an effective therapeutic approach for\nAIP.22, 23,\n24 We excluded also subjects with other\nautoimmune diseases different from AIP as indication for AZA treatment, and those\ntreated with other immunosuppressants (methotrexate, cyclosporine and mycophenolate\nmofetil), suggested or used in previous studies.25, 26 Indeed, the main end\npoint of this study was to clarify the efficacy of AZA for AIP and not\nimmunosuppressant at all.\n\nWe retrospectively studied AZA+ group patients compared with\nAZA− group to evaluate the indications for AZA in our Center. The\nresults show that patients with type 1 (n=20) and NOS\n(n=3) AIP, but not with type 2 AIP, were treated with AZA, according\nto previous studies showing a higher disease relapse rate after steroids in type 1\nand NOS AIP.3, 4,\n7, 10, 17 All the other features differentiating the two\ngroups are related to this data. Indeed, patients treated with AZA were older, showed\nmore often an elevation of serum IgG4, had more frequently disease relapses, and\npresented more often extra pancreatic involvement. Therefore, type 1 AIP patients\nwith extra pancreatic involvement and serum IgG4 elevation, have a higher probability\nto be treated with AZA. This clinical profile seem to identify patients with an\nIgG4-related disease.27\n\nAZA treatment seems to be effective as maintenance therapy of AIP since 70% of\npatients treated with AZA did not show disease recurrence in a mean follow-up of 30\nmonths. Survival curve for disease relapse shows that 75% of treated patients\nmaintained remission up to 36 months. This evidence is even more significant since\npatients treated have a more aggressive disease and AZA can keep in remission a\nnoteworthy proportion of them for a long time. We observed also a decrease of sIgG4\nlevels after steroid treatment and a further decrease after AZA treatment in\nAZA+ group, as well as a significant improvement of the exocrine\npancreatic function evaluated with fecal elastase 1 after AZA treatment. These\nsurrogate laboratory data support the efficacy of AZA as maintenance therapy in\nAIP.\n\nThese results are in accordance with a recent multicenter study from UK in the use of\nAZA in IgG4-related disease, involving in 92% of case the pancreas, where AZA\nwas able to maintain 20 out of 28 patients (71%) in remission, excluding those\nintolerant to the drug.18\n\nDisease relapses during AZA treatment were observed in all but one patient mainly in\nthe pancreas. We therefore suggest to schedule an imaging follow-up in patients with\nAIP treated with AZA. We did not find predictive factors of disease relapse, probably\ndue to the small sample size (n=20). However, extra pancreatic organ\ninvolvement and high sIgG4 before may be predictor factors of disease relapse during\nAZA treatment, but other studies are needed to confirm this data.\n\nWe observed three adverse effects (13%), leading to drug discontinuation. This\nrate is similar to that observed in the AZA treatment of other gastrointestinal\nautoimmune diseases.28 Furthermore, no\nacute pancreatitis has been observed in our cohort. Therefore, despite acute\npancreatitis is described in AZA-treated patients,29 these results seems to suggest the safety of AZA therapy in\nAIP.\n\nRecently, some studies suggested a risk to develop extra pancreatic neoplasia in\nAIP17, 30,\n31 (10% within the first 5 years\nfrom AIP diagnosis), and it is still debated if it is increased compared with the\ngeneral population or only age-related. In any case, AZA treatment may further\nincrease this risk, as suggested in other gastrointestinal inflammatory disease (that\nis, IBD). However, a maintenance therapy with low dose of steroids leads to adverse\neffects, particularly in the elderly (osteoporosis, diabetes). Therefore, a\nmaintenance therapy should be evaluated considering the risk-benefit balance of these\ndifferent approaches, and the previous diagnosis of any cancer.\n\nPatients who presented a second relapse during AZA maintenance therapy were\nre-treated with steroids, continuing the immunosuppressant, and only two patients had\na further relapse. This approach was forced since biologics (RTX) were not available.\nIndeed, the use of RTX in AIP has not been yet approved by the Italian Drug Agency\n(AIFA) and it must be justified as off-label for single patient on the basis of a\nrecent study in 12 patients by Mayo Clinic. The possible use of biologics will\nintroduce also in AIP the possibility of a step-up vs. a top down approach, similarly\nto other inflammatory chronic disease (that is, Crohn disease). Applying forcedly a\nstep-up approach (steroid→AZA→RTX), only a limited proportion of them may\nhave an indication for RTX (three AZA intolerant and six relapsing in AZA).\nConsidering this low number of patients, the high cost of RTX and the absence of\nrandomized controlled trial, we believe that a step-up approach should be preferred\nin presence of a 30% relapse rate observed in our AIP patients.\n\nThe immediate administration of AZA concomitant to the steroid therapy and prolonged\nafter steroid withdrawal (“primary maintenance therapy”) may be\nconsidered in untreated patients with a high risk of recurrence such as patients with\nhigh serum IgG4 and patients with other organ’s involvement (especially biliary\ntree). However, the definitive data supporting this strategy are lacking.\n\nA critical issue not yet clarified is how long we can treat AIP patients with AZA.\nOur behavior is to try to stop AZA after a 5-year treatment, similar to that\nsuggested in Crohn’s disease, even considering that this approach exposes AIP\npatients to disease relapse. However, this approach is only theoretical, and need to\nbe confirmed by future studies.\n\nThe main limitation of the present study is the lack of an appropriate relapsing type\n1 AIP control group. This is consequence of the retrospective nature of the study.\nHowever, future prospective studies focused mainly on relapsing type 1 AIP patients\nmight investigate this aspect.\n\nIn conclusion, AZA seems to be effective to prevent disease relapse and safe as\nmaintenance therapy in patients suffering from AIP. Prospective randomized trials are\nnecessary to confirm these retrospective data.\n\nStudy Highlights\n\n\n\n\nGuarantor of the article: Luca Frulloni, MD, PhD.\n\nSpecific author contributions: Conception or design of the work: Luca Frulloni\nand Armando Gabbrielli. Acquisition of the data: Nicolò de Pretis, Antonio\nAmodio, Laura Bernardoni, Pietro Campagnola, Fabiana Capuano, Stefano Crinò,\nArianna Massella. Analysis or interpretation of data: Nicolò de Pretis, Antonio\nAmodio and Luca Frulloni. Drafting the work: Nicolò de Pretis and Luca Frulloni.\nRevising it critically for important intellectual content: Suresh Chari, Mark Topazian\nand Luca Frulloni. Final approval of the version published: all authors.\n\nPotential competing interests: None.\n\nFinancial support: None.\n\nFigure 1 Summary of the outcome in 23 patients treated with AZA.\n\nFigure 2 Relapse-free survival curve for AIP patients treated with AZA.\n\nFigure 3 Correlation between sIgG4 before steroids and after steroids/before AZA in 18\npatients of AZA+ group.\n\nFigure 4 Correlation between sIgG4 after steroids/before AZA and after AZA (at least 6\nmonths) in 18 patients of AZA+ group.\n\nTable 1 Characteristics of AZA+ group and AZA− group\n\nParameter\n\t\nAZA\n\n+\n\n\t\nAZA\n−\n\t\n\nP\n\n\t\n\nN\n\t23\t97\t–\t\nMale sex\t18 (78%)\t58 (60%)\tns\t\nAge at onset (years)\t54±11\t45±18\t0.043\t\nFollow-up (years)\t4.9±4.1\t2.7±3\t0.005\t\nDrop-out\t0%\t15%\t0.07\t\nDrinkers\t4/21 (19%)\t27/93 (29%)\tns\t\nSmokers\t5/21 (24%)\t24/92 (24%)\tns\t\n \t \t \t \t\n\nAIP type (according to the ICDC)\n\t\n Type 1 AIP\t20 (87%)\t50 (51%)\t0.006\t\n Type 2 AIP\t0\t19 (20%)\t \t\n AIP-NOS\t3 (13%)\t28 (29%)\t \t\n \t \t \t \t\n\nEnlargement of pancreas\n\t\n Focal\t11 (48%)\t53 (55%)\tns\t\n Diffuse\t12 (52%)\t44 (45%)\t \t\n \t \t \t \t\n\nSymptom at clinical onset\n\t\n Acute pancreatitis\t3 (13%)\t27 (28%)\tns\t\n Jaundice\t18 (78%)\t35 (36%)\t<0.0001\t\n Body weight loss\t20/22 (91%)\t63/92 (68%)\t0.035\t\n Diabetes\t4 (17%)\t10 (10%)\tns\t\n Steatorrhoea\t1 (4%)\t5 (5%)\tns\t\n \t \t \t \t\nElevated sIgG4 at onset (>135 mg/dl)\t17/21 (74%)\t42/84 (50%)\t0.013\t\nsIgG4 at onset (mg/dl)\t758±625\t311±409\t<0.001\t\n \t \t \t \t\n\nOther organ involvement (OOI)\n\t19 (83%)\t47 (48%)\t0.002\t\n Bile duct\t12 (52%)\t17 (17%)\t<0.0001\t\n Kidney\t8 (35%)\t4 (4%)\t<0.0001\t\n Salivary glands\t4 (17%)\t3 (3%)\t0.025\t\n Colon\t1 (4%)\t26 (27%)\t0.024\t\n Retroperitoneal fibrosis\t0\t4 (4%)\tns\t\n >1\t5 (22%)\t7 (7%)\t0.052\t\n \t \t \t \t\nSteroid treatment at clinical onset\t23 (100%)\t91 (94%)\tns\t\n \t \t \t \t\n\nRecurrences\na\n\t\n 0\t5 (22%)\t83 (86%)\t<0.0001\t\n 1\t13 (56%)\t11 (11%)\t \t\n >1\t5 (22%)\t3 (3%)\t \t\nAIP, autoimmune pancreatitis; AZA, azathioprine; ICDC, International\nConsensus Diagnostic Criteria; NOS, not otherwise specified; ns, not\nspecofied.\n\na For AZA+ group only recurrences before immunosuppressant\ntreatment were considered.\n==== Refs\nZamboni G, Luttges J, Capelli P et al. Histopathological features of diagnostic and clinical relevance in autoimmune\npancreatitis: a study on 53 resection specimens and 9 biopsy specimens . Virchows Arch \n2004 ; 445 : 552 –563.15517359 \nChari ST, Kloeppel G, Zhang L et al. Histopathologic and clinical subtypes of autoimmune pancreatitis: the Honolulu\nconsensus document . Pancreas \n2010 ; 39 : 549 –554.20562576 \nZhang L, Chari S, Smyrk TC et al. Autoimmune pancreatitis (AIP) type 1 and type 2: an international consensus\nstudy on histopathologic diagnostic criteria . Pancreas \n2011 ; 40 : 1172 –1179.21975436 \nSah RP, Chari ST, Pannala R et al. Differences in clinical profile and relapse rate of type 1 versus type 2\nautoimmune pancreatitis. Gastroenterology 2010 ; 139 : 140 –148.\nDetlefsen S, Zamboni G, Frulloni L et al. Clinical features and relapse rates after surgery in type 1 autoimmune\npancreatitis differ from type 2: a study of 114 surgically treated European\npatients . Pancreatology \n2012 ; 12 : 276 –283.22687385 \nShimosegawa T, Chari ST, Frulloni L et al. International consensus diagnostic criteria for autoimmune pancreatitis:\nguidelines of the International Association of Pancreatology . Pancreas \n2011 ; 40 : 352 –358.21412117 \nKamisawa T, Chari ST, Giday SA et al. Clinical profile of autoimmune pancreatitis and its histological subtypes: an\ninternational multicenter survey . Pancreas \n2011 ; 40 : 809 –814.21747310 \nHart PA, Kamisawa T, Brugge WR et al. Long-term outcomes of autoimmune pancreatitis: a multicentre, international\nanalysis . Gut \n2013 ; 62 : 1771 –1776.23232048 \nFrulloni L, Scattolini C, Falconi M et al. Autoimmune pancreatitis: differences between the focal and diffuse forms in 87\npatients . Am J Gastroenterol \n2009 ; 104 : 2288 –2294.19568232 \nIkeura T, Manfredi R, Zamboni G et al. Application of international consensus diagnostic criteria to an Italian series\nof autoimmune pancreatitis . United European Gastroenterol J \n2013 ; 1 : 276 –284.\nIto T, Nishimori I, Inoue N et al. Treatment for autoimmune pancreatitis: consensus on the treatment for patients\nwith autoimmune pancreatitis in Japan . J Gastroenterol \n2007 ; 42 (Suppl 18): 50 –58.17520224 \nKalaitzakis E, Webster GJ. Review article: autoimmune pancreatitis—management of an emerging\ndisease . Aliment Pharmacol Ther \n2011 ; 33 : 291 –303.21138452 \nPannala R, Chari ST. Corticosteroid treatment for autoimmune pancreatitis . Gut \n2009 ; 58 : 1438 –1439.19834112 \nMaire F, Le Baleur Y, Rebours V et al. Outcome of patients with type 1 or 2 autoimmune pancreatitis . Am J Gastroenterol \n2011 ; 106 : 151 –156.20736934 \nChurch NI, Pereira SP, Deheragoda MG et al. Autoimmune pancreatitis: clinical and radiological features and objective\nresponse to steroid therapy in a UK series . Am J Gastroenterol \n2007 ; 102 : 2417 –2425.17894845 \nSandanayake NS, Church NI, Chapman MH et al. Presentation and management of post-treatment relapse in autoimmune\npancreatitis/immunoglobulin G4-associated cholangitis . Clin Gastroenterol Hepatol \n2009 ; 7 : 1089 –1096.19345283 \nHart PA, Topazian MD, Witzig TE et al. Treatment of relapsing autoimmune pancreatitis with immunomodulators and\nrituximab: the Mayo Clinic experience . Gut \n2013 ; 62 : 1607 –1615.22936672 \nHuggett MT, Culver EL, Kumar M et al. Type 1 autoimmune pancreatitis and IgG4-related sclerosing cholangitis is\nassociated with extrapancreatic organ failure, malignancy, and mortality in a\nprospective UK cohort . Am J Gastroenterol \n2014 ; 109 : 1675 –1683.25155229 \nHamano H, Kawa S, Horiuchi A et al. High serum IgG4 concentrations in patients with sclerosing pancreatitis . N Engl J Med \n2001 ; 344 : 732 –738.11236777 \nManfredi R, Frulloni L, Mantovani W et al. Autoimmune pancreatitis: pancreatic and extrapancreatic MR imaging-MR\ncholangiopancreatography findings at diagnosis, after steroid therapy, and at\nrecurrence . Radiology \n2011 ; 260 : 428 –436.21613442 \nManfredi R, Graziani R, Cicero C et al. Autoimmune pancreatitis: CT patterns and their changes after steroid\ntreatment . Radiology \n2008 ; 247 : 435 –443.18430876 \nHardacre JM, Iacobuzio-Donahue CA, Sohn TA et al. Results of pancreaticoduodenectomy for lymphoplasmacytic sclerosing\npancreatitis . Ann Surg \n2003 ; 237 : 853 –858.12796582 \nSchnelldorfer T, Lewin DN, Adams DB. Long-term results after surgery for autoimmune sclerosing pancreatitis . J Gastrointest Surg \n2007 ; 11 : 56 –58.17390187 \nClark CJ, Morales-Oyarvide V, Zaydfudim V et al. Short-term and long-term outcomes for patients with autoimmune pancreatitis\nafter pancreatectomy: a multi-institutional study . J Gastrointest Surg \n2013 ; 17 : 899 –906.23319396 \nSeleznik G, Graf R. Alternatives to steroids?! Beneficial effects of immunosuppressant drugs in\nautoimmune pancreatitis . Gut \n2014 ; 63 : 376 –377.23633291 \nRaina A, Yadav D, Krasinskas AM et al. Evaluation and management of autoimmune pancreatitis: experience at a large US\ncenter . Am J Gastroenterol \n2009 ; 104 : 2295 –2306.19532132 \nStone JH, Zen Y, Deshpande V. IgG4-related disease . N Engl J Med \n2012 ; 366 : 539 –551.22316447 \nDubinsky MC. Azathioprine, 6-mercaptopurine in inflammatory bowel disease: pharmacology,\nefficacy, and safety . Clin Gastroenterol Hepatol \n2004 ; 2 : 731 –743.15354273 \nWeersma RK, Peters FT, Oostenbrug LE et al. Increased incidence of azathioprine-induced pancreatitis in Crohn's disease\ncompared with other diseases . Aliment Pharmacol Ther \n2004 ; 20 : 843 –850.15479355 \nHart PA, Law RJ, Dierkhising RA et al. Risk of cancer in autoimmune pancreatitis: a case-control study and review of\nthe literature . Pancreas \n2014 ; 43 : 417 –421.24622072 \nShiokawa M, Kodama Y, Yoshimura K et al. 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"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2155-384X",
"issue": "8(4)",
"journal": "Clinical and translational gastroenterology",
"keywords": null,
"medline_ta": "Clin Transl Gastroenterol",
"mesh_terms": null,
"nlm_unique_id": "101532142",
"other_id": null,
"pages": "e90",
"pmc": null,
"pmid": "28448071",
"pubdate": "2017-04-27",
"publication_types": "D016428:Journal Article",
"references": "21747310;15517359;25155229;15354273;11236777;23232048;17894845;22936672;20736934;15479355;19532132;23633291;21975436;12796582;23318486;22687385;17390187;18430876;20353791;24622072;24917972;21613442;19834112;20562576;22316447;19345283;21138452;17520224;19568232;23319396;21412117",
"title": "Azathioprine Maintenance Therapy to Prevent Relapses in Autoimmune Pancreatitis.",
"title_normalized": "azathioprine maintenance therapy to prevent relapses in autoimmune pancreatitis"
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"abstract": "BACKGROUND\nZidovudine (ZDV) has been associated with risk of haematological toxicity. Safety data from clinical trials is generally limited to 48 weeks. We assessed the short- and mid-term toxicity of ZDV/lamivudine (3TC) fixed-dose combination scored tablets in HIV-infected children followed in the European Pregnancy and Paediatric HIV Cohort Collaboration (EPPICC) network.\n\n\nMETHODS\nFourteen cohorts provided data on patients <18 years of age taking ZDV/3TC scored tablets between 2008 and 2012. Rates of Division of AIDS (DAIDS) grade ≥3 laboratory adverse events (AEs) for hepatobiliary and haematological disorders were estimated by duration on drug (<12, 12-24, >24 months). Clinical adverse events and reasons for tablet discontinuation were described.\n\n\nRESULTS\nOf 541 patients on ZDV/3TC, 388 (72%) had weight and dose data available, of whom 350 (90%) weighed ≥14 kg and were eligible for tablet use; 161 (41%) were aged <10 years on an approved dose, 189 (49%) aged ≥10 years on an approved dose, and 30 (8%) were on an unapproved dose. Median age at ZDV/3TC start was 10 years, and 79% had taken ART previously (60% had prior exposure to ZDV/3TC). Overall rates of grade ≥3 AEs for absolute neutrophil counts, bilirubin, haemoglobin, platelet counts, white blood cell counts (WBC), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were ≤2/100 person years (PY) for patients taking approved doses. Two hundred thirty-three (43%) patients were not on ZDV/3TC tablets at most recent follow-up; a small number (17 (7%)) discontinued due to AEs (17 (7%)), and the most common reason for discontinuation was treatment simplification (73 (31%)).\n\n\nCONCLUSIONS\nScored ZDV/3TC tablets, both approved and taken off-label, appear to be well tolerated with few side effects. Few patients discontinued treatment due to toxicity. As ZDV/3TC tablets are taken with other antiretrovirals, it is difficult to infer association between toxicities and specific agents, highlighting the importance of widening long-term pharmacovigilance to a broader spectrum of drug combinations.",
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"doi": "10.1007/s00228-016-2182-2",
"fulltext": "\n==== Front\nEur J Clin PharmacolEur. J. Clin. PharmacolEuropean Journal of Clinical Pharmacology0031-69701432-1041Springer Berlin Heidelberg Berlin/Heidelberg 218210.1007/s00228-016-2182-2Pharmacoepidemiology and PrescriptionSafety of zidovudine/lamivudine scored tablets in children with HIV infection in Europe and Thailand The European Pregnancy and Paediatric HIV Cohort Collaboration (EPPICC) study group in EuroCoordBailey Heather Thompson Lindsay Childs Tristan Collins Intira Jeannie Tostevin Anna Goodall Ruth Goetghebuer Tessa Spoulou Vana Galli Luisa Marczynska Magda Marques Laura Ene Luminita Samarina Anna Rosenberg Vladimir Dodonov Konstantin Okhonskaia Liubov Noguera Julian Antoni Rojo Conejo Pablo Ramos Amador Jose Tomas Naver Lars Jourdain Gonzague Thorne Claire Giaquinto Carlo Judd Ali a.judd@ucl.ac.uk 0000000121901201grid.83440.3bMRC Clinical Trials Unit at UCL, Institute of Clinical Trials and Methodology, Ali Judd, University College London, Aviation House, 125 Kingsway, London, WC2B 6NH UK 27 12 2016 27 12 2016 2017 73 4 463 468 19 10 2016 12 12 2016 © The Author(s) 2017\nOpen Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.Background\nZidovudine (ZDV) has been associated with risk of haematological toxicity. Safety data from clinical trials is generally limited to 48 weeks. We assessed the short- and mid-term toxicity of ZDV/lamivudine (3TC) fixed-dose combination scored tablets in HIV-infected children followed in the European Pregnancy and Paediatric HIV Cohort Collaboration (EPPICC) network.\n\nMethods\nFourteen cohorts provided data on patients <18 years of age taking ZDV/3TC scored tablets between 2008 and 2012. Rates of Division of AIDS (DAIDS) grade ≥3 laboratory adverse events (AEs) for hepatobiliary and haematological disorders were estimated by duration on drug (<12, 12–24, >24 months). Clinical adverse events and reasons for tablet discontinuation were described.\n\nResults\nOf 541 patients on ZDV/3TC, 388 (72%) had weight and dose data available, of whom 350 (90%) weighed ≥14 kg and were eligible for tablet use; 161 (41%) were aged <10 years on an approved dose, 189 (49%) aged ≥10 years on an approved dose, and 30 (8%) were on an unapproved dose. Median age at ZDV/3TC start was 10 years, and 79% had taken ART previously (60% had prior exposure to ZDV/3TC). Overall rates of grade ≥3 AEs for absolute neutrophil counts, bilirubin, haemoglobin, platelet counts, white blood cell counts (WBC), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were ≤2/100 person years (PY) for patients taking approved doses. Two hundred thirty-three (43%) patients were not on ZDV/3TC tablets at most recent follow-up; a small number (17 (7%)) discontinued due to AEs (17 (7%)), and the most common reason for discontinuation was treatment simplification (73 (31%)).\n\nConclusions\nScored ZDV/3TC tablets, both approved and taken off-label, appear to be well tolerated with few side effects. Few patients discontinued treatment due to toxicity. As ZDV/3TC tablets are taken with other antiretrovirals, it is difficult to infer association between toxicities and specific agents, highlighting the importance of widening long-term pharmacovigilance to a broader spectrum of drug combinations.\n\nKeywords\nPharmacovigilanceChildrenAntiretroviral therapyNRTIsHIVhttp://dx.doi.org/10.13039/100004330GlaxoSmithKlinehttp://dx.doi.org/10.13039/501100004963Seventh Framework Programmeissue-copyright-statement© Springer-Verlag Berlin Heidelberg 2017\n==== Body\nIntroduction\nZidovudine (ZDV)/lamivudine (3TC) is a first-line NRTI backbone for paediatric HIV infection. A fixed-dose combination of 300 mg ZDV with 150 mg 3TC (Combivir®) was initially approved in Europe in 1998. Subsequently, a scored tablet formulation of ZDV/3TC was approved in 2008 for paediatric HIV treatment for those weighing ≥14 kg or requiring dose adjustment, or patients experiencing dose-limiting adverse reactions. Dosing of ZDV/3TC is by weight bands [1].\n\nZDV has been associated with the risk of haematological toxicity [2], and WHO guidelines recommend avoiding ZDV for first-line treatment for patients with severe anaemia [1]. However, the ARROW and CHAPAS-3 trial data [3, 4] indicated no increased anaemia risk among children on ZDV, suggesting this may be caused predominantly by chronic HIV or other infections rather than ART. The CNAA3006 study provided safety data on the use of ZDV/3TC in patients aged 6 months to 13 years; however, this study did not evaluate the scored tablet formulation [5]. They found that ZDV/3TC was well tolerated with <10% of participants experiencing a treatment-limiting adverse event (AE) and only 3% of patients experiencing a grade 3/4 anaemia abnormality.\n\nLonger-term follow-up is essential to understand the safety of antiretroviral drugs beyond the 48 weeks of licencing trials. We investigated the short- and mid-term toxicity among children receiving ZDV/3TC scored tablets as part of routine care. Patients were followed in observational cohorts participating in the European Pregnancy and Paediatric HIV Cohort Collaboration (EPPICC), within which a pharmacovigilance programme has been running since 2009 [6, 7].\n\nMethods\nHIV-infected paediatric patients, aged <18 years from 14 cohorts participating in EPPICC’s pharmacovigilance programme (part of the EuroCoord network) who ever received ZDV/3TC scored tablets between 2008 and 2012, were included. Individual participating cohorts were responsible for gaining their own ethics approval. Data collected included demographics, deaths, losses to follow-up and follow-up data (both pre- and post-ZDV/3TC scored tablets) for patient weight, ART, Centres for Disease Control and Prevention (CDC) category C (AIDS) events, CD4 and HIV-1 RNA, key haematology and biochemistry results and serious adverse events (SAEs). Data up to February 2014 were merged, using the HIV Cohorts Data Exchange Protocol specification (www.hicdep.org).\n\nPatients were considered to be on an approved dose if taking ZDV/3TC scored tablets as licenced, i.e. ≥14–< 20 kg, half a tablet (75/150 mg) b.i.d; ≥20–< 30 kg, half a tablet (75/150 mg) in morning, whole tablet (150/300 mg) in evening; and ≥30 kg, whole tablet (150/300 mg) b.i.d. Patients on other doses within these weight bands or weighing <14 kg were considered to be on an unapproved dose.\n\nBiochemical results were graded using the Division of AIDS (DAIDS) categorisation for paediatric AEs (Appendix Table 2) [8]. Rates of grade ≥3 AEs were calculated within four distinct time periods on scored tablet (<12, 12–24 and >24 months) and age starting scored tablet (<10 and ≥10 years) where there were n ≥ 30 patients in each group in follow-up for approved doses. Laboratory analyses were restricted to patients with ≥3-month follow-up after start of the tablets and were censored at 30 days after tablet discontinuation. Patients were censored at their first grade ≥3 event within each time period. Clinical SAEs and reasons for tablet discontinuation were also described. Analyses were undertaken using Stata version 14.0 (Stat Corp, College Station, TX, USA).\n\nResults\nOverall, 541/3139 (17%) patients <18 years on ART in 14 cohorts ever took ZDV/3TC scored tablets between 2008 and 2012. The majority were from the Thai (38%), UK/Ireland (18%) and Russian (17%) cohorts, and among those with known mode of HIV acquisition, almost all were perinatally HIV-infected (Table 1). Twenty-five (5%) patients were co-infected with hepatitis-C virus and 23 (4%) with hepatitis-B virus. Of the 145 (27%) patients ever diagnosed with AIDS, 22 (15%) were after tablet start. At the start of ZDV/3TC scored tablets, 190 (35%) had previously received 1–3, 215 (40%) 4–7, and 24 (4%) ≥8 ART drugs; 327 (60%) ZDV and 3TC.Table 1 Characteristics of patients taking ZDV/3TC scored tablets (n = 541)\n\n\t\nN (%) / median [IQR]\t\nCountry\t\n UK/Ireland\t96\t(18)\t\n Other European countriesa\n\t152\t(28)\t\n Russia\t90\t(17)\t\n Thailand\t203\t(38)\t\nMale gender\t250\t(46)\t\nEthnic group\t\n White\t151\t(28)\t\n Black African\t104\t(19)\t\n Asian and other\t236\t(44)\t\n Unknown\t50\t(9)\t\nMode of HIV infection\t\n MTCT\t450\t(83)\t\n Other\t13\t(2)\t\n Unknown\t78\t(14)\t\nEver AIDS event\t145\t(27)\t\nMedian age at ART start (years)\t6\t[2, 9]\t\nMedian age at ZDV/3TC scored tablet start (years)\t10\t[7, 13]\t\nART experienced (≥1 ART drug) before ZDV/3TC scored tablets\t429\t(79)\t\nMedian duration on ART before ZDV/3TC scored tablet start (years)\t4\t[1, 6]\t\nExposure to ZDV and 3TC before starting ZDV/3TC scored tablets\t327\t(60)\t\nMedian VL at ZDV/3TC start (log10c/mL)\t1.7\t[1.6, 3.3]\t\nMedian CD4 cell count ZDV/3TC start (cells/mm3)\t660\t[416, 972]\t\nMedian CD4% at ZDV/3TC start\t28\t[19, 34]\t\nMedian time on ZDV/3TC scored tablets (months)b\n\t30\t[17, 56]\t\nTime to discontinuation of ZDV/3TC (n = 233)\t\n <1 month\t11\t(5)\t\n 1–<6 months\t29\t(12)\t\n 6–<12 months\t32\t(14)\t\n ≥12 months\t161\t(69)\t\nReasons for stopping tablets (n = 233)\t\n Treatment failure (immunological/virological)\t42\t(18)\t\n Toxicity/side effects\t17\t(7)\t\n Death\t7\t(3)\t\n Non-compliance\t9\t(4)\t\n Patient’s wish/decision\t7\t(3)\t\n Co-morbidity\t1\t(0)\t\n Physician’s decision\t3\t(1)\t\n Simplified treatment available\t73\t(31)\t\n Better safety profile\t1\t(0)\t\n Unknown\t73\t(31)\t\n\naOther European countries are Belgium, Greece, Italy, Poland, Portugal, Romania, Spain and Sweden\n\n\nbFor those still on ZDV/3TC at the last follow-up\n\n\n\n\nOverall, 388 (72%) had weight and dose data available at start of ZDV/3TC tablets, of whom 350 (90%) weighed ≥14 kg and were taking an approved dose for weight (161 (46%) aged <10 years and 189 (54%) ≥10 years); 30 (8%) weighed ≥14 kg and were taking an unapproved dose for weight (26 patients were under-dosed and 4 were over-dosed), and 8 (2%) had weight <14 kg on any dose. Thirty-two percent of patients <18 years on ART were taking an NNRTI and 60% a boosted PI.\n\nThe incidence rates of DAIDS grade ≥3 events were generally low (Fig. 1). Five (4%) patients aged <10 years and 6 (4%) ≥10 years at start of ZDV/3TC tablets had grade ≥3 neutropenia. Two (1%) patients aged <10 years had a grade ≥3 alanine aminotransferase (ALT) event (one <12 and one 12–24 months after starting ZDV/3TC) and two (1%) ≥10 years. One patient aged <10 years (<1%) had a grade ≥3 aspartate aminotransferase (AST) event 12–24 months after starting ZDV/3TC. Five (4%) patients aged <10 years had grade ≥3 hyperbilirubinemia and five patients (4%) ≥10 years (four within 12 months of starting ZDV/3TC). Five (4%) patients aged <10 years had grade ≥3 anaemia (four within 12 months of starting ZDV/3TC) and 4 (2%) ≥10 years. Two (2%) patients aged <10 years had grade ≥3 platelet results (both <12 months after starting ZDV/3TC) and 2 (1%) ≥10 years (1 within 12 months, and 1 after 24 months). There was only 1 grade ≥3 WBC event among patients aged ≥10 years.Fig. 1 Incidence of grade ≥3 adverse events by duration of ZDV/3TC scored tablets (n = 145 < 10 years with weight ≥14 kg, n = 166 ≥ 10 years with weight ≥14 kg)\n\n\n\n\nAmong 22 patients taking unapproved doses of ZDV/3TC with ≥1 laboratory test, 4/15 (20%) had grade ≥3 neutropenia, of which two subsequently resolved; all the four were aged ≥10 years at the time of the grade ≥3 result. One (5%) had grade ≥3 hyperbilirubinemia reported <12 months after starting ZDV/3TC and again at 12–24 months. Of the eight patients with weight <14 kg one had grade ≥3 hyperbilirubinemia.\n\nAmong 159 patients on approved dose with clinical data, there were five SAEs causally related to ZDV/3TC, all aged <10 years at start of ZDV/3TC; anaemia (n = 4) and neutropenia (n = 1). There were no clinical SAEs considered causally related to the tablets for patients aged ≥10 years at start of ZDV/3TC on an approved or unapproved dose.\n\nDuring follow-up, 12 (2%) patients died, of whom seven were taking ZDV/3TC at death. Nine deaths were patients aged ≥10 years at start of ZDV/3TC and on an approved dose, and the deaths were reported as HIV-related (n = 5) or AIDS-defining (n = 1) events, suicide (n = 1) or unknown causes (n = 2; 21 and 22 months after starting ZDV/3TC scored tablets). In the unapproved dose group, two deaths were reported during follow-up, one from HIV-related causes and one an AIDS-defining event. One death occurred in the <14-kg weight category and one in a patient with missing dose; one was taking ZDV/3TC at time of death.\n\n Overall, 233 (43%) patients were not on ZDV/3TC tablets at the last follow-up, and the main reasons for discontinuations were treatment simplification (31%) and treatment failure (18%) (Table 1). Most patients discontinued ≥12 months after starting ZDV/3TC. Seventeen patients discontinued due to toxicity, including abnormal fat redistribution (n = 3), dyslipidaemia (n = 2) haematological (n = 4), liver (n = 2), nervous system (n = 2), hypersensitivity reaction (n = 2) and unspecified (n = 2).\n\nDiscussion\nThe findings from this study suggest that ZDV/3TC scored tablets were received by nearly one in five children currently on ART in cohorts in Europe and Thailand. In patients taking the approved doses, rates of grade ≥3 AEs were generally low and were comparable across children aged <10 and ≥10 years at the start of ZDV/3TC tablets. These results are comparable to those of the CNAA3006 study that showed grade ≥3 AEs occurred in ≤30% of participants and were mild/moderate in intensity; <10% of the participants experienced a treatment-limiting AE. Rates of grade ≥3 AEs were also similarly low to those in children in our collaboration taking fosamprenavir-, darunavir- and atazanavir-containing regimens [6, 7]. Discontinuations in this study, most of which occurred at least 12 months after starting treatment, were mainly due to treatment simplification. A small number of children died, for whom the most common causes were HIV- or AIDS-related. This is comparable with CNAA3006 where there was only 1 death in 103 participants in the ZDV/3TC group, considered unrelated to the study drug.\n\nA limitation of this analysis is that EPPICC cohorts do not routinely capture mild AEs such as diarrhoea, vomiting, nausea and choking; thus, it was not possible to estimate their frequency in this report. Also due to the small number of grade ≥3 lab events, it was not possible to stratify rates by country, or to present rates for those taking unapproved doses. We were also unable to compare characteristics of patients with and without SAEs due to the small numbers. As 60% of patients were exposed to ZDV and 3TC prior to starting ZDV/3TC scored tablets, the incidence of AEs in this population may not be generalizable to children newly exposed to ZDV/3TC. Similarly, since ZDV/3TC is routinely taken with other antiretroviral drugs, it is difficult to attribute causality for these occurrences to any one specific agent, highlighting the importance of widening long-term pharmacovigilance studies to a broader spectrum of drug combinations.\n\nIn summary, ZDV/3TC-containing regimens, both approved and unapproved, appear to be well tolerated in the paediatric population in Europe and Thailand. No major post-licencing short- to medium-term safety concerns were identified in our study.\n\nAppendix\n\nTable 2 Division of AIDS table for grading the severity of adult and paediatric adverse events version 1.0, December, 2004; clarification August 2009\n\nParameter\tGrade 1 mild\tGrade 2 moderate\tGrade 3 severe\tGrade 4 potentially life threatening\t\nAbsolute neutrophil count\t\n Adult and paediatric >7 days\t1000–1300/mm3\n\n1.000 × 109–1.300 × 109/L\t750–999/mm3\n\n0.750 × 109–0.999 × 109/L\t500–749/mm3\n\n0.500 × 109–0.749 × 109/L\t<500/mm3\n\n<0.500 × 109/L\t\nAlanine aminotransferase (ALT)\t1.25–2.5 × ULN\t2.6–5.0 × ULN\t5.1–10.0 × ULN\t>10.0 × ULN\t\nAspartate aminotransferase (AST)\t1.25–2.5 × ULN\t2.6–5.0 × ULN\t5.1–10.0 × ULN\t>10.0 × ULN\t\nBilirubin (total)\t\n Adult and paediatric >14 days\t1.1–1.5 × ULN\t1.6–2.5 × ULN\t2.6–5.0 × ULN\t>5.0 × ULN\t\nHaemoglobin\t\n Adult and paediatric ≥57 days (HIV positive only)\t8.5–10.0 g/dL\n5.24–6.23 mmol/L\t7.5–8.4 g/dL\n4.62–5.23 mmol/L\t6.50–7.4 g/dL\n4.03–4.61 mmol/L\t<6.5 g/dL\n<4.03 mmol/L\t\nPlatelets, decreased\t100,000–124,999/mm3\n\n100.000 × 109–124.999 × 109/L\t50,000–99,999/mm3\n\n50.000 × 109–99.999 × 109/L\t25,000–49,999/mm3\n\n25.000 × 109–49.999 × 109/L\t<25,000/mm3\n\n<25.000 × 109/L\t\nWhite blood cells, decreased\t2000–2500/mm3\n\n2.000 × 109–2.500 × 109/L\t1500–1999/mm3\n\n1.500 × 109–1.999 × 109/L\t1000–1499/mm3\n\n1.000 × 109–1.499 × 109/L\t<1000/mm3\n\n<1.000 × 109/L\t\n(Reproduced from http://rsc.tech-res.com/docs/default-source/safety/table_for_grading_severity_of_adult_pediatric_adverse_events.pdf)\n\n\n\n\nThe original publication of the paper contains a mistake. There should be no author name present in the article.\n\nAn erratum to this article is available at http://dx.doi.org/10.1007/s00228-017-2201-y.\n\nAcknowledgements\nWe would like to thank Vani Vannappagari and colleagues from GSK/ViiV for the input into the study protocol and reports.\n\nAuthor contributions\nAli Judd, Heather Bailey, Intira Jeannie Collins and Carlo Giaquinto were responsible for the study concept and design. Tristan Childs, Lindsay Thompson, Anna Tostevin and Ruth Goodall undertook statistical analyses. Lindsay Thompson wrote the first draft and undertook revisions to subsequent drafts. Tessa Goetghebuer, Vana Spoulou, Luisa Galli, Magda Marczynska, Laura Marques, Luminita Ene, Anna Samarina, Vladimir Rosenberg, Konstantin Dodonov, Liubov Okhonskaia, Antoni Noguera Julian, Pablo Rojo Conejo, Jose Tomas Ramos Amador, Lars Naver, Gonzague Jourdain, Pat Tookey and Ali Judd provided data for the study. All members of the writing group participated in discussions about the design of the study. They also critically reviewed the article and approved its final version to be submitted.\n\nCompliance with ethical standards\nIndividual participating cohorts were responsible for gaining their own ethics approval.\n\nFunding\nThis work received funding from the GlaxoSmithKline/ViiV and from the European Union’s 7th Framework Programme for research, technological development and demonstration under EuroCoord grant agreement no. 260694.\n\nConflict of interest\nThe author declares that she has no competing interests.\n\nParticipating cohorts\nHospital St Pierre Cohort, Brussels, Belgium (T Goetghebuer); Paediatric cohort, Greece (V Spoulou); Italian Register for HIV infection in children, Italy (L Galli); Paediatric Cohort, Poland (M Marczynska); Centro Hospitalar do Porto, Portugal (L Marques); “Victor Babes” Hospital Cohort, Romania (L Ene); The City HIV Centre, St Petersburg, Russia (A Samarina); Irkutsk HIV Centre, Russia (V Rosenberg); The Republican Hospital of Infectious Diseases, St Petersburg, Russia (E Voronin and L Okhonskaia); CoRISPE-cat, Catalonia, Spain (A Noguera Julian); CoRISPES-1, rest of Spain cohort, Spain (P Rojo and J Tomas Ramos Amador); Karolinska University Hospital, Stockholm, Sweden (L Naver); Thailand Program for HIV Prevention and Treatment (PHPT) Study Group, Thailand (G Jourdain); National Study of HIV in Pregnancy and Childhood, UK and Ireland (P Tookey); Collaborative HIV Paediatric Study, UK and Ireland (A Judd). Coordination and statistical analyses at MRC CTU at UCL: H Bailey, L Thompson, T Childs, IJ Collins, A Tostevin, R Goodall and A Judd; and at PENTA: C Giaquinto.\n\nWriting group (ordered by project team first and in last position, and then other contributors by country and cohort name):\nHeather Bailey (MRC Clinical Trials Unit, University College London, London, UK).\n\nLindsay Thompson (MRC Clinical Trials Unit, University College London, London, UK).\n\nTristan Childs (MRC Clinical Trials Unit, University College London, London, UK).\n\nIntira Jeannie Collins (MRC Clinical Trials Unit, University College London, London, UK).\n\nAnna Tostevin (MRC Clinical Trials Unit, University College London, London, UK).\n\nRuth Goodall (MRC Clinical Trials Unit, University College London, London, UK).\n\nTessa Goetghebuer (Hopital St Pierre, Brussels, Belgium),\n\nVana Spoulou (Paediatric cohort, Greece).\n\nLuisa Galli (Italian Register for HIV infection in children, Italy).\n\nMagda Marczynska (Paediatric cohort, Poland).\n\nLaura Marques (Centro Hospitalar do Porto, Portugal).\n\nLuminita Ene (“Victor Babes” Hospital Cohort, Romania).\n\nAnna Samarina (The City HIV Centre, St Petersburg, Russia).\n\nVladimir Rosenberg (Irkutsk HIV Centre, Russia).\n\nKonstantin Dodonov and Liubov Okhonskaia (The Republican Hospital of Infectious Diseases, St Petersburg, Russia).\n\nAntoni Noguera Julian (CoRISPE-cat, Catalonia, Spain).\n\nPablo Rojo Conejo and Jose Tomas Ramos Amador (CoRISPES-1, rest of Spain cohort, Spain).\n\nLars Naver (Karolinska University Hospital, Stockholm, Sweden).\n\nGonzague Jourdain (Thailand Program for HIV Prevention and Treatment (PHPT) Study Group, Thailand).\n\nClaire Thorne (National Study of HIV in Pregnancy and Childhood, UK/Ireland).\n\nCarlo Giaquinto (PENTA network).\n\nAli Judd (MRC Clinical Trials Unit, University College London, London, UK)\n==== Refs\nReferences\n1. World Health Organization, Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection (2016) World Health Organization: Geneva\n2. Nielsen-Saines K Three postpartum antiretroviral regimens to prevent intrapartum HIV infection N Engl J Med 2012 366 25 2368 2379 10.1056/NEJMoa1108275 22716975 \n3. ARROW Trial team Routine versus clinically driven laboratory monitoring and first-line antiretroviral therapy strategies in African children with HIV (ARROW): a 5-year open-label randomised factorial trial Lancet 2013 381 9875 1391 1403 10.1016/S0140-6736(12)62198-9 23473847 \n4. Mulenga V Abacavir, zidovudine, or stavudine as paediatric tablets for African HIV-infected children (CHAPAS-3): an open-label, parallel-group, randomised controlled trial Lancet Infect Dis 2016 16 2 169 179 10.1016/S1473-3099(15)00319-9 26481928 \n5. Saez-Llorens X A randomized, double-blind study of triple nucleoside therapy of abacavir, lamivudine, and zidovudine versus lamivudine and zidovudine in previously treated human immunodeficiency virus type 1-infected children. The CNAA3006 Study Team Pediatrics 2001 107 1 E4 10.1542/peds.107.1.e4 11134468 \n6. Judd A Post-licensing safety of fosamprenavir in HIV-infected children in Europe Pharmacoepidemiol Drug Saf 2013 23 3 321 325 10.1002/pds.3543 \n7. European Pregnancy and Paediatric HIV Cohort Collaboration (EPPICC) study group in EuroCoord (2015) Safety of darunavir and atazanavir in HIV-infected children in Europe and Thailand. Antivir Ther\n8. Division of AIDS, Division of AIDS table for grading the severity of adult and pediatric adverse events (2009) Version 1.0, December 2004; clarification August 2009. Bethesda, MD: National Institutes of Health\n\n",
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"journal": "European journal of clinical pharmacology",
"keywords": "Antiretroviral therapy; Children; HIV; NRTIs; Pharmacovigilance",
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"mesh_terms": "D019380:Anti-HIV Agents; D002648:Child; D005060:Europe; D015658:HIV Infections; D006801:Humans; D019259:Lamivudine; D013607:Tablets; D013785:Thailand; D015215:Zidovudine",
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"title": "Safety of zidovudine/lamivudine scored tablets in children with HIV infection in Europe and Thailand.",
"title_normalized": "safety of zidovudine lamivudine scored tablets in children with hiv infection in europe and thailand"
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"abstract": "Pentastomiasis, a zoonotic parasite infection, is typically found in the respiratory tract and viscera of the host, including humans. Here, we report for the first time an extremely rare case of intraosseous pentastomiasis in the human maxilla suffering from medication related osteonecrosis of the jaw (MRONJ). A 55-year-old male had continuously visited the hospital for MRONJ which had primarily developed after bisphosphonate and anti-neoplastic administration for previous bone metastasis of medullary thyroid cancer. Pain, bone exposure, and pus discharge in the right mandible and left maxilla were seen. Osteolysis with maxillary cortical bone perforation at the left buccal vestibule, palate, nasal cavity, and maxillary sinus was observed by radiologic images. A biopsy was done at the left maxilla and through pathological evaluation, a parasite with features of pentastome was revealed within the necrotic bone tissue. Further history taking and laboratory evaluation was done. The parasite was suspected to be infected through maxillary open wounds caused by MRONJ. Awareness of intraosseous pentastomiasis should be emphasized not to be missed behind the MRONJ. Proper evaluation and interpretation for past medical history may lead to correct differential diagnosis and therapeutic intervention for parasite infections.",
"affiliations": "Department of Oral Pathology, Oral Cancer Research Institute, Yonsei University College of Dentistry, Seoul 03722, Korea.;Department of Oral and Maxillofacial Surgery, Yonsei University College of Dentistry, Seoul 03722, Korea.;Department of Oral and Maxillofacial Surgery, Yonsei University College of Dentistry, Seoul 03722, Korea.;Department of Environmental Medical Biology, Institute of Tropical Medicine & Arthropods of Medical Importance Bank, Yonsei University College of Medicine, Seoul 03722, Korea.;Department of Environmental Medical Biology, Institute of Tropical Medicine & Arthropods of Medical Importance Bank, Yonsei University College of Medicine, Seoul 03722, Korea.;Department of Internal Medicine and AIDS Research Institute, Yonsei University College of Medicine, Seoul 03722, Korea.;Department of Oral Pathology, Oral Cancer Research Institute, Yonsei University College of Dentistry, Seoul 03722, Korea.",
"authors": "Cho|Eunae Sandra|ES|;Jung|Seung Wook|SW|;Jung|Hwi-Dong|HD|;Lee|In Yong|IY|;Yong|Tai-Soon|TS|;Jeong|Su Jin|SJ|;Kim|Hyun Sil|HS|",
"chemical_list": "D000970:Antineoplastic Agents",
"country": "Korea (South)",
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"doi": "10.3347/kjp.2017.55.4.433",
"fulltext": "\n==== Front\nKorean J ParasitolKorean J. ParasitolThe Korean Journal of Parasitology0023-40011738-0006The Korean Society for Parasitology and Tropical Medicine 2887757710.3347/kjp.2017.55.4.433kjp-55-4-433Case ReportA Case of Pentastomiasis at the Left Maxilla Bone in a Patient with Thyroid Cancer Cho Eunae Sandra 1Jung Seung Wook 2Jung Hwi-Dong 2Lee In Yong 3Yong Tai-Soon 3Jeong Su Jin 4Kim Hyun Sil 1*\n1 Department of Oral Pathology, Oral Cancer Research Institute, Yonsei University College of Dentistry, Seoul 03722, Korea\n2 Department of Oral and Maxillofacial Surgery, Yonsei University College of Dentistry, Seoul 03722, Korea\n3 Department of Environmental Medical Biology, Institute of Tropical Medicine & Arthropods of Medical Importance Bank, Yonsei University College of Medicine, Seoul 03722, Korea\n4 Department of Internal Medicine and AIDS Research Institute, Yonsei University College of Medicine, Seoul 03722, Korea* Corresponding author (khs@yuhs.ac)8 2017 31 8 2017 55 4 433 437 25 4 2017 16 6 2017 17 6 2017 Copyright © 2017 by The Korean Society for Parasitology and Tropical Medicine2017This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Pentastomiasis, a zoonotic parasite infection, is typically found in the respiratory tract and viscera of the host, including humans. Here, we report for the first time an extremely rare case of intraosseous pentastomiasis in the human maxilla suffering from medication related osteonecrosis of the jaw (MRONJ). A 55-year-old male had continuously visited the hospital for MRONJ which had primarily developed after bisphosphonate and anti-neoplastic administration for previous bone metastasis of medullary thyroid cancer. Pain, bone exposure, and pus discharge in the right mandible and left maxilla were seen. Osteolysis with maxillary cortical bone perforation at the left buccal vestibule, palate, nasal cavity, and maxillary sinus was observed by radiologic images. A biopsy was done at the left maxilla and through pathological evaluation, a parasite with features of pentastome was revealed within the necrotic bone tissue. Further history taking and laboratory evaluation was done. The parasite was suspected to be infected through maxillary open wounds caused by MRONJ. Awareness of intraosseous pentastomiasis should be emphasized not to be missed behind the MRONJ. Proper evaluation and interpretation for past medical history may lead to correct differential diagnosis and therapeutic intervention for parasite infections.\n\nPentastomidaparasiteosteonecrosisbisphosphonate-associated osteonecrosis of the jaw (BRONJ)\n==== Body\nINTRODUCTION\nPentastomiasis is a blood sucking, zoonotic parasite infection caused by pentastomes belonging to the phylum Pentastomida. Pentastomes acquired its title for 2 pairs of hooks around the mouth making 5 appendages at the head, which were formerly misunderstood all to be mouths [1]. Although reptiles are the most typical hosts, mammals, including humans, are definite and intermediate hosts in the genus Linguatula [1,2]. Human infections have been reported predominantly in the Middle East, Africa, and Southeast Asia [1–5]. Infection is caused by intake of contaminated water sources, vegetation, raw meat of infected intermediate hosts, or close contact with secretion of infected dogs or livestock [2,6,7]. Pentastomes commonly infect the respiratory system, and human soft tissue infections have been noticed at the lung [8,9], nasal cavity [10–12], eye [13–15], oropharynx [4,16], and other viscera [3,5,6,17,18]. Unlike soft tissue infection, intraosseous pentastomiasis has not been reported yet.\n\nHere, we report for the first time a case of intraosseous pentastomiasis in the human maxilla suffering from medication related osteonecrosis of the jaw (MRONJ).\n\nCASE REPORT\nA 55-year-old male had continuously visited the Department of Oral and Maxillofacial Surgery at Yonsei University College of Dentistry for MRONJ which had primarily developed after zoledronic acid and capecitabine administration for previous bone metastasis of medullary thyroid cancer. Pain, bone exposure, and pus discharge in the right mandible and left maxilla first occurred 5 years after discontinuing bisphosphonate and capecitabine administration. At that time, the patient was going through chemotherapy with another antineoplastic drug, everolimus. Clinical, radiological features of both jaws, and pathological evaluation of the mandible confirmed the diagnosis as MRONJ.\n\nSymptoms of the left maxilla started as chronic apical abscess with tooth mobility in the left premolars. Primary bone exposure with osteonecrosis at the left maxilla was observed after extraction of these teeth in a local clinic. The remaining sockets showed delayed bone healing with pus discharge and incomplete soft tissue covering.\n\nRadiologic examination by CT (Fig. 1A) revealed that there was an irregularly mixed radiolucent/radiopaque area in the left maxilla with discontinuity of the cortical barrier adjacent to the left buccal vestibule, palate, nasal cavity, and maxillary sinus. Mucosal thickening was seen in the left maxillary sinus and nasal cavity. These radiologic features persisted in the additional CT views taken 2 years later (data not shown).\n\nAfter a year of conservative treatment and another year and a half without periodic follow-up, the patient re-visited the hospital for recurrent bone exposure in the left maxilla with pus discharge. An ill-defined radiolucent/radiopaque lesion with definite alveolar bone loss was seen at the left maxilla on panoramic views (Fig. 1B). The exposed sequestra were removed and sent for pathological evaluation.\n\nOn pathological examinations, the tissue specimen revealed mostly several necrotic bone fragments with surrounding nonspecific bacterial colonies and necrotic soft tissue. The bone fragments had mature calcified matrix and irregular margins without any vital osteoblastic or osteoclastic rimming. The lacunae were empty of osteocytes, indicating bone necrosis. Pathological features were consistent with MRONJ, and there was no evidence of metastatic medullary thyroid cancer. Interestingly, between the bone fragments, there was a worm-shaped organism with several false annuli (pseudosegmentation) along the body and features of a hook or claw-like structure at the broader cephalic-end (Fig. 2). Focal areas of necrosis were noticed within the parasite. Due to these features, the organism was diagnosed as a pentastome by further evaluation at the Department of Internal Medicine and the Department of Environmental Medical Biology.\n\nBy further oral history taking, the patient disclosed that he had been occupied for about 10 years in foreign trade business since his thirties, with local food exposure in the Middle East, Southeast Asia, and Africa. Short subsequent visits every year continued in several countries. There were no specific symptoms at that time. The patient did not have any specific signs or symptoms of other visceral pentastomiasis. The patient had performed periodic whole blood laboratory tests for thyroid cancer treatment, and the results were evaluated. Right before parasite discovery at the Department of Oral and Maxillofacial Surgery, the laboratory results showed eosinophilia (eosinophil count: 507.6/μl). Laboratory antibody screening for other types of parasite infections revealed positive for toxocariasis IgG, and parasiticidal treatments for both pentastomiasis and toxocariasis (albendazole 800 mg/day ×5 days) were prescribed [3]. Since then, periodic follow-up along with supportive care for thyroid cancer is being done.\n\nDISCUSSION\nPentastomiasis is exceptional in the Republic of Korea with only 1 case of visceral infection reported [8], in which the patient had an occupational history at the Middle East and Southeast Asia. In our case, the remarkable risk factors for pentastomiasis were history of regular cosmopolitan visits to the Middle East, Africa, and Southeast Asia with local food consumption, and most importantly, MRONJ at the maxilla.\n\nThe limitations of this case were that an intact worm specimen was not found during the examination, and the parasite infection was only presented through a few sections of histopathologic images and indirect evidence of eosinophilia. Whether the sectioned parasite and lesion were an active parasitic infection or embedded traces of a previous infection could not be determined. Serologic tests and PCR techniques for pentastomiasis diagnosis is not easily available with only a few reports of PCR diagnosis in certain Armillifer species [6,17,19]. One report discussed that the presence of necrotic tissues in PCR hampers the success rate of molecular diagnosis [19]. Thus, histopathological diagnosis is yet mainly required in pentastomiasis [6]. Our case had only a few sections of available parasite tissue with partial necrosis which was not suitable for PCR and was diagnosed mainly by the histopathological evaluation. The patient did not show any specific signs or symptoms of other visceral infections, but since pentastomiasis can be silent, parasiticidal treatment with albendazole [3] was prescribed.\n\nMRONJ, formerly named as BRONJ (bisphosphonate related osteonecrosis of the jaw) [20], is a clinically obstinate osteonecrotic condition of the jaw characterized by delayed healing, spontaneous bone exposure, pain, inflammation, and/or combined infection [21,22]. It is a problematic side effect which develops in about 0.1–12% of patients with history of bisphosphonate or antiangiogenic drug administration, and yet the pathogenesis is poorly understood [22,23]. In addition to the more well-known MRONJ inducer zoledronic acid [24,25], there has been a few reports suspected of everolimus induced osteonecrosis [26–28]. Microorganism infections are frequently related with MRONJ, and the composition varies among studies [21,29]. They were mainly bacterial or fungal species of the normal oral flora that could easily be contaminated through an open wound in the oral cavity [22,30].\n\nHematogenous migration of pentastome larvae or eggs to the bone may be theoretically possible, as other intraosseous parasites are known to principally infect relatively abundant vascularized sites of the bone, for instance the spine, pelvis, long bone, and major joints [31,32]. However, with the presence of MRONJ in this case, there is a higher probability of the migrants to have directly entered the maxilla via cortical bone perforation from its original habitat, the respiratory tract, oropharyngeal, or nasal cavity.\n\nThis is the first case of intraosseous pentastomiasis, as well as the first case of parasitic infection in MRONJ to be reported. Intraosseous echinococcosis, leishmaniasis, and proliferative sparganosis have been mentioned in other sites besides the jaw with/without pathological fracture or trauma [32–35]. MRONJ, frequently noticed in the practice of dentistry, is characterized with open wounds prone to infection specifically at the jaw and might create intraosseous chambers of bone marrow infection, including parasitic infection as observed in our case. Intraosseous parasitic infection is uncommon, so routine bone examination during systemic evaluation is not necessary in hosts with known parasite infection. However, if the host has MRONJ, a more detailed examination and pathological evaluation for intraosseous parasitic spread at the jaw might be required.\n\nAlthough the maxillary defect showed fair healing after removal of the parasite, it is difficult to directly associate the clinical symptoms to intraosseous pentastomiasis with limits of a single case and short follow-up duration. Patients suffering from MRONJ may experience constant switches of osteonecrotic and healing stages [22], making it difficult to judge whether complete treatment of parasite infection was accomplished. If MRONJ is accompanied with specific infections rather than non-specific oral flora, either symptoms of MRONJ or the specific infection (in this case parasitic) may be camouflaged by the other, which may delay proper diagnosis and treatment. Therefore, in cases with prolonged symptoms of MRONJ, further investigation for additional infection sources should be considered.\n\nACKNOWLEDGMENTS\nThis work was supported by grants from the National Research Foundation of Korea (NRF-2017R1C1B1012464, NRF-2016R1E1A1A01942724) funded by the Korea government (MSIP) and a grant from the National Research Foundation of Korea (NRF-2014R1A6A3A04055110) funded by the Korea government (MOE).\n\nCONFLICT OF INTEREST\n\nWe have no conflict of interest related to this study.\n\nFig. 1 Radiography of the patient. (A) CT view after primary maxillary bone exposure: osteolytic lesion with sequestra suspected calcification in the left maxilla perforating the cortical bone of the buccal vestibule (v), palate (p), nasal cavity (n), and maxillary sinus (m). (B) Panoramic view of the recurrent maxillary bone exposure with ill-defined radiolucent lesion (arrows) and alveolar bone loss in the left maxilla.\n\nFig. 2 Pathological findings of the incisional biopsy (scale bar=60 μm). (A) Histopathological view showing the caudal end of a pentastome with several false annuli (pseudosegmentation; arrows) along the body surrounded by necrotic bone fragments (HE stain, ×400). (B) Schematic drawing of Fig. 2A. (C) Serial section of Fig. 2A revealing a hook or claw-like structure (asterisks) at the cephalic end (HE stain, ×400). (D) Schematic drawing of Fig. 2C. Inset of Fig. 2D shows a more definite image of the hook/claw-like structure of the pentastome.\n==== Refs\nREFERENCES\n1 Drabick JJ Pentastomiasis Rev Infect Dis 1987 9 1087 1094 3321358 \n2 Riley J The biology of pentastomids Adv Parasitol 1986 25 45 128 3535437 \n3 Vanhecke C Le-Gall P Le Breton M Malvy D Human pentastomiasis in Sub-Saharan Africa Med Mal Infect 2016 46 269 275 27004769 \n4 Sulyok M Rózsa L Bodó I Tappe D Hardi R Ocular pentastomiasis in the Democratic Republic of the Congo PLoS Negl Trop Dis 2014 8 e3041 25058608 \n5 Latif B Omar E Heo CC Othman N Tappe D Human pentastomiasis caused by Armillifer moniliformis in Malaysian Borneo Am J Trop Med Hyg 2011 85 878 881 22049042 \n6 Tappe D Buttner DW Diagnosis of human visceral pentastomiasis PLoS Negl Trop Dis 2009 3 e320 19238218 \n7 Neva FA Brown HW Basic Clinical Parasitology 6th ed Norwalk, Connecticut Appleton & Lange 1994 \n8 Park CS Kim MW Hong WK Lee HB Lee DW Kang DY Chai JY Lee SH Pentastomiasis which caused eosinophilic pneumonia: report of a case J Korean Med Assoc 1985 28 1141 1146 \n9 Jisieike-Onuigbo NN Odenigbo CU Kalu OA Eze KC Armillifer armillatus infection Niger J Clin Pract 2011 14 501 503 22248961 \n10 Yazdani R Sharifi I Bamorovat M Mohammadi MA Human linguatulosis caused by Linguatula serrata in the city of Kerman, South-eastern Iran-case report Iran J Parasitol 2014 9 282 285 25848397 \n11 Papadakis AM Hourmouziadis AN Human infestation with Linguatula serrata ; report of a case Trans R Soc Trop Med Hyg 1958 52 454 455 13592887 \n12 Morsy TA El-Sharkawy IM Lashin AH Human nasopharyngeal linguatuliasis (Pentasomida) caused by Linguatula serrata J Egypt Soc Parasitol 1999 29 787 790 12561918 \n13 Bhende M Biswas J Raman M Bhende PS Linguatula serrata in the anterior chamber of the eye Indian J Ophthalmol 2014 62 1159 1161 25579362 \n14 Koehsler M Walochnik J Georgopoulos M Pruente C Boeckeler W Auer H Barisani-Asenbauer T Linguatula serrata tongue worm in human eye, Austria Emerg Infect Dis 2011 17 870 872 21529398 \n15 Lazo RF Hidalgo E Lazo JE Bermeo A Llaguno M Murillo J Teixeira VP Ocular linguatuliasis in Ecuador: case report and morphometric study of the larva of Linguatula serrata Am J Trop Med Hyg 1999 60 405 409 10466969 \n16 Yilmaz H Cengiz ZT Cicek M Dulger AC A nasopharyngeal human infestation caused by Linguatula serrata nymphs in Van province: a case report Turkiye Parazitol Derg 2011 35 47 49 21618193 \n17 Tappe D Dijkmans AC Brienen EA Dijkmans BA Ruhe IM Netten MC van Lieshout L Imported Armillifer pentastomiasis: report of a symptomatic infection in The Netherlands and mini-review Travel Med Infect Dis 2014 12 129 133 24211241 \n18 Wang HY Zhu GH Luo SS Jiang KW Childhood pentastomiasis: a report of three cases with the following-up data Parasitol Int 2013 62 289 292 23474414 \n19 Tappe D Sulyok M Rozsa L Muntau B Haeupler A Bodo I Hardi R Molecular diagnosis of abdominal Armillifer grandis pentastomiasis in the Democratic Republic of Congo J Clin Microbiol 2015 53 2362 2364 25948609 \n20 Ruggiero SL Dodson TB Fantasia J Goodday R Aghaloo T Mehrotra B O’Ryan F American Association of Oral and Maxillofacial Surgeons position paper on medication-related osteonecrosis of the jaw--2014 update J Oral Maxillofac Surg 2014 72 1938 1956 25234529 \n21 Boff RC Salum FG Figueiredo MA Cherubini K Important aspects regarding the role of microorganisms in bisphosphonate-related osteonecrosis of the jaws Arch Oral Biol 2014 59 790 799 24859766 \n22 Ruggiero SL Woo SB Biophosphonate-related osteonecrosis of the jaws Dent Clin North Am 2008 52 111 128 18154867 \n23 Lombard T Neirinckx V Rogister B Gilon Y Wislet S Medication-related osteonecrosis of the jaw: new insights into molecular mechanisms and cellular therapeutic approaches Stem Cells Int 2016 2016 8768162 27721837 \n24 Bamias A Kastritis E Bamia C Moulopoulos LA Melakopoulos I Bozas G Koutsoukou V Gika D Anagnostopoulos A Papadimitriou C Terpos E Dimopoulos MA Osteonecrosis of the jaw in cancer after treatment with bisphosphonates: incidence and risk factors J Clin Oncol 2005 23 8580 8587 16314620 \n25 Cetiner S Sucak GT Kahraman SA Aki SZ Kocakahyaoglu B Gultekin SE Cetiner M Haznedar R Osteonecrosis of the jaw in patients with multiple myeloma treated with zoledronic acid J Bone Miner Metab 2009 27 435 443 19240969 \n26 Fusco V Santini D Armento G Tonini G Campisi G Osteonecrosis of jaw beyond antiresorptive (bone-targeted) agents: new horizons in oncology Expert Opin Drug Saf 2016 15 925 935 27074901 \n27 Giancola F Campisi G Lo Russo L Muzio LL Di Fede O Osteonecrosis of the jaw related to everolimus and bisphosphonate: a unique case report? Ann Stomatol (Roma) 2013 4 suppl 20 21 \n28 Kim DW Jung YS Park HS Jung HD Osteonecrosis of the jaw related to everolimus: a case report Br J Oral Maxillofac Surg 2013 51 e302 304 24094895 \n29 Wei X Pushalkar S Estilo C Wong C Farooki A Fornier M Bohle G Huryn J Li Y Doty S Saxena D Molecular profiling of oral microbiota in jawbone samples of bisphosphonate-related osteonecrosis of the jaw Oral Dis 2012 18 602 612 22443347 \n30 Sedghizadeh PP Kumar SK Gorur A Schaudinn C Shuler CF Costerton JW Microbial biofilms in osteomyelitis of the jaw and osteonecrosis of the jaw secondary to bisphosphonate therapy J Am Dent Assoc 2009 140 1259 1265 19797556 \n31 Arkun R Parasitic and fungal disease of bones and joints Semin Musculoskelet Radiol 2004 8 231 242 15478026 \n32 Abd El Bagi ME Sammak BM Al Shahed MS Yousef BA Demuren OA Al Jared M Thagafi MA Rare bone infections “excluding the spine” Eur Radiol 1999 9 1078 1087 10415238 \n33 Laovachirasuwan P Mootsikapun P Maleewong W Intapan PM Intraosseous proliferative sparganosis presenting as a pathologic fracture: A case report and review of the literature Southeast Asian J Trop Med Public Health 2015 46 558 563 26867374 \n34 Rajabi MT Akbari-Kamrani M Gharib MH Rajabi MB Amoli FA Abrishami Y Oestreicher J Intraosseous orbital hydatid cyst: report of a rare case Can J Ophthalmol 2014 49 e40 43 24767237 \n35 Arik HO Arican M Cetin NK Sarp U Primary intraosseous hydatid cyst of femur Iran Red Crescent Med J 2015 17 e21070 25838934\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "0023-4001",
"issue": "55(4)",
"journal": "The Korean journal of parasitology",
"keywords": "Pentastomida; bisphosphonate-associated osteonecrosis of the jaw (BRONJ); osteonecrosis; parasite",
"medline_ta": "Korean J Parasitol",
"mesh_terms": "D000818:Animals; D000970:Antineoplastic Agents; D059266:Bisphosphonate-Associated Osteonecrosis of the Jaw; D006801:Humans; D008297:Male; D008437:Maxilla; D008439:Maxillary Diseases; D008875:Middle Aged; D010272:Parasitic Diseases; D057078:Pentastomida; D013964:Thyroid Neoplasms",
"nlm_unique_id": "9435800",
"other_id": null,
"pages": "433-437",
"pmc": null,
"pmid": "28877577",
"pubdate": "2017-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "25579362;24211241;27004769;24353782;26867374;24767237;22248961;19240969;25948609;3321358;25058608;22443347;19238218;25234529;27074901;25838934;24094895;15478026;13592887;25848397;19797556;16314620;10466969;18154867;22049042;12561918;3535437;24859766;10415238;27721837;21529398;21618193;23474414",
"title": "A Case of Pentastomiasis at the Left Maxilla Bone in a Patient with Thyroid Cancer.",
"title_normalized": "a case of pentastomiasis at the left maxilla bone in a patient with thyroid cancer"
} | [
{
"companynumb": "KR-ROCHE-2003707",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ZOLEDRONIC ACID"
},
"drugadditional": "2",
"... |
{
"abstract": "OBJECTIVE\nTo compare 2% sub-Tenon and 1% intra-cameral lidocaine for cataract surgery in relation to the incidence and severity of IFIS. Prospective randomized clinical study.\n\n\nMETHODS\nFrom 81 eligible, we included 71 men aged from 59 to 90 years (mean 76.5 ± 6.8) undergoing routine cataract surgery and taking oral α-adrenergic antagonists, for urological reasons, for more than 1 year. Following randomization 34 men, aged from 62 to 90 years (mean 77.4 ± 8.1) received sub-Tenon injection of 2.5 ml of 2% lidocaine and the remaining 37 men aged from 59 to 89 years (mean 75.2 ± 7.2) received 1% preservative free intra-cameral lidocaine. Outcome measures were the incidence of IFIS, severity of intra-operative pupillary constriction and iris prolapse.\n\n\nRESULTS\nIntra-operative floppy iris syndrome (IFIS) was noted in 3 of 34 patients (8.8%) receiving sub-Tenon lidocaine and in 18 of 37 patients (48.6%) receiving intra-cameral lidocaine (p = 0.00). Severe IFIS was observed only in 3 of 37 patients (8.1%) receiving intra-cameral lidocaine. Pupil diameter at the end of surgery was 4.37 ± 1.07 mm in the sub-Tenon lidocaine group and 4.02 ± 1.06 mm in the intra-cameral lidocaine group (p = 0.00). Iris prolapse was noted in two cases in the sub-Tenon lidocaine group and in 10 cases in the intra-cameral lidocaine group (p = 0.00). Twenty-five patients were receiving tamsulosin. The incidence of IFIS in tamsulosin subgroup was 76.9% (10 of 13 patients) in the intra-cameral lidocaine group and 16.6% (2 of 12 patients) in the sub-Tenon lidocaine group (p = 0.00).\n\n\nCONCLUSIONS\nSub-Tenon lidocaine reduces significantly the incidence of IFIS in patients taking oral α-adrenergic inhibitors as compared with intra-cameral lidocaine.",
"affiliations": "Department of Ophthalmology, Medical University of Lodz, Lodz, PolandDepartment of Ophthalmology, Hospital of the Ministry of Internal Affairs and Administration, Lodz, Poland.",
"authors": "Klysik|Anna|A|;Korzycka|Dorota|D|",
"chemical_list": "D058668:Adrenergic alpha-1 Receptor Antagonists; D000779:Anesthetics, Local; D009184:Mydriatics; D008012:Lidocaine",
"country": "England",
"delete": false,
"doi": "10.1111/aos.12205",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1755-375X",
"issue": "92(6)",
"journal": "Acta ophthalmologica",
"keywords": "cataract surgery; intra-operative floppy iris syndrome (IFIS); iris prolapse; postoperative complications; pupillary diameter; sub-Tenon’s anaesthesia",
"medline_ta": "Acta Ophthalmol",
"mesh_terms": "D058668:Adrenergic alpha-1 Receptor Antagonists; D000368:Aged; D000369:Aged, 80 and over; D000779:Anesthetics, Local; D006801:Humans; D056965:Injections, Intraocular; D007431:Intraoperative Complications; D007499:Iris Diseases; D019654:Lens Implantation, Intraocular; D008012:Lidocaine; D008297:Male; D008875:Middle Aged; D009184:Mydriatics; D018918:Phacoemulsification; D011391:Prolapse; D011446:Prospective Studies; D011470:Prostatic Hyperplasia; D058475:Tenon Capsule",
"nlm_unique_id": "101468102",
"other_id": null,
"pages": "535-40",
"pmc": null,
"pmid": "23890368",
"pubdate": "2014-09",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Sub-Tenon injection of 2% lidocaine prevents intra-operative floppy iris syndrome (IFIS) in male patients taking oral α-adrenergic antagonists.",
"title_normalized": "sub tenon injection of 2 lidocaine prevents intra operative floppy iris syndrome ifis in male patients taking oral adrenergic antagonists"
} | [
{
"companynumb": "PL-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2014-BI-49797YA",
"fulfillexpeditecriteria": "1",
"occurcountry": "PL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TAMSULOSIN HYDROCHLORIDE"
... |
{
"abstract": "Acute purulent pericarditis is rarely caused by anaerobic bacteria and it is almost always a complication of another disease process. Esophagomediastinal fistula, odontogenic, or pleuropulmonary infections have been reported to be the primary source of purulent pericarditis. If not diagnosed and treated promptly, purulent pericarditis is usually a fatal disease. We describe a case of bronchomediastinal fistula as sequels from a necrotizing parenchymal infection, leading on to secondary mediastinitis and pleuropericardial involvement in an immunocompetent patient. <Learning objective: Eikenella corrodens is an important pathogen associated with a spectrum of intrathoracic suppurative infections. Purulent pericarditis can be fatal if not recognized early enough. Physicians should be aware of such a presentation.>.",
"affiliations": "Creighton University Medical Center, Cardiology Department, Omaha, NE, USA.;Creighton University Medical Center, Cardiology Department, Omaha, NE, USA.;Creighton University Medical Center, Cardiology Department, Omaha, NE, USA.;Creighton University Medical Center, Cardiology Department, Omaha, NE, USA.;Creighton University Medical Center, Cardiology Department, Omaha, NE, USA.;Creighton University Medical Center, Cardiology Department, Omaha, NE, USA.;Creighton University Medical Center, Cardiology Department, Omaha, NE, USA.;Creighton University Medical Center, Cardiology Department, Omaha, NE, USA.",
"authors": "Smer|Aiman|A|;Saurav|Alok|A|;Abuzaid|Ahmed|A|;Bansal|Ojas|O|;Abuhamidah|Nawras|N|;Mohamed|Ayan|A|;Patel|Natchiket|N|;Aryan|Mooss|M|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": "10.1016/j.jccase.2014.09.007",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1878-5409",
"issue": "11(1)",
"journal": "Journal of cardiology cases",
"keywords": "Anaerobic; Fistula; Immunocompetent; Pericarditis",
"medline_ta": "J Cardiol Cases",
"mesh_terms": null,
"nlm_unique_id": "101549579",
"other_id": null,
"pages": "35-37",
"pmc": null,
"pmid": "30546532",
"pubdate": "2015-01",
"publication_types": "D002363:Case Reports",
"references": "1775853;1321537;19352300;3047902;15951913;11446395",
"title": "Bronchomediastinal fistula presenting as purulent pericarditis in a healthy 32-year-old man.",
"title_normalized": "bronchomediastinal fistula presenting as purulent pericarditis in a healthy 32 year old man"
} | [
{
"companynumb": "US-JNJFOC-20150114725",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IBUPROFEN"
},
"drugadditional": null,
"... |
{
"abstract": "OBJECTIVE\nThe aim of this work was to describe the use of a combination of fidaxomicin and fecal microbiota therapy (FMT) in Clostridium difficile infection (CDI).\n\n\nMETHODS\nA 78-year-old female, who was admitted for surgery due to acute diverticulitis caused by postoperative complications and broad antibiotic therapy, developed CDI-induced colitis. Despite the introduction of metronidazole and vancomycin therapy, her clinical condition continued to deteriorate. She was transferred to the intensive care unit where FMT followed by fidaxomicin were performed because her C-reactive protein and leucocyte levels remained elevated. Further clinical improvement and the resolution of colitis was observed.\n\n\nCONCLUSIONS\nIn this case, severe CDI colitis was successfully treated with the combination of FMT and fidaxomicin.",
"affiliations": "Department of Internal Medicine, Thuringia Clinic Saalfeld, Teaching Hospital of the University of Jena, Saalfeld, Germany.",
"authors": "Konturek|Peter C|PC|;Haziri|Drilon|D|;Helfritzsch|Harry|H|;Hess|Thomas|T|;Harsch|Igor A|IA|",
"chemical_list": "D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D000077732:Fidaxomicin",
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000455126",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1011-7571",
"issue": "26(2)",
"journal": "Medical principles and practice : international journal of the Kuwait University, Health Science Centre",
"keywords": null,
"medline_ta": "Med Princ Pract",
"mesh_terms": "D000368:Aged; D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D016360:Clostridioides difficile; D003015:Clostridium Infections; D004761:Enterocolitis, Pseudomembranous; D000069467:Fecal Microbiota Transplantation; D005260:Female; D000077732:Fidaxomicin; D006801:Humans",
"nlm_unique_id": "8901334",
"other_id": null,
"pages": "182-184",
"pmc": null,
"pmid": "27978522",
"pubdate": "2017",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "27065726;26956066;25721003;23323867;25567105;26374258;22236835;26744587;27185076;23809712",
"title": "Successful Therapy of Severe Pseudomembranous Clostridium difficile Colitis Using a Combination of Fecal Microbiota Therapy and Fidaxomicin.",
"title_normalized": "successful therapy of severe pseudomembranous clostridium difficile colitis using a combination of fecal microbiota therapy and fidaxomicin"
} | [
{
"companynumb": "DE-AXELLIA-001078",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VANCOMYCIN"
},
"drugadditional": "3",
"drug... |
{
"abstract": "Anoxic brain injury can manifest with various abnormal movements. We describe acute chorea in a young patient with anoxic brain injury due to chlordiazepoxide toxicity who had delayed radiographic lesions in bilateral globus pallidus. Although brain MRI 8days after the anoxic event was unremarkable, repeat brain MRI 15days after the event showed T2 hyperintensities and enhancement within the bilateral globus pallidi. It is possible that MRI brain findings of bilateral basal ganglia lesions may appear later than onset of chorea in anoxic brain injury. However, given the normal brain MRI in between, other etiologies cannot be excluded entirely.",
"affiliations": "Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01655, USA. Electronic address: Mehdi.Ghasemi@umassmemorial.org.;Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01655, USA.;Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01655, USA.;Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01655, USA. Electronic address: Margaret.Owegi@umassmemorial.org.",
"authors": "Ghasemi|Mehdi|M|;Kaddouh|Firas|F|;Deb|Anindita|A|;Owegi|Margaret A|MA|",
"chemical_list": "D002707:Chlordiazepoxide",
"country": "United States",
"delete": false,
"doi": "10.1016/j.clinimag.2017.10.004",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0899-7071",
"issue": "48()",
"journal": "Clinical imaging",
"keywords": "Anoxic brain injury; Basal ganglia; Brain MRI; Chorea; Globus pallidus",
"medline_ta": "Clin Imaging",
"mesh_terms": "D000328:Adult; D001479:Basal Ganglia; D001921:Brain; D001930:Brain Injuries; D002707:Chlordiazepoxide; D002819:Chorea; D005917:Globus Pallidus; D006801:Humans; D000860:Hypoxia; D002534:Hypoxia, Brain; D008279:Magnetic Resonance Imaging; D008297:Male",
"nlm_unique_id": "8911831",
"other_id": null,
"pages": "22-25",
"pmc": null,
"pmid": "29028509",
"pubdate": "2018",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Delayed-onset MRI findings in acute chorea related to anoxic brain injury.",
"title_normalized": "delayed onset mri findings in acute chorea related to anoxic brain injury"
} | [
{
"companynumb": "US-TEVA-824481USA",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "QUETIAPINE"
},
"drugadditional": "1",
"drug... |
{
"abstract": "BACKGROUND\nThere is a current debate regarding the association of human herpesvirus 6 (HHV-6) infection and drug reaction with eosinophilia and systemic symptoms (DRESS).\n\n\nMETHODS\nSeven consecutive patients hospitalized with DRESS were enrolled in a prospective study to evaluate evidence of active HHV-6 infection.\n\n\nMETHODS\nThe imputable drugs were carbamazepine (5 patients), ibuprofen (1 patient), and sulfasalazine (1 patient). All patients were seropositive for anti-HHV-6 IgG antibodies. Anti-HHV-6 IgM antibodies were detected in 4 of the 7 patients with a seroconversion in 2 patients. Neither anti-cytomegalovirus nor anti-Epstein-Barr virus early antigen IgM antibody was detected. Human herpesvirus 6 genome was not detected by polymerase chain reaction in the first serum sample of all patients. It was weakly detected in skin lesions in the last patient tested by polymerase chain reaction but was not found in uninvolved skin.\n\n\nCONCLUSIONS\nThe results suggest an association between HHV-6 active infection (primo-infection or reactivation) and severe DRESS. Absence of anti-cytomegalovirus or anti-Epstein-Barr virus early antigen IgM antibodies argues against a nonspecific viral reactivation. Human herpesvirus 6 infection may play a role in the development of DRESS in susceptible patients. Some drugs with reactive metabolites could favor reactivation and propagation of HHV-6.",
"affiliations": "Dermatology Department, Hôpital Bichat-Claude Bernard, 46 rue Henri Huchard, 75018 Paris, France. vincent.descamps@bch.ap-hop-paris.fr",
"authors": "Descamps|V|V|;Valance|A|A|;Edlinger|C|C|;Fillet|A M|AM|;Grossin|M|M|;Lebrun-Vignes|B|B|;Belaich|S|S|;Crickx|B|B|",
"chemical_list": "D000914:Antibodies, Viral; D004279:DNA, Viral; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D002220:Carbamazepine; D012460:Sulfasalazine; D007052:Ibuprofen",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0003-987X",
"issue": "137(3)",
"journal": "Archives of dermatology",
"keywords": null,
"medline_ta": "Arch Dermatol",
"mesh_terms": "D000328:Adult; D000914:Antibodies, Viral; D002220:Carbamazepine; D004279:DNA, Viral; D003875:Drug Eruptions; D004802:Eosinophilia; D006566:Herpesviridae Infections; D015654:Herpesvirus 6, Human; D006801:Humans; D007052:Ibuprofen; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D011446:Prospective Studies; D012867:Skin; D012460:Sulfasalazine; D013577:Syndrome",
"nlm_unique_id": "0372433",
"other_id": null,
"pages": "301-4",
"pmc": null,
"pmid": "11255328",
"pubdate": "2001-03",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Association of human herpesvirus 6 infection with drug reaction with eosinophilia and systemic symptoms.",
"title_normalized": "association of human herpesvirus 6 infection with drug reaction with eosinophilia and systemic symptoms"
} | [
{
"companynumb": "FR-PFIZER INC-2019164931",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IBUPROFEN"
},
"drugadditional": "3",
... |
{
"abstract": "In spite of life-threatening nature of serotonin syndrome (SS), it remains an under-diagnosed condition. The availability of epidemiological data about SS, especially in the ICU setting, may help physicians make early diagnoses and interventions.\n\n\n\nThis was a 6-month prospective study in a medical ICU of a tertiary hospital to find out the prevalence of SS. All consecutive adult patients admitted to the medical ICU were evaluated to see if they fulfilled the Hunter criteria of SS. Patients who met the Hunter criteria were evaluated further for other details.\n\n\n\nOverall, 309 patients were identified of which 24 (7.8%) met the Hunter criteria. The mean age was 52.4 years, and 75% were male. Most patients received two or more serotonergic drugs. Ondansetron was the most common serotonergic drug (58%), followed by tramadol (38%), and cough syrup (dextromethorphan or chlorpheniramine, 21%). None of the patients received a diagnosis of SS by the treating physicians. Chronic obstructive pulmonary disease exacerbation with respiratory failure and metabolic encephalopathy were the two most common admission diagnoses (17% each). Twenty-two patients received cyproheptadine. There were no fatalities.\n\n\n\nSS is not uncommon in the ICU setting. There is a need to increase awareness among physicians.",
"affiliations": "Department of Neurology, Smt. B. K. Shah Medical Institute and Research Centre, Sumandeep Vidyapeeth, Piparia, Waghodia, Vadodara 391760, Gujarat, India. Electronic address: drprakashs@yahoo.co.in.;Department of Neurology, Smt. B. K. Shah Medical Institute and Research Centre, Sumandeep Vidyapeeth, Piparia, Waghodia, Vadodara 391760, Gujarat, India. Electronic address: cbrathore@rediffmail.com.;Department of Neurology, Smt. B. K. Shah Medical Institute and Research Centre, Sumandeep Vidyapeeth, Piparia, Waghodia, Vadodara 391760, Gujarat, India.",
"authors": "Prakash|Sanjay|S|;Rathore|Chaturbhuj|C|;Rana|Kaushik|K|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.jcrc.2020.12.014",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0883-9441",
"issue": "63()",
"journal": "Journal of critical care",
"keywords": "Cyproheptadine; Serotonin syndrome; Serotonin toxicity",
"medline_ta": "J Crit Care",
"mesh_terms": "D000328:Adult; D006801:Humans; D007362:Intensive Care Units; D008297:Male; D008875:Middle Aged; D015995:Prevalence; D011446:Prospective Studies; D012131:Respiratory Insufficiency; D020230:Serotonin Syndrome",
"nlm_unique_id": "8610642",
"other_id": null,
"pages": "92-97",
"pmc": null,
"pmid": "33621893",
"pubdate": "2021-06",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": null,
"title": "The prevalence of serotonin syndrome in an intensive care unit: A prospective observational study.",
"title_normalized": "the prevalence of serotonin syndrome in an intensive care unit a prospective observational study"
} | [
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"companynumb": "IN-JNJFOC-20210331630",
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"occurcountry": "IN",
"patient": {
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"activesubstancename": "RISPERIDONE"
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{
"abstract": "Various mechanisms contribute to anemia in inflammatory bowel diseases (IBD), drug-related causes being less frequent. The hematological and other adverse events of azathioprine (AZA) therapy are well documented, but drug-associated pure red cell aplasia (PRCA) is an uncommon event. We hereby describe two cases of AZA-associated PRCA in patients with Crohn's disease. The diagnosis was supported by pathological reports, and prompt hematological recovery was seen with discontinuation of the offending drug. This report highlights the need to consider this rare entity in IBD patients in appropriate settings and for adopting adequate precautionary measures.",
"affiliations": "Department of Gastroenterology and Hepatology, Kasturba Medical College, Manipal University, Manipal, Karnataka, India.;Department of Gastroenterology and Hepatology, Kasturba Medical College, Manipal University, Manipal, Karnataka, India.;Medical Student, CHRU Lille, Faculty Henri Warembourg, University of Lille2, Lille, France.",
"authors": "Kamath|Nagesh|N|;Pai|C Ganesh|CG|;Deltombe|Thylbert|T|",
"chemical_list": "D007166:Immunosuppressive Agents; D001379:Azathioprine",
"country": "India",
"delete": false,
"doi": "10.4103/0253-7613.174569",
"fulltext": "\n==== Front\nIndian J PharmacolIndian J PharmacolIJPharmIndian Journal of Pharmacology0253-76131998-3751Medknow Publications & Media Pvt Ltd India IJPharm-48-8610.4103/0253-7613.174569Drug WatchPure red cell aplasia due to azathioprine therapy for Crohn's disease Kamath Nagesh Pai C. Ganesh Deltombe Thylbert 1Department of Gastroenterology and Hepatology, Kasturba Medical College, Manipal University, Manipal, Karnataka, India1 Medical Student, CHRU Lille, Faculty Henri Warembourg, University of Lille2, Lille, FranceCorrespondence to: Dr. C. Ganesh Pai, E-mail: cgpai@yahoo.co.inJan-Feb 2016 48 1 86 87 30 4 2015 04 6 2015 04 12 2015 Copyright: © Indian Journal of Pharmacology2016This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.Various mechanisms contribute to anemia in inflammatory bowel diseases (IBD), drug-related causes being less frequent. The hematological and other adverse events of azathioprine (AZA) therapy are well documented, but drug-associated pure red cell aplasia (PRCA) is an uncommon event. We hereby describe two cases of AZA-associated PRCA in patients with Crohn's disease. The diagnosis was supported by pathological reports, and prompt hematological recovery was seen with discontinuation of the offending drug. This report highlights the need to consider this rare entity in IBD patients in appropriate settings and for adopting adequate precautionary measures.\n\nKEY WORDS\nAnemiaazathioprineCrohn's diseasepure red cell aplasia\n==== Body\nIntroduction\nAnemia, a common problem in patients with inflammatory bowel diseases (IBD), is reported in 6–74% of patients.[1] The important causes include overt blood loss by itself or by causing iron deficiency, seen more often in ulcerative colitis, and Vitamin B12 deficiency due to ileal involvement seen typically in Crohn's disease (CD). Anemia can also be secondary to the underlying chronic disease or extensive bowel resection or rarely due to aplastic anemia and myelodysplastic syndrome.[2]\n\nAzathioprine (AZA) and 6 mercaptopurine are immunosuppressant, thiopurine analogs effective in maintaining steroid-free remission in IBD. Leukopenia occurs in 5–25% of patients on the drug, of which 3% have a severe decrease in white blood cells (WBCs).[3] Pure red cell aplasia (PRCA) is a rare adverse event characterized by normocytic, normochromic anemia associated with reticulocytopenia, normal granulocyte and platelet (PLT) counts, and isolated erythroblastopenia in the bone marrow.[4] We report two cases of PRCA in patients with CD while on AZA therapy who recovered promptly on discontinuing the drug.\n\nCase Reports\n\nCase 1\nA 14-year-old girl with ileocolonic CD presented with progressive fatigue, headache, fever, sore throat, and vomiting over 3 weeks. She had been maintaining well during regular follow-up with periodic laboratory checks on AZA 75 mg/day over the previous 6 months. There was no overt bleeding from the gut or from other sites. Physical examination was remarkable only for severe pallor.\n\nThe hemoglobin (Hb) was 2.5 g/dl, hematocrit (HCT) 7.3%, WBC count 6800/μl and PLT count 243.0 × 103/μl. The serum liver, renal, and iron profile were normal. The blood smear revealed a sparse distribution of normocytic, normochromic red blood cells (RBCs) showing mild anisopoikilocytosis and polychromasia. No other abnormalities were seen in the RBCs. The WBCs were normal in number and distribution. The absolute reticulocyte count was normal 0.1087 × 106/μl (0.02–0.11), but the reticulocyte index of 0.3% indicated suppressed erythropoiesis. Bone marrow aspirate showed suppression of the erythroid series with normoblastic maturation, relatively increased leukopoiesis with normal maturation, a myeloid to the erythroid ratio of 4:1, and normal megakaryocytes. Abnormal cells were not seen, and the iron store was normal.\n\nThe patient received two units of packed RBC, and AZA was replaced with oral mesalamine 400 mg 3 times a day. Her anemia resolved over the next few weeks, and she has been symptom-free over the following 22 months.\n\nCase 2\nA 39-year-old male was diagnosed with isolated small bowel CD when he presented with a sub-acute intestinal obstruction that necessitated the resection of 100 cm of jejunum bearing 5 strictures, the histopathology revealing fissuring ulcers, transmural inflammation, and granulomas suggestive of CD. Postoperatively, he was initiated on oral AZA the dose of which was gradually stepped up to 125 mg/day. Before initiation of AZA, his Hb was 11.9 g/dl, HCT 37.2%, WBC count 12,100/μl, and PLT count 340.0 × 103/μl. Five months later, while, on regular follow-up with periodic laboratory checks, he complained of increasing fatigability over 1 week. He had no symptoms to suggest active bowel disease or intestinal blood loss.\n\nHis Hb was 6.8 g/dl, WBC count 3700/956;l and PLT count 180.0 × 103/μl. Hb was absent in urine. Serum lactate dehydrogenase, serum renal and liver profiles were normal. The blood smear revealed sparsely distributed normocytic, normochromic RBCs, showing aniso-poikilocytosis and polychromasia and the WBCs were normal in the distribution of cell types. Coomb's tests were negative. The absolute reticulocyte count was 0.0144 × 106/μl (0.02–0.11), and the reticulocyte index was 0.1% indicating suppressed erythropoiesis. Bone marrow examination was not done. AZA was discontinued, and his Hb and HCT normalized over the next few weeks in the absence of any RBC transfusions. He has been maintaining remission on parenteral and later oral methotrexate following a subsequent relapse.\n\nThe causality assessment in the two cases was found to be probable as per Naranjo probability scale (+7), and the World Health Organization Uppsala Monitoring Center causality category and the severity assessed as severe for the first case and moderate in the second case.[5]\n\nDiscussion\nThe report highlights two patients without any prior hematological abnormalities maintaining remission on AZA, rapidly developing symptoms of anemia from PRCA, which resolved on discontinuation of the drug. Myelosuppression with thiopurines frequently occurs during the first 8 weeks after drug initiation but has been reported up to 11 years, occurring either suddenly or gradually over several months. AZA-associated red cell aplasia is a rare variant of this which was first reported in two patients in 1975.[6] So far, more than 20 cases have been reported in the literature. This drug is commonly prescribed in renal transplant patients, systemic sclerosis, autoimmune hepatitis, systemic lupus erythematosus with lupus nephritis, and rheumatoid arthritis.\n\nThe mechanisms involved in the development of PRCA secondary to TP are unknown. This untoward event could develop due to the excessive inhibition of DNA synthesis or direct cellular toxicity within the erythroid precursors brought about by the drug metabolite 6 thioguanine (6TGN).[7] Higher levels of this metabolite have been associated with bone marrow aplasia, but the correlation between 6TGN levels and this latter adverse event is at best modest. There may be other as yet unknown metabolites that are responsible for PRCA. Transient aplastic crisis can be seen with parvovirus B19 infection.[8] Bone marrow aspirates in such cases show giant proerythroblasts, large eosinophilic nuclear inclusion bodies, and cytoplasmic vacuolization that were absent in our patient. Blood smear or the bone marrow aspirate did not show any malignant cells. Hence, hematologic malignancy was ruled out in our patients. Furthermore, blood counts improved after discontinuation of the drug.\n\nPRCA encompasses a variety of inherited and acquired disorders characterized by an isolated failure of red cell production with preservation of proliferation of the other lineages. The drugs associated with PRCA include phenytoin, AZA, chloramphenicol, procainamide, and isoniazid. It should be suspected in patients with normochromic normocytic anemia with reticulocytopenia in the right clinical setting, the bone marrow appearance characteristically showing a markedly raised myeloid: Erythroid ratio.\n\nTreatment of PRCA is aimed at restoring erythrocyte production by addressing the cause, if any and maintaining Hb at an adequate level with red cell transfusions and if necessary, erythropoietin.[9]\n\nConclusion\nThe above cases highlight the need to consider PRCA, a rare adverse effect of thiopurines, as a cause of anemia in patients with IBD on these drugs. Early recognition and intervention can avoid serious and possibly fatal outcome.\n\n\nFinancial Support and Sponsorship\nNil.\n\nConflicts of Interest\nThere are no conflicts of interest.\n==== Refs\n1 Kulnigg S Gasche C Systematic review: Managing anaemia in Crohn's disease Aliment Pharmacol Ther 2006 24 1507 23 17206940 \n2 Gasche C Berstad A Befrits R Beglinger C Dignass A Erichsen K Guidelines on the diagnosis and management of iron deficiency and anemia in inflammatory bowel diseases Inflamm Bowel Dis 2007 13 1545 53 17985376 \n3 Derijks LJ Gilissen LP Hooymans PM Hommes DW Review article: Thiopurines in inflammatory bowel disease Aliment Pharmacol Ther 2006 24 715 29 16918876 \n4 Dessypris EN Hoffman R Benz EJ Jr Shattil SJ Pure red cell aplasia Hematology Basic Principles and Practice 2000 3rd ed New York Churchill Livingstone 342 54 \n5 Tripati KD Adverse Drug Effects. Essentials of Medical Pharmacology 2013 7th ed New Delhi Jaypee Brothers Medical Publishers (P) Ltd 82 3 \n6 McGrath BP Ibels LS Raik E Hargrave MJ Erythroid toxicity of azathioprin. Macrocytosis and selective marrow hypoplasis Q J Med 1975 44 57 63 1098090 \n7 Connell WR Kamm MA Ritchie JK Lennard-Jones JE Bone marrow toxicity caused by azathioprine in inflammatory bowel disease: 27 years of experience Gut 1993 34 1081 5 8174958 \n8 Young NS Lichtman MA Ernest K Thomas JS Pure red cell aplasia Williams Hematology 2010 8th ed New York McGraw-Hill Health Professions Division 485 94 \n9 Dessypris EN Lipton JM Greer JP Foerster J Lukens JN Red cell aplasia Wintrobe's Clinical Hematology 2004 11th ed Philadelphia Lippincott Williams and Wilkins 1421 7\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0253-7613",
"issue": "48(1)",
"journal": "Indian journal of pharmacology",
"keywords": "Anemia; Crohn's disease; azathioprine; pure red cell aplasia",
"medline_ta": "Indian J Pharmacol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D001379:Azathioprine; D003424:Crohn Disease; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D008297:Male; D012010:Red-Cell Aplasia, Pure",
"nlm_unique_id": "7902477",
"other_id": null,
"pages": "86-7",
"pmc": null,
"pmid": "26997730",
"pubdate": "2016",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "1098090;8174958;17985376;17206940;16918876",
"title": "Pure red cell aplasia due to azathioprine therapy for Crohn's disease.",
"title_normalized": "pure red cell aplasia due to azathioprine therapy for crohn s disease"
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"companynumb": "IN-MYLANLABS-2016M1008845",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
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"activesubstancename": "AZATHIOPRINE"
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{
"abstract": "BACKGROUND\nThe parasite Entamoeba histolytica is the causal agent of amoebiasis, a worldwide emerging disease. Amebic brain abscess is a form of invasive amebiasis that is both rare and frequently lethal. This condition always begins with the infection of the colon by E. histolytica trophozoites, which subsequently travel through the bloodstream to extraintestinal tissues.\n\n\nMETHODS\nWe report a case of a 71-year-old female who reported an altered state of consciousness, disorientation, sleepiness and memory loss. She had no history of hepatic or intestinal amoebiasis. A preliminary diagnosis of colloidal vesicular phase neurocysticercosis was made based on nuclear magnetic resonance imaging (NMRI). A postsurgery immunofluorescence study was positive for the 140 kDa fibronectin receptor of E. histolytica, although a serum analysis by ELISA was negative for IgG antibodies against this parasite. A specific E. histolytica 128 bp rRNA gene was identified by PCR in biopsy tissue. The final diagnosis was cerebral amoebiasis. The patient underwent neurosurgery to eliminate amoebic abscesses and was then given a regimen of metronidazole, ceftriaxone and dexamethasone for 4 weeks after the neurosurgery. However, a rapid decline in her condition led to death.\n\n\nCONCLUSIONS\nThe present case of an individual with a rare form of cerebral amoebiasis highlights the importance of performing immunofluorescence, NMRI and PCR if a patient has brain abscess and a poorly defined diagnosis. Moreover, the administration of corticosteroids to such patients can often lead to a rapid decline in their condition.",
"affiliations": "Departamento de Anatomía Patológica, Hospital General de Zona 3 IMSS Jesús María, Prolongación General Ignacio Zaragoza 905, Jesús María, CP 20908, Aguascalientes, AGS, Mexico.;Departamento de Anestesiología, Hospital General de Zona 3 IMSS Jesús María, Prolongación General Ignacio Zaragoza 905, Jesús María, CP 20908, Aguascalientes, AGS, Mexico.;Departamento de Neurocirugía, Hospital General de Zona 3 IMSS Jesús María, Prolongación General Ignacio Zaragoza 905, Jesús María, CP 20908, Aguascalientes, AGS, Mexico.;Departamento de Morfología, Centro de Ciencias Básicas, Universidad Autónoma de Aguascalientes, Ed. 202 Av Universidad # 940, Ciudad Universitaria, CP 20131, Aguascalientes, AGS, Mexico.;Departamento de Morfología, Centro de Ciencias Básicas, Universidad Autónoma de Aguascalientes, Ed. 202 Av Universidad # 940, Ciudad Universitaria, CP 20131, Aguascalientes, AGS, Mexico.;Departamento de Química, Centro de Ciencias Básicas, Universidad Autónoma de Aguascalientes, CP 20131, Aguascalientes, AGS, Mexico.;Departamento de Morfología, Centro de Ciencias Básicas, Universidad Autónoma de Aguascalientes, Ed. 202 Av Universidad # 940, Ciudad Universitaria, CP 20131, Aguascalientes, AGS, Mexico.;Departamento de Microbiología, Centro de Ciencias Básicas, Universidad Autónoma de Aguascalientes, CP 20131, Aguascalientes, AGS, Mexico.;Departamento de Optometría, Centro de Ciencias de la Salud, Universidad Autónoma de Aguascalientes, CP 20131, Aguascalientes, AGS, Mexico.;Departamento de Morfología, Centro de Ciencias Básicas, Universidad Autónoma de Aguascalientes, Ed. 202 Av Universidad # 940, Ciudad Universitaria, CP 20131, Aguascalientes, AGS, Mexico. jventur@correo.uaa.mx.",
"authors": "Victoria-Hernández|Joaquin Alvaro|JA|;Ventura-Saucedo|Anayansi|A|;López-Morones|Aurelio|A|;Martínez-Hernández|Sandra Luz|SL|;Medina-Rosales|Marina Nayeli|MN|;Muñoz-Ortega|Martín|M|;Ávila-Blanco|Manuel Enrique|ME|;Cervantes-García|Daniel|D|;Barba-Gallardo|Luis Fernando|LF|;Ventura-Juárez|Javier|J|https://orcid.org/0000-0002-3083-0131",
"chemical_list": "D016054:DNA, Protozoan; D008795:Metronidazole; D002443:Ceftriaxone; D003907:Dexamethasone",
"country": "England",
"delete": false,
"doi": "10.1186/s12879-020-05391-y",
"fulltext": "\n==== Front\nBMC Infect Dis\nBMC Infect. Dis\nBMC Infectious Diseases\n1471-2334 BioMed Central London \n\n5391\n10.1186/s12879-020-05391-y\nCase Report\nCase report: multiple and atypical amoebic cerebral abscesses resistant to treatment\nVictoria-Hernández Joaquin Alvaro joaquina_06@yahoo.com.mx 1 Ventura-Saucedo Anayansi isna25@hotmail.com 2 López-Morones Aurelio aurelio.lomor@gmail.com 3 Martínez-Hernández Sandra Luz slmartih@correo.uaa.mx 4 Medina-Rosales Marina Nayeli marinamedina35@gmail.com 4 Muñoz-Ortega Martín martinenol@hotmail.com 5 Ávila-Blanco Manuel Enrique meab21@gmail.com 4 Cervantes-García Daniel cervantes.daniel@gmail.com 67 Barba-Gallardo Luis Fernando lfbarba@correo.uaa.mx 8 https://orcid.org/0000-0002-3083-0131Ventura-Juárez Javier jventur@correo.uaa.mx 4 1 Departamento de Anatomía Patológica, Hospital General de Zona 3 IMSS Jesús María, Prolongación General Ignacio Zaragoza 905, Jesús María, CP 20908 Aguascalientes, AGS Mexico \n2 Departamento de Anestesiología, Hospital General de Zona 3 IMSS Jesús María, Prolongación General Ignacio Zaragoza 905, Jesús María, CP 20908 Aguascalientes, AGS Mexico \n3 Departamento de Neurocirugía, Hospital General de Zona 3 IMSS Jesús María, Prolongación General Ignacio Zaragoza 905, Jesús María, CP 20908 Aguascalientes, AGS Mexico \n4 grid.412851.b0000 0001 2296 5119Departamento de Morfología, Centro de Ciencias Básicas, Universidad Autónoma de Aguascalientes, Ed. 202 Av Universidad # 940, Ciudad Universitaria, CP 20131 Aguascalientes, AGS Mexico \n5 grid.412851.b0000 0001 2296 5119Departamento de Química, Centro de Ciencias Básicas, Universidad Autónoma de Aguascalientes, CP 20131 Aguascalientes, AGS Mexico \n6 grid.412851.b0000 0001 2296 5119Departamento de Microbiología, Centro de Ciencias Básicas, Universidad Autónoma de Aguascalientes, CP 20131 Aguascalientes, AGS Mexico \n7 grid.418270.80000 0004 0428 7635Consejo Nacional de Ciencia y Tecnología, CONACYT, 03940 Ciudad de México, Mexico \n8 grid.412851.b0000 0001 2296 5119Departamento de Optometría, Centro de Ciencias de la Salud, Universidad Autónoma de Aguascalientes, CP 20131 Aguascalientes, AGS Mexico \n14 9 2020 \n14 9 2020 \n2020 \n20 6692 1 2020 2 9 2020 © The Author(s) 2020Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.Background\nThe parasite Entamoeba histolytica is the causal agent of amoebiasis, a worldwide emerging disease. Amebic brain abscess is a form of invasive amebiasis that is both rare and frequently lethal. This condition always begins with the infection of the colon by E. histolytica trophozoites, which subsequently travel through the bloodstream to extraintestinal tissues.\n\nCase presentation\nWe report a case of a 71-year-old female who reported an altered state of consciousness, disorientation, sleepiness and memory loss. She had no history of hepatic or intestinal amoebiasis. A preliminary diagnosis of colloidal vesicular phase neurocysticercosis was made based on nuclear magnetic resonance imaging (NMRI). A postsurgery immunofluorescence study was positive for the 140 kDa fibronectin receptor of E. histolytica, although a serum analysis by ELISA was negative for IgG antibodies against this parasite. A specific E. histolytica 128 bp rRNA gene was identified by PCR in biopsy tissue. The final diagnosis was cerebral amoebiasis. The patient underwent neurosurgery to eliminate amoebic abscesses and was then given a regimen of metronidazole, ceftriaxone and dexamethasone for 4 weeks after the neurosurgery. However, a rapid decline in her condition led to death.\n\nConclusions\nThe present case of an individual with a rare form of cerebral amoebiasis highlights the importance of performing immunofluorescence, NMRI and PCR if a patient has brain abscess and a poorly defined diagnosis. Moreover, the administration of corticosteroids to such patients can often lead to a rapid decline in their condition.\n\nKeywords\nCerebral amoebiasisEntamoeba histolyticaNMRIPCR140 kDa fibronectin receptorBrain abscessConsejo Nacional de Ciencia y Tecnología286184issue-copyright-statement© The Author(s) 2020\n==== Body\nBackground\nEntamoeba histolytica is the causal agent of amoebiasis, an emerging disease found worldwide [1]. This disease is prevented by improving sanitation. Although usually manifested in the human intestine [2], this agent can spread to the liver or brain and generate abscesses. Over 25 years ago, the molecular characterization of E. histolytica [3] provided an epidemiological pyramid in which 10% of the world population is infected by a noninvasive form of the parasite and 1% by an invasive form [2]. According to epidemiological evidence from PCR, amoebiasis ranks among the 20 most common causes of death in Mexico [1].\n\nCerebral amoebiasis, a very rare form of the disease, is often difficult to diagnose due to the limited availability of proper diagnostic tools. This disease has rarely been reported (see the following reviews: [4–6]), with only 133 documented cases [7–10], which chiefly occurred in young and middle-aged adults (22–65 years old) suffering from hepatic abscess or intestinal amoebiasis. The associated symptoms are headaches, altered mental status, meningeal disorders, seizure and vomiting. Of the 133 cases in the literature, 10 were given a timely diagnosis and adequate treatment (metronidazole and dehydroemetine), resulting in complete recovery [7]. In the other cases, it was not possible to make an accurate diagnosis. Consequently, proper therapy was not provided, and the patients died [10]. In Japan, a country with excellent public health measures, persons found to have cerebral amoebiasis are offered highly efficacious treatments that often lead to total recovery [7, 8]. We herein present a case report of cerebral abscesses caused by E. histolytica in a woman with no history of hepatic or intestinal amoebiasis. Her clinical condition very rapidly declined and ended in death.\n\nCase presentation\nThe 71-year-old female was a healthy housewife with no record of medical interventions. She had a family history of cerebral cancer. August 4, 2018, marked the onset of a series of symptoms, including an altered state of consciousness, disorientation and sleepiness and no presence of fever. She first consulted a doctor in private practice and was diagnosed with transient cerebral ischemia. The onset of memory loss and the persistence of the previous symptoms led the patient to seek medical attention in a public hospital where she was admitted and blood analysis was performed. The only alteration in the basic blood panel was high blood pressure, with a value of 149/100 mmHg. Pallor was observed in the skin and integuments. Neurological examination only showed cognitive impairment with bradypsychia, disorientation in time and space and difficulty in carrying out simple calculations, with no fever or meningeal signs. Nuclear magnetic resonance imaging using gadolinium contrast (NMRI) of the brain revealed multiple bilateral cystic lesions containing varying amounts of fluid (white arrows in Fig. 1Ab). The lesions were detected in several brain locations: the frontal, temporal and occipital lobes (Fig. 1Aa-d) and in the supra- and infratentorial zones (Fig. 1Ba-d). Since some of the lesions were compatible with a diagnosis of colloidal vesicular phase neurocysticercosis, because the hospital did not have a stereotaxic frame and due to the multiple locations of the abscesses, the patient was submitted to a right temporal craniotomy under general anesthesia on August 25, 2018. The layers of tissue were separated, working from the skin to the brain and through the superior temporal sulcus. A cyst (without capsule) was removed from the right temporal lobe, which had a diameter of approximately 5 mm, contents with a milky not suppurative aspect and a periphery composed of soft whitish tissue (see supplementary video). A fragment of biopsy-extracted tissue was fixed in formaldehyde at 10% to be processed for histopathological examination. The surgical lesion was closed in layers from the dura to the skin.\nFig. 1 Cranial nuclear magnetic resonance image. A. Multiple cystic lesions with ring enhancement after contrast administration, without restricted diffusion, in temporal and occipital lobes. (a) Axial T1SE, (b) Axial T2 Propeller, (c) Axial T1 SE + gadolinium, (d) Axial DWI. B. Gadolinium contrast brain NMRI showing ring-enhanced lesions with multilobar distribution. (a) and (b) Sagittal T1 SE + gadolinium, (c) coronal T1 SE + gadolinium with supra- and infratentorial lesions, (d) coronal T1 SE + gadolinium with temporal and intraventricular lesions\n\n\n\nThe patient was discharged on September 3, 2018 with a diagnosis of probable neurocysticercosis and possible hydatid cysts. The sample was not grown in bacterial culture, and the medical ethics committee decided to perform a histopathological study and ELISA to obtain a definitive diagnosis.\n\nBrain biopsy tissue showed a large necrotic area with an amoeboid structure (red arrow) on the periphery of the brain tissue abscess (Fig. 2). The presence of E. histolytica trophozoites in cerebral biopsy specimens was confirmed by immunohistochemistry using a rabbit polyclonal anti-E. histolytica antibody [11] (Fig. 3a) and mouse anti-140 kDa fibronectin (FN)-binding protein (EhFNR) [12] (Fig. 3c). Furthermore, staining with rhodamine phalloidin revealed amoebic structures rich in actin filaments that formed adhesion plaques and macropinosomes (Fig. 3b, yellow arrows). The rest of the brain tissue was positive for glial fibrillary acidic protein (GFAP) (Fig. 3d) by immunofluorescence.\nFig. 2 E. histolytica trophozoites are revealed in amoebic brain abscesses by histopathological study. A broad area of necrotic nerve tissue can be observed. Trophozoites are widely distributed in the abscess (red arrow), as illustrated by the light microscopic images (X50). An amoebic trophozoite is shown with H&E staining (box in the upper right corner, X400)\n\nFig. 3 Immunodetection of E. histolytica trophozoites in brain tissue by immunohistochemistry and immunofluorescence. Identification of the E. histolytica 140 kDa fibronectin (FN)-binding protein (EhFNR) and glial fibrillary acidic protein (GFAP) in brain tissue by immunofluorescence. a Amoebic trophozoites stained using peroxidase-labeled rabbit anti-E. histolytica polyclonal antibody (X 1000). b\nE. histolytica actin cytoskeleton dynamics and distribution in amebic brain abscesses. Actin was stained with rhodamine-phalloidin (1:40, red), forming plate adhesions, as shown by the yellow arrow (X 400). c\nE. histolytica trophozoites stained positive for EhFNR (red), GFAP (green) and nuclei (Hoechst 1:1000, blue) in amebic brain abscess tissue (X400). d GFAP-immunoreactive cells in brain sections (green) and nuclei (blue) (X400)\n\n\n\nThe presence of E. histolytica in the cerebral tissue was corroborated by PCR, and an 128 bp amplicon of the E. histolytica rRNA gene (NCBI Accession number X65163.1) was cloned from cerebral tissue with the CloneJET PCR Cloning Kit (Thermo Scientific). DNA sequencing was performed in the Unit of Molecular Biology of the Institute of Cellular Physiology (National Autonomous University of Mexico) (Fig. 4). Interestingly, the ELISA of the patient serum did not find IgG antibodies against E. histolytica or amoebic proteins. Absorbance data analysis showed a cutoff for the negative control of 186.38; the median for amoebic cerebral abscess patients was 111.5, a number below that of the negative control; however, the median for the positive control was 477.3 (Fig. 5a and b). Based on a diagnosis of amoebic brain abscess, the patient was treated with ceftriaxone (2 g IV every 12 h), metronidazole (750 mg IV every 8 h), and dexamethasone (8 mg IV every 8 h) for 4 weeks, and no antiepileptic drugs were administered. A deteriorating condition led to her readmission to the hospital on October 14, 2018, and she died four days later.\nFig. 4 PCR, cloning and sequencing. Total DNA was extracted from 100 mg paraffin-embedded cerebral tissue using the Wizard Genomic DNA purification kit (Promega, Madison, WI, USA). DNA was quantified in a NanoDrop 2000 (Thermo Scientific, Waltham, MA, USA), obtaining an E. histolytica 128 bp amplicon for the rRNA gene, which was cloned with the CloneJET PCR Cloning Kit (Thermo Scientific) using a pJET1.2/blunt cloning vector. Then, the ligation mixture was used for transformation of Escherichia coli DH5a calcium-competent cells. Plasmid DNA was extracted from heat-shocked cells with the Zyppy Plasmid Miniprep (Zymo Research, Irvine, CA, USA). Clones were analyzed by PCR to verify the insertion of the amplicon into the pJET1.2/blunt vector. The plasmid sequence shows forward and reverse primers (electropherograms) that correspond to the E. histolytica rRNA gene sequence. Hu = 120 bp amplicon for human β-actin; M = bp marker; Eh = 128 bp amplicon for the E. histolytica rRNA 18 s gene, NTC = no template control\n\nFig. 5 ELISA. a The ELISA plate displays a slight reaction to a negative control (1, 1: 5000; 2, 1: 10000). The positive reaction is evident from the application of anti-E. histolytica antibodies to the serum of an individual with amoebic liver abscess (3, 1: 5000; 4, 1: 10000). There was a negative reaction to anti-E. histolytica antibodies in the serum of the patient under study despite the presence of brain abscesses (5, 1: 5000; 6, 1: 10000). b The graph shows the significant difference between the positive control (1:5000) and the patient in the current case study (1:5000) (***) ANOVA\n\n\n\nDiscussion and conclusion\nAmoebic brain abscess is considered to occur in individuals with associated infections [13]. The current case began with signs of neurological alterations, muscle weakness, loss of memory and disorientation but without fever, diarrhea or amebic damage to the intestines or liver. Due to the absence of associated infections, this case was very different from the cases described by Orbison et al. [4] and Petri and Haque [6].\n\nThe surprising inability of the humoral immune response to detect E. histolytica prevented the organism from eliminating the trophozoites present in the brain; however, the identification of amoebic trophozoites was performed by applying a specific polyclonal monospecific 140 kDa amoebic protein antibody that acts as a fibronectin receptor [12].\n\nIn response to a diagnosis of probable neurocysticercosis and possible hydatid cysts, the patient received metronidazole and dexamethasone during the last 4 weeks of her life. The administration of metronidazole was successful in treating individuals with amoebic cerebral abscesses [7, 8, 14, 15]. However, some cases have been treated with intravenous and oral metronidazole without positive results [9] in patients where treatment is not effective, and the aggravating factor may be the poor state of health of the patient.\n\nHowever, the use of prednisolone in our patient apparently had a negative effect, consistent with a recent review by Shirley and Moonah [16]. Of 525 case reports of fulminant amoebic colitis, 24 of the subjects received corticosteroid therapy. However, 14 (58%) were incorrectly diagnosed with inflammatory colitis and underwent a very rapid progression of amoebiasis.\n\nIn our case, the patient’s clinical features were insidious, and several laboratory and cabinet studies had to be carried out to obtain a precise diagnosis of cerebral amebiasis in such a way that the intravenous metronidazole did not eliminate the parasite and the patient died. Similar cases have been reported by Akhaddar [17]. Furthermore, Bansal et al. [18] and Ehrenkaufer et al. [19] reported a partial resistance of the parasite to the treatment, and Petri and Haque [6] observed that 40–60% of the treated patients maintained the parasite in the colon lumen.\n\nOur patient did not have a history of hepatic or intestinal amoebiasis, and serum analysis was negative for IgG antibodies against E. histolytica. This result illustrates the importance of adopting a series of basic laboratory tests, including immunofluorescence, NMRI and PCR, for patients with brain abscesses. Moreover, it must be taken into account that the administration of corticosteroids to such patients has often led to a rapid decline in their condition.\n\nAbbreviations\nE. histolyticaEntamoeba histolytica\n\nELISAenzyme-linked immunosorbent assay\n\nNMRInuclear magnetic resonance imaging\n\nCD59protectin\n\nPCR polymerase chain reaction\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nWe thank Dr. Quintanar-Stephano Jose Luis of Universidad Autónoma de Aguascalientes, Mexico, for donating the GFAP antibody and Dr. Talamás-Rohana Patricia of CINVESTAV-IPN, Mexico for donating the 140 kDa antibody.\n\nAuthors’ contributions\nPatient management was carried out by LMA and the case report preparation by VHJA and VSA. Design, acquisition, analysis and interpretation of morphological and ELISA data were carried out by MRMN and ABME. DNA Extraction from cerebral tissue, integrity analysis and PCR development were done by MOMH. The literature review was conducted by VJJ and BGLF. PCR analysis for sequencing was performed by CGD, and the manuscript and references were elaborated by VJJ, finally, MHSL have drafted the work and substantively revised it. All authors have read and approved the final version of the manuscript.\n\nFunding\nThe present study was supported by the Consejo Nacional de Ciencia y Tecnología, Mexico (CONACYT, grant #286184), which is the source of federal funds for research activities in Mexico. UAA PIBB 16–2 is the registration number of the current project in the Universidad Autónoma de Aguascalientes, Mexico, an institution that also contributed financial resources for the study.\n\nAvailability of data and materials\nThe most relevant data generated or analyzed during the current study are included in this report. Additional data examined by neurosurgery to eliminate amoebic abscesses are available in the video “Cerebral amebiasis” at https://www.synapse.org/#!Synapse:syn22236751, DOI: 10.7303/syn22236751.1, 10.7303/syn22236751.1\n\nEthics approval and consent to participate\nThe treatment of the patient and permission to elaborate a case report was approved by Instituto Mexicano del Seguro Social (IMSS), Office number 1, Official Mexican Standard NOM-004-SSA3–2012.\n\nConsent for publication\nWritten informed consent was obtained from the patient’s daughter for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.\n\nCompeting interests\nThe authors declare that they have no conflicts of interest.\n==== Refs\nReferences\n1. Ximénez C Morán P Rojas L Valadez A Gómez A Reassessment of the epidemiology of amebiasis: state of the art Infect Genet Evol 2009 9 1023 1032 10.1016/j.meegid.2009.06.008 19540361 \n2. WHO. Amoebiasis. Wkly Epidemiol Rec. 1997;72:97–98.\n3. Clark CG Diamond LS Entamoeba histolytica : a method for isolate identification Exp Parasitol 1993 77 450 455 10.1006/expr.1993.1105 8253158 \n4. Orbison JA Reeves N Leedham CL Blumberg JM Amebic brain abscess; review of the literature and report of five additional cases Medicine (Baltimore) 1951 30 247 282 10.1097/00005792-195109000-00003 14881991 \n5. Lombardo L Alonso P Saenzarroyo L Brandt H Humbertomateos J Cerebral amebiasis: report of 17 cases J Neurosurg 1964 21 704 709 10.3171/jns.1964.21.8.0704 14197100 \n6. Petri WA Haque R Entamoeba histolytica brain abscess Handb Clin Neurol 2013 114 147 152 10.1016/B978-0-444-53490-3.00009-1 23829905 \n7. Ohnishi K Murata M Kojima H Takemura N Tsuchida T Tachibana H Brain abscess due to infection with Entamoeba histolytica Am J Trop Med Hyg 1994 51 180 182 10.4269/ajtmh.1994.51.180 7915500 \n8. Morishita A Yamamoto H Aihara H A case of amebic brain abscess No Shinkei Geka 2007 35 919 925 17867313 \n9. Castillo De La Cruz M José Luis GB Mendizábal Guerra R Félix I Rivas A Absceso cerebral multicéntrico causado por Entamoeba histolytica Arch Neurocienc 2004 9 59 62 \n10. Maldonado-Barrera CA Campos-Esparza Mdel R Muñoz-Fernández L Victoria-Hernández JA Campos-Rodríguez R Talamás-Rohana P Clinical case of cerebral amebiasis caused by E. histolytica Parasitol Res 2012 110 1291 1296 10.1007/s00436-011-2617-8 21870245 \n11. Ventura-Juárez J Campos-Rodríguez R Tsutsumi V Early interactions of Entamoeba histolytica trophozoites with parenchymal and inflammatory cells in the hamster liver: an immunocytochemical study Can J Microbiol 2002 48 123 131 10.1139/w01-136 11958565 \n12. Talamás-Rohana P Rosales-Encina JL Gutiérrez MC Hernández VI Identification and partial purification of an Entamoeba histolytica membrane protein that binds fibronectin Arch Med Res 1992 23 119 123 1340272 \n13. Rana TA Hameed T Rao N Cerebral amoebiasis J Pak Med Assoc 1993 43 78 80 8230659 \n14. Tamer GS Öncel S Gökbulut S Arisoy ES A rare case of multilocus brain abscess due to Entamoeba histolytica infection in a child Saudi Med J 2015 36 356 358 10.15537/smj.2015.3.10178 25737180 \n15. Chou A Austin RL Entamoeba histolytica . In: StatPearls 2020 Treasure Island, FL StatPearls Publishing \n16. Shirley DA Moonah S Fulminant amebic colitis after corticosteroid therapy: a systematic review PLoS Negl Trop Dis 2016 10 e0004879 10.1371/journal.pntd.0004879 27467600 \n17. Akhaddar A Other parasitic infections of the central nervous system Atlas of infections in neurosurgery and spinal surgery 2017 Cham Springer International Publishing 311 316 \n18. Bansal D Malla N Mahajan RC Drug resistance in amoebiasis Indian J Med Res 2006 123 115 118 16575108 \n19. Ehrenkaufer GM Suresh S Solow-Cordero D Singh U High-throughput screening of entamoeba identifies compounds which target both life cycle stages and which are effective against metronidazole resistant parasites Front Cell Infect Microbiol 2018 8 276 10.3389/fcimb.2018.00276 30175074\n\n",
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"mesh_terms": "D000368:Aged; D000818:Animals; D001922:Brain Abscess; D002443:Ceftriaxone; D020807:Central Nervous System Parasitic Infections; D003131:Combined Modality Therapy; D016054:DNA, Protozoan; D003907:Dexamethasone; D004359:Drug Therapy, Combination; D004748:Entamoeba histolytica; D004749:Entamoebiasis; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D008795:Metronidazole; D019635:Neurosurgical Procedures; D012698:Serologic Tests",
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"title": "Case report: multiple and atypical amoebic cerebral abscesses resistant to treatment.",
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"abstract": "Rocky Mountain spotted fever (RMSF) is a disease spread by an infected tick and it is lethal if patient is not treated on time. Symptom similarities with other exanthematous diseases may delay the diagnosis, which leads to its mortality.\n\n\n\nWe show the lethal case of a patient with medical record of high blood pressure and no history of travel, who lived in Sonora, Mexico. At the beginning, it was suspected that the patient had a dengue virus infection, which was confirmed positive by an ELISA test. Patient’s rapid deterioration, multi-organic failure and the characteristics of her exanthema led to the suspicion of the presence of RMSF. We started doxycycline treatment; however, patient died after seven days of evolution. It was confirmed a co-infection of Rickettssia spp. and dengue virus.\n\n\n\nIn rickettsial endemic zones, treatment with doxycycline should be employed in patients with similar symptoms, even though there is evidence of the presence of other etiologic agents.",
"affiliations": "Universidad de Sonora, Departamento de Medicina y Ciencias de la Salud. Hermosillo, Sonora, México",
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"title": "Fatal case of co-infected of rickettiosis and dengue virus in Mexico",
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"abstract": "Amiodarone, the most commonly used antiarrhythmic drug, can cause either hypothyroidism by inhibiting iodide transport into the thyroid gland or hyperthyroidism. We present a rare case of type 2 amiodarone-induced thyrotoxicosis with hypercalcemia. A 64-year-old man with systolic heart failure, hypertension, and hyperthyroidism presented with complaints of dyspnea on exertion, orthopnea, and vomiting for several days. Laboratory tests showed low thyroid stimulating hormone <0.01 mIU/L, high free triiodothyronine (FT3) of 24.8 ng/dL, free thyroxine (FT4) of >5.0 ng/dL, and hypercalcemia of 12.9 mg/dL. Hypercalcemia, a rare presentation of AIT, was treated with calcitonin and intravenous fluids. The patient was taken off methimazole and started on propylthiouracil for the persistent elevation of thyroid hormones, especially FT3, and to reduce the conversion of T4 to T3. The patient was not completely responding to treatment with propylthiouracil alone, so prednisone was added to the regimen on day 12, effectively returning the patient to the euthyroid state.",
"affiliations": "Division of Endocrinology, Diabetes and Metabolism, University of Tennessee Health Science Center, Memphis, TN, USA.;College of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee, USA.;Department of Internal Medicine, University of Tennessee Health Science Center, Memphis, Tennessee, USA.;Endocrine and Research Services of VA Medical Center, Memphis, Tennessee, USA. Electronic address: ssolomon@uthsc.edu.",
"authors": "Ganesan|Kavitha|K|;Bradley|Bobby|B|;Jones|David W|DW|;Solomon|Dr Solomon|DS|",
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"title": "A Case Report on Type 2 Amiodarone Induced Thyrotoxicosis and Hypercalcemia.",
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"abstract": "A 50-year-old man was in the emergency department treated for acute asthma with repeated doses of nebulized salbutamol according to guidelines, and as a result of this treatment he developed marked lactate acidosis. Lactate acidosis is not commonly listed as a side effect to nebulized salbutamol. House officers in the emergency department handling acute asthma should be aware of this paradox, though the condition may resolve in spite of continued treatment with salbutamol.",
"affiliations": "Kardiologisk og Endokrinologisk Afdeling, Hillerød Hospital, Dyrehavevej 29, 3400 Hillerød, Denmark. liselau@hotmail.com",
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"title": "Nebulized salbutamol as a possible cause of lactate acidosis in a patient with acute asthma.",
"title_normalized": "nebulized salbutamol as a possible cause of lactate acidosis in a patient with acute asthma"
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"abstract": "Obsessive-compulsive disorder (OCD) is one of the most difficult additional diagnoses to manage in patients with bipolar disorder (BD) since the gold standard treatment for one disease (antidepressants for OCD) can worsen the other. This case report describes the efficacy of aripiprazole augmentation as maintenance therapy in a young patient with comorbid BD-OCD. Our patient presented complete remission of affective and obsessive-compulsive symptoms with remarkable improvement in social and occupational functioning for 24 months. Adverse drug reactions were not severe enough to result in drug discontinuation. In consideration of the important nosological, clinical and therapeutic implications, future research efforts may lead to more grounded guidelines, which are greatly needed in patients with comorbid BD-OCD.",
"affiliations": "Inpatient Mental Health Service, SS. Antonio e Biagio e Cesare Arrigo Hospital, Alessandria, Italy.;School of Medicine, Vita-Salute San Raffaele University, Milan, Italy.",
"authors": "Amerio|Andrea|A|;Odone|Anna|A|",
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"fulltext": "\n==== Front\nGen PsychiatrGen PsychiatrgpsychgpsychGeneral Psychiatry2517-729XBMJ Publishing Group BMA House, Tavistock Square, London, WC1H 9JR 30582130gpsych-2018-10000710.1136/gpsych-2018-100007Case Report1506Aripiprazole augmentation in treating comorbid bipolar disorder and obsessive-compulsive disorder Amerio Andrea 12*Odone Anna 3\n1 \nInpatient Mental Health Service, SS. Antonio e Biagio e Cesare Arrigo Hospital, Alessandria, Italy\n\n2 \nMood Disorders Program, Tufts Medical Center, Boston, Massachusetts, USA\n\n3 \nSchool of Medicine, Vita-Salute San Raffaele University, Milan, Italy\nCorrespondence to Dr Andrea Amerio; andrea.amerio@ospedale.al.it2018 10 11 2018 31 3 e10000724 8 2018 16 10 2018 22 10 2018 © Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.2018This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0Obsessive-compulsive disorder (OCD) is one of the most difficult additional diagnoses to manage in patients with bipolar disorder (BD) since the gold standard treatment for one disease (antidepressants for OCD) can worsen the other. This case report describes the efficacy of aripiprazole augmentation as maintenance therapy in a young patient with comorbid BD-OCD. Our patient presented complete remission of affective and obsessive-compulsive symptoms with remarkable improvement in social and occupational functioning for 24 months. Adverse drug reactions were not severe enough to result in drug discontinuation. In consideration of the important nosological, clinical and therapeutic implications, future research efforts may lead to more grounded guidelines, which are greatly needed in patients with comorbid BD-OCD.\n\naripiprazolebipolarobsessive-compulsivecomorbidityspecial-featureunlocked\n==== Body\nIntroduction\nObsessive-compulsive disorder (OCD) is one of the most difficult additional diagnoses to manage in patients with bipolar disorder (BD), and the meaning of this comorbidity has not been clarified yet.\n\nThe results from our meta-analysis showed higher comorbidity rates in youths (24.2%, 95% CI 10.36 to 41.60, n=345, z=−9.5) compared with adults (13.56%, 95% CI 10.4 to 16.25, n=4539),1 with the majority of patients who experienced the onset of OCD prior to the onset of BD.2 Patients with BD-OCD presented higher prevalence of family history for mood disorders and lower prevalence of family history for OCD than patients without BD-OCD.3 Moreover, compared with non-comorbid subjects, patients with BD-OCD have a more episodic course of obsessive-compulsive symptoms, typically with worsening during depression and improvement during mania/hypomania.4\n\n\nBD-OCD comorbidity has important clinical implications: how to treat the comorbidity since the main treatment (serotonin reuptake inhibitors, SRIs) for OCD can worsen BD?5\n\n\nWe present the case of a patient with severe BD who developed obsessive-compulsive symptoms during treatment with clozapine.\n\nCase history\nThe patient is a 25-year-old Caucasian unmarried man with a positive family history of recurrent depression.\n\nWhen he was 20, he experienced a manic episode with mood-incongruent psychotic features (Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria) and he was treated with lithium carbonate 900 mg/day and olanzapine 25 mg/day. Olanzapine was gradually decreased and lithium was continued with mood stabilisation and remission of affective symptoms.\n\nOne year later, he developed a severe mixed episode with similar paranoid delusions. His therapy was modified to lithium carbonate 900 mg/day and risperidone 4 mg/day; however, paranoid and affective symptoms were only partially controlled.\n\nAlmost 1 year later, manic symptoms and paranoid delusions increased prominently. Risperidone 37.5 mg intramuscular every 2 weeks was added to lithium carbonate 900 mg/day. Risperidone was stopped because of adverse drug reactions (hyperprolactinemia and weight gain), and his therapy was modified to clozapine 300 mg/day and lithium carbonate 900 mg/day.\n\nHowever, as clozapine was gradually increased to 450 mg/day, the patient started presenting sexual obsessions with intrusive thoughts that met DSM-5 criteria for OCD. He was treated with paroxetine 30 mg/day without satisfactory control of obsessive-compulsive symptoms.\n\nAfter 8 weeks, he developed a new manic episode. Paroxetine and clozapine were stopped and the addition of aripiprazole 30 mg/day to lithium carbonate, gradually decreased to 15 mg/day, helped to achieve mood stabilisation and remission of obsessive-compulsive symptoms for the following 24 months.\n\nNo further hospitalisation was needed and the patient presented a remarkable improvement in social and occupational functioning.\n\nDiscussion\nThis case report describes the efficacy of aripiprazole augmentation in BD-OCD maintenance therapy. Our patient presented complete remission of obsessive-compulsive symptoms and mood stabilisation without further hospitalisations.\n\nAripiprazole is an atypical antipsychotic that acts as a partial agonist at the D2 and 5-HT1A receptors, as well as an antagonist at 5-HT2A receptor. Recent studies showed the efficacy of aripiprazole monotherapy or in addition to mood stabilisers in managing acute mania and stabilisation phases in BD, and in addition to SRIs in refractory OCD. Futhermore, there is evidence that aripiprazole augmentation to mood stabilisers, even at low doses, is also effective in patients with BD-OCD comorbidity.6\n\n\nIn our case, positive family history for affective disorders, improvement of affective and obsessive-compulsive symptoms with mood stabilisers and atypical antipsychotics, and manic switch induced by antidepressant, support the hypothesis of an underlying OCD comorbidity unmasked by the use of clozapine to manage treatment-resistant BD.\n\nThe results from a recent systematic review showed that mood stabilisation should be the first objective in patients with apparent BD-OCD, as opposed to immediate treatment with SRIs. Addition of SRI agents seems unnecessary in most cases, although it may be needed in refractory OCD.7\n\n\nProgress in this area would serve to shed light on the best clinical management of BD-OCD comorbidity. In consideration of the important nosological, clinical and therapeutic implications, future research efforts may lead to more grounded guidelines, which are greatly needed in patients with comorbid BD-OCD.\n\nContributors: AA has contributed to data acquisition. AA and AO have been involved in data interpretation and drafting the manuscript. Our manuscript has been approved by all authors.\n\nFunding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.\n\nCompeting interests: None declared.\n\nPatient consent: Obtained.\n\nEthics approval: Comitato Etico Azienda USL di Parma.\n\nProvenance and peer review: Not commissioned; externally peer reviewed.\n\n Andrea Amerio, MD, PhD, is a psychiatrist at the Department of Mental Health of Alessandria (Italy). Since January 2013 he has been a research fellow at the Mood Disorders Program, Tufts University – Boston, MA (USA). Supervised by Professor Ghaemi SN his research focuses on psychiatric comorbidities in bipolar disorders.\n==== Refs\nReferences\n1. \nAmerio A , Stubbs B , Odone A , et al \nThe prevalence and predictors of comorbid bipolar disorder and obsessive-compulsive disorder: a systematic review and meta-analysis . J Affect Disord \n2015 ;186 :99 –109 . 10.1016/j.jad.2015.06.005 \n26233320 \n2. \nTonna M , Amerio A , Odone A , et al \nComorbid bipolar disorder and obsessive-compulsive disorder: which came first? \nAust N Z J Psychiatry \n2016 ;50 :695 –8 . 10.1177/0004867415621395 \n\n3. \nAmerio A , Tonna M , Odone A , et al \nHeredity in comorbid bipolar disorder and obsessive-compulsive disorder patients . Shanghai Arch Psychiatry \n2015 ;27 :307 –10 . 10.11919/j.issn.1002-0829.215123 \n26977128 \n4. \nAmerio A , Tonna M , Odone A , et al \nCourse of illness in comorbid bipolar disorder and obsessive-compulsive disorder patients . Asian J Psychiatr \n2016 ;20 :12 –14 . 10.1016/j.ajp.2016.01.009 \n27025465 \n5. \nPacchiarotti I , Bond DJ , Baldessarini RJ , et al \nThe International Society for Bipolar Disorders (ISBD) task force report on antidepressant use in bipolar disorders . Am J Psychiatry \n2013 ;170 :1249 –62 . 10.1176/appi.ajp.2013.13020185 \n24030475 \n6. \nLai J , Lu Q , Zhang P , et al \nAripiprazole augmentation in managing comorbid obsessive-compulsive disorder and bipolar disorder: a case with suicidal attempts . Neuropsychiatr Dis Treat \n2017 ;13 :87 –90 . 10.2147/NDT.S122316 \n28096676 \n7. \nAmerio A , Odone A , Marchesi C , et al \nTreatment of comorbid bipolar disorder and obsessive-compulsive disorder: a systematic review . J Affect Disord \n2014 ;166 :258 –63 . 10.1016/j.jad.2014.05.026 \n25012439\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2517-729X",
"issue": "31(3)",
"journal": "General psychiatry",
"keywords": "aripiprazole; bipolar; comorbidity; obsessive-compulsive",
"medline_ta": "Gen Psychiatr",
"mesh_terms": null,
"nlm_unique_id": "101735271",
"other_id": null,
"pages": "e100007",
"pmc": null,
"pmid": "30582130",
"pubdate": "2018",
"publication_types": "D002363:Case Reports",
"references": "26233320;25012439;26685183;24030475;28096676;26977128;27025465",
"title": "Aripiprazole augmentation in treating comorbid bipolar disorder and obsessive-compulsive disorder.",
"title_normalized": "aripiprazole augmentation in treating comorbid bipolar disorder and obsessive compulsive disorder"
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"activesubstancename": "RISPERIDONE"
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"abstract": "Drug-induced injury to the liver can mimic any form of acute or chronic liver disease. Acute injury to the liver frequently is due to the action of cytochrome P450, which breaks down drugs into electrophiles or free radicals; these reactive metabolites can covalently bind to protein and unsaturated fatty acids or induce lipid peroxidation, respectively. These events may impair vital functions of the cell, such as maintenance of calcium homeostasis, leading to death; or hypothetically they may elicit a hypersensitivity reaction directed mainly at the liver. Glutathione and tocopherol play critical roles in cellular defense. Cholestatic disease caused by drugs results from a selective disturbance in bile secretion. Agents such as estrogens, chlorpromazine, and monohydroxy bile acids alter the chemical and physical properties of membranes, leading to impaired activity of carriers and pumps for bile acids and electrolytes. Certain drugs produce chronic liver disease that is pathologically identical to chronic active hepatitis, biliary cirrhosis, or alcoholic liver disease.",
"affiliations": null,
"authors": "Kaplowitz|N|N|;Aw|T Y|TY|;Simon|F R|FR|;Stolz|A|A|",
"chemical_list": "D001647:Bile Acids and Salts; D003278:Contraceptives, Oral, Hormonal; D005609:Free Radicals; D008054:Lipid Peroxides; D000082:Acetaminophen; D003577:Cytochrome P-450 Enzyme System; D005978:Glutathione; D010100:Oxygen; D002746:Chlorpromazine",
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"issue": "104(6)",
"journal": "Annals of internal medicine",
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"medline_ta": "Ann Intern Med",
"mesh_terms": "D000082:Acetaminophen; D001646:Bile; D001647:Bile Acids and Salts; D001711:Biotransformation; D002470:Cell Survival; D056486:Chemical and Drug Induced Liver Injury; D056487:Chemical and Drug Induced Liver Injury, Chronic; D002746:Chlorpromazine; D002779:Cholestasis; D002908:Chronic Disease; D003278:Contraceptives, Oral, Hormonal; D003577:Cytochrome P-450 Enzyme System; D004734:Energy Metabolism; D005609:Free Radicals; D005978:Glutathione; D006801:Humans; D008658:Inactivation, Metabolic; D008054:Lipid Peroxides; D008099:Liver; D008103:Liver Cirrhosis; D008105:Liver Cirrhosis, Biliary; D008107:Liver Diseases; D009336:Necrosis; D010084:Oxidation-Reduction; D010100:Oxygen",
"nlm_unique_id": "0372351",
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"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't; D013486:Research Support, U.S. Gov't, Non-P.H.S.; D013487:Research Support, U.S. Gov't, P.H.S.; D016454:Review",
"references": null,
"title": "Drug-induced hepatotoxicity.",
"title_normalized": "drug induced hepatotoxicity"
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"abstract": "Christianson syndrome (CS) is a X-linked neurodevelopmental disorder, including severe intellectual disability (ID), progressive microcephaly, ataxia, autistic behaviour (ASD), near absent speech, and epilepsy. Electrical status epilepticus in sleep (ESES) has been reported in two patients. We describe five male patients from three unrelated families with Christianson syndrome caused by a pathogenic nucleotide variation or a copy-number variation involving SLC9A6. ESES was present in three out of the five patients in the critical age window between 4 and 8 years. All patients presented with severe intellectual disability, autistic features, and hyperactivity. Epilepsy onset occurred within the first two years of life. Seizures were of various types. In the two boys with a 20-years follow-up, epilepsy was drug-resistant during childhood, and became less active in early adolescence. Psychomotor regression was noted in two patients presenting with ESES. It was difficult to assess to what extent ESES could have contributed to the pathophysiological process, leading to regression of the already very limited communication skills. The two published case reports and our observation suggests that ESES could be a constitutive feature of Christianson syndrome, as it has already been shown for other Mendelian epileptic disorders, such as GRIN2A and CNKSR2-related developmental epileptic encephalopathies. Sleep EEG should be performed in patients with Christianson syndrome between 4 and 8 years of age. ESES occurring in the context of ID, ASD and severe speech delay, could be helpful to make a diagnosis of CS.",
"affiliations": "Neuropaediatrics Department, Femme Mère Enfant Hospital, Lyon, France; Claude Bernard Lyon 1 University, Lyon, France.;Department of Paediatric Clinical Epileptology, Sleep Disorders and Functional Neurology, Member of the European Reference Network EpiCARE, Hospices Civils de Lyon, Lyon, France.;Department of Medical Genetics, Lyon University Hospital, Lyon, France.;Department of Paediatric Intensive Care, Le Mans Hospital, Le Mans, France.;Department of Medical Genetics, Lyon University Hospital, Lyon, France.;Department of Medical Genetics, Lyon University Hospital, Lyon, France; Claude Bernard Lyon 1 University, Lyon, France; INSERM U1028, CNRS UMR5292, Lyon Neuroscience Research Centre (CRNL), Lyon, France.;Department of Medical Genetics, Lyon University Hospital, Lyon, France; Claude Bernard Lyon 1 University, Lyon, France; INSERM U1028, CNRS UMR5292, Lyon Neuroscience Research Centre (CRNL), Lyon, France.;Reference Centre for Rare Epilepsies, APHP, Necker-Enfants Malades Hospital, Imagine Institute, Paris, France; INSERM U1129, Paris, France; Paris Descartes University, CEA, Gif sur Yvette, France.;Neuropaediatrics Department, Femme Mère Enfant Hospital, Lyon, France; Claude Bernard Lyon 1 University, Lyon, France.;Department of Paediatric Clinical Epileptology, Sleep Disorders and Functional Neurology, Member of the European Reference Network EpiCARE, Hospices Civils de Lyon, Lyon, France.;Department of Paediatric Clinical Epileptology, Sleep Disorders and Functional Neurology, Member of the European Reference Network EpiCARE, Hospices Civils de Lyon, Lyon, France; DYCOG Team, Lyon Neuroscience Research Centre (CRNL), INSERM U1028, CNRS UMR 5292, Lyon, France.;Department of Medical Genetics, Lyon University Hospital, Lyon, France; Claude Bernard Lyon 1 University, Lyon, France; INSERM U1028, CNRS UMR5292, Lyon Neuroscience Research Centre (CRNL), Lyon, France. Electronic address: gaetan.lesca@chu-lyon.fr.",
"authors": "Mathieu|Marie-Laure|ML|;de Bellescize|Julitta|J|;Till|Marianne|M|;Flurin|Vincent|V|;Labalme|Audrey|A|;Chatron|Nicolas|N|;Sanlaville|Damien|D|;Chemaly|Nicole|N|;des Portes|Vincent|V|;Ostrowsky|Karine|K|;Arzimanoglou|Alexis|A|;Lesca|Gaëtan|G|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1016/j.ejpn.2018.07.004",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1090-3798",
"issue": "22(6)",
"journal": "European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society",
"keywords": "Christianson syndrome; Copy-number variation; Electrical status epilepticus during slow-wave sleep; Epilepsy; Mutation; SCL6A9",
"medline_ta": "Eur J Paediatr Neurol",
"mesh_terms": "D000293:Adolescent; D001259:Ataxia; D001321:Autistic Disorder; D002648:Child; D002675:Child, Preschool; D004569:Electroencephalography; D004827:Epilepsy; D040181:Genetic Diseases, X-Linked; D006801:Humans; D008607:Intellectual Disability; D007805:Language Development Disorders; D008297:Male; D008831:Microcephaly; D015835:Ocular Motility Disorders; D010375:Pedigree; D012890:Sleep; D013226:Status Epilepticus",
"nlm_unique_id": "9715169",
"other_id": null,
"pages": "1124-1132",
"pmc": null,
"pmid": "30126759",
"pubdate": "2018-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Electrical status epilepticus in sleep, a constitutive feature of Christianson syndrome?",
"title_normalized": "electrical status epilepticus in sleep a constitutive feature of christianson syndrome"
} | [
{
"companynumb": "FR-MYLANLABS-2019M1003710",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CLOBAZAM"
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"drugadditional": "3",
... |
{
"abstract": "Urinary retention is a well-documented adverse effect of antipsychotic medications and is thought to be mediated by anticholinergic, adrenergic, and other neurotransmitter effects. Whereas urinary retention has been reported with typical and some atypical antipsychotics, there have been no reports of urinary retention with the novel antipsychotic cariprazine. We report on a case of urinary retention associated with cariprazine. Possible mechanisms for this adverse effect are discussed.",
"affiliations": "New York-Presbyterian Hospital, Weill Cornell Medical Center, New York, NY.",
"authors": "Kapulsky|Leonid|L|;Brody|Benjamin D|BD|",
"chemical_list": "D014150:Antipsychotic Agents; D010879:Piperazines; C533287:cariprazine",
"country": "United States",
"delete": false,
"doi": "10.1097/WNF.0000000000000301",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0362-5664",
"issue": "41(6)",
"journal": "Clinical neuropharmacology",
"keywords": null,
"medline_ta": "Clin Neuropharmacol",
"mesh_terms": "D000328:Adult; D014150:Antipsychotic Agents; D006801:Humans; D008297:Male; D010879:Piperazines; D012559:Schizophrenia; D016055:Urinary Retention",
"nlm_unique_id": "7607910",
"other_id": null,
"pages": "230-231",
"pmc": null,
"pmid": "30273189",
"pubdate": "2018",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Urinary Retention Associated With Cariprazine: A Case Report.",
"title_normalized": "urinary retention associated with cariprazine a case report"
} | [
{
"companynumb": "US-ALLERGAN-1902102US",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CARIPRAZINE HYDROCHLORIDE"
},
"drugadditional": "... |
{
"abstract": "We treated a 51-year-old Japanese man with chronic hepatitis B (viral load 7.6 LC/mL, genotype C). Hepatitis B virus DNA and HBe antigen were undetectable during the administration of the nucleic acid analogs (NUCs) lamivudine and adefovir, although the concentration of HBs antigen (HBsAg) was 851.2 IU/mL. The HBsAg levels were reduced 150-fold when pegylated-interferon (Peg-IFN) α-2a was administered weekly for 48 weeks and did not increase during the rest period. Therefore, Peg-IFNα-2a was administered twice each week. During this time, HBsAg reached undetectable concentrations, and HBs antibody was detected and continued to be detectable during the three-year follow-up. These unprecedented findings suggest that IFN may contribute to the seroclearance of HBsAg in patients treated with NUCs.",
"affiliations": "Department of Gastroenterology and Neurology, Kagawa University School of Medicine/Graduate School of Medicine, Japan.;Department of Gastroenterology and Neurology, Kagawa University School of Medicine/Graduate School of Medicine, Japan.;Department of Gastroenterology and Neurology, Kagawa University School of Medicine/Graduate School of Medicine, Japan.;Department of Gastroenterology and Neurology, Kagawa University School of Medicine/Graduate School of Medicine, Japan.;Department of Gastroenterology and Neurology, Kagawa University School of Medicine/Graduate School of Medicine, Japan.;Department of Gastroenterology and Neurology, Kagawa University School of Medicine/Graduate School of Medicine, Japan.;Department of Gastroenterology and Neurology, Kagawa University School of Medicine/Graduate School of Medicine, Japan.;Department of Gastroenterology and Neurology, Kagawa University School of Medicine/Graduate School of Medicine, Japan.;Department of Gastroenterology and Neurology, Kagawa University School of Medicine/Graduate School of Medicine, Japan.;Department of Gastroenterology and Neurology, Kagawa University School of Medicine/Graduate School of Medicine, Japan.;Department of Gastroenterology and Neurology, Kagawa University School of Medicine/Graduate School of Medicine, Japan.;Department of Gastroenterology and Neurology, Kagawa University School of Medicine/Graduate School of Medicine, Japan.;Department of Gastroenterology and Neurology, Kagawa University School of Medicine/Graduate School of Medicine, Japan.;Department of Gastroenterology and Neurology, Kagawa University School of Medicine/Graduate School of Medicine, Japan.",
"authors": "Tadokoro|Tomoko|T|;Fujita|Koji|K|;Takuma|Kei|K|;Nakahara|Mai|M|;Oura|Kyoko|K|;Mimura|Shima|S|;Sakamoto|Teppei|T|;Nomura|Takako|T|;Tani|Joji|J|;Morishita|Asahiro|A|;Yoneyama|Hirohito|H|;Kobara|Hideki|H|;Himoto|Takashi|T|;Masaki|Tsutomu|T|",
"chemical_list": "D000998:Antiviral Agents; D004279:DNA, Viral; D006514:Hepatitis B Surface Antigens; D006513:Hepatitis B e Antigens; D009696:Nucleic Acids; D011994:Recombinant Proteins; D011092:Polyethylene Glycols",
"country": "Japan",
"delete": false,
"doi": "10.2169/internalmedicine.5783-20",
"fulltext": "\n==== Front\nIntern Med\nIntern Med\nInternal Medicine\n0918-2918\n1349-7235\nThe Japanese Society of Internal Medicine\n\n33456036\n10.2169/internalmedicine.5783-20\nCase Report\nPeg-IFNα-2a Contributed to HBs Antigen Seroclearance in a Patient with Chronic Hepatitis B Administered Nucleic Acid Analogs: A Three-year Follow-up\nTadokoro Tomoko 1\nFujita Koji 1\nTakuma Kei 1\nNakahara Mai 1\nOura Kyoko 1\nMimura Shima 1\nSakamoto Teppei 1\nNomura Takako 1\nTani Joji 1\nMorishita Asahiro 1\nYoneyama Hirohito 1\nKobara Hideki 1\nHimoto Takashi 1\nMasaki Tsutomu 1\n1 Department of Gastroenterology and Neurology, Kagawa University School of Medicine/Graduate School of Medicine, Japan\nCorrespondence to Dr. Tsutomu Masaki, tmasaki@med.kagawa-u.ac.jp\n\n15 1 2021\n15 6 2021\n60 12 18351838\n4 7 2020\n25 10 2020\nCopyright © 2021 by The Japanese Society of Internal Medicine\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ The Internal Medicine is an Open Access journal distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (https://creativecommons.org/licenses/by-nc-nd/4.0/).\nWe treated a 51-year-old Japanese man with chronic hepatitis B (viral load 7.6 LC/mL, genotype C). Hepatitis B virus DNA and HBe antigen were undetectable during the administration of the nucleic acid analogs (NUCs) lamivudine and adefovir, although the concentration of HBs antigen (HBsAg) was 851.2 IU/mL. The HBsAg levels were reduced 150-fold when pegylated-interferon (Peg-IFN) α-2a was administered weekly for 48 weeks and did not increase during the rest period. Therefore, Peg-IFNα-2a was administered twice each week. During this time, HBsAg reached undetectable concentrations, and HBs antibody was detected and continued to be detectable during the three-year follow-up. These unprecedented findings suggest that IFN may contribute to the seroclearance of HBsAg in patients treated with NUCs.\n\ncase reports\nchronic hepatitis B\ninterferon\nHBs antigen\nHBs antibody\n==== Body\nIntroduction\n\nIn chronic hepatitis B, the levels of hepatitis B virus (HBV) DNA and the viral HBs antigen (HBsAg) serve as risk factors for liver carcinogenesis, and increases in their levels are significantly associated with a higher incidence of hepatocellular carcinoma (HCC) (1,2). Reductions in the levels of HBV DNA are readily achieved when patients are treated with nucleic acid analogs (NUCs). Furthermore, the inhibition of the production of HBV-DNA by NUCs significantly reduces the frequency of HCC (3-6). However, when levels of HBV-DNA are low, the residual levels of HBsAg are significantly associated with the occurrence of HCC (7). As such, the continued detection of HBsAg may be significantly associated with hepatocarcinogenesis. The goal of treating HBV hepatitis is thus the seroclearance of HBsAg (8).\n\nClearance of HBsAg significantly decreases the risk of HCC for patients with chronic hepatitis (other than those with liver cirrhosis) or patients ＜50 years old (9). However, specific treatment guidelines for reducing the serum levels of HBsAg are unavailable, and our understanding of the patient characteristics associated with beneficial responses to therapy is insufficient.\n\nShort-term treatment with pegylated-interferon (Peg-IFN) aims to achieve a sustained effect (10). Unlike NUCs, IFN acts by binding to type I IFN receptors on target cell membranes but does not directly inhibit the HBV life cycle (10). IFNα-induced activation of the Janus kinase (JAK)/Signal Transducers and Activator of transcription (STAT) signal transduction pathway leads to increased expression of IFN-stimulated genes, which is required for antiviral activity and closely associated with the efficacy of IFN treatment (11). As described above, the activation of innate or adaptive immunity, or both, of the host may be achieved using IFN but not NUCs.\n\nIFN has been used to treat virus infections in Japan since 1987, and Peg-IFNα-2a has been available since 2011 (8). However, only Peg-IFNα-2a is used to treat hepatitis B in Japan (8).\n\nWe herein report a case of HBsAg seroclearance induced by supplemental Peg-IFNα-2a treatment of a patient with chronic hepatitis B who was being concurrently administered NUCs.\n\nCase Report\n\nA 51-year-old Japanese man with a history of chronic hepatitis B had an HBV (genotype C) load of 7.6 log copies (LC)/mL. There was no special mention of this in the patient's or family's medical history. He had been our patient since being admitted to our hospital with chronic hepatitis B in 2001. Lamivudine administration began in October 2001, and resistance was detected in April 2005, at which time combination therapy with adefovir was started. HBV-DNA subsequently reached undetectable levels, although HBsAg tests were positive. Therefore, we started by adding Peg-IFNα-2a to the NUCs (lamivudine and adefovir).\n\nTable 1 shows the laboratory data before Peg-IFNα-2a was administered. The AST and ALT levels were within the normal range, HBV DNA was undetectable, and the HBsAg concentration was 851.2 UI/mL. A liver biopsy was performed before the first Peg-IFNα-2a treatment. The histopathological findings of liver tissue were equivalent to A1F1, according to the New Inuyama classification (12) (Fig. 1). HBV-DNA remained undetectable while NUCs were administered, but seroclearance of HBsAg was not achieved. We informed the patient of the effectiveness of Peg-IFN therapy for seroclearance of HBsAg to reduce the chance of carcinogenesis and explained the potential adverse effects of treatment. The patient then granted his consent for further treatment.\n\nTable 1. Laboratory Data before Administering Peg-IFNα-2a Together with NUCs.\n\nMetric\tValue\tUnit\tReference\t\nTP\t7.0\tg/dL\t6.5-8.2\t\nAlb\t4.8\tg/dL\t3.5-5.5\t\nBUN\t11.6\tmg/dL\t7-20\t\nCr\t0.7\tmg/dL\t0.5-1\t\nT-bil\t1.3\tmg/dL\t0.1-1.2\t\nD-bil\t0.4\tmg/dL\t0.1-0.6\t\nAST\t25\tU/L\t10-35\t\nALT\t27\tU/L\t5-40\t\nALP\t196\tU/L\t100-340\t\nLDH\t204\tU/L\t110-220\t\nγ-GTP\t19\tU/L\t0-30\t\nNa\t142\tmmol/L\t135-146\t\nK\t4\tmmol/L\t3.5-4.6\t\nCl\t106\tmmol/L\t96-110\t\nWBC\t3,530\t/µL\t4,700-8,700\t\nRBC\t494×104\t/µL\t370-490\t\nHb\t15.9\tg/dL\t11-15\t\nHt\t45.5\t%\t35-45\t\nPlt\t12.9×104\t/µL\t15-35\t\nNeut\t42\t%\t38-71.9\t\nEos\t1.7\t%\t0.2-6.8\t\nBaso\t0.3\t%\t0-1\t\nLym\t51.8\t%\t26-46.6\t\nMono\t4.2\t%\t2.3-7.7\t\nPT\t100\t%\t80-100\t\nHBV-DNA\t-\tLIU/mL\t-\t\nHBs Antigen\t851.2\tIU/mL\t0-0.05\t\nHBs Antibody\t-\tmIU/mL\t0-10\t\nHBe Antigen\t-\tng/mL\t-\t\nHBe Antibody\t-\t\t-\t\nHBcr Antigen\t4.2\tLog U/mL\t0-3\t\nAFP\t5\tng/mL\t\t\nDCP\t17\tmAU/mL\t\t\nHyaluronic acid\t87.8\tng/mL\t0-50\t\n\nFigure 1. Liver tissue before Peg-IFN treatment. Hematoxylin and Eosin staining, ×20 magnification. In the portal area, there was slight infiltration of inflammatory lymphocytes, piecemeal necrosis was present around the portal area, and fibrosis was present around Gleason’s sheath and the central vein (confirmed using azan stain). The histopathological grade of liver tissue was equivalent to A1F1, according to the New Inuyama classification. Peg-IFN: pegylated-interferon\n\nFrom the start of this modified treatment (Peg-IFNα-2a once weekly for 48 weeks), the HBsAg concentration was markedly reduced from 851.2 IU/mL to 5.64 IU/mL. The ALT levels, which had been mildly elevated during IFN administration, returned to normal upon completion of Peg-IFNα-2a treatment. No serious side effects were observed during treatment.\n\nThe HBsAg levels were not elevated during the resting period (Fig. 2). When HBV-DNA or HBsAg is low, HBsAg clearance by IFN can be expected (13). We therefore administered Peg-IFNα-2a biweekly for 24 weeks. HBsAg was subsequently undetectable, and interestingly, anti-HBs antibodies (HBsAbs) were detected 28 months after the start of treatment. When we simultaneously discontinued the administration of NUCs and Peg-IFNα-2a, HBsAg and HBV-DNA were undetectable, and anti-HBsAb was still positive (Fig. 2). Hyaluronic acid levels decreased after treatment, and other fibrotic markers were undetectable at the end of treatment. HBe antigen and antibody were unexpectedly undetectable before and after treatment (Table 2).\n\nFigure 2. The patient with chronic hepatitis B infection has been treated with the nucleic acid analogs (NUCs) lamivudine and adefovir since 2000. Although the HBV-DNA levels were undetectable, the test for HBs antigen (HBsAg) was positive. Peg-interferon (IFN) administered once weekly for 48 weeks together with the NUCs reduced the levels of HBsAg from 851.2 to 5.64 IU/mL. Although the HBsAg levels were not reduced during the resting period, resuming biweekly treatment with Peg-IFNα-2a biweekly reduced the levels of HBsAg below the limit of detection, and tests for anti-HBsAbs were positive. Upon completion of Peg-IFNα-2a therapy, the ALT levels normalized.\n\nTable 2. Laboratory Data for the Patient after Administering Peg-IFNα-2a.\n\nVariable\tValue\tUnit\tReference\t\nTP\t6.8\tg/dL\t6.5-8.2\t\nAlb\t4.4\tg/dL\t3.5-5.5\t\nA/G\t1.83\t\t1-1.8\t\nBUN\t17.3\tmg/dL\t7-20\t\nCr\t0.72\tmg/dL\t0.5-1\t\nT-bil\t0.8\tmg/dL\t0.1-1.2\t\nD-bil\t0.2\tmg/dL\t0.1-0.6\t\nAST\t21\tU/L\t10-35\t\nALT\t22\tU/L\t5-40\t\nALP\t219\tU/L\t100-340\t\nLDH\t201\tU/L\t110-220\t\nγ-GTP\t19\tU/L\t0-30\t\nNa\t142\tmmol/L\t135-146\t\nK\t4.1\tmmol/L\t3.5-4.6\t\nCl\t110\tmmol/L\t96-110\t\nWBC\t5,190\t/µL\t4,700-8,700\t\nRBC\t419×104\t/µL\t370-490\t\nHb\t14\tg/dL\t11-15\t\nHt\t40.9\t%\t35-45\t\nPlt\t14.7×104\t/µL\t15-35\t\nNeut\t53.2\t%\t38-71.9\t\nEos\t1.7\t%\t0.2-6.8\t\nBaso\t0.6\t%\t0-1\t\nLym\t39.7\t%\t26-46.6\t\nMono\t4.8\t%\t2.3-7.7\t\nPT\t100\t%\t80-100\t\nHBV-DNA\t-\tLIU/mL\t-\t\nHBs Antigen\t-\tIU/mL\t0-0.05\t\nHBs Antibody\t49\tmIU/mL\t0-10\t\nHBe Antigen\t-\tng/mL\t-\t\nHBe Antibody\t-\t\t-\t\nHBcr Antigen\t3.1\tlogU/mL\t0-3\t\nAFP\t2\tng/mL\t\t\nDCP\t16\tmAU/mL\t\t\nM2BPGi\t-\t\t-\t\n7S domain of type IV collagen\t3.7\tng/mL\t0-6\t\nHyaluronic acid\t30.9\tng/mL\t0-50\t\n\nWhen this manuscript was submitted, the patient's AST and ALT levels were within normal limits.\n\nDiscussion\n\nNUCs are frequently administered to patients with chronic HBV infection to prevent the induction of HCC and the progression of liver fibrosis. However, few cases (0.6-8%) become HBsAg-negative, even after long-term administration of NUCs (9). The incidence of HCC is significantly decreased in patients with undetectable levels of HBsAg. Furthermore, low levels of detected HBsAg at treatment initiation are associated with an increased frequency of a subsequent response (14). When the HBsAg level is low after IFN therapy, it may be possible to consider readministering IFN while paying attention to the adverse as well as therapeutic effects.\n\nThe present patient was first treated with NUCs and then subsequently and simultaneously treated with Peg-IFN, which resulted in significant seroclearance of HBsAg. Notably, anti-HBsAbs were detected subsequent to the seroclearance of HBsAg. This finding indicates that, although infrequent (9), Peg-IFN contributes to an immune response against HBV.\n\nWe previously reported that reduced serum levels of miR-6126 are associated with a sustained reduction of HBsAg at 48 weeks after the initiation of Peg-IFN therapy (15). MiR-6126 may therefore serve as a marker for selecting patients likely to respond to Peg-IFN therapy, which may reduce the levels of HBsAg (15). However, the present patient exhibited a low miR-6126 signal, similar to the findings in non-responders (15). Although the reason for this is unclear, we hypothesized that it was due to the administration of lamivudine and adefovir. Nucleoside analogs (lamivudine or entecavir) differ from nucleotide analogs (adefovir or tenofovir) in that their mechanism of antiviral activity involves the induction of IFN-λ3 expression (16). However, the potential association with miR-6126 levels requires further study.\n\nAlthough the present case is rare, our findings suggest that NUCs may be discontinued when Peg-IFN contributes to a reduction in HBsAg levels, which will improve treatment outcomes and thus reduce costs.\n\nThe authors state that they have no Conflict of Interest (COI).\n==== Refs\n1. Chen CJ , Yang HI , Su J , et al . Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level. JAMA 295 : 65-73, 2006.16391218\n2. Tseng TC , Liu CJ , Yang HC , et al . High levels of hepatitis B surface antigen increase risk of hepatocellular carcinoma in patients with low HBV load. Gastroenterology 142 : 1140-1149, 2012.22333950\n3. Sakamoto K , Beppu T , Hayashi H , et al . Antiviral therapy and long-term outcome for hepatitis B virus-related hepatocellular carcinoma after curative liver resection in a Japanese cohort. Anticancer Res 35 : 1647-1655, 2015.25750323\n4. Zhou Y , Zhang Z , Zhao Y , et al . Antiviral therapy decreases recurrence of hepatitis B virus-related hepatocellular carcinoma after curative resection: a meta-analysis. World J Surg 38 : 2395-2402, 2014.24791945\n5. Liu GM , Huang XY , Shen SL , et al . Adjuvant antiviral therapy for hepatitis B virus-related hepatocellular carcinoma after curative treatment: A systematic review and meta-analysis. Hepatol Res 46 : 100-110, 2016.26331530\n6. Yin J , Li N , Han Y , et al . Effect of antiviral treatment with nucleotide/nucleoside analogs on postoperative prognosis of hepatitis B virus-related hepatocellular carcinoma: a two-stage longitudinal clinical study. J Clin Oncol 31 : 3647-3655, 2013.24002499\n7. Tseng TC , Liu CJ , Yang HC , et al . High levels of hepatitis B surface antigen increase risk of hepatocellular carcinoma in patients with low HBV load. Gastroenterology 142 : 1140-1149, 2012.22333950\n8. JSH Guidelines for the Management of Hepatitis B Virus Infection Drafting Committee for Hepatitis Management Guidelines and the Japan Society of Hepatology. Hepatol Res 44 （Suppl ）: 1-58, 2014.\n9. Yuen MF , Wong DK , Fung J , et al . HBsAg seroclearance in chronic hepatitis B in Asian patients: replicative level and risk of hepatocellular carcinoma. Gastroenterology 135 : 1192-1199, 2008.18722377\n10. Simonetti J , Bulkow L , McMahon BJ , et al . Clearance of hepatitis B surface antigen and risk of hepatocellular carcinoma in a cohort chronically infected with hepatitis B virus. Hepatology 51 : 1531-1537, 2010.20087968\n11. Giannakopoulos NV , Luo JK , Papov V , et al . Proteomic identification of proteins conjugated to ISG15 in mouse and human cells. BiochemBiophys Res Commun 336 : 496-506, 2005.\n12. Ichida F , Tsuji T , Omata M , et al . New Inuyama classification; new criteria for histological assessment of chronic hepatitis. Int Hepatol Commun 6 : 112-119, 1996.\n13. Brunetto MR , Moriconi F , Bonino F , et al . Hepatitis B virus surface antigen levels: a guide to sustained response to peginterferon alfa-2a in HBeAg-negative chronic hepatitis B. Hepatology 49 : 1141-1150, 2009.19338056\n14. Piratvisuth T , Marcellin P , Popescu M , et al . Hepatitis B surface antigen: association with sustained response to peginterferon alfa-2a in hepatitis B e antigen-positive patients. Hepatol Int 7 : 429-436, 2013.21701902\n15. Fujita K , Mimura S , Iwama H , et al . Serum miRNAs predicting sustained HBs antigen reduction 48 weeks after pegylated interferon therapy in HBe antigen-negative patients. Int J Mol Sci 19 : 1940, 2018.\n16. Murata K , Asano M , Matsumoto A , et al . Induction of IFN-λ3 as an additional effect of nucleotide, not nucleoside, analogues: a new potential target for HBV infection. Gut 67 : 362-371, 2016.27789659\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0918-2918",
"issue": "60(12)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": "HBs antibody; HBs antigen; case reports; chronic hepatitis B; interferon",
"medline_ta": "Intern Med",
"mesh_terms": "D000998:Antiviral Agents; D004279:DNA, Viral; D005500:Follow-Up Studies; D006514:Hepatitis B Surface Antigens; D006513:Hepatitis B e Antigens; D006515:Hepatitis B virus; D019694:Hepatitis B, Chronic; D006801:Humans; D008297:Male; D008875:Middle Aged; D009696:Nucleic Acids; D011092:Polyethylene Glycols; D011994:Recombinant Proteins",
"nlm_unique_id": "9204241",
"other_id": null,
"pages": "1835-1838",
"pmc": null,
"pmid": "33456036",
"pubdate": "2021-06-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "18722377;30004437;26331530;21701902;22333950;27789659;16391218;24791945;24002499;25750323;16139798;20087968;19338056;24397839",
"title": "Peg-IFNα-2a Contributed to HBs Antigen Seroclearance in a Patient with Chronic Hepatitis B Administered Nucleic Acid Analogs: A Three-year Follow-up.",
"title_normalized": "peg ifn 2a contributed to hbs antigen seroclearance in a patient with chronic hepatitis b administered nucleic acid analogs a three year follow up"
} | [
{
"companynumb": "JP-GLAXOSMITHKLINE-JP2021GSK016650",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "LAMIVUDINE"
},
"drugadditional": nul... |
{
"abstract": "BACKGROUND\nNew oral anticoagulants are increasingly used in women of childbearing age, but apart from one case report there is no published experience with rivaroxaban exposure during pregnancy.\n\n\nMETHODS\nFrom October 2008 to December 2014, the German Embryotox Pharmacovigilance Centre identified 63 exposed pregnancies among 94 requests concerning rivaroxaban use during childbearing age. Follow-up included paediatric checks until 6 weeks after birth.\n\n\nRESULTS\nAll pregnancies with completed follow-up were exposed at least during the first trimester. Treatment indications included venous thromboembolism, knee surgery, and atrial fibrillation. 37 pregnancies were prospectively ascertained and resulted in six spontaneous abortions, eight elective terminations of pregnancy, and 23 live births. All women had discontinued rivaroxaban after recognition of pregnancy, mostly in the first trimester, but in one woman treatment continued until gestational week 26. There was one major malformation (conotruncal cardiac defect) among the 37 prospectively ascertained pregnancies in a woman with complex medication and a previous foetus with cardiac malformation without exposure to rivaroxaban. Only one case of bleeding concerning a retrospective report of surgery for missed abortion was observed in our case series.\n\n\nCONCLUSIONS\nOur results might give reassurance to those women, who were inadvertently exposed to rivaroxaban in early pregnancy. However, our limited cohort size does not allow ruling out an increased malformation risk and does not support the use of rivaroxaban during pregnancy. In all cases of (inadvertent) rivaroxaban exposure during 1st trimester, anticoagulation regimen should be reconsidered and a detailed ultrasound assessment recommended to confirm normal foetal development.",
"affiliations": "Berlin Institute for Clinical Teratology and Drug Risk Assessment in Pregnancy, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany. maria.hoeltzenbein@charite.de.;Berlin Institute for Clinical Teratology and Drug Risk Assessment in Pregnancy, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany.;Berlin Institute for Clinical Teratology and Drug Risk Assessment in Pregnancy, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany.;Berlin Institute for Clinical Teratology and Drug Risk Assessment in Pregnancy, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany.;Berlin Institute for Clinical Teratology and Drug Risk Assessment in Pregnancy, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany.",
"authors": "Hoeltzenbein|M|M|;Beck|E|E|;Meixner|K|K|;Schaefer|C|C|;Kreutz|R|R|",
"chemical_list": "D000925:Anticoagulants; D000069552:Rivaroxaban",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00392-015-0893-5",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1861-0684",
"issue": "105(2)",
"journal": "Clinical research in cardiology : official journal of the German Cardiac Society",
"keywords": "New oral anticoagulants; Non-vitamin K antagonist oral anticoagulants; Pregnancy; Rivaroxaban; Venous thromboembolism",
"medline_ta": "Clin Res Cardiol",
"mesh_terms": "D000328:Adult; D000925:Anticoagulants; D001281:Atrial Fibrillation; D005260:Female; D005500:Follow-Up Studies; D005858:Germany; D006470:Hemorrhage; D006801:Humans; D060735:Pharmacovigilance; D011247:Pregnancy; D011248:Pregnancy Complications; D011256:Pregnancy Outcome; D011446:Prospective Studies; D012189:Retrospective Studies; D012306:Risk; D000069552:Rivaroxaban; D013923:Thromboembolism",
"nlm_unique_id": "101264123",
"other_id": null,
"pages": "117-26",
"pmc": null,
"pmid": "26195125",
"pubdate": "2016-02",
"publication_types": "D016428:Journal Article",
"references": "23669868;23014816;23179135;24830515;24549552;21873418;22584383;24687618;26109251;23233582;24861799;14608641;25416564;25055834;24468894;22159895;26026286;24394737;24963045;23932014;24859719;16258340;24658395;23726261;22315276;25270038;24315724;25707763;12797461;19683809;18620043;22133273;20492464;23701516;23999974;24858823;23689957;22840412;25509060;25643952;23436575",
"title": "Pregnancy outcome after exposure to the novel oral anticoagulant rivaroxaban in women at suspected risk for thromboembolic events: a case series from the German Embryotox Pharmacovigilance Centre.",
"title_normalized": "pregnancy outcome after exposure to the novel oral anticoagulant rivaroxaban in women at suspected risk for thromboembolic events a case series from the german embryotox pharmacovigilance centre"
} | [
{
"companynumb": "PHHY2015DE091766",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ALISKIREN"
},
"drugadditional": "4",
"drugad... |
{
"abstract": "OBJECTIVE\nTo report a case of recurrent cytomegalovirus (CMV) corneal endotheliitis after penetrating keratoplasty.\n\n\nMETHODS\nPenetrating keratoplasty (PK) was performed in a 49-year-old man with bullous keratopathy. Pigmented keratic precipitates (KPs) were found in the corneal endothelium of the graft 13 days after surgery, with the subsequent appearance of coin-shaped lesions. Confocal microscopy was performed on the corneal endothelium. Aqueous humor was analyzed for viral DNA by polymerase chain reaction (PCR).\n\n\nRESULTS\nCMV DNA was detected from the excised corneal button, and aqueous humor revealed positive results for CMV and HSV1 by PCR. Confocal microscopy showed large corneal endothelial cells, consistent with the typical owl's eye morphology of CMV endotheliitis. After systemic ganciclovir was administered, the pigmented KPs and coin-shaped lesions gradually decreased.\n\n\nCONCLUSIONS\nStress from surgery and corticosteroid usage can revitalize CMV activity. PCR and confocal microscopy are valuable for the diagnosis of CMV corneal endotheliitis.",
"affiliations": "Department of Ophthalmology, Zhongxing Branch, Taipei City Hospital, Taiwan.",
"authors": "Wang|Shih-Chien|SC|;Tsai|I-Lun|IL|;Lin|Hsiao-Cheng|HC|;Kuo|Li-Lin|LL|;Tsai|Ching-Yao|CY|;Liou|Shiow-Wen|SW|",
"chemical_list": "D004279:DNA, Viral",
"country": "United States",
"delete": false,
"doi": "10.1177/112067211002000231",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1120-6721",
"issue": "20(2)",
"journal": "European journal of ophthalmology",
"keywords": null,
"medline_ta": "Eur J Ophthalmol",
"mesh_terms": "D001082:Aqueous Humor; D003587:Cytomegalovirus; D003586:Cytomegalovirus Infections; D004279:DNA, Viral; D003937:Diagnosis, Differential; D004728:Endothelium, Corneal; D015828:Eye Infections, Viral; D006801:Humans; D007634:Keratitis; D015948:Keratoplasty, Penetrating; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D013530:Surgical Wound Infection; D041623:Tomography, Optical Coherence",
"nlm_unique_id": "9110772",
"other_id": null,
"pages": "457-9",
"pmc": null,
"pmid": "20037910",
"pubdate": "2010",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Recurrent cytomegalovirus corneal endotheliitis after penetrating keratoplasty.",
"title_normalized": "recurrent cytomegalovirus corneal endotheliitis after penetrating keratoplasty"
} | [
{
"companynumb": "TW-BAUSCH-BL-2021-007880",
"fulfillexpeditecriteria": "1",
"occurcountry": "TW",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "FLUMETHASONE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nWe evaluated the efficacy of gemcitabine and docetaxel chemotherapy (GEM + DOC) in children and adolescents with recurrent or refractory osteosarcoma.\n\n\nMETHODS\nData of 28 patients (20 male, 8 female) who received gemcitabine (675 or 900 mg/m(2) on days 1 and 8) and docetaxel (100 mg/m(2) on day 8) at Korea Cancer Center Hospital were retrospectively reviewed.\n\n\nRESULTS\nPatients (ages 5.0-19.7 years) received a total of 96 courses of chemotherapy (median 3 courses; range, 1-8 courses) and were followed for a median of 14.9 months (range, 0.6-81.4 months). Eleven patients received GEM + DOC after surgery as adjuvant chemotherapy. Seventeen patients received GEM + DOC as palliative therapy, and were eligible for response evaluation; there were three (17.6%) complete response (CR, including two metabolic CR), one (5.9%) partial responses (PR), and three (29.4%) stable disease (SD). The objective response rate (CR + PR) and tumor control rate (CR + PR + SD) were 23.5% and 41.2%, respectively. The median duration of response was 11.2 months (range, 2.8-14.6 months). Dose of gemcitabine (675 or 900 mg/m(2)) did not influence the response rate. Overall survival at 1-year was 53.6 ± 9.4% and patients who received GEM + DOC as adjuvant chemotherapy fared better than those who received GEM + DOC as palliative therapy (72.7 ± 13.4% vs. 35.3 ± 11.6%, P = 0.006).\n\n\nCONCLUSIONS\nGEM + DOC showed some activity in osteosarcoma. Better than expected survival after GEM + DOC was seen both in patients with and without surgery. These results may indicate that dose dense combinations of gemcitabine and taxanes (e.g., gemcitabine + nab-paclitaxel) should be investigated in bone sarcomas.",
"affiliations": "Department of Pediatrics, Korea Cancer Center Hospital, Seoul, Republic of Korea.",
"authors": "Song|Bong Sup|BS|;Seo|Juhee|J|;Kim|Dong Ho|DH|;Lim|Jung Sub|JS|;Yoo|Ji Young|JY|;Lee|Jun Ah|JA|",
"chemical_list": "D043823:Taxoids; D003841:Deoxycytidine; D000077143:Docetaxel; C056507:gemcitabine",
"country": "United States",
"delete": false,
"doi": "10.1002/pbc.25035",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1545-5009",
"issue": "61(8)",
"journal": "Pediatric blood & cancer",
"keywords": "docetaxel; gemcitabine; osteosarcoma; recurrent; refractory",
"medline_ta": "Pediatr Blood Cancer",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D002648:Child; D002675:Child, Preschool; D003841:Deoxycytidine; D018572:Disease-Free Survival; D000077143:Docetaxel; D005260:Female; D006801:Humans; D008297:Male; D012516:Osteosarcoma; D056910:Republic of Korea; D012189:Retrospective Studies; D015996:Survival Rate; D043823:Taxoids",
"nlm_unique_id": "101186624",
"other_id": null,
"pages": "1376-81",
"pmc": null,
"pmid": "24692087",
"pubdate": "2014-08",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article",
"references": null,
"title": "Gemcitabine and docetaxel for the treatment of children and adolescents with recurrent or refractory osteosarcoma: Korea Cancer Center Hospital experience.",
"title_normalized": "gemcitabine and docetaxel for the treatment of children and adolescents with recurrent or refractory osteosarcoma korea cancer center hospital experience"
} | [
{
"companynumb": "KR-SA-2021SA256526",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "GEMCITABINE HYDROCHLORIDE"
},
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"abstract": "BACKGROUND\nPopulation studies showed that patients with JAK2 V617F mutation had increased mortality, and increased risk of any cancer, hematologic cancer, and myeloproliferative disease.\n\n\nMETHODS\nA 68-year-old Asian male with JAK2 V617F mutation developed four different hematologic and non-hematologic neoplastic processes. In 2009, he was diagnosed with stage IA lung adenocarcinoma and also noted to have worsening leukocytosis and thrombocytosis with peak platelet count of 1,054,000/mL). Bone marrow biopsy was consistent with myeloproliferative neoplasm. His monocyte percentage increased in 2011 and met criteria for chronic myelomonocytic leukemia. In 2013, he was admitted for proximal small bowel obstruction, with biopsy confirming stage IE diffuse large B-cell lymphoma. In 2014, a bone marrow biopsy performed for worsening leukocytosis was consistent with acute myeloid leukemia with monocytic differentiation.\n\n\nCONCLUSIONS\nThis is a rare case depicting the association of JAK2 V617F mutation with myeloproliferative, lymphoproliferative and solid neoplasms.",
"affiliations": "Department of Medical Oncology, Montefiore Medical Center, Bronx, NY 10467 USA.;Department of Medical Oncology, Montefiore Medical Center, Bronx, NY 10467 USA.;Department of Medical Oncology, Montefiore Medical Center, Bronx, NY 10467 USA.;Department of Medical Oncology, Montefiore Medical Center, Bronx, NY 10467 USA.;Department of Medical Oncology, Montefiore Medical Center, Bronx, NY 10467 USA.;Department of Medical Oncology, Montefiore Medical Center, Bronx, NY 10467 USA.;Department of Medical Oncology, Montefiore Medical Center, Bronx, NY 10467 USA.",
"authors": "Liu|Kenneth G|KG|;Verma|Amit|A|;Derman|Olga|O|;Kornblum|Noah|N|;Janakiram|Murali|M|;Braunschweig|Ira|I|;Battini|Ramakrishna|R|",
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"doi": "10.1186/s40364-016-0073-4",
"fulltext": "\n==== Front\nBiomark ResBiomark ResBiomarker Research2050-7771BioMed Central London 7310.1186/s40364-016-0073-4Case ReportJAK2 V617F mutation, multiple hematologic and non-hematologic processes: an association? Liu Kenneth G. kliu@montefiore.org Verma Amit averma@montefiore.org Derman Olga oderman@montefiore.org Kornblum Noah nkornblu@montefiore.org Janakiram Murali mjanakir@montefiore.org Braunschweig Ira ibraunsc@montefiore.org Battini Ramakrishna 718-920-4826rkbattini@yahoo.com Department of Medical Oncology, Montefiore Medical Center, Bronx, NY 10467 USA 19 10 2016 19 10 2016 2016 4 1921 8 2016 4 10 2016 © The Author(s). 2016\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nPopulation studies showed that patients with JAK2 V617F mutation had increased mortality, and increased risk of any cancer, hematologic cancer, and myeloproliferative disease.\n\nCase presentation\nA 68-year-old Asian male with JAK2 V617F mutation developed four different hematologic and non-hematologic neoplastic processes. In 2009, he was diagnosed with stage IA lung adenocarcinoma and also noted to have worsening leukocytosis and thrombocytosis with peak platelet count of 1,054,000/mL). Bone marrow biopsy was consistent with myeloproliferative neoplasm. His monocyte percentage increased in 2011 and met criteria for chronic myelomonocytic leukemia. In 2013, he was admitted for proximal small bowel obstruction, with biopsy confirming stage IE diffuse large B-cell lymphoma. In 2014, a bone marrow biopsy performed for worsening leukocytosis was consistent with acute myeloid leukemia with monocytic differentiation.\n\nConclusion\nThis is a rare case depicting the association of JAK2 V617F mutation with myeloproliferative, lymphoproliferative and solid neoplasms.\n\nKeywords\nCase reportLung adenocarcinomaMyeloproliferative neoplasmChronic myelomonocytic leukemiaDiffuse large B-cell lymphomaAcute myeloid leukemiaJAK2 V617FMontefiore Medical Center issue-copyright-statement© The Author(s) 2016\n==== Body\nBackground\nMyeloproliferative neoplasm (MPN) and chronic myelomonocytic leukemia (CMML) have the potential to progress into acute myeloid leukemia (AML), and some data also suggests an association between myeloproliferative and lymphoproliferative neoplasms (LPN's). In this article, we describe a patient with JAK2 V617F mutation who developed 4 different neoplastic processes: adenocarcinoma of the lung, MPN/CMML, diffuse large B-cell lymphoma (DLBCL), acute myeloid leukemia with monocytic differentiation (AML-M5). The patient also had a translocation of chromosome 4 and 11, which is only seen in a few case reports in therapy-related AML's following exposure to topoisomerase II inhibitors [1]. He received doxorubicin, a topoisomerase II inhibitor, as part of chemotherapy regimen for his DLBCL approximately 6-9 months prior to the diagnosis of AML-M5. What is even more intriguing about this case is the fact that the patient had a JAK2 V617F mutation, which has been reported to be associated with an increased risk of cancer and mortality [2]. The coexistence of four hematologic and non-hematologic disorders in the same patient with JAK2 V617F mutation is very rare, and we review here the literature on the association of these processes.\n\nCase presentation\nA 68-year-old Asian male has significant medical history of hypertension, chronic obstructive pulmonary disease, coronary artery disease requiring percutaneous coronary intervention, right lower extremity deep venous thrombosis/pulmonary embolism and peripheral vascular disease. The patient was a former long-time smoker but quitted cigarette smoking about 20 years ago. His family history was non-contributory. In 2009, patient was diagnosed with stage IA adenocarcinoma of the lung (Fig. 1), and he underwent a video-assisted thoracoscopic left upper lobe segmentectomy. At the same time, he was noted to have worsening leukocytosis and thrombocytosis. A complete blood count (CBC) at the time showed white blood cell count (WBC) 28,500/μL with a neutrophil predominance of 86.2 %, a hemoglobin of 14.7 gm/dL, and a platelet count of 737,000/mL. The patient was found to be JAK2 V617F mutation positive and BCR/ABL negative in his peripheral blood. At one point, his platelet count peaked at 1,054,000/mL. A bone marrow biopsy in October 2010 demonstrated markedly hypercellular marrow with marked megakaryocytes and mild myeloid hyperplasia consistent with MPN (Fig. 2). The patient was started on hydroxyurea with close monitoring of the blood counts. Of note, since around April 2011, patient's white blood cell monocyte percentage persistently ranged between 20-40 % and the absolute monocyte count ranged between 2,000/μL and 5,000/μL, meeting the criteria for CMML [3]. His thrombocytosis had markedly improved by that time.Fig. 1 H&E stain of the patient's lung adenocarcinoma specimen under 20x magnification\n\n\nFig. 2 H&E stain of the patient's bone marrow biopsy consistent with MPN under 40x magnification\n\n\n\n\nIn December 2013, the patient was admitted for proximal small bowel obstruction after presenting with multiple episodes of bloody bowel movements and abdominal pain. An esophagogastroduodenoscopy revealed erythematous and thickened duodenal folds. Biopsy was consistent with DLBCL (Fig. 3) and patient was staged as stage IE. Bone marrow biopsy in January 2014 did not show evidence of lymphoma but did show hypercellular marrow with myeloid hyperplasia with left shift and trilineage dyspoiesis and increased kappa restricted clonal plasma cells by flow cytometry (1 %). Given this new lymphoma diagnosis, hydroxyurea was held and chemotherapy with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) for 6 cycles were administered and completed in May 2014. His course was complicated by respiratory symptoms (coughing, shortness of breath) with pulmonary infiltrates and hilar/mediastinal lymphadenopathy noted on imaging and positive acid-fast bacillus culture for mycobacterium avium intracellulare (MAI). Fine-needle aspiration of lymph nodes showed reactive bronchial cells.Fig. 3 CD20 immunostain of the patient's small bowel biopsy consistent with DLBCL\n\n\n\n\nIn September 2014, the patient was noted to have a WBC of 57,800/μL (manual differentiation showing 68 % neutrophils, 4 % bands, 3 % metameylocytes, 3 % myelocytes, 2 % lymphocytes, 8 % promonocytes, 10 % monocytes, 2 % basophils), a hemoglobin of 11.8 gm/dL, and a platelet count of 243,000/mL. Given these findings, a bone marrow biopsy was performed, which demonstrated hypercellularity approaching 100 %. There was a prominent population of mature and immature/atypical monocytes comprising 77 % of analyzed WBC. These cells uniformly expressed CD11c, CD13, CD33 and CD64, with partial aberrant CD56 and variable HLA-DR consistent with left-shifted/dyspoietic maturation. These findings were consistent with acute myeloid leukemia with monocytic differentiation (AML-M5) (Fig. 4). CD34 positive myeloblasts comprised 1-2 % of cells. There was no evidence of lymphoma. Cytogenetics showed 2 of 22 metaphases had translocation of chromosome 4 and 11, loss of chromosome 9, and an additional copy of chromosome 11. Mixed lineage leukemia (MLL) gene rearrangement was noted in 57.5 % of cells. Nucleophosmin1 (NPM1) and FMS-like tyrosine kinase-3 (FLT-3) mutations were not sent as the cytogenetics placed him in the high risk AML category.Fig. 4 H&E stain of the patient's bone marrow biopsy consistent with AML-M5 under 40x magnification\n\n\n\n\nThe patient was subsequently admitted in September 2014 for initiation of induction chemotherapy and considerations for allogeneic stem cell transplantation. At the time of admission, he reported night sweats and nonspecific weight loss for a few weeks. He was started on standard \"7 + 3\" induction chemotherapy with idarubicin 12 mg/m2 on days 1-3 and cytarabine 100 mg/m2 on days 1-7. His course was complicated by tumor lysis syndrome, cytopenias, and elevated liver enzymes. A repeat bone marrow biopsy after induction therapy in October 2014 was performed, which unfortunately showed hypercellular marrow 90 % with 13 % promonocytes/monoblasts, consistent with residual acute myeloid leukemia with monocytic differentiation. Between November and December 2014, patient had received 2 cycles of decitabine while a search for a match-unrelated donor was going on.\n\nIn January 2015, the patient developed symptoms of hyperviscosity from thrombocytosis with a platelet count greater than two million. He underwent thrombocytapheresis with an improvement in platelet count and symptoms. In March 2015, patient was admitted again with thrombocytosis to platelet count over two million. He was started on hydroxyurea to control his counts, then received haploidentical allogeneic stem cell transplant from his daughter with fludarabine/melphalan/anti-thymocyte globulin conditioning. His course was complicated by neutropenic sepsis, acute kidney and liver injuries, gastrointestinal bleed, atrial fibrillation, cardiomyopathy, volume overload and skin graft-versus-host disease. In July 2015, repeat engraftment studies showed only 9 % donor engraftment. His subsequent decreasing blood counts and monocytosis confirmed on flow cytometry were also consistent with leukemia relapse. The patient expired in September 2015 while he was on best supportive care alone.\n\nDiscussion\nMPN's (previously chronic myeloproliferative diseases) are characterized by effective clonal myeloproliferation (for example, peripheral blood granulocytosis, thrombocytosis or erythrocytosis) in the absense of dyserythropoiesis, granulocytic dysplasia or monocytosis. Based on the 2008 World Health Organization Classification Scheme, MPN's are further subdivided into \"classical\" (which includes chronic myelogenous leukemia (CML), polycythemia vera (PV), essential thrombocythemia (ET), primary myelofibrosis (PMF)) and \"atypical\" subgroups. The patient presented here met the criteria for ET, which is characterized by megakaryocyte proliferation with large and mature morphology associated with thrombocytosis in the absence of reactive thrombocytosis. Demonstration of JAK2 V617F mutation or other clonal marker is often helpful in making the diagnosis [4, 5].\n\nAs a group, MPN's have been associated with disease transformation to myelodysplasias (MDS) and/or acute myeloid leukemia (AML). The reported incidence of AML in patients with MPN's varies typically between 5-10 % depending on the specific type of MPN after 10 years of observation [6, 7]. This risk seems to be related to the underlying disease mechanism itself, but can also be due to therapy for disease treatment. Population-based data from Sweden showed that patients with MPN's who received radioactive phosphorus (P(32)) greater than 1,000 MBq and alkylating agents greater than 1 gram had a 4.6-fold (95 % CI, 2.1-9.8; P = 0.002) and 3.4-fold (95 % CI, 1.1-10.6; P = 0.015) increased risk of AML/MDS, respectively. Of note, 41 (25 %) of 162 patients with MPN's with AML/MDS development were never exposed to alkylating agents, P32 or hydroxyurea, suggesting a major role in non-treatment related factors [8].\n\nRecent studies have also demonstrated an association between MPN's and LPN's. An Italian study reported that patients with MPN's had a 3.44-fold increased risk of developing LPN's compared with the general population, ranging from 2.86 for plasma cell disorders, 3.44 for non-Hodgkin's lymphoma, to 12.42 for chronic lymphocytic leukemia. The risk of developing non-Hodgkin's lymphoma was substantially increased to 5.71-fold in the presence of a JAK2 V617F mutation [9].\n\nThe patient was initially diagnosed with a JAK2 positive MPN, but subsequently developed monocytosis while his thrombocytosis improved. He met the World Health Organization criteria for CMML, which is defined as having > 10 % of the entire white blood cell differential, an absolute monocyte count >1,000/μL, absent BCR-ABL1 fusion gene, < 20 % myeloblasts, monoblasts and promonocytes, and dysplasia in one or more myeloid lineages [3]. CMML has both myeloproliferative and myelodysplastic features, and therefore is classified as a myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN) [10]. The median age at diagnosis is around 70 years of age, with a 2:1 male predominance [11]. The pathogenesis of CMML is also not entirely clear. Current approaches suggested that there might be preferred order of somatic genetic mutations: TET2 or ASXL1 first, SRSF2 or an alternative splice gene second, then a signaling gene mutation inducing GM-CSF hypersensitivity and myeloproliferation in 35-40 % of cases [12].\n\nThe patient subsequently developed AML-M5. Cytogenetic studies demonstrated translocation (4;11)(q21;q24), monosomy 9 and trisomy 11. MLL gene rearrangement, which involves the chromosome band 11q23, was noted in 57.5 % of the abnormal myeloid cells. In general, chromosome abnormalities of the same types seen in primary AML are also seen in therapy-related AML/MDS [13]. It has been described in the literature that deletions or loss of chromosome arm 5q or 7q or loss of the entire chromosome (5q-/-5 and 7q-/-7) can be seen in AML/MDS after treatment with alkylating agents, whereas balanced aberrations with a rearrangement are characteristic of that related to topoisomerase II inhibitors. These balanced chromosomal aberrations include the MLL, AML1/CBFB, RARA, or NUP98 genes [14]. The MLL gene is highly conserved among species and is associated with \"mixed-lineage\" leukemia, where blast cells display both myeloid and lymphoid characteristics. While myeloid and lymphoid phenotypes are evenly distributed among de novo leukemia cases with these abnormalities, the vast majority (>90 %) of therapy-related AML are associated with the myeloid phenotype. Topoisomerase II inhibitors, such as the anthracyclines (e.g., doxorubicin), mitoxantrone and dactinomycin have been associated with MLL gene rearrangement, which typically has a latency period of median 30-34 months [15]. It should be noted that the MLL gene rearrangement itself cannot definitively rule out de novo AML. In one study, the incidence of AML with MLL gene rearrangement was noted to be 9.4 % in therapy-related AML vs. 2.6 % in de novo AML (P < 0.001) [16]. Given our patient's long history of MPN/CMML and his AML developing within 8 months following the use of doxorubicin with a distinct cytogenetic profile and MLL gene rearrangement, this is more suggestive of AML related to either MPN/CMML, although prior anthracycline use may play a role as well.\n\nAs noted, our patient was discovered to have a JAK2 V617F mutation while undergoing workup for MPN/CMML. The JAK2 V617F mutation has long been described as dominant gain-of-function mutation that contributes to the expansion of MPN clones. It is not only important in the diagnosis of MPN's, but is also associated with a significantly longer duration of disease and a higher rate of complications [17]. While this mutation is present in the majority of patients with MPN's, it has also been seen in the peripheral blood of healthy donors, with the percentage quoted to range between 1-10 % depending on the assay used [18, 19]. The significance of the mutation in this setting is unclear. However, in a Danish study, out of 10,507 participants were screened for the presence of JAK2 V617F and followed for up to 17.6 years after blood sampling. Prevalence of the mutation in this predominantly Caucasian population was 0.2 % (n = 18). Participants with the mutation were associated with increased mortality, corresponding to a multifactorially adjusted hazard ratio of 3.0 (95 % CI, 1.9-4.9). The multifactorially adjusted hazard ratios for any cancer and hematologic cancer were 3.7 (95 % CI, 1.7-8.0) and 58 (95 % CI, 13-261), respectively [2]. Thus, the results of this study suggests that the presence of the JAK2 V617F mutation may be a marker for increased risk of developing future malignancies and increased mortality.\n\nConclusion\nIn this report, we presented a case in which a patient with a JAK2 V617F mutation developed four different hematologic and non-hematologic neoplastic processes: lung adenocarcinoma, MPN/CMML, DLBCL, and AML-M5. While the causality between JAK2 mutation and the various malignancies cannot be established in this case, we believe that this is not a mere coincidence and that the presence of JAK2 mutation is associated with the subsequent development of both hematologic and non-hematologic malignancies [2]. Identification of downstream markers of JAK2 can potentially confirm causality, although this was not performed as the extra information would not have changed management at the time. During the past decade, cancer-related gene mutation panels have been increasingly used, with some mutations yielding potential diagnostic, prognostic and therapeutic information in various malignancies [20]. The case presented here is one good example of how the presence of an activating mutation may provide insight into the subsequent development of neoplastic processes.\n\nBased on data from the North American Association of Central Cancer Registries (NAACCR), the average annual age-adjusted incidence rates of MDS, MPN and CMML are 3.3, 2.1 and 0.3 per 100,000 people. Based on follow up data through 2004 from the Surveillance, Epidemiology, and End Results (SEER) Program, the 3-year relative survival (comparing observed survival with expected survival from a set of people with the same characteristics as the patient cohort) for MDS, MPN and CMML are 45 %, 80 % and 21 % respectively [21]. Given these statistics, there is a need for not only early recognition of these disease entities, but also improvement in therapeutics for this patient population. Further research is necessary to determine the relationships among these distinct yet closely related hematologic disorders and to evaluate the significance of the JAK2 V617F mutation in the development of both hematologic and non-hematologic malignancies.\n\nAcknowledgements\nNone.\n\nFunding\nNone.\n\nAvailability of data and materials\nNot applicable.\n\nAuthors' contributions\nKL prepared, wrote and edited the manuscript. AV, OD, NK, MJ and IB all gathered information, reviewed and contributed to the final manuscript. RB wrote, reviewed and contributed to the final manuscript.\n\nCompeting interests\nThe authors declared that they have no competing interests.\n\nConsent for publication\nInformed consent was obtained from the patient to report individual patient data, use of pathology specimen pictures/photos.\n\nEthics approval and consent to participate\nNot applicable.\n==== Refs\nReferences\n1. Sait SN Claydon MA Conroy JM Nowak NJ Barcos M Baer MR Translocation (4;11)(p12;q23) with rearrangement of FRYL and MLL in therapy-related acute myeloid leukemia Cancer Genet Cytogenet 2007 177 143 146 10.1016/j.cancergencyto.2007.05.021 17854671 \n2. Nielsen C Birgens HS Nordestgaard Bø G Kjær L Bojesen SE The JAK2 V617F somatic mutation, mortality and cancer risk in the general population Haematologica 2011 96 450 453 10.3324/haematol.2010.033191 21160067 \n3. Swerdlow SH Campo E Harris NL Jaffe ES Pileri SA Stein H Thiele J Vardiman JW WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues 2008 4 Lyon IARC Press \n4. Tefferi A Vardiman JW Classification and diagnosis of myeloproliferative neoplasms: the 2008 World Health Organization criteria and point-of-care diagnostic algorithms Leukemia 2008 22 14 22 10.1038/sj.leu.2404955 17882280 \n5. Tefferi A Thiele J Vardiman JW The 2008 World Health Organization classification system for myeloproliferative neoplasms: order out of chaos Cancer 2009 115 3842 3847 10.1002/cncr.24440 19472396 \n6. Barbui T The leukemia controversy in myeloproliferative disorders: is it a natural progression of disease, a secondary sequela of therapy, or a combination of both? Semin Hematol 2004 41 15 17 10.1053/j.seminhematol.2004.02.006 15190518 \n7. Cervantes F Alvarez-Larran A Talarn C Gomez M Montserrat E Myelofibrosis with myeloid metaplasia following essential thrombocythaemia: actuarial probability, presenting characteristics and evolution in a series of 195 patients Br J Haematol 2002 118 786 790 10.1046/j.1365-2141.2002.03688.x 12181046 \n8. Bjorkholm M Derolf AR Hultcrantz M Kristinsson SY Ekstrand C Goldin LR Andreasson B Birgegard G Linder O Malm C Treatment-related risk factors for transformation to acute myeloid leukemia and myelodysplastic syndromes in myeloproliferative neoplasms J Clin Oncol 2011 29 2410 2415 10.1200/JCO.2011.34.7542 21537037 \n9. Vannucchi AM Masala G Antonioli E Chiara Susini M Guglielmelli P Pieri L Maggi L Caini S Palli D Bogani C Increased risk of lymphoid neoplasms in patients with Philadelphia chromosome-negative myeloproliferative neoplasms Cancer Epidemiol Biomarkers Prev 2009 18 2068 2073 10.1158/1055-9965.EPI-09-0353 19531676 \n10. Orazi A Germing U The myelodysplastic/myeloproliferative neoplasms: myeloproliferative diseases with dysplastic features Leukemia 2008 22 1308 1319 10.1038/leu.2008.119 18480833 \n11. Parikh SA Tefferi A Chronic myelomonocytic leukemia: 2012 update on diagnosis, risk stratification, and management Am J Hematol 2012 87 610 619 10.1002/ajh.23203 22615103 \n12. Itzykson R Solary E An evolutionary perspective on chronic myelomonocytic leukemia Leukemia 2013 27 1441 1450 10.1038/leu.2013.100 23558522 \n13. Pedersen-Bjergaard J Insights into leukemogenesis from therapy-related leukemia N Engl J Med 2005 352 1591 1594 10.1056/NEJMe048336 15829541 \n14. Pedersen-Bjergaard J Rowley JD The balanced and the unbalanced chromosome aberrations of acute myeloid leukemia may develop in different ways and may contribute differently to malignant transformation Blood 1994 83 2780 2786 8180374 \n15. Pui CH Relling MV Topoisomerase II inhibitor-related acute myeloid leukaemia Br J Haematol 2000 109 13 23 10.1046/j.1365-2141.2000.01843.x 10848777 \n16. Schoch C Schnittger S Klaus M Kern W Hiddemann W Haferlach T AML with 11q23/MLL abnormalities as defined by the WHO classification: incidence, partner chromosomes, FAB subtype, age distribution, and prognostic impact in an unselected series of 1897 cytogenetically analyzed AML cases Blood 2003 102 2395 2402 10.1182/blood-2003-02-0434 12805060 \n17. Kralovics R Passamonti F Buser AS Teo SS Tiedt R Passweg JR Tichelli A Cazzola M Skoda RC A gain-of-function mutation of JAK2 in myeloproliferative disorders N Engl J Med 2005 352 1779 1790 10.1056/NEJMoa051113 15858187 \n18. Sidon P El Housni H Dessars B Heimann P The JAK2V617F mutation is detectable at very low level in peripheral blood of healthy donors Leukemia 2006 20 1622 10.1038/sj.leu.2404292 16775613 \n19. Xu X Zhang Q Luo J Xing S Li Q Krantz SB Fu X Zhao ZJ JAK2(V617F): Prevalence in a large Chinese hospital population Blood 2007 109 339 342 10.1182/blood-2006-03-009472 16946305 \n20. Meldrum C Doyle MA Tothill RW Next-Generation Sequencing for Cancer Diagnostics: a Practical Perspective Clin Biochem Rev 2011 32 177 195 22147957 \n21. Rollison DE Howlader N Smith MT Strom SS Merritt WD Ries LA Edwards BK List AF Epidemiology of myelodysplastic syndromes and chronic myeloproliferative disorders in the United States, 2001-2004, using data from the NAACCR and SEER programs Blood 2008 112 45 52 10.1182/blood-2008-01-134858 18443215\n\n",
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"journal": "Biomarker research",
"keywords": "Acute myeloid leukemia; Case report; Chronic myelomonocytic leukemia; Diffuse large B-cell lymphoma; JAK2 V617F; Lung adenocarcinoma; Myeloproliferative neoplasm",
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"title": "JAK2 V617F mutation, multiple hematologic and non-hematologic processes: an association?",
"title_normalized": "jak2 v617f mutation multiple hematologic and non hematologic processes an association"
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"abstract": "COVID-19 is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which was first reported in Wuhan, China in December 2019, and is ongoing pandemic. While a majority of patients with SARS-CoV-2 infection shows asymptomatic or mild disease, hospitalized patients can develop critical condition, such as pneumonia, sepsis, and respiratory failure. Some cases deteriorate into sever systemic disease and multiorgan failure. Many patients of severe COVID-19 show hypercoagulable state and complicate with venous thromboembolism and atrial thrombosis. We herein reported a case of COVID-19 who developed cerebral venous thrombosis (CVT) co-incidence with pulmonary thromboembolism (PTE). A 56-year-old Japanese man was presented with fever and malaise and diagnosed with COVID-19. He was treated with ciclesonide and azithromycin, but his respiratory condition deteriorated. Thus, systemic corticosteroids and favipiravir were initiated and these treatments resulted in afebrile state, improving malaise and respiratory failure. However, he suddenly developed severe headache and vomiting with increased concentration of D-dimer. Brain CT and MRI showed typical images of CVT in the left transvers sinus and CT pulmonary angiography showed PE. Administration of unfractionated heparin followed by edoxaban treatment reduced the levels of D-dimer and improved his clinical presentation and thrombosis. Monitoring coagulopathy is important in COVID-19 patients and in case of venous thromboembolism, including cerebral venous system, appropriate anticoagulant therapy should be initiated.",
"affiliations": "Department of Respiratory Medicine, National Hospital Organization Kobe Medical Center, Japan. Electronic address: m05047ys@jichi.ac.jp.;Department of Respiratory Medicine, National Hospital Organization Kobe Medical Center, Japan.;Stroke Center and Division of Neurology, Department of Medicine, Jichi Medical University, Japan.;Department of Respiratory Medicine, National Hospital Organization Kobe Medical Center, Japan.;Department of Radiology, National Hospital Organization Kobe Medical Center, Japan.;Department of Neurosurgery, National Hospital Organization Kobe Medical Center, Japan.;Department of Respiratory Medicine, National Hospital Organization Kobe Medical Center, Japan.;Department of Respiratory Medicine, National Hospital Organization Kobe Medical Center, Japan.",
"authors": "Sugiyama|Yohsuke|Y|;Tsuchiya|Takaaki|T|;Tanaka|Ryota|R|;Ouchi|Aiko|A|;Motoyama|Arata|A|;Takamoto|Takeshi|T|;Hara|Natsumi|N|;Yanagawa|Yoshitaka|Y|",
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"doi": "10.1016/j.jocn.2020.07.038",
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"journal": "Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia",
"keywords": "COVID-19; Cerebral venous thrombosis; D-dimer; Edoxaban; Pulmonary thromboembolism",
"medline_ta": "J Clin Neurosci",
"mesh_terms": "D000073640:Betacoronavirus; D000086382:COVID-19; D018352:Coronavirus Infections; D005338:Fibrin Fibrinogen Degradation Products; D006493:Heparin; D006801:Humans; D020767:Intracranial Thrombosis; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D058873:Pandemics; D011024:Pneumonia, Viral; D011725:Pyridines; D000086402:SARS-CoV-2; D013844:Thiazoles; D014057:Tomography, X-Ray Computed; D020246:Venous Thrombosis",
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"pages": "30-32",
"pmc": null,
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"pubdate": "2020-09",
"publication_types": "D002363:Case Reports",
"references": "32503088;32324102;32502594;29923367;32302438;32485418;32275288;32492712",
"title": "Cerebral venous thrombosis in COVID-19-associated coagulopathy: A case report.",
"title_normalized": "cerebral venous thrombosis in covid 19 associated coagulopathy a case report"
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"dru... |
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"abstract": "OBJECTIVE\nCritical illness is hallmarked by low plasma ACTH in the face of high plasma cortisol. We hypothesized that frequently used drugs could play a role by affecting the hypothalamic-pituitary-adrenal axis.\n\n\nMETHODS\nObservational association study.\n\n\nMETHODS\nA total of 156 medical-surgical critically ill patients.\n\n\nMETHODS\nPlasma concentrations of ACTH and total/free cortisol were quantified upon ICU admission and throughout the first 3 ICU days. The independent associations between drugs administered 24 h prior to ICU admission and plasma ACTH and cortisol concentrations upon ICU admission were quantified with use of multivariable linear regression analyses.\n\n\nRESULTS\nUpon ICU admission, compared with healthy subjects, patients had low mean±SEM plasma ACTH concentrations (2·7 ± 0·6 pmol/l vs 9·0 ± 1·6 pmol/l, P < 0·0001) in the face of unaltered total plasma cortisol (336·7 ± 30·4 nmol/l vs 300·8 ± 16·6 nmol/l, P = 0·3) and elevated free plasma cortisol concentrations (41·4 ± 5·5 nmol/l vs 5·5 ± 0·8 nmol/l, P = 0·04). Plasma ACTH concentrations remained low (P < 0·001) until day 3, whereas plasma (free) cortisol concentrations steeply increased and remained high (P < 0·001). No independent correlations with plasma ACTH were found. In contrast, the total admission plasma cortisol concentration was independently and negatively associated with the cumulative opioid (P = 0·001) and propofol (P = 0·02) dose, the use of etomidate (P = 0·03), and positively with the cumulative dobutamine dose (P = 0·0007).\n\n\nCONCLUSIONS\nBesides the known suppressive effect of etomidate, opioids and propofol may also suppress and dobutamine increases plasma cortisol in a dose-dependent manner. The observed independent associations suggest drug effects not mediated centrally via ACTH, but rather peripherally by a direct or indirect action on the adrenal cortex.",
"affiliations": "Clinical Division and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium.;Clinical Division and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium.;Clinical Division and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium.;Clinical Division and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium.;Clinical Division and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium.;Clinical Division and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium.",
"authors": "Peeters|Bram|B|;Güiza|Fabian|F|;Boonen|Eva|E|;Meersseman|Philippe|P|;Langouche|Lies|L|;Van den Berghe|Greet|G|",
"chemical_list": "D000324:Adrenocorticotropic Hormone; D006854:Hydrocortisone",
"country": "England",
"delete": false,
"doi": "10.1111/cen.13155",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0300-0664",
"issue": "86(1)",
"journal": "Clinical endocrinology",
"keywords": null,
"medline_ta": "Clin Endocrinol (Oxf)",
"mesh_terms": "D000324:Adrenocorticotropic Hormone; D000368:Aged; D016022:Case-Control Studies; D016638:Critical Illness; D005260:Female; D006801:Humans; D006854:Hydrocortisone; D007030:Hypothalamo-Hypophyseal System; D007362:Intensive Care Units; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D010913:Pituitary-Adrenal System",
"nlm_unique_id": "0346653",
"other_id": null,
"pages": "26-36",
"pmc": null,
"pmid": "27422812",
"pubdate": "2017-01",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": null,
"title": "Drug-induced HPA axis alterations during acute critical illness: a multivariable association study.",
"title_normalized": "drug induced hpa axis alterations during acute critical illness a multivariable association study"
} | [
{
"companynumb": "BE-JNJFOC-20161225395",
"fulfillexpeditecriteria": "1",
"occurcountry": "BE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "SEVOFLURANE"
},
"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nThis study assessed the incidence of serious adverse events of diabetic ketoacidosis (DKA) among patients with type 2 diabetes treated with canagliflozin.\n\n\nMETHODS\nAll serious adverse events of DKA and related events (ketoacidosis, metabolic acidosis, and acidosis) from 17,596 patients from randomized studies of canagliflozin through 11 May 2015 were analyzed.\n\n\nRESULTS\nSerious adverse events of DKA and related events were reported in 12 patients (0.07%), including 4 (0.07%), 6 (0.11%), and 2 (0.03%) treated with canagliflozin 100 and 300 mg and comparator, respectively; corresponding incidence rates were 0.522, 0.763, and 0.238 per 1,000 patient-years, respectively. Most patients with DKA and related events had a blood glucose >300 mg/dL (16.7 mmol/L) at presentation of DKA, were on insulin, and had DKA-precipitating factors, including some with type 1 diabetes/latent autoimmune diabetes of adulthood.\n\n\nCONCLUSIONS\nDKA and related events occurred at a low frequency in the canagliflozin type 2 diabetes program, with an incidence consistent with limited existing observational data in the general population with type 2 diabetes.",
"affiliations": "Janssen Research & Development, LLC, Raritan, NJ.;Janssen Research & Development, LLC, Raritan, NJ.;Janssen Research & Development, LLC, Raritan, NJ.;Janssen Research & Development, LLC, Raritan, NJ gmeining@its.jnj.com.",
"authors": "Erondu|Ngozi|N|;Desai|Mehul|M|;Ways|Kirk|K|;Meininger|Gary|G|",
"chemical_list": "D001786:Blood Glucose; D007004:Hypoglycemic Agents; D000068896:Canagliflozin",
"country": "United States",
"delete": false,
"doi": "10.2337/dc15-1251",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0149-5992",
"issue": "38(9)",
"journal": "Diabetes care",
"keywords": null,
"medline_ta": "Diabetes Care",
"mesh_terms": "D000328:Adult; D001786:Blood Glucose; D000068896:Canagliflozin; D003924:Diabetes Mellitus, Type 2; D016883:Diabetic Ketoacidosis; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents; D015994:Incidence; D008297:Male; D008875:Middle Aged; D016032:Randomized Controlled Trials as Topic; D012107:Research Design",
"nlm_unique_id": "7805975",
"other_id": null,
"pages": "1680-6",
"pmc": null,
"pmid": "26203064",
"pubdate": "2015-09",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "18644074;23279307;23464594;23564919;23680739;23850055;23895803;24026211;24073995;24118688;24463448;24463454;24528605;24965700;25205142;25468945;25495720;25894829;26025388;26417418;29159083",
"title": "Diabetic Ketoacidosis and Related Events in the Canagliflozin Type 2 Diabetes Clinical Program.",
"title_normalized": "diabetic ketoacidosis and related events in the canagliflozin type 2 diabetes clinical program"
} | [
{
"companynumb": "UA-JNJFOC-20140511013",
"fulfillexpeditecriteria": "1",
"occurcountry": "UA",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CANAGLIFLOZIN"
},
"drugadditional": null,
... |
{
"abstract": "Nocardiosis is a rare infection caused by Nocardia spp., a gram-positive bacteria non-commensal of the human flora. Nocardiosis usually presents with lung infection but may disseminate to other organs, most frequently the brain. The major risk factor is immunosuppression, but lung diseases also increase the risk of infection. Treatment with antibiotics is usually prolonged. In this study, we made a retrospective analysis of pulmonary nocardiosis cases and a review of the available literature.\nWe made a retrospective analysis of all pulmonary nocardiosis cases from 13 years (January 2005 to December 2017) in our institution, selecting patients from pulmonology and infectious diseases consultation.\nWe found four patients diagnosed with pulmonary nocardiosis, three males (patients 1, 2 and 3) and one female (patient 4). Median age was 71 ± 15 years old. Different specimens were identified (N. cyriacigeorgica, Nocardia spp., N. nova, and N. wallacei/transvalensis). Bronchofibroscopy with bronchoalveolar lavage culture was the most frequent diagnostic procedure (patients 1 and 4). Only patient 2 presented an unfavorable response to treatment and died from septic shock.\nPulmonary nocardiosis has a good prognosis if diagnosed early and treated adequately. It should always be considered in the differential diagnosis of pulmonary infections concomitant with brain or other soft tissue lesion, especially in immunocompromised patients.",
"affiliations": "Pulmonology Department, Pedro Hispano Hospital, Matosinhos, Portugal.;Pulmonology Department, Pedro Hispano Hospital, Matosinhos, Portugal.;Infectious Diseases Department, Pedro Hispano Hospital, Matosinhos, Portugal.;Infectious Diseases Department, Pedro Hispano Hospital, Matosinhos, Portugal.;Microbiology Department, Pedro Hispano Hospital, Matosinhos, Portugal.;Pulmonology Department, Pedro Hispano Hospital, Matosinhos, Portugal.;Pulmonology Department, Pedro Hispano Hospital, Matosinhos, Portugal.",
"authors": "Oliveira Cabrita|Bruno Miguel|BM|;Correia|Sílvia|S|;Jordão|Sofia|S|;Correia de Abreu|R|R|;Alves|Valquíria|V|;Seabra|Bárbara|B|;Ferreira|Jorge|J|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1016/j.rmcr.2020.101175",
"fulltext": "\n==== Front\nRespir Med Case Rep\nRespir Med Case Rep\nRespiratory Medicine Case Reports\n2213-0071 Elsevier \n\nS2213-0071(20)30389-0\n10.1016/j.rmcr.2020.101175\n101175\nCase Report\nPulmonary nocardiosis: A Single Center Study\nOliveira Cabrita Bruno Miguel Bruno.Cabrita@ulsm.min-saude.pta∗ Correia Sílvia Silvia.Correia@ulsm.min-saude.pta Jordão Sofia Sofia.Jordao@ulsm.min-saude.ptb Correia de Abreu R. Correia.Abreu@ulsm.min-saude.ptb Alves Valquíria Valquiria.Alves@ulsm.min-saude.ptc Seabra Bárbara Barbara.Seabra@ulsm.min-saude.pta Ferreira Jorge Jorge.Ferreira@ulsm.min-saude.pta a Pulmonology Department, Pedro Hispano Hospital, Matosinhos, Portugal\nb Infectious Diseases Department, Pedro Hispano Hospital, Matosinhos, Portugal\nc Microbiology Department, Pedro Hispano Hospital, Matosinhos, Portugal\n∗ Corresponding author. Pulmonology Department, Pedro Hispano Hospital, Dr. Eduardo Torres Street, Sra. Da Hora, Matosinhos, Portugal. Bruno.Cabrita@ulsm.min-saude.pt\n25 7 2020 \n2020 \n25 7 2020 \n31 10117515 2 2020 13 7 2020 20 7 2020 © 2020 The Authors2020This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Objectives\nNocardiosis is a rare infection caused by Nocardia spp., a gram-positive bacteria non-commensal of the human flora. Nocardiosis usually presents with lung infection but may disseminate to other organs, most frequently the brain. The major risk factor is immunosuppression, but lung diseases also increase the risk of infection. Treatment with antibiotics is usually prolonged. In this study, we made a retrospective analysis of pulmonary nocardiosis cases and a review of the available literature.\n\nMethods\nWe made a retrospective analysis of all pulmonary nocardiosis cases from 13 years (January 2005 to December 2017) in our institution, selecting patients from pulmonology and infectious diseases consultation.\n\nResults\nWe found four patients diagnosed with pulmonary nocardiosis, three males (patients 1, 2 and 3) and one female (patient 4). Median age was 71 ± 15 years old. Different specimens were identified (N. cyriacigeorgica, Nocardia spp., N. nova, and N. wallacei/transvalensis). Bronchofibroscopy with bronchoalveolar lavage culture was the most frequent diagnostic procedure (patients 1 and 4). Only patient 2 presented an unfavorable response to treatment and died from septic shock.\n\nConclusions\nPulmonary nocardiosis has a good prognosis if diagnosed early and treated adequately. It should always be considered in the differential diagnosis of pulmonary infections concomitant with brain or other soft tissue lesion, especially in immunocompromised patients.\n\nKeywords\nLungInfectionNocardiosisNocardia\n==== Body\n1 Introduction\nNocardiosis is an infection caused by Nocardia spp., a gram-positive aerobic bacteria non-commensal of the human flora, usually found in soils, decomposing organic matter, water or air. Hence, its microbiological identification in human samples is highly suggestive of infection [[1], [2], [3], [4], [5], [6], [7], [8], [9]]. The prevalence of the disease is currently unknown, due to the scarce reported cases. However, it appears to be gradually increasing, mostly due to higher clinical suspicion and improvement of diagnostic methods. Despite this, pulmonary nocardiosis remains a rare infection [10].\n\nThe main risk factor for infection is immunosuppression (prolonged corticosteroid therapy, malignancy, organ transplantation, or human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS)). However, nocardiosis may also affect immunocompetent individuals, in 33% of cases, and should not be considered an opportunistic infection. Other important risk factors include male gender (3:1 ratio), diabetes mellitus, alcohol abuse, alveolar proteinosis, inflammatory bowel disease, chronic obstructive pulmonary disease (COPD), asthma, bronchiectasis, tuberculosis and Mycobacterium avium complex (MAC) infections [[2], [3], [4], [5], [6],8,9,[11], [12], [13]]. It can be caused by inhalation of dust particles or result from nosocomial infection in patients with injured skin, such as catheterized patients or those submitted to surgical procedures. There is no evidence of human-to-human transmission [3].\n\nNocardia spp. may cause focal or systemic infections. The main form of presentation is pulmonary disease, in 73–77% of cases [[2], [3], [4],7]. Exclusive pulmonary forms of infection occur in 39% of all cases, and up to 50% disseminate to other organs, usually the brain [1]. Nocardia asteroids complex (N. asteroides, N. farcinica, N. nova, and N. transvalensis complex) is responsible for 85% of nocardiosis and most of pulmonary cases [[1], [2], [3],7]. There are no pathognomonic signs or symptoms of the disease, but they usually include fever, cough, chest pain, nocturnal sweating and/or weight loss. For these reasons, nocardiosis should be suspected in the presence of cerebral or skin lesions, concomitant with recent pulmonary radiological changes [3,6].\n\nCommon radiographic findings include nodules, diffuse reticulonodular infiltrates or, sometimes, pleural effusions. Some cases present with empyema. Thorax computed tomography (CT) scan usually shows multifocal consolidations, but also solitary or multiple nodules (more common in the disseminated disease), abscess or cavitary lesions (33% of patients). Upper lung lobes are usually more affected and the combination of these findings with unspecific clinical manifestations commonly lead to misdiagnosis with tuberculosis, fungal disease or malignancy [1,6,9].\n\nThe microbiological identification of the bacteria is usually a difficult and slow process [8]. However, faster molecular methods are available: polymerase chain reaction (PCR), polymorphisms analysis, 16S ribosomal RNA or DNA sequencing, which is, currently, the favorite technique [2,3,[5], [6], [7]].\n\nThere is no consensual treatment in nocardiosis, and so, antibiotic susceptibility test (AST) is required [11]. In most cases, empiric treatment with trimethoprim-sulfamethoxazole (TMP-SMX), 5–10 mg/kg (TMP) and 25–50 mg/kg (SMX), divided in 2–4 daily doses, is preferred until further adjustment based on AST results [2,3,5,9,11]. Higher doses can be used in extensive disease. In severe cases, imipenem/meropenem and/or amikacin may be added to the antibiotic regimen [2,11]. Treatment duration is prolonged and depends on the severity of the disease, immunocompromise and clinical evolution. Usually it is recommended a total of 6–12 months of treatment, but it can be extended in immunocompromised patients or in cases of central nervous system involvement [9,11]. Some cases of abscess and empyema may need surgical intervention for drainage and debridement [1].\n\nIn this study we aimed at making a retrospective analysis of all cases from our institution and review the available literature on pulmonary nocardiosis.\n\n2 Materials and methods\n2.1 Study design\nWe performed a retrospective single center analysis of all cases of pulmonary nocardiosis, between January 2005 and December 2017. We used our institutional software SClínico and SAM to obtain clinical data.\n\n2.2 Data collection\nWe collected relevant clinical information, including age, gender, smoking habits, previous lung disease and risk factors for immunosuppression, clinical manifestations, analytical findings (C-reactive protein (CRP), leukocytes, neutrophils, arterial blood gases), radiological findings (chest radiograph and CT scan), presumptive diagnosis, length of stay, identified microorganisms and respective diagnostic procedure, treatment and follow-up, to analyze and compare between patients.\n\nDiagnostic procedures included bronchoalveolar lavage, sputum, blood cultures or tissue biopsy. Diagnostic molecular techniques included genetic sequencing procedures for microorganism identification.\n\n2.3 Patient eligibility\nIn this study, all cases of nocardiosis were selected for analysis.\n\nPatients with no pulmonary involvement were excluded.\n\n2.4 Data analysis\nPatients’ characteristics and clinical data were summarized for comparison.\n\nMean and median values were calculated with IBM SPSS Statistics v23.\n\n2.5 Ethics approval\nThis study was approved by our Hospital Ethics Commission and Administrative Council.\n\n3 Results\n3.1 Study population\nA total of four patients were diagnosed with pulmonary nocardiosis: three men (patients 1, 2 and 3) and one woman (patient 4). Median age was 71 ± 15 years old. Patients characteristics are summarized in Table 1 for comparison.Table 1 Patients characteristics.\n\nTable 1Characteristics\tPatient 1\tPatient 2\tPatient 3\tPatient 4\tMedian ± IQR\t\nAge (years)\t75\t77\t60\t66\t71 ± 15\t\nGender\tMale\tMale\tMale\tFemale\t\t\nSmoking habits\tFormer smoker\tFormer smoker\tNone\tNone\t\t\nLung disease\tBronchiectasis, MAC infection\tCOPD, bronchiectasis\tNone\tBronchiectasis\t\t\nImmunosuppression\tIdiopathic lymphopenia\tNone\tITP under CST\tNone\t\t\nClinical manifestations\tConstitutional symptoms\tDyspnea, cough, fever\tCough, hemoptysis, pleuritic chest pain\tCough, fever\t\t\nAnalytical findings\t\t\t\t\t\t\nCRP (mg/L)\t157,4\t40\t23,2\t3,8\t31,6 ± 119,4\t\nLeuk (EXP3/μL)\t11,4\t8,6\t2\t7,39\t8 ± 7,4\t\nNeutr (%)\t89,5\t71,1\t74,5\t47,1\t72,8 ± 32,7\t\nBlood gases\tNo RF\tHypoxemic RF\tNo RF\tNo RF\t\t\nChest radiograph\tNodular opacities (right middle lung field)\tBilateral nodular opacities\tBilateral opacities in the lower lung fields\tNA\t\t\nThorax CT scan\tBilateral consolidations, micronodules, tree-in-bud pattern\tDiffuse consolidations with air bronchogram\tConsolidation with air bronchogram in the lingula, diffuse nodules\tBilateral micronodules, tree-in-bud pattern\t\t\nPresumptive diagnosis\tInfected bronchiectasis\tAcute tracheobronchitis, heart failure\tCAP\tCAP/Infected bronchiectasis\t\t\nHospitalization (days)\t30\t28\t49\tNA\t30 ± 12\t\nMicroorganism\tN. cyriacigeorgica\tNocardia spp.\tNocardia nova\tN. wallacei/N. transvalensis\t\t\nDiagnostic procedure\tBFC with BAL\tBlood cultures\tSputum culture, nodule biopsy\tBFC with BAL\t\t\nDefinite diagnosis\tPulmonary nocardiosis\tPulmonary nocardiosis with sepsis\tDisseminated nocardiosis\tPulmonary nocardiosis\t\t\nTreatment\tImipenem + TMP-SMX (iv, 4w), TMP-SMX (po, 12m)\tTMP-SMX (iv)\tTMP-SMX + Ceftriaxone + Amikacin (iv, 6w), TMP-SMX (po, 12m)\tTMP-SMX + Amoxicillin-clavulanate (po, 6m)\t13 ± 4(m)\t\nOutcome\tFavorable\tUnfavorable\tFavorable\tFavorable\t\t\nIQR, Interquartile range; PYU, Pack-year units; MAC, Mycobacterium avium complex; COPD, Chronic obstructive pulmonary disease; ITP, Idiopathic thrombocytopenic purpura; CST, Corticosteroid therapy; CRP, C-reactive protein; Leuk, Leukocytes; Neutr, Neutrophils; RF, Respiratory failure; NA, not available/applicable; CAP, Community-acquired pneumonia; BFC, Bronchofibroscopy; BAL, Bronchoalveolar lavage; TMP-SMX, Trimethoprim-sulfamethoxazole; PCR, Protein-chain reaction; iv, intravenous; po, oral dosing; w, weeks; m, months.\n\n\n\n3.2 Cases description\n3.2.1 Clinical case 1\nMale patient, 75 years old, former smoker (20 pack-year units (PYU)), with clinical background of idiopathic lymphopenia, bronchiectasis and previous MAC infection (completed 11 months of treatment with clarithromycin and ethambutol). Due to new onset of constitutional symptoms with 6-months evolution, a thorax CT scan was performed. It showed bilateral consolidations and micronodules with tree-in-bud pattern in the left upper lobe (Fig. 1). He was submitted to bronchofibroscopy with bronchoalveolar lavage, which allowed the identification of Nocardia cyriacigeorgica in microbiological culture. The patient was hospitalized with the diagnosis of pulmonary nocardiosis. Extrapulmonary sites of infection were excluded by cranial magnetic resonance imaging (MRI), lumbar puncture with cerebrospinal fluid analysis, abdominal CT scan and ophthalmologic examination. He was treated with intravenous imipenem and TMP-SMX for 4 weeks, with good clinical evolution. At hospital discharge, he kept follow-up in infectious diseases consultation, completing 12 months of oral TMP-SMX, with good clinical and radiological evolution.Fig. 1 Patient 1 radiological findings. A: Chest radiograph (posteroanterior incidence) shows bilateral nodular opacities, more evident in the right middle lung field. B: Thorax CT scan shows bilateral ground-glass and consolidations (posterior segment of right upper lung lobe), centrilobular micronodules with tree-in-bud pattern (apicoposterior segment of left upper lung lobe).\n\nFig. 1\n\n3.2.2 Clinical case 2\nMale patient, 77 years old, former smoker (40 PYU), with clinical background of COPD and bronchiectasis. He was admitted in the Emergency Room (ER) for dyspnea, non-productive cough and fever. Chest radiograph revealed increased cardiothoracic ratio with nodular opacities predominant in the lower lung fields (Fig. 2). It was assumed a COPD exacerbation due to acute tracheobronchitis with congestive heart failure exacerbation. He started treatment with amoxicillin-clavulanate, for 10 days, with good analytical response, but with no clinical resolution of symptoms. Due to the persistence of fever, antibiotic treatment was changed to piperacillin-tazobactam and vancomycin. Thorax CT scan was performed, showing bilateral consolidations with air bronchogram, suggestive of nosocomial bilateral pneumonia (Fig. 2). Nocardia spp. was identified in blood cultures, and TMP-SMX added to antibiotic regimen. However, the patient presented unfavorable evolution, development of septic shock with multiorgan dysfunction, refractory to all therapeutic measures, and died.Fig. 2 Patient 2 radiological findings. A: Chest radiograph (posteroanterior incidence) shows increased cardiothoracic ratio and bilateral nodular opacities, in both lower lung fields, more evident in the right lung. B: Thorax CT scan shows bilateral multifocal consolidations with air bronchogram and ground-glass densifications.\n\nFig. 2\n\n3.2.3 Clinical case 3\nMale patient, 60 years old, with clinical background of idiopathic thrombocytopenic purpura treated with long-term corticosteroid therapy. He was admitted in the ER for hemoptysis and pleuritic chest pain. He was hospitalized and underwent a thorax CT scan that showed a consolidation in the lung lingula and diffuse nodules (Fig. 3). He was diagnosed with community-acquired pneumonia (CAP) and ceftriaxone with azithromycin was initiated empirically. Considering the patient was immunocompromised, bronchofibroscopy was performed and showed no evident endobronchial lesions. Bronchoalveolar lavage analysis revealed inflammation, no evidence of malignant cells, and the patient was posteriorly discharged from the hospital. He was readmitted in the ER, the following month, with abdominal pain, vomiting and presented diffuse skin nodules. Abdominal CT scan revealed a retroperitoneal adenopathy conglomerate. In the suspicion of a metastatic lung cancer, excisional biopsies of chest and cervical nodules were performed, with no identification of malignant cells or microbiological agent. Sputum samples, however, allowed the identification of Nocardia nova, and so, treatment with TMP-SMX, ceftriaxone and amikacin was initiated (after the AST results), for 6 weeks. To confirm the possibility of disseminated disease, the patient underwent a forearm subcutaneous nodule biopsy. Microbiological analysis identified the same microorganism, confirming the diagnosis of a disseminated nocardiosis, affecting lung, skin and retroperitoneal regions. After hospital discharge, with clinical improvement, he completed maintenance treatment with oral TMP-SMX, for 12 months.Fig. 3 Patient 3 radiological findings. A: Chest radiograph (posteroanterior incidence) shows homogeneous opacity with air bronchogram (left lower lung field) and nodular opacities in the right lower lung field. B: Thorax CT scan shows consolidation with air bronchogram in the lingula.\n\nFig. 3\n\n3.2.4 Clinical case 4\nFemale patient, 66 years old, with pathological background of bronchiectasis, recurrent lung infections and several antibiotic treatment courses. She developed productive cough with purulent sputum and fever, with one-week evolution and no response to levofloxacin treatment. Thorax CT scan showed diffuse centrilobular nodules with tree-in-bud pattern (Fig. 4). Bronchofibroscopy with bronchoalveolar lavage was performed, with no malignant cells identified, but microbiological analysis (DNA PCR) isolated Nocardia wallacei and/or Nocardia transvalensis, undistinguishable between them. Considering the patient was clinically stable, with no respiratory failure or other severity criteria, oral therapy with TMP-SMX and amoxicillin-clavulanate was initiated, for 6 months. Cerebral lesions were excluded with brain CT scan. The patient showed significant clinical and radiological improvement in follow-up consultations.Fig. 4 Patient 4 radiological findings. Thorax CT scan shows bilateral centrilobular nodules with tree-in-bud pattern.\n\nFig. 4\n\n3.3 Patients characteristics\nPatients characteristics were resumed and displayed in the form of a table for comparison (Table 1). Median age was 71 ± 15 years old (60–77 years). Study population included three male patients (patients 1, 2 and 3) and one female (patient 4). Two patients had previous smoking habits. Three patients had structural lung disease, including COPD and/or bronchiectasis (patients 1, 2 and 4).\n\nThe main risk factors for immunosuppression were idiopathic lymphopenia (patient 1) and idiopathic thrombocytopenic purpura treated with long-term corticosteroids (patient 3).\n\n3.4 Clinical presentation\nPatients clinical manifestations were unspecific, and the most common symptom was cough. Patient 1 was the only who presented constitutional symptoms (asthenia, anorexia, non-quantified weight loss). Only two patients (2 and 4) presented with fever at hospital admission. Only patient 3 presented extrapulmonary manifestations of nocardiosis.\n\nAnalytical parameters at hospital admission showed increased CRP values in all patients, except for patient 4. Only one patient was admitted with respiratory failure (hypoxemic).\n\n3.5 Radiological presentation\nAll patient performed chest radiograph at hospital admission, except for patient 4. The most common radiological findings were undefined nodular opacities, most frequently located in medial and lower lung fields.\n\nAll patients were evaluated with thorax CT scan. The most common findings were consolidations with air bronchogram and diffuse nodular densifications or centrilobular micronodules with tree-in-bud pattern (Fig. 1, Fig. 2, Fig. 3, Fig. 4).\n\n3.6 Diagnosis\nNo patient had suspicion of pulmonary nocardiosis at hospital admission. Main presumptive diagnosis were CAP and infected bronchiectasis.\n\nTo achieve definite diagnosis of nocardiosis, the isolation of the bacteria was necessary. It was made with bronchofibroscopic bronchoalveolar lavage with microbiological culture of the respiratory samples (patients 1 and 4), blood cultures (patient 2), sputum culture and nodule biopsy (patient 3).\n\n3.7 Hospitalization\nThe length of hospital stay was 30 ± 12 days.\n\nPatient 4, the only patient who didn't require hospitalization, kept regular follow-up in pulmonology consultations.\n\n3.8 Treatment\nAll patients began treatment with empiric antibiotic regimen at hospital admission, assuming a diagnosis of CAP, acute tracheobronchitis or infected bronchiectasis.\n\nAfter the establishment of the correct diagnosis, patients 1 and 3 started intravenous treatment (mean duration of 5 weeks) with TMP-SMX associated with imipenem (patient 1), or ceftriaxone and amikacin (patient 3). At discharge, both kept treatment with oral TMP-SMX for 12 months. Patient 2, who also started intravenous TMP-SMX, presented with unfavorable evolution and did not finish treatment. Patient 4, who didn't require hospitalization, was treated with TMP-SMX and amoxicillin-clavulanate, orally, for 6 months.\n\nGlobally, antibiotic treatment time was 13 ± 4 months. Excluding patient 2, all cases presented good clinical, analytical and radiological response to treatment.\n\n3.9 Outcomes\nPatient 2 was the only one who presented unfavorable evolution, dying in the context of septic shock from pulmonary nocardiosis, refractory to all therapeutic measures.\n\n4 Discussion\nPulmonary nocardiosis is a rare infection with a progressively increasing number of reported cases, concomitant with the increasing number of immunocompromised patients. It affects mainly the respiratory system, but may disseminate to any organ. When dissemination occurs, up to 50% of cases, brain tissue is the most frequent site [[1], [2], [3],5,7]. In this study, all cases had pulmonary nocardiosis and in one case (patient 3) there was also extrapulmonary dissemination, affecting the skin and retroperitoneal region. No patient had central nervous system lesions, excluded by cerebrospinal fluid analysis, brain CT or MRI scans.\n\nSymptoms are unspecific and commonly seen in common disorders like CAP. To achieve early diagnosis it is crucial to have clinical suspicion of pulmonary nocardiosis in the presence of lung infection concomitant with cerebral, skin or other soft tissues lesions, especially in patients with risk factors for immunosuppression or structural lung disease [3,6]. Two patients in this study had no risk factors for immunosuppression, besides structural lung disease (patients 2 and 4). A higher prevalence of the disease among male individuals has been reported, as seen in this population.\n\nNocardia asteroides complex was predominant in this population (including N. nova and N. transvalensis, identified in patients 3 and 4, respectively), in accordance with the literature. Patient 2 had Nocardia spp. identified in blood cultures, although this diagnostic method only rarely allows the identification of this bacteria.\n\nPulmonary nocardiosis is commonly misdiagnosed with fungal infection, tuberculosis or malignancy, leading to a delay in the correct diagnosis, treatment and worsening of prognosis, usually favorable [[1], [2], [3],5,7]. In this study, one of the patients had unfavorable outcome and died. Antibiotic treatment is prolonged, as seen in the described clinical cases (13 ± 4 months). However, relapse or disease progression is frequent, despite the treatment [1,2]. In a review study, the mortality attributed to nocardiosis was 38,7%, increasing to 64% in cases of disseminated disease, or even up to 100% if there was central nervous system infection. Therefore, it is fundamental to search for signs of disseminated disease at the diagnosis [9].\n\n5 Conclusion\nIn this review of 13 years from our institution, we found only four cases of pulmonary nocardiosis. Nocardiosis is a rare disease with good prognosis, if diagnosed early and treated adequately. It should be suspected in the presence of pulmonary infection concomitant with brain or other soft tissue lesion, especially in immunocompromised patients.\n\nStudy institution\nThis study was conducted in Pedro Hispano Hospital, Matosinhos, Portugal.\n\nAuthors contributions\nEvery author was involved in the conception and planning of the study, analysis and interpretation of the results, redaction and/or revision of the article.\n\nSponsorship\nNone to declare.\n\nDeclaration of competing interest\nNone.\n==== Refs\nReferences\n1 Kane J. Yandow D. Mohammed T. CT findings of pulmonary nocardiosis AJR 197 2011 266 272 10.2214/AJR.10.6208 \n2 Shariff M. Gunasekaran J. Pulmonary nocardiosis: review of cases and an update Can. Respir. J. J. Can. Thorac. Soc. 2016 10.1155/2016/7494202 \n3 Kandi V. Human Nocardia infections: a review of pulmonary nocardiosis Cureus 7 8 2015 e304 10.7759/cureus.304 26430578 \n4 Eshraghi S. Heidarzadeh S. Soodbakhsh A. Pulmonary nocardiosis associated with cerebral abscess successfully treated by co-trimoxazole: a case report Folia Microbiol. 2014 10.1007/s12223-013-0298-7 \n5 Li S. Song X. Zhao Y. Clinical analysis of pulmonary nocardiosis in patients with autoimmune disease Medicine 94 39 2015 1 8 10.1097/MD.0000000000001561 \n6 Kurahara Y. Tachibana K. Tsuyuguchi K. Pulmonary nocardiosis: a clinical analysis of 59 cases Respir. Invest. 52 2014 160 166 10.1016/j.resinv.2013.09.004 \n7 Chen Y. Lee C. Chien C. Pulmonary nocardiosis in southern Taiwan J. Microbiol. Immunol. Infect. 46 2013 441 447 10.1016/j.jmii.2012.07.017 23017691 \n8 Chen J. Zhou H. Xu P. Clinical and radiographic characteristics of pulmonary nocardiosis: clues to earlier diagnosis PloS One 9 3 2014 e90724 10.1371/journal.pone.0090724 \n9 Patil M. Shivaprasad C. Varghese J. A fatal case of pulmonary nocardiosis BMJ Case Rep. 2012 10.1136/bcr.09.2011.4875 \n10 Corti M. Fioti M. Nocardiosis: a review Int. J. Infect. Dis. 7 2003 243 250 10.1016/S1201-9712(03)90102-0 14656414 \n11 Takiguchi Y. Ishizaki S. Kobayashi T. Pulmonary nocardiosis: a clinical analysis of 30 cases Intern. Med. 56 2017 1485 1490 10.2169/internalmedicine.56.8163 28626172 \n12 Yagi K. Ishii M. Namkoong H. Pulmonary nocardiosis caused by Nocardia cyriacigeorgica in patients with Mycobacterium avium complex lung disease: two case reports BMC Infect. Dis. 14 2014 684 10.1186/s12879-014-0684-z 25491030 \n13 Kontogiorgi M. Opsimoulis P. Kopterides P. Pulmonary nocardiosis in an immunocompetent patient with COPD: the role of defective innate response Heart Lung 42 2013 247 250 10.1016/j.hrtlng.2013.03.007 23680413\n\n",
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"issn_linking": "2213-0071",
"issue": "31()",
"journal": "Respiratory medicine case reports",
"keywords": "Infection; Lung; Nocardia; Nocardiosis",
"medline_ta": "Respir Med Case Rep",
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"title": "Pulmonary nocardiosis: A Single Center Study.",
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"abstract": "OBJECTIVE\nTo report the onset of neuro-ophthalmological adverse effects in two children treated with metronidazole for amoebic dysentery.\n\n\nMETHODS\nA 6-year-old child and his 8-year-old sister presented with sudden bilateral vision loss and diplopia associated with intense headache and vomiting. The medical history revealed amoebic dysentery 3 weeks before treated orally with metronidazole for 2 weeks. The ophthalmic examination was similar in the two children and revealed visual acuity of 3/10 bilaterally, binocular diplopia, normal oculomotor function, quiet anterior segment, altered afferent pupil light reflex associated with normal fundus examination, and most particularly absence of optic disc edema. The kinetic visual field showed restriction of isopters and blind spot enlargement and the Lancaster test showed discrete paresis of the lateral rectus muscle of the left eye. Orbitocranial computed tomography and magnetic resonance imaging were normal and visual evoked potential results were compatible with optic neuropathy. Clinical progression consisted in spontaneous resolution of general symptoms, total regression of diplopia, improvement of visual acuity, and normalization of visual evoked potentials after treatment interruption. Regression of symptomatology after interruption of the treatment allowed us to retain the toxic origin.\n\n\nCONCLUSIONS\nMetronidazole may have neuro-ophthalmological side effects. These complications are rare but can be severe and are reversible after treatment interruption. Regular follow-up is necessary in children receiving this treatment.",
"affiliations": "Service d'ophtalmologie B, institut Hédi-Rais, boulevard 9-avril, 1006 Tunis, Tunisie.;Service d'ophtalmologie B, institut Hédi-Rais, boulevard 9-avril, 1006 Tunis, Tunisie.;Service d'ophtalmologie B, institut Hédi-Rais, boulevard 9-avril, 1006 Tunis, Tunisie. Electronic address: mejdabouladi@yahoo.fr.;Service d'ophtalmologie B, institut Hédi-Rais, boulevard 9-avril, 1006 Tunis, Tunisie.;Service d'ophtalmologie B, institut Hédi-Rais, boulevard 9-avril, 1006 Tunis, Tunisie.",
"authors": "Bouraoui|R|R|;Limaiem|R|R|;Bouladi|M|M|;Mghaieth|F|F|;El Matri|L|L|",
"chemical_list": "D000981:Antiprotozoal Agents; D008795:Metronidazole",
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"issue": "23(2)",
"journal": "Archives de pediatrie : organe officiel de la Societe francaise de pediatrie",
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"medline_ta": "Arch Pediatr",
"mesh_terms": "D000981:Antiprotozoal Agents; D002648:Child; D004172:Diplopia; D005260:Female; D006801:Humans; D008297:Male; D008795:Metronidazole; D014786:Vision Disorders",
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"title": "Neuro-ophthalmic adverse effects of metronidazole treatment in children: Two case studies.",
"title_normalized": "neuro ophthalmic adverse effects of metronidazole treatment in children two case studies"
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"abstract": "BACKGROUND\nNontuberculous mycobacteria belonging to the Mycobacterium avium complex are recognized as opportunistic pathogens to humans. Mycobacterium arosiense is one of the novel members of the Mycobacterium avium complex. The organism has only rarely been reported in human clinical cases and may be routinely misidentified.\n\n\nMETHODS\nAn adult male with a history of a discus prolapse and sarcoidosis presented with high fever and a strong back pain with projection to the extremities. A Magnetic Resonance Imaging scan of columna revealed a tumor suspect process at thoracic vertebrae 11/12 with changes at the second lumbar vertebra, which was partly removed by laminectomy. Biopsy smears revealed acid-fast bacilli and turned out to be Mycobacterium tuberculosis complex PCR negative. The routine line probe assay INNO-LiPa v2 (INNOGENETICS NV, Gent), which differentiates 16 mycobacterial species indicated the presence of a not readily identifiable NTM species. Whereas, the GenoType Mycobacterium CM v2.0 (HAIN Lifescience GmbH) that routinely differentiates 14 clinically relevant mycobacteria revealed a Mycobacterium intracellulare species. However, additional diagnostic sequencing of the 16S rRNA gene confirmed the presence of a Mycobacterium arosiense species.\n\n\nCONCLUSIONS\nThis is the second unusual case of osteomyelitis with clinical significance ever to be reported, caused by Mycobacterium arosiense and complicated by an underlying sarcoidosis. Mycobacterium arosiense has rarely been reported clinically and the first description of the species was identified as the cause of osteomyelitis in a child with a hereditary partial interferon gamma deficiency. Symptoms attributed to sarcoidosis waned on Mycobacterium arosiense treatment and it is inconclusive whether the patient ever suffered from sarcoidosis. Mycobacterium arosiense was misidentified by the GenoType as Mycobacterium intracellulare and implicates that the diagnosis requires supplemental sequencing of the 16S rRNA gene.",
"affiliations": "Virus & Microbiological Special Diagnostics, Infectious Disease Preparedness, Statens Serum Institut, Copenhagen, Denmark. dvb@ssi.dk.;International Reference Laboratory of Mycobacteriology, Statens Serum Institut, Copenhagen, Denmark.;Department of infectious Diseases, Rigshospitalet, Copenhagen, Denmark.",
"authors": "Bang|Didi|D|http://orcid.org/0000-0002-7490-5369;Rasmussen|Erik Michael|EM|;Andersen|Aase Bengaard|AB|",
"chemical_list": "D012336:RNA, Ribosomal, 16S",
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"fulltext": "\n==== Front\nBMC Infect DisBMC Infect. DisBMC Infectious Diseases1471-2334BioMed Central London 463810.1186/s12879-019-4638-3Case ReportMycobacterium arosiense, an unexpected cause of osteomyelitis in a patient with sarcoidosis: a case report http://orcid.org/0000-0002-7490-5369Bang Didi + 45 32683268dvb@ssi.dk 1Rasmussen Erik Michael mre@ssi.dk 2Andersen Aase Bengaard Aase.Bengaard.Andersen@regionh.dk 31 0000 0004 0417 4147grid.6203.7Virus & Microbiological Special Diagnostics, Infectious Disease Preparedness, Statens Serum Institut, Copenhagen, Denmark 2 0000 0004 0417 4147grid.6203.7International Reference Laboratory of Mycobacteriology, Statens Serum Institut, Copenhagen, Denmark 3 grid.475435.4Department of infectious Diseases, Rigshospitalet, Copenhagen, Denmark 26 11 2019 26 11 2019 2019 19 9947 8 2019 18 11 2019 © The Author(s). 2019Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nNontuberculous mycobacteria belonging to the Mycobacterium avium complex are recognized as opportunistic pathogens to humans. Mycobacterium arosiense is one of the novel members of the Mycobacterium avium complex. The organism has only rarely been reported in human clinical cases and may be routinely misidentified.\n\nCase presentation\nAn adult male with a history of a discus prolapse and sarcoidosis presented with high fever and a strong back pain with projection to the extremities. A Magnetic Resonance Imaging scan of columna revealed a tumor suspect process at thoracic vertebrae 11/12 with changes at the second lumbar vertebra, which was partly removed by laminectomy. Biopsy smears revealed acid-fast bacilli and turned out to be Mycobacterium tuberculosis complex PCR negative. The routine line probe assay INNO-LiPa v2 (INNOGENETICS NV, Gent), which differentiates 16 mycobacterial species indicated the presence of a not readily identifiable NTM species. Whereas, the GenoType Mycobacterium CM v2.0 (HAIN Lifescience GmbH) that routinely differentiates 14 clinically relevant mycobacteria revealed a Mycobacterium intracellulare species. However, additional diagnostic sequencing of the 16S rRNA gene confirmed the presence of a Mycobacterium arosiense species.\n\nConclusions\nThis is the second unusual case of osteomyelitis with clinical significance ever to be reported, caused by Mycobacterium arosiense and complicated by an underlying sarcoidosis. Mycobacterium arosiense has rarely been reported clinically and the first description of the species was identified as the cause of osteomyelitis in a child with a hereditary partial interferon gamma deficiency. Symptoms attributed to sarcoidosis waned on Mycobacterium arosiense treatment and it is inconclusive whether the patient ever suffered from sarcoidosis. Mycobacterium arosiense was misidentified by the GenoType as Mycobacterium intracellulare and implicates that the diagnosis requires supplemental sequencing of the 16S rRNA gene.\n\nKeywords\nNontuberculous myobacteriaMycobacterium arosienseMycobacterium avium complexVertebral osteomyelitisBone infectionissue-copyright-statement© The Author(s) 2019\n==== Body\nBackground\nMost nontuberculous mycobacteria (NTM) may occasionally be the causative agents of osteomyelitis. The Mycobacterium avium complex (MAC) bacteria are NTM recognized as opportunistic pathogens of humans. In Denmark, Mycobacterium avium complex has been isolated from nonpulmonary sites in 16% of cases [1]. Vertebral osteomyelitis is a rare manifestation of MAC in persons with human immunodeficiency virus or suffering from other immunocompromise, but is even less common in persons without immunocompromising conditions.\n\nClassically, the MAC predominately consisted of two species, Mycobacterium avium and Mycobacterium intracellulare. However, new molecular methods of nucleotide identities reveal that the MAC currently consists of 12 valid species [2]. Mycobacterium arosiense, a slow growing, yellow-pigmented, scotochromogenic, NTM is one of the novel species of the MAC. Mycobacterium arosiense was isolated for the first time from osteomyelitic lesions of a child with an underlying partial interferon gamma (IFN-γ) receptor alpha-1 deficiency in 2008 [3]. The reporting of pathogens with clinical relevance within the MAC is of utmost importance. Mycobacterium arosiense may not readily be routinely identified. We report here a rare case of vertebral osteomyelitis in an adult with a presumed underlying diagnosis of sarcoidosis.\n\nCase presentation\nAn adult male of 35-years of age with a medical history of a discus prolapse more than a decade ago and a diagnosis of sarcoidosis 6 years previously based on a chest X-ray with bilateral infiltrations, and hilar lymphadenopathy. A testicular biopsy taken for fertility assessment, showed non-casseous changes. The biopsy was smear-negative for acid-fast bacilli (AFB) and cultures for bacteria and mycobacteria were negative. In support of the sarcoidosis diagnosis elevated C-reactive protein (CRP), erythrocyte sedimentation rate, and angiotensin-converting enzyme (ACE) levels were found. PET-CT scans showed metabolically active glands in the retroperitoneum and activity in the left upper lobe of the lungs. The sarcoidosis had been treated with steroids intermittently for years and was currently treated with prednisolone 2.5 mg q.d monotherapy at the time of diagnosis, and monitored with ACE measurements. Otherwise, the patient was healthy with no known allergies, other immune deficiencies, cardiovascular disorders or diabetes mellitus.\n\nOne week prior to ambulatory care the patient presented with uncharacteristic symptoms and experienced strong back pains with a stinging pain in the extremities and left side of the chest not unlike prior discus prolapse symptoms. However, with a high fever and sweat tendency. Mild analgesics in the form of oral paracetamol and NSAID caused symptoms to wane and the temperature normalized. A neurological examination was normal and no neurological focal signs or urinary functional problems were found. A slight dry cough and breathlessness, and a high pulse rate of 130 were observed. An elevated CRP of 70 (< 10 mg/L) and a normal ACE level of 93 (30–115 U/l) was interpreted as no sign of sarcoidosis reactivation. The p-basic phosphatase level was slightly elevated to 181 U/L (30–105), which however normalized. Electrocardiogram was normal. A chest X-ray showed regression of infiltrates but unchanged hilar lymphadenopathy. Sputum smear was negative for acid-fast bacilli and culture. A pulmonary function test showed reduced diffusion capacity and vital capacity to 70% of expected, which until now had been considered due to sarcoidosis.\n\nOne month later a Magnetic Resonance imaging scan of columna revealed a tumor suspect process extradurally at thoracic vertebrae 11/12 with changes at the second lumbar vertebra. A fortnight later, decompression of thoracic vertebrae and lumbar biopsies were performed. Thoracic laminectomy revealed a tumor-like process from which pus exuded. The tumor was partially removed and the biopsies and pus were sent for smear, bacterial culture including Mycobacteria and pathology. Smear revealed few to moderate AFB in all four biopsies. On suspicion of a diagnosis of tuberculosis anti-tuberculosis oral medication was started with rifampin 600 mg q.d., isoniazid 300 mg q.d., ethambutol 1200 mg q.d., pyrazinamide 2000 mg q.d., and pyridoxine 20 mg q.d. The prednisolone treatment was ceased. At this point the CRP was elevated at 59 (< 10 mg/L) with normal hematology, liver and kidney laboratory results. A human immunodeficiency virus test was negative. Sputum samples for tuberculosis diagnostics were negative. Biopsy material turned out to be Mycobacterium tuberculosis complex PCR negative, and the routine line probe assay INNO-LiPa v2 (INNOGENETICS NV, Gent), which differentiates 16 mycobacterial species indicated the presence of a not readily identifiable NTM species. On suspicion of tuberculosis, anti-tuberculosis treatment was continued. Additional identification by the line probe assay GenoType Mycobacterium CM v2.0 (HAIN Lifescience GmbH), which differentiates 14 clinically relevant mycobacteria indicated the presence of a Mycobacterium intracellulare.\n\nAlmost 3 weeks after the biopsy was performed supplemental diagnostic sequencing of the 16S rRNA gene revealed a rare Mycobacterium arosiense, a NTM belonging to the Mycobacterium avium complex [2]. Medication was changed to rifabutin 300 mg q.d., clarithromycin 500 mg b.i.d. and ethambutol 1200 mg q.d. Anti-tuberculosis treatment was ceased. However, signs of bone marrow toxicity in the form of leucopenia 0.7–0.9 × 109/L, low CD4 cell counts at 150–200 × 106 cells/L, and thrombocytopenia at 143 × 109/L were observed. The rifabutin dose was decreased to 150 mg q.d.. Immunoglobulin subclasses results were unspecific. The patient completed 6 months oral anti-NTM medication before ceasing medication. Respiratory breathlessness that was present through many years disappeared during NTM treatment.\n\nDiscussion and conclusions\nMycobacterium arosiense has rarely been reported clinically and the first description of the species was identified from several osteomylitic bone lesion sites of a girl with a hereditary partial IFN-γ receptor alpha-1 deficiency [3]. Complete absence of the IFN-γ receptor alpha-1 results in a deficiency that leads to early onset and severe mycobacterial infections [4]. Recessive null IFN-γ receptor-1 mutations preclude the expression of IFN-γ receptor-1 on the cell surface, or recognition of the ligand IFN-γ by surface expressed receptors. Affected patients therefore fail to respond to IFN-γ and have high concentrations of IFN-γ after infection. Numerous reports from such patients that have suffered from disseminated infections caused by NTM and/or Bacille Calmette-Guerin vaccines, with impaired granuloma formation have been described. Only one other clinical case of pulmonary disease has ever been reported, where Mycobacterium arosiense was found in an adult male with a history of Hodgkin’s lymphoma, gastric carcinoma and splenectomy [5].\n\nWe report the second unusual osteomyelitic case ever reported complicated by an underlying sarcoidosis. According to American Thoracic Society guidelines [6] several factors increase the likelihood of clinical significance of NTM isolates, including recovery from multiple specimens or sites, recovery of the organism in large quantities, AFB smear-positive specimens, or recovery of the organism from sterile sites such as bone material. The present case fulfills all these criteria of clinical significance.\n\nImmune analysis showed the IFN-γ receptor signal ring was normal with no suspicion of changes in the interleukin-12/IFN-γ axis signal ring. Analysis of immunoglobulin (Ig) G classes and subclasses were normal for IgA, IgM and IgG, but were decreased for IgG2 and IgG4. Humoral B lymphocytes were slightly reduced. In reflection of slight leucopenia, with no thrombocytopenia, and normal hemoglobin throughout it was difficult to conclude on an actual immune defect. It is inconclusive whether the patient ever suffered from sarcoidosis. The previously observed increase of ACE may have been due to granuloma dissolving and not due to progression in sarcoidosis.\n\nSarcoidosis is an inflammatory condition of the immune system with development and accumulation of granulomas commonly involving several organs [7]. The cause of sarcoidosis is still unknown, although environmental, immunological and bacterial causes have been implicated as triggers of immune responses resulting in sarcoidosis. Scientists have recovered mycobacteria and propionibacteria RNA and DNA from sarcoidal tissues. Likewise, serum antibodies to mycobacterial antigens, including recombinant Mycobacterium tuberculosis katG, heat-shock protein 70 and 18, and mycolyl transferase antigen 85A.19 have been retrieved from patients with sarcoidosis.\n\nRetrospectively, the patient experienced neuritis vestibularis and a facialis paresis together with pulmonary symptoms, which were perceived as sarcoidosis. The patient also had bilateral hilar lymph node swelling, which all could be explained by sarcoidosis, and the biopsy showed signs of sarcoidosis and not NTM. However, the fact that the sarcoidosis symptoms disappeared on treatment for a NTM, support the theory that the infection may have been present for a long time. Infiltrations on Chest-X rays resolved, although some degree of hilar lymphadenopathy remained. As proposed chronic corticosteroid therapy may pose a greater risk for MAC vertebral osteomyelitis than previously recognized [8].\n\nFollow-up several months after the medication was ceased revealed that the patient continued to have leucopenia at 3 × 109/L with low granulocytes at 1.4 × 109/L and lymphocytes at 0.76 × 109/L. The thrombocyte level had normalized and the presence of a permanent immunosuppression was discussed though not confirmed.\n\nAs in the present case Mycobacterium arosiense has been misidentified by the GenoType CM as Mycobacterium intracellulare [5]. Implications of misidentification indicate that Mycobacterium arosiense may be less rare than considered and supplemental diagnostic sequencing of the 16S rRNA gene on all routine Mycobacterium intracellulare strains is required. The consequences of differentiation of the Mycobacterium arosiense from the MAC are unknown. Some organisms within the MAC complex such as Mycobacterium chimaera have poor treatment responses [9]. The recent introduction of affordable sequencing platforms may increase our knowledge on the management and treatment of patients suffering from Mycobacterium arosiense infections.\n\nAbbreviations\nACEAngiotensin-converting enzyme\n\nAFBAcid-fast bacilli\n\nCRPC-reactive protein\n\nCTComputed tomography\n\nIFN-γInterferon gamma\n\nIgImmunoglobulin\n\nMACMycobacterium avium complex\n\nNTMNontuberculous mycobacteria\n\nPETPositron emission tomography\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAcknowledgements\nNot applicable.\n\nAuthor’s contribution\nABA treated the patient. DB designed and implemented the research. Together DB, EMA, and ABA analyzed the results and DB wrote the first draft of the manuscript. All authors contributed to the writing of the manuscript. All authors read and approved the final manuscript.\n\nAuthors’ information\n1Virus & Microbiological Special Diagnostics, Infectious Disease Preparedness, Statens Serum Institut, Denmark, 2International Reference Laboratory of Mycobacteriology, Statens Serum Institut, Denmark, 3Department of infectious Diseases, Rigshospitalet, Denmark.\n\nFunding\nNot applicable.\n\nAvailability of data and materials\nAll data generated or analyzed during this study are included in this published article.\n\nEthics approval and consent to participate\nThis case report has been described in accordance with the ethical standards laid down in the “Declaration of Helsinki 1964” and its later amendments or comparable ethical standards. A written informed consent form was signed by the patient.\n\nConsent for publication\nWritten informed consent was obtained from the patient for publication of this case report. A copy of the written consent is available for review by the Editor of this journal.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n==== Refs\nReferences\n1. Hermansen TS Ravn P Svensson E Lillebaek T Nontuberculous mycobacteria in Denmark, incidence and clinical importance during the last quarter-century Sci Rep 2017 7 1 8 10.1038/s41598-017-06931-4 28127051 \n2. Van Ingen J Turenne CY Tortoli E Wallace RJ Brown-Elliott BA A definition of the Mycobacterium avium complex for taxonomical and clinical purposes, a review Int J Syst Evol Microbiol 2018 68 3666 3677 10.1099/ijsem.0.003026 30231956 \n3. Bang D Herlin T Stegger M Andersen AB Torkko P Tortoli E Mycobacterium arosiense sp. nov., a slowly growing, scotochromogenic species causing osteomyelitis in an immunocompromised child Int J Syst Evol Microbiol 2008 58 2398 2402 10.1099/ijs.0.65503-0 18842863 \n4. Storgaard M Varming K Herlin T Obel N Novel mutation in the interferon-γ-receptor gene and susceptibility to mycobacterial infections Scand J Immunol 2006 64 137 139 10.1111/j.1365-3083.2006.01775.x 16867158 \n5. Tortoli E Adriani B Baruzzo S Degl’Innocenti R Galanti I Lauria S Pulmonary disease due to Mycobacterium arosiense , an easily misidentified pathogenic novel mycobacterium J Clin Microbiol 2009 47 1947 1949 10.1128/JCM.02449-08 19386835 \n6. Griffith DE Aksamit T Brown-Elliott BA Catanzaro A Daley C Gordin F An official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases Am J Respir Crit Care Med 2007 175 367 416 10.1164/rccm.200604-571ST 17277290 \n7. Lannuzzi MC Rybicki BA Teirstein A Sarcoidosis N Engl J Med 2017 357 2153 2165 10.1056/NEJMra071714 \n8. Gray ME Liu PW Wispelwey B Mycobacterium avium complex vertebral osteomyelitis in the absence of HIV infection: a case report and review BMC Infect Dis 2018 18 235 10.1186/s12879-018-3143-4 29788907 \n9. Kasperbauer Shannon H Daley Charles L Mycobacterium chimaera Infections Related to the Heater–Cooler Unit Outbreak: A Guide to Diagnosis and Management Clinical Infectious Diseases 2018 68 7 1244 1250 10.1093/cid/ciy789\n\n",
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"mesh_terms": "D000328:Adult; D006801:Humans; D008297:Male; D009161:Mycobacterium; D009164:Mycobacterium Infections; D010019:Osteomyelitis; D016133:Polymerase Chain Reaction; D012336:RNA, Ribosomal, 16S; D012507:Sarcoidosis",
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"pubdate": "2019-11-26",
"publication_types": "D016428:Journal Article",
"references": "17277290;28751677;19386835;16867158;29788907;18842863;18032765;30371755;30231956",
"title": "Mycobacterium arosiense, an unexpected cause of osteomyelitis in a patient with sarcoidosis: a case report.",
"title_normalized": "mycobacterium arosiense an unexpected cause of osteomyelitis in a patient with sarcoidosis a case report"
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"abstract": "The most common fatal complication of liver cirrhosis is haemorrhaging caused by variceal rupture. The prevention of the first variceal bleed is, therefore, an important clinical goal. Little is known about patients' experience of treatments geared towards this, or of their perceptions of treatments prior to being exposed to them.\n\n\n\nTo explore the factors impacting patient preference for, and actual experience of carvedilol and variceal band ligation.\n\n\n\nSemistructured interviews were conducted with 30 patients from across the UK at baseline, prior to random allocation to either carvedilol or variceal band ligation. Twenty patients were interviewed a second time at 6-month follow-up. Five patients who declined the trial were also interviewed. Data were analysed using thematic analysis.\n\n\n\nThere was no clear preference for either treatment pathway at baseline. Key factors reported by patients to influence their treatment preference included: negative experiences with key treatment processes; how long-term or short-term treatment was perceived to be; treatment misconceptions; concerns around polypharmacy and worries around treatment adherence. Patient treatment experience was influenced by their perceptions of treatment effectiveness; clinical surveillance; clinician interaction and communication, or lack thereof. Carvedilol-specific experience was also influenced by the manifestation of side effects and patient dosage routine. Variceal band ligation-specific experience was positively influenced by the use of sedation, and negatively influenced by the procedure recovery period.\n\n\n\nThese data do not support a view that the patient experience of beta-blockade for prevention of variceal bleeds is likely to be superior to variceal band ligation.",
"affiliations": "Institute of Applied Health Research, University of Birmingham, Birmingham, Birmingham, UK c.poyner@bham.ac.uk.;University of Birmingham, Birmingham, UK.;Institute of Applied Health Research, University of Birmingham, Birmingham, Birmingham, UK.",
"authors": "Poyner|Chris|C|0000-0001-6271-2626;Tripathi|Dhiraj|D|0000-0001-9043-6382;Mathers|Jonathan|J|",
"chemical_list": "D000077261:Carvedilol",
"country": "England",
"delete": false,
"doi": "10.1136/bmjgast-2021-000684",
"fulltext": "\n==== Front\nBMJ Open Gastroenterol\nBMJ Open Gastroenterol\nbmjgast\nbmjgast\nBMJ Open Gastroenterology\n2054-4774\nBMJ Publishing Group BMA House, Tavistock Square, London, WC1H 9JR\n\nbmjgast-2021-000684\n10.1136/bmjgast-2021-000684\nGastrointestinal Bleeding\n1506\nExploring patients’ perceptions and experiences of treatments for the prevention of variceal bleeding: a qualitative study\nhttp://orcid.org/0000-0001-6271-2626\nPoyner Chris 1\nhttp://orcid.org/0000-0001-9043-6382\nTripathi Dhiraj 23\nMathers Jonathan 1\n1 Institute of Applied Health Research, University of Birmingham, Birmingham, Birmingham, UK\n2 University of Birmingham, Birmingham, UK\n3 Liver Unit, Queen Elizabeth Hospital, Birmingham, Birmingham, UK\nCorrespondence to Dr Chris Poyner; c.poyner@bham.ac.uk\n2021\n16 8 2021\n8 1 e00068419 4 2021\n22 7 2021\n© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.\n2021\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See: https://creativecommons.org/licenses/by/4.0/.\n\nBackground\n\nThe most common fatal complication of liver cirrhosis is haemorrhaging caused by variceal rupture. The prevention of the first variceal bleed is, therefore, an important clinical goal. Little is known about patients’ experience of treatments geared towards this, or of their perceptions of treatments prior to being exposed to them.\n\nAims\n\nTo explore the factors impacting patient preference for, and actual experience of carvedilol and variceal band ligation.\n\nMethods\n\nSemistructured interviews were conducted with 30 patients from across the UK at baseline, prior to random allocation to either carvedilol or variceal band ligation. Twenty patients were interviewed a second time at 6-month follow-up. Five patients who declined the trial were also interviewed. Data were analysed using thematic analysis.\n\nResults\n\nThere was no clear preference for either treatment pathway at baseline. Key factors reported by patients to influence their treatment preference included: negative experiences with key treatment processes; how long-term or short-term treatment was perceived to be; treatment misconceptions; concerns around polypharmacy and worries around treatment adherence. Patient treatment experience was influenced by their perceptions of treatment effectiveness; clinical surveillance; clinician interaction and communication, or lack thereof. Carvedilol-specific experience was also influenced by the manifestation of side effects and patient dosage routine. Variceal band ligation-specific experience was positively influenced by the use of sedation, and negatively influenced by the procedure recovery period.\n\nConclusions\n\nThese data do not support a view that the patient experience of beta-blockade for prevention of variceal bleeds is likely to be superior to variceal band ligation.\n\nliver cirrhosis\nportal hypertension\nendoscopic procedures\noesophageal varices\nNational Institute for Health Research (NIHR) 16/99/02 special-featureunlocked\n==== Body\nSummary box\n\nWhat is already known about this subject?\n\nThe relative clinical effectiveness of competing treatments (carvedilol vs variceal band ligation), for the primary prevention of variceal bleeds is contested.\n\nThere is limited quantitative evidence from the USA suggesting that both treatment-naïve patients and clinicians are more likely to state a preference for variceal band ligation as first-line treatment.\n\nTo date, there have not been any qualitative research studies that have examined cirrhotic patients’ views and experiences of treatments for the prevention of variceal bleeding.\n\nWhat are the new findings?\n\nThe preferences of treatment-naïve patients are varied.\n\nPatient perceptions of variceal band ligation were positively influenced by their experience of this treatment pathway.\n\nThe patient experience of beta-blockade for prevention of variceal bleeds is not likely to be superior to variceal band ligation.\n\nHow might it impact on clinical practice in the foreseeable future?\n\nEnsuring patients are fully informed of the nature of treatments may improve their experience of treatment processes and also improve adherence.\n\nOur findings may help to inform clinical decision making when considering treatment options for patients with medium to large varices.\n\nIntroduction\n\nEstimates suggest that globally liver cirrhosis is responsible for 1.16 million deaths annually.1 In the UK, cases have risen from 6999 in 2012 to 7630 in 2016, an increase of 8.3%.2 Liver cirrhosis is the fifth largest cause of death3 and the third largest cause of premature death in the UK.4 The lived experience of liver cirrhosis, often understood using qualitative research methods, is poorly evidenced, with patient perceptions of treatments representing a key gap.5 Much of the qualitative research evidence that does exist relates to patients eligible for liver transplantation, for example, examining patients’ experiences pretransplantation6 7 and post-transplantation.8–10 These patients are not necessarily representative of the wider liver cirrhosis patient population, with most ineligible for a transplant.11\n\nA major common complication of liver cirrhosis is oesophageal varices, due to portal hypertension. At diagnosis approximately 30% of patients have oesophageal varices, rising to 90% after 10 years.12 13 At least 3000 patients are admitted to hospital in England per year with variceal bleeding, with inpatient mortality of 15% and 1-year mortality of up to 40%.14 The prevention of the first variceal bleed is therefore an important clinical goal.\n\nTreatments aiming to prevent variceal bleeds include non-selective beta blockers, such as carvedilol, and/or variceal band ligation (VBL).15 16 Currently, there is inconsistency within best practice guidance in the UK, with the British Society of Gastroenterology recommending a non-selective beta-blocker as first-line therapy,15 and the National Institute for Health and Care Excellence (NICE) recommending VBL.13 Although at present the NICE guideline is under review, the relative clinical effectiveness of each treatment remains contested.\n\nThere is limited quantitative evidence from the USA suggesting that both treatment-naïve patients and clinicians are more likely to state a preference for VBL as first-line treatment, despite the predominance of beta-blockade in practice.17 To date, however, there have not been any qualitative research studies that have examined cirrhotic patients’ views and experiences of treatments in depth. Information relating to patients’ treatment preferences and the acceptability of treatment options provides a crucial adjunct to evidence of the clinical efficacy of treatment options in clinical decision making. The carvedilol versus variceal band ligation in primary prevention of variceal bleeding in liver cirrhosis study (CALIBRE) is a randomised controlled trial (RCT) investigating the effectiveness of carvedilol versus VBL for the prevention of variceal bleeds.14 This paper presents findings from the qualitative research component of the CALIBRE study which aimed first to explore patients’ preferences for treatment, and second to describe their actual experience of VBL and carvedilol.14\n\nMaterials and methods\n\nStudy design\n\nThis qualitative research study was conducted during an internal pilot trial of the CALIBRE study, a multicentre RCT comparing carvedilol and VBL for the primary prevention of variceal bleeds from medium and large varices.\n\nTo meet the inclusion criteria for CALIBRE patients need to have been assessed by a consultant gastroenterologist as having medium (grade II) or large (grade III) varices as defined in the British Society of Gastroenterology guidelines15 that have never bled.\n\nSampling and recruitment\n\nFor the qualitative research study, we sampled patients randomised to carvedilol and VBL, as well as those who were eligible but declined to participate in CALIBRE. Potential participants were identified by research teams recruiting to CALIBRE at hospital sites in England, Scotland and Wales and provided with written information about the qualitative study. Patients expressing an interest in participation were consented to provide contact details to the qualitative research team at the University of Birmingham, UK. A qualitative researcher (CP) then contacted patients to answer any questions and to arrange a convenient date and time for interview. Audiorecorded consent was taken prior to interview.\n\nData collection\n\nSemistructured one-to-one interviews provide rich data relating to individuals’ perspectives and lived experience of disease and treatments. Patients randomised to carvedilol and VBL were invited to interview at two time points; within 1 month of randomisation and after 6 months of trial participation. At index interview ten of the 15 VBL patients had experienced their first procedure. All 15 carvedilol patients had commenced treatment. Baseline interviews with patients were conducted between February and September 2019. Follow-up interviews were conducted between August and March 2020. Patients declining participation in CALIBRE took part in a one-off interview. The majority of interviews were conducted over the phone (n=52), with a small number (n=3) conducted face to face in a private room at the University of Birmingham. Prior to data collection, it was estimated that interviews with approximately 15 patients in each trial group would allow saturation of core analytical themes.\n\nInterview schedules guided interview conduct and were refined iteratively following initial interviews (see online supplemental file A). Baseline interviews with trial participants focused primarily on the acceptability of CALIBRE, exploring patients’ perspectives on the recruitment process and their treatment preferences prior to randomisation. To contextualise these perspectives participants were also asked to briefly discuss their prior experience of liver cirrhosis and its impact on daily life. Follow-up interviews focused on patients’ experience of treatment with carvedilol or VBL. Topics for discussion included the occurrence of side effects and their impact on health and quality of life, the experience of undergoing treatment (eg, medication routines, the VBL procedure and recovery) and how patients felt about the diagnosis of varices and the risk of bleed following treatment. Prior to the follow-up interview, the interviewer (CP) reread the transcript of the initial interview, and noted additional areas for follow-up with the interviewee based on prior discussion. Interviews with patients declining the trial focused on their reasons for this decision, including associated treatment preferences.\n\n10.1136/bmjgast-2021-000684.supp1 Supplementary data\n\nInterviews were audiorecorded and transcribed clean verbatim by a professional transcription company. Data were analysed with reference to interview transcripts, recordings and notes taken during and after interview. Data collection and analysis proceeded iteratively. At the point at which initial sample estimates for baseline interviews were attained, it was judged that data saturation of core analytic content had been achieved and recruitment to the qualitative study was ceased.18\n\nAt follow-up, it was judged that saturation pertaining to patients’ experience of treatment for varices had also been attained.\n\nData analysis\n\nAn inductive thematic analysis informed by framework was undertaken.19 Each transcript was read multiple times to aid familiarisation, and each recording was listened back to check the accuracy of the transcript. A sample of transcripts were independently coded by CP and JM, then discussed. This process informed further iterative coding. Codes were grouped into categories and all data were indexed. Relationships between categories were examined in order to interpret overarching themes. Preliminary descriptive analytical accounts were shared between CP and JM to aid this process. Emerging interpretations were discussed among the broader research team. Associative analysis, comparing the accounts of patients allocated to VBL with those allocated to carvedilol, was undertaken. Data were managed via Nvivo qualitative data analysis software (V.12).\n\nResults\n\nThirty trial participants were interviewed at baseline (table 1). Of these, 20 were available for interview at follow-up. Of the 30, 15 were allocated to carvedilol (10 followed up) and 15 to VBL (10 followed up); 17 were male and the median age was 60 (range 27–80). Five patients who declined consent to CALIBRE were also interviewed.\n\nTable 1 Sample characteristics of interviewees who were CALIBRE trial participants\n\nTreatment\tCarvedilol\t15 (50%)\t\n\tVBL\t15 (50%)\t\nPresence of hepatic decompensation\tYes\t4 (13.33%)\t\n\tNo\t26 (86.66%)\t\nAlcohol-related liver disease\tYes\t10 (33.33%)\t\n\tNo\t20 (66.66%)\t\nGrade of varices\tGrade 2\t26 (13.33%)\t\n\tGrade 3\t4 (86.66%)\t\nAge at randomisation\t18–50 years\t7 (23.33%)\t\n\t51–70 years\t19 (63.33%)\t\n\t>70 years\t4 (13.33%)\t\n\tMedian=60\t\t\nGender\tMale\t17 (56.66%)\t\n\tFemale\t13 (43.33%)\t\nCountry\tEngland\t23 (76.66%)\t\n\tScotland\t6 (20.00%)\t\n\tWales\t1 (03.33%)\t\nVBL, variceal band ligation.\n\nThemes\n\nFindings are presented in three sections. First, data related to interviewees’ treatment preferences at baseline, prior to randomisation, are reported. Next, patients’ actual experience of treatment at follow-up are described. Finally, the ‘peace of mind’ afforded to patients by treatment is considered. Within each section, findings related to carvedilol and VBL are presented separately. Themes, subthemes and findings are summarised in table 2.\n\nTable 2 Summary table of themes, subthemes and findings\n\nTheme\tTreatment\tSubtheme\tSummary findings\t\nTreatment preferences at baseline interview\tCarvedilol\tAversion to gastroscopic procedures\tAll patients had experienced at least one gastroscopy previously and preference for carvedilol was often influenced by this experience.\t\nCarvedilol\tMisconceptions around the nature of the VBL procedure\tSome patients described VBL inaccurately, that is, as surgery, or not requiring sedation to justify their preference for carvedilol.\t\nCarvedilol\tThe causal mechanism of carvedilol\tA small number of patients mentioned the causal mechanism of carvedilol as the key reason for their stated preference.\t\nVBL\tConcern about polypharmacy\tSome patients described already taking several medications as a concern, or a more general dislike of taking tablets\t\nVBL\tCarvedilol adherence\tSome participants went on to report a concern about their capacity to remember to take carvedilol on a daily basis\t\nVBL\tHistory of mental health challenges\tIn a small number of cases, patients with a history of mental health issues were concerned that taking medication could cause such issues to resurface\t\nVBL\tVBL as the quicker solution\tSome participants perceived VBL as a quicker solution due to the long-term nature of carvedilol prescription, and a perception that the issue of variceal bleeding is dealt with once varices have been banded\t\nVBL\tLower blood pressure as problematic\tA small number of patients felt that having their blood pressure lowered would negatively impact their health or quality of life due to a fear of blacking out or fainting.\t\nReasons given for a stated lack of treatment preference\tNeither\tLack of knowledge on which to base a preference\tSlightly fewer than half of the trial participants interviewed reported no clear treatment preference at the baseline interview. Most commonly, patients who did not have a clear preference were most concerned by overall health outcomes.\t\nPatients’ actual experience of treatment\tCarvedilol\tSide effects\tA lack of side effects contributed to satisfaction with treatment as did a perception of improved health outcomes. A slight majority of participants did report at least one negative side effect. Reported side effects included: dizziness, fainting, nausea, diarrhoea, palpitations, fatigue and low mood. The most commonly discussed side effect was fatigue.\t\nCarvedilol\tImportance of dosage routine to positive experience of carvedilol\tFor some patients, side effects lessened or were alleviated after the first month or so of taking the medication. Dosage routine alterations were often key to this.\t\nVBL\tSedation as key to a better patient experience than anticipated\tPatients who described anxiety around VBL due to previous negative experiences of endoscopy, reported a better than anticipated experience due to the positive impact of sedation.\t\nVBL\tTrust in clinician conducting procedure\tTreatment acceptability was reported as low by patients where they were not confident in the clinician performing the procedure. In many cases patients suggested that trusting relationships with their consultants were key to a positive VBL procedure experience\t\nVBL\tPain during VBL recovery period\tThe recovery from VBL was reported as the most challenging aspect. Pain and nausea were reported. Patients described the need to eat, soft and cold foods. Some felt underprepared for their recovery.\t\nBoth\tPeace of mind related to perceptions of treatment effectiveness\tIn most cases, carvedilol patients expressed concern regarding a lack of continued monitoring and desired reassurance that the treatment was working. For VBL patients, a key positive of the experience was what was perceived as knowledge that their varices had been, or were in the process of being eradicated.\t\nVBL, variceal band ligation.\n\nData from interviews with patients declining the trial are included in the first section as they further illustrate treatment preferences for patients who are treatment-naïve.\n\nTreatment preferences at baseline interview\n\nAmong the patients participating in the pilot trial there was no clear preference for either treatment. Broadly these interviewees were evenly split between those with a strong preference for carvedilol or VBL, and those without a strong preference for either treatment. Patients declining the trial all expressed an aversion to gastroscopy and hence VBL. Patients’ reasoning behind stated preferences are detailed below.\n\nReasons given for a stated preference to be allocated to carvedilol\n\nAn aversion to gastroscopic procedure\n\nIn many cases, for those with a preference for carvedilol, an aversion to gastroscopy was key, rather than any perceived benefits associated with carvedilol. All patients had experienced at least one gastroscopy previously and preference for carvedilol was often influenced by this experience. Distressing previous gastroscopies were commonly reported:\n\nIt was pretty horrendous and I was aware I was choking all the way through, it was horrible. So I thought please let it be the other one… (Interviewee 3)\n\nPatients declining to participate in CALIBRE all described this as a key factor in the decision to do so, not wanting to be allocated to VBL:\n\nI went I am not doing it. I am not going to have an endoscopy every month. (Decliner Interviewee D3)\n\nMisconceptions around the nature of the VBL procedure\n\nSome apparent misconceptions about the nature and detail of VBL seem to have impacted on preferences and acceptability to some patients. One case was clearly demonstrative of this:\n\nAs I say my GP… gave me a printout… obviously when you have the banding you have to be put out… I might be strong enough to be put out. So I don’t know whether it’s going to go ahead. (Interviewee 27)\n\nHere, the patient with a planned VBL trial procedure discussed a consultation with their general practitioner. This patient had had a preoperative assessment for a surgical procedure that had raised concerns about their ability to tolerate a general anaesthetic. Their anxiety related to VBL appeared largely to be based on an incorrect interpretation of ‘VBL as surgery’, thereby requiring a general anaesthetic. Indeed, another patient mentioned how the explanation of VBL as ‘not cutting me up’ was key in informing their consent:\n\n… if they had said there’s a bit of extra cutting me or procedures like that… I would have probably said no… because everything was explained to me, that was fine. (Interviewee 15)\n\nOther patients reported being unaware VBL was performed under sedation. Indeed, one patient reported not knowing about the sedation until being told by a clinician just prior to their VBL procedure:\n\nI always just have the throat spray for endoscope, but when I got into the room they said oh no for the banding you have to be sedated. (Interviewee 23)\n\nThe causal mechanism of carvedilol\n\nAs mentioned, an aversion to elements of VBL was key, rather than any perceived benefit of taking carvedilol itself. Despite this, a small number of patients mentioned the causal mechanism of carvedilol as the key reason for their stated preference:\n\nI reasoned… the beta blockers were doing something to all of the veins, and it seemed to me more logic, but then that’s an engineer talking. (Interviewee 26)\n\nReasons given for a stated preference to be allocated to VBL\n\nConcern about polypharmacy\n\nSimilar to carvedilol, preferences for VBL were often associated with concerns regarding the alternate treatment rather than a positive view of VBL. Some patients described already taking several medications as a concern, or a more general dislike of taking tablets:\n\nI am taking enough tablets and everything, so… I would rather have the banding, it’s dead simple, get it over and done with… (Interviewee 16)\n\nCarvedilol adherence\n\nSome participants went on to report a concern about their capacity to remember to take carvedilol on a daily basis:\n\nI struggle to keep up to date with them, because it’s not as if I can take them all at the one, there’s a couple I take at lunchtime and the other ones to be taken at night, so I do get confused some days… (Interviewee 12)\n\nHere, the focus was adherence in the context of polypharmacy. The number of tablets was not the only issue. The daily timing of medications was also highlighted. There were points during other interviews where respondents mentioned a failure to adhere strictly to taking the required carvedilol dose due to human error.\n\nHistory of mental health challenges\n\nIn a small number of cases, patients with a history of mental health issues were concerned that taking medication could cause such issues to resurface:\n\n… because of my history… [of mental health issues] I would have preferred the banding. (Interviewee 8)\n\nVBL as the quicker solution\n\nSome participants perceived VBL as a quicker solution to varices than carvedilol, due to the long-term nature of carvedilol prescription, and a perception that the issue of variceal bleeding is dealt with once varices have been banded. This was often reinforced by an aversion to taking tablets:\n\nI am not really the keenest person for taking tablets and things like that so being sedated for 10/15 minutes and the job is done sort of thing, which it was basically. (Interviewee 1)\n\nLower blood pressure as problematic\n\nA small number of patients felt that having their blood pressure lowered would negatively impact their health or quality of life due to a fear of blacking out or fainting. Lowered blood pressure was therefore perceived by some as a negative result of taking carvedilol despite the positive impact this may have on the likelihood of a variceal bleed:\n\n…lowering your blood pressure and all that, and I am thinking that could just be causing more problems. (Interviewee 4)\n\nReasons given for a stated lack of treatment preference\n\nLack of knowledge on which to base a preference\n\nSlightly fewer than half of the trial participants interviewed reported no clear treatment preference at the baseline interview. Most commonly, patients who did not have a clear preference were most concerned by overall health outcomes, and as Interviewee 29 described, they had no basis to think that one treatment was superior to the other:\n\nNo, not really, no. I’ve got no basis… so just on the back of the clinicians. (Interviewee 29)\n\nPatients’ actual experience of treatment—follow up interviews\n\nCarvedilol\n\nSide effects\n\nSome patients did not report any side effects:\n\n…there’s been no side effects from taking them anyhow, so it’s like I am quite happy at the moment with that. (Interviewee 14)\n\nA lack of side effects contributed to satisfaction with treatment as did a perception of improved health outcomes, such as lowered blood pressure:\n\nSo I am happier… it’s brought my blood pressure down. (Interviewee 5)\n\nHowever, a slight majority of participants did report at least one negative side effect, at least when initially taking the full recommended dose of carvedilol. Reported side effects included: dizziness, fainting, nausea, diarrhoea, palpitations, fatigue and low mood. Weight gain, chest pain and breathlessness were also reported.\n\nThe most commonly discussed side effect was fatigue. Interviewees often identified fatigue as a pre-existent issue, but felt that their carvedilol dose was exacerbating it:\n\nNo, I read the things, side effects I probably am a little more tired than I used to be, mind you part of that is age. (Interviewee 21)\n\nDizziness was also discussed by multiple participants and was not perceived to be a pre-existing issue:\n\nBut probably the first thing I got a bit dizzy. (Interviewee 15)\n\nDespite patients reporting several different side effects, some pointed out how it was challenging to pinpoint carvedilol as the cause in the context of polypharmacy or multiple comorbidities:\n\nRelatively recent [start of muscle fatigue]… the weakness does seem to have increased. Again whether that’s got anything to do with the trial or the drug I don’t know… (Interviewee 26)\n\nA small number of interviewees reported concerns about side effects to the point of having thought about crossover or withdrawal:\n\nAt first I did, yeah, I am not going to lie to you, when I was getting a bit dizzy and what have you, I thought maybe it’s not for me this… (Interviewee 28)\n\nIn the case of interviewee 28, a dosage reduction from the full 12.5 mg dose to 6.25 mg daily, was key in facilitating their continuation. However, despite having their dosage reduced, interviewee 24 felt they would be unable to tolerate carvedilol beyond the trial:\n\nIf this is it and they feel this [dizziness and headaches] is definitely a side effect of the carvedilol then I would say well I need to try something else. (Interviewee 24)\n\nImportance of dosage routine to positive experience of carvedilol\n\nFor some patients, side effects lessened or were alleviated after the first month or so of taking the medication. The following interviewee described altering their dosage routine after their 4-week trial follow-up:\n\nWhen I was first taking it I was taking it in the morning and you could guarantee about two or three hours after I had taken it I came out in a hot sweat, felt faint, felt dizzy. I now take it at night and I’ve overcome that. (Interviewee 5)\n\nRoutine was also described as key to adherence. In most cases patients described having little to no issue with remembering to take their carvedilol on a daily basis as a result of strictly keeping to their medication regimen:\n\nFine, I’ve now got my routine, I have my breakfast and then take the pill. (Interviewee 8)\n\nVariceal band ligation\n\nSedation as key to a better patient experience than anticipated\n\nWhile some interviewees talked about being nervous in anticipation of VBL, due to poor experiences of previous endoscopies, most described how their actual experience challenged this preconception. For example, Interviewee 9 described the whole experience as ‘smooth’:\n\n[VBL was] Smooth as in I really don’t really remember much about it at all, sedation as I said it was excellent. (Interviewee 9)\n\nThe pain and discomfort patients described during investigative endoscopies, when without sedation, was not an issue in the majority of cases. Interviewee 23 made the comparison between the sensation of gastroscopy without sedation, and the VBL with sedation, suggesting they felt less during their VBL procedure:\n\n… because they do sedate you, you don’t feel quite as much, because before my endoscopies I’ve never been sedated, I’ve always had them without sedation. (Interviewee 23)\n\nAnother interviewee mentioned how they had anticipated feeling the VBL procedure being performed, but were surprised when this was not the case:\n\nEven when they did the banding I never felt a thing, because I thought I would feel it but no never felt a thing. (Interviewee 16)\n\nTrust in clinician conducting procedure\n\nTreatment acceptability was reported as low by patients where they were not confident in the clinician performing the procedure, for example, if a registrar performed a VBL procedure instead of the patient’s consultant. A small number of patients experienced this, with one stating that they would consider withdrawal if their consultant did not agree to conduct future procedures:\n\nI stated that if I didn’t get the same person doing the procedure I wasn’t carrying on with it, because I really had real confidence in him. (Interviewee 9)\n\nIn many cases patients suggested that trusting relationships with their consultants were key to the VBL procedure experience:\n\nI think it’s been the relationship I’ve got with the consultant obviously… I think the main thing has been just feeling comfortable doing it [VBL procedure]. (Interviewee 16)\n\nPain during VBL recovery period\n\nThe recovery from VBL was consistently reported as the most challenging aspect. Postprocedure, interviewees described issues with pain, nausea, discomfort and swallowing:\n\nSometimes I think it’s how much it’s banded, but sometimes can be fine, other times can take ten days before I can eat properly, and very painful, I didn’t really expect that. (Interviewee 6)\n\nInterviewee 6 reported a variable length of time to fully recover and begin eating normally again. They hypothesised that this was associated with the number of bands being attached during a session. Intense pain was also reported by some patients:\n\nSometimes at night I would wake up and it feels like someone has kicked me in the gut so to speak, and it feels very bruised and you feel like your body is full of acid, and you can feel quite sick. (Interviewee 19)\n\nAll patients who experienced pain during recovery described the need to carefully select specific types of food to eat, such as soft and cold foods including yoghurt, ice cream and some cereals:\n\n… since the procedure was done just had a soft cold diet… I literally could only tolerate products, Weetabix, that sort of food. (Interviewee 17)\n\nAlthough patients reported knowing that they would need to recover from the VBL procedure, which may involve some pain and short term dietary alterations, the period of recovery was underestimated by some. This caused some issues for patients in terms of their diet, and/or needing time off work:\n\nI ended up being off for a whole week because for me it was quite painful once it was done. (Interviewee 1)\n\nInterviewees seemed unaware of this prior to the procedure suggesting a lack of discussion with clinicians concerning the duration of the post VBL recovery period.\n\nPeace of mind related to perceptions of treatment effectiveness\n\nCarvedilol\n\nOne aspect that seemed to influence the experience of treatments was how confident patients’ felt about the effectiveness of their treatment. In most cases, patients allocated to carvedilol expressed some concern regarding a lack of continued monitoring and desired reassurance that the treatment was working for them via endoscopic surveillance, despite some interviewees having stated a preference for carvedilol to avoid additional endoscopic procedures:\n\nThis is a question I asked, that how do I know if this is working… I was surprised that there’s no [gastroscopy] not that I relished them because they’re a horrible procedure… (Interviewee 24)\n\nVariceal band ligation\n\nFor patients allocated to the VBL pathway, a key positive of the experience was what was perceived as knowledge that their varices had been, or were in the process of being eradicated, meaning they were no longer a concern:\n\n… I actually received a letter from the clinic saying they have been obliterated so that’s good from that point of view. (Interviewee 17)\n\nHere, VBL was perceived as highly effective as varices are no longer ‘there’ or have been ‘obliterated’. Patients seemed to have gained peace of mind and reassurance as a result, something that patients allocated to carvedilol did not achieve. Peace of mind was also associated with consultant feedback received by patients allocated to VBL. Final endoscopic confirmation at the end of the banding process appeared to help confirm the effectiveness of the procedure in the patient’s mind, securing a sense of confidence in the treatment pathway:\n\nI went back for my last [VBL session] … the doctor said, ‘there’s nothing else to band.’… well that was great for me. (Interviewee 6)\n\nDiscussion\n\nWhile overall there was no clear preference for VBL or carvedilol among patients consenting to the CALIBRE pilot trial, some hoped to be allocated to carvedilol in order to avoid VBL and vice versa. Previous research has suggested a preference for VBL in treatment-naïve patients who receive detailed information about procedures and potential side effects, due to concerns around hypotension and shortness of breath.17 Our findings support the premise that patient preferences for treatment of varices are often underpinned by perceptions of potential negative outcomes associated with their least preferred option. Patients who expressed a treatment preference tended to rationalise this by highlighting fears held about taking carvedilol (due to low blood pressure, concerns around polypharmacy and issues with adherence) or undergoing a VBL procedure. All of the interviewees who declined the trial also expressed an aversion to VBL. Some of these views were influenced by clear misinterpretations of the procedure, such as perceiving VBL as surgery. However, most often patients were concerned VBL would mirror previous distressing experiences of gastroscopy.\n\nMemories of previous endoscopies have been found to shape perceptions of endoscopies going forward20 21 and induce feelings of fear or nervousness in patients faced with the prospect of further endoscopies. Previous qualitative research also suggests that experience of gastroscopy influences future patient adherence.22 This highlights the importance of clear communication with patients that sets out the experiential differences between VBL and non-sedated gastroscopy, described by the patients in this study. Ensuring patients’ experiences of gastroscopies are as comfortable as possible may also contribute to alleviating VBL procedure concerns for some patients. As evidenced by follow-up interviews with patients allocated to VBL, the use of sedation clearly delineates the VBL procedure experientially from routine diagnostic gastroscopy. Many expressed surprise at the relative comfort of the banding procedure. Post hoc the recovery period and accurate information concerning that were far more significant for patients than the experience of the procedure itself. In some cases, patients felt underprepared for the period of recovery and underestimated the duration that issues, such as pain, would last. A small number of patients related the trust they had in the clinician performing the procedure, to the quality of the procedure experience and the nature and duration of the recovery period. It is hoped our findings hold implications for, and will be of value to, those recruiting patients into the CALIBRE trial. These findings have been communicated through internal reports and guidance materials.\n\nWhile acknowledging that this research cannot provide binary views of which treatment is better experientially, these qualitative data suggest that the actual (in practice) experience for patients allocated to VBL is relatively favourable. Patients allocated to both groups on the whole expressed satisfaction with trial treatments, but the side effects of carvedilol were a significant issue for some patients, as was adherence. Side effects reportedly decreased in severity or ceased due to patient adaptation after continued exposure and/or alterations to the dosage routine. Most interviewees appeared to be adhering to their prescribed carvedilol regime, although a small number stated that they were not taking carvedilol or were taking it intermittently without reporting this to clinicians. Moreover, some patients described being doubtful of their will to continue their carvedilol prescription beyond the 12-month trial follow-up. Although this is the first qualitative study to explore the experience of patients with cirrhosis prescribed beta blockers, challenges with medication regimes have been shown to reduce the likelihood of adherence in patients with heart disease.23 24 Side effects were the most important barrier to adherence, with other contributory factors including polypharmacy, healthcare system barriers and comorbidities.23 24\n\nAn important component of perceived treatment effectiveness that patient interviewees spoke about, was the peace of mind treatments for varices could afford them, especially considering the potentially grave outcomes of a variceal bleed. ‘End-of-treatment’ reassurance of the eradication of varices contributed to greater reassurance on the part of patients allocated to VBL. Our data also suggest the therapeutic relationships VBL patients have with their consultant, due to repeat VBL sessions, may also positively influence perceptions of treatment effectiveness. This was a key reason for patient satisfaction expressed with the VBL treatment pathway, while the lack of clinical engagement was of concern to many carvedilol patients. Other studies have shown that clinicians are crucial in fostering patients’ engagement along all the phases of treatment processes, including patient adherence to medication regimes.25 Research in cirrhosis suggest that communication with health professionals can influence patients’ mental and physical well-being, that patients can be poorly informed about the severity of their condition and their future health needs,6 26 27 resulting in unmet emotional needs among this patient group.28\n\nThe in-depth qualitative approach, involving interviews at two time points, enabled the collection of rich accounts of patient treatment preferences and their post hoc reported experience of those treatments. Thus, we have been able to observe how patients’ perceptions of the treatments were influenced over time by their experience (both positively and negatively) and understand how this experience could potentially be improved for patients with medium to large varices. The depth and quality of the data collected was enhanced due to the interviewer being a qualitative researcher, independent of the patients’ medical care. Patients were able to discuss their experiences openly, safe in the knowledge that discussions would not impact on their care. The interview dataset comprises 55 in-depth interviews and data saturation regarding views and experiences of VBL and carvedilol was judged to be attained within this sample, with a balance between patients allocated to carvedilol and VBL. Patients were recruited from sites across the UK.\n\nHowever, it should be noted that the study made use of a sample derived from a clinical trial. Some patients with strong feelings towards either treatment, may have refused participation outright, to choose their preferred treatment outside of the trial context. Indeed, the small number of those we interviewed who declined the trial, cited an aversion to the VBL pathway as a key factor in their decision. Thus, we cannot make claims regarding the prevalence of pre-treatment views of VBL relative to carvedilol in the general population of patients with cirrhosis and indeed that is not the aim of qualitative studies such as this. Five of the VBL patients interviewed had no treatment exposure prior to index interview, whereas all carvedilol patients had begun treatment at this point. It is possible that initial experiences of treatment may have influenced how initial preferences were reported. Of the 30 patients interviewed at baseline, 20 completed a follow-up interview. In the majority of cases (n=7) drop-out was due to participants being uncontactable at follow-up. However, one participant refused a follow-up interview, and two others had withdrawn from the pilot trial. Drop-out was evenly distributed across both treatment groups, suggesting this was not associated with treatment. Key themes related to the experience of both treatments were consistently recounted by participants in follow-up interviews.\n\nConclusion\n\nIn this study, we have described the views of patients with medium to large varices on VBL or carvedilol, for primary prevention of variceal bleeding, both before and after treatment exposure. Our findings demonstrate that the preferences of treatment-naïve patients are varied, with some stating a preference for either carvedilol or VBL, and some having no firm preference. On the whole, patient perceptions of VBL were positively influenced by their experience of this treatment pathway. Despite this, many patients in the VBL arm described longer than expected recovery periods during interview and it would appear that some patients in the carvedilol arm may have benefitted from guidance regarding side effect management (eg, timing of dose). Our findings hold important implications for clinical practice, including the discussions which clinicians hold with their patients about treatment options. Further research examining the effective communication of patients’ experiences of these treatments is warranted. Ensuring patients are fully informed of the nature of treatments may improve their experience of treatment processes and also improve adherence. Further evidence related to the effectiveness of VBL versus carvedilol in the primary prevention of variceal bleeds is required. This is of particular importance in a post-COVID-19 context, whereby the use of carvedilol may become more prevalent, for example, if emergency guidance for carvedilol use (such as that issued by the British Society of Gastroenterology)29 influences postpandemic use. These data do not support a view that the patient experience of beta-blockade for prevention of variceal bleeds is likely to be superior to VBL.\n\nThe authorship team would like to thank the PIs and research staff at the following hospitals for their key role in recruiting patient research participants: Aberdeen Royal Infirmary (Dr Ashis Mukhopadhya), Addenbrooke’s Hospital (Dr William Griffiths), Aintree University Hospital (Dr Cyril Sieberhagen), Birmingham Heartlands Hospital (Dr Andrew King), Bradford Teaching Hospitals (Dr Sulleman Moreea), Glasgow Royal Infirmary (Dr Adrian Stanley), Kings College Hospital (Dr Brian Hogan), Ninewells Hospital, Dundee (Dr Michael Miller), Queen Elizabeth Hospital, Birmingham (Dr Neil Rajoriya), Queen Elizabeth University Hospital, Glasgow (Dr Judith Morris), Royal Derby Hospital (Dr Andrew Austin), Royal Infirmary of Edinburgh (Dr Peter Hayes), Scarborough General Hospital (Dr John Hutchinson), Swansea Bay University Hospitals (Dr Chin Lye Ch'ng), The Royal Liverpool University Hospital (Dr Imran Patanwala), University Hospital Southampton (Dr Janisha Patel), York Hospital (Dr John Hutchinson). The CALIBRE Trial Management group are grateful to all of the patient and professional research participants who made this study possible.\n\nData availability statement\n\nData are available on reasonable request. The data are not in a repository at present. The data are securely held in an encrypted University of Birmingham server, accessible by Chris Poyner Orchid ID: 0000-0001-6271-2626.\n\nEthics statements\n\nPatient consent for publication\n\nNot required.\n\nEthics approval\n\nCALIBRE was approved by the North East-York—Research Ethics Committee (reference 18/NE/0296).\n\nContributors: CP will act as the article guarantor. CP collected the data and recruited participants. JM and DT designed the study. CP and JM produced data collection materials and analysed the data. CP, DT and JM collaborated to write the manuscript.\n\nFunding: The CALIBRE study is funded by the National Institute for Health Research (NIHR) Health Technology Assessment (HTA), project number: 16/99/02.\n\nDisclaimer: The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care.\n\nIt is declared that this manuscript is original, has not been published before and is not currently being considered for publication elsewhere. We confirm that the manuscript has been read and approved by all named authors and that there are no other persons who satisfied the criteria for authorship but are not listed. We further confirm that the order of authors listed in the manuscript has been approved by all of us. We understand that the corresponding author is the sole contact for the editorial process, and is responsible for communicating with the other authors about progress, submissions of revisions and final approval of proofs.\n\nCompeting interests: None declared.\n\nProvenance and peer review: Not commissioned; externally peer reviewed.\n\nSupplemental material: This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.\n==== Refs\nReferences\n\n1 World Health Organization. WHO Global health estimates 2015: deaths by cause, age, sex, by country and by region 2000–2016. [Online]. Geneva, 2016. Available: https://www.who.int/healthinfo/global_burden_disease/estimates/en/\n2 WilliamsR, AlexanderG, ArmstrongI, et al . Disease burden and costs from excess alcohol consumption, obesity, and viral hepatitis: fourth report of the Lancet standing Commission on liver disease in the UK. Lancet 2018;391 :1097–107. 10.1016/S0140-6736(17)32866-0 29198562\n3 EnglandPH. The 2nd atlas of variation in risk factors and healthcare for liver disease in England, 2017. Available: http://tools.england.nhs.uk/images/LiverAtlas17/atlas.html\n4 WilliamsR, AspinallR, BellisM, et al . Addressing liver disease in the UK: a blueprint for attaining excellence in health care and reducing premature mortality from lifestyle issues of excess consumption of alcohol, obesity, and viral hepatitis. Lancet 2014;384 :1953–97. 10.1016/S0140-6736(14)61838-9 25433429\n5 KimbellB, MurraySA. What is the patient experience in advanced liver disease? A scoping review of the literature. BMJ Support Palliat Care 2015;5 :471–80. 10.1136/bmjspcare-2012-000435\n6 WainwrightSP. Transcending chronic liver disease: a qualitative study. J Clin Nurs 1997;6 :43–53. 10.1111/j.1365-2702.1997.tb00282.x 9052109\n7 BrownJ, SorrellJH, McClarenJ, et al . Waiting for a liver transplant. Qual Health Res 2006;16 :119–36. 10.1177/1049732305284011 16317180\n8 DudleyT, ChaplinD, CliffordC, et al . Quality of life after liver transplantation for hepatitis C infection. Qual Life Res 2007;16 :1299–308. 10.1007/s11136-007-9244-y 17665316\n9 SargentS, WainwrightSP. A qualitative study exploring patients perceived quality of life following an emergency liver transplant for acute liver failure. Intensive Crit Care Nurs 2007;23 :272–80. 10.1016/j.iccn.2007.03.005 17614286\n10 RodrigueJR, HantoDW, CurryMP. Patients' expectations and success criteria for liver transplantation. Liver Transpl 2011;17 :1309–17. 10.1002/lt.22355 21656656\n11 NorthupPG, IntagliataNM, ShahNL, et al . Excess mortality on the liver transplant waiting list: unintended policy consequences and model for end-stage liver disease (MELD) inflation. Hepatology 2015;61 :285–91. 10.1002/hep.27283 24995689\n12 et alLaBrecqueD, DiteP, FriedM. Esophageal varice: world gastroenterology organisation practice guidelines, 2013. Available: https://www.worldgastroenterology.org/\n13 National Institute for Health and Care Excellence. Cirrhosis in over 16s: assessment and management [NICE guideline No. 50], 2016. Available: https://www.nice.org.uk/guidance/ng50\n14 TripathiD, HayesPC, RichardsonP, et al . Study protocol for a randomised controlled trial of carvedilol versus variceal band ligation in primary prevention of variceal bleeding in liver cirrhosis (calibre trial). BMJ Open Gastroenterol 2019;6 :e000290–1704. 10.1136/bmjgast-2019-000290\n15 TripathiD, StanleyAJ, HayesPC, et al . U.K. guidelines on the management of variceal haemorrhage in cirrhotic patients. Gut 2015;64 :1680–704. 10.1136/gutjnl-2015-309262 25887380\n16 MeeshaM, AttiaM. Esophageal varices. Treasure Island (FL): StatPearls Publishing, 2018.\n17 LongacreAV, ImaedaA, Garcia-TsaoG, et al . A pilot project examining the predicted preferences of patients and physicians in the primary prophylaxis of variceal hemorrhage. Hepatology 2008;47 :169–76. 10.1002/hep.21945 17935182\n18 FuschPI, NessLR. Are we there yet? data saturation in qualitative research. Qual Rep 2015;20 :1408–16.\n19 RitchieJ, LewisJ. Qualitative research practice: a guide for social science students and researchers. London: Sage, 2003.\n20 ErskineA, MorleyS, PearceS. Memory for pain: a review. Pain 1990;41 :255–65. 10.1016/0304-3959(90)90002-U 1697054\n21 Hinojosa-LindseyM, ArneyJ, HeberligS, et al . Patients' intuitive judgments about surveillance endoscopy in Barrett's esophagus: a review and application to models of decision-making. Dis Esophagus 2013;26 :682–9. 10.1111/dote.12028 23383987\n22 ArneyJ, Hinojosa-LindseyM, StreetRL, et al . Patient experiences with surveillance endoscopy: a qualitative study. Dig Dis Sci 2014;59 :1378–85. 10.1007/s10620-014-3035-4 24500449\n23 LevitanEB, Van DykeMK, LoopMS, et al . Barriers to beta-blocker use and Up-Titration among patients with heart failure with reduced ejection fraction. Cardiovasc Drugs Ther 2017;31 :559–64. 10.1007/s10557-017-6764-8 29181610\n24 TenmozhiP, PriyaT. Factors contributing for noncompliance of follow up care among post cardiac patients. Int J Pharm Pharm Sci 2019;11 :22–5.\n25 BarelloS, GraffignaG, VegniE, et al . 'Engage me in taking care of my heart': a grounded theory study on patient-cardiologist relationship in the hospital management of heart failure. BMJ Open 2015;5 :e005582. 10.1136/bmjopen-2014-005582\n26 KimbellB, BoydK, KendallM, et al . Managing uncertainty in advanced liver disease: a qualitative, multiperspective, serial interview study. BMJ Open 2015;5 :e009241. 10.1136/bmjopen-2015-009241\n27 CarbonneauM, DavydukeT, SpiersJ, et al . Patient views on advance care planning in cirrhosis: a qualitative analysis. Can J Gastroenterol Hepatol 2018;2018 :1–8. 10.1155/2018/4040518\n28 LowJTS, RohdeG, PittordouK, et al . Supportive and palliative care in people with cirrhosis: international systematic review of the perspective of patients, family members and health professionals. J Hepatol 2018;69 :1260–73. 10.1016/j.jhep.2018.08.028 30243996\n29 British Society of Gastroenterology. Endoscopy activity and COVID-19: BSG and JAG guidance [Online], 2020. Available: https://www.bsg.org.uk/covid-19-advice/endoscopy-activity-and-covid-19-bsg-and-jag-guidance/\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2054-4774",
"issue": "8(1)",
"journal": "BMJ open gastroenterology",
"keywords": "endoscopic procedures; liver cirrhosis; oesophageal varices; portal hypertension",
"medline_ta": "BMJ Open Gastroenterol",
"mesh_terms": "D000077261:Carvedilol; D004932:Esophageal and Gastric Varices; D006471:Gastrointestinal Hemorrhage; D006801:Humans; D008026:Ligation; D010465:Perception",
"nlm_unique_id": "101660690",
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"pages": null,
"pmc": null,
"pmid": "34400438",
"pubdate": "2021-08",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "23383987;24995689;29198562;25887380;21656656;17614286;17665316;31139428;25776041;29181610;9052109;16317180;17935182;30243996;24500449;26586325;24644180;25433429;1697054;30079330",
"title": "Exploring patients' perceptions and experiences of treatments for the prevention of variceal bleeding: a qualitative study.",
"title_normalized": "exploring patients perceptions and experiences of treatments for the prevention of variceal bleeding a qualitative study"
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"abstract": "A previously well 59-year-old man required a prolonged intensive care unit stay due to severe COVID-19 symptoms. During the admission, he developed a cytokine storm, also known as secondary haemophagocytic lymphohistocytosis, and multiorgan failure. Despite recovering from his other organ failures, his liver function continued to deteriorate. Magnetic resonance cholangiopancreatography and subsequent endoscopic retrograde cholangiopancreatography revealed extensive intrahepatic duct dilatation with 'beading' but common bile duct sparing. Given the patient had no primary liver disease prior to admission, we considered secondary causes of cholestatic liver injury; this led us to an unusual diagnosis of secondary sclerosing cholangitis in critically ill patients. This case demonstrates a rare disease that has developed specifically in the context of SARS-CoV-2 infection. A review of current literature and the underlying pathophysiology for this rare disease are discussed, particularly in relation to COVID-19.",
"affiliations": "Gastroenterology, Nevill Hall Hospital, Abergavenny, UK kate.edwards8@wales.nhs.uk.;Gastroenterology, Nevill Hall Hospital, Abergavenny, UK.;Gastroenterology, Nevill Hall Hospital, Abergavenny, UK.",
"authors": "Edwards|Kate|K|;Allison|Miles|M|;Ghuman|Sekina|S|",
"chemical_list": null,
"country": "England",
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"doi": "10.1136/bcr-2020-237984",
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"issn_linking": "1757-790X",
"issue": "13(11)",
"journal": "BMJ case reports",
"keywords": "adult intensive care; infectious diseases; liver disease",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000073640:Betacoronavirus; D001659:Biliary Tract; D000086382:COVID-19; D002760:Cholangiopancreatography, Endoscopic Retrograde; D049448:Cholangiopancreatography, Magnetic Resonance; D015209:Cholangitis, Sclerosing; D018352:Coronavirus Infections; D016638:Critical Illness; D003937:Diagnosis, Differential; D006801:Humans; D008297:Male; D008875:Middle Aged; D058873:Pandemics; D011024:Pneumonia, Viral; D035583:Rare Diseases; D000086402:SARS-CoV-2",
"nlm_unique_id": "101526291",
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"pages": null,
"pmc": null,
"pmid": "33168538",
"pubdate": "2020-11-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "23108773;16488506;29023905;32266307;16015689;20721884;18264887;32251717;11246328;32299776;11438505;26656347;12692054;17531010;18431237;32250385;25981516;21112000;28752474;32464112;32302453;16505643;25886728;26468312;19222477;9118653;26069199;32423583;23259907;32302438;24415157;27190777;32200645;28554673;32360679",
"title": "Secondary sclerosing cholangitis in critically ill patients: a rare disease precipitated by severe SARS-CoV-2 infection.",
"title_normalized": "secondary sclerosing cholangitis in critically ill patients a rare disease precipitated by severe sars cov 2 infection"
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"abstract": "We report two cases of non-cardiogenic pulmonary edema as a complication of basiliximab induction therapy in young pediatric renal transplant patients identified following a retrospective review of all pediatric renal transplant cases performed in the National Paediatric Transplant Centre, Childrens University Hospital, Temple Street, Dublin, Ireland. Twenty-eight renal transplantations, of which five were living-related (LRD) and 23 were from deceased donors (DD), were performed in 28 children between 2003 and 2006. In six cases, transplantations were pre-emptive. Immunosuppression was induced pre-operatively using a combination of basiliximab, tacrolimus and methylprednisolone in all patients. Basiliximab induction was initiated 2 h prior to surgery in all cases and, in 26 patients, basiliximab was re-administered on post-operative day 4. Two patients, one LRD and one DD, aged 6 and 11 years, respectively, developed acute non-cardiogenic pulmonary edema within 36 h of surgery. Renal dysplasia was identified as the primary etiological factor for renal failure in both cases. Both children required assisted ventilation for between 4 and 6 days. While both grafts had primary function, the DD transplant patient subsequently developed acute tubular necrosis and was eventually lost within 3 weeks due to thrombotic microangiopathy and severe acute antibody-mediated rejection despite adequate immunosuppression. Non-cardiogenic pulmonary edema is a potentially devastating post-operative complication of basiliximab induction therapy in young pediatric patients following renal transplantation. Early recognition and appropriate supportive therapy is vital for patient and, where possible, graft survival.",
"affiliations": "Department of Nephrology, Children's University Hospital, Dublin, Ireland. dolanniamh@eircom.net",
"authors": "Dolan|Niamh|N|;Waldron|Mary|M|;O'Connell|Marie|M|;Eustace|Nick|N|;Carson|Kevin|K|;Awan|Atif|A|",
"chemical_list": "D000911:Antibodies, Monoclonal; D007166:Immunosuppressive Agents; D011993:Recombinant Fusion Proteins; D000077552:Basiliximab",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00467-009-1244-4",
"fulltext": null,
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"issn_linking": "0931-041X",
"issue": "24(11)",
"journal": "Pediatric nephrology (Berlin, Germany)",
"keywords": null,
"medline_ta": "Pediatr Nephrol",
"mesh_terms": "D000208:Acute Disease; D000911:Antibodies, Monoclonal; D000077552:Basiliximab; D002648:Child; D006801:Humans; D007166:Immunosuppressive Agents; D016030:Kidney Transplantation; D007686:Kidney Tubules, Distal; D019520:Living Donors; D008297:Male; D009336:Necrosis; D011654:Pulmonary Edema; D011859:Radiography; D011993:Recombinant Fusion Proteins; D012189:Retrospective Studies; D014019:Tissue Donors; D014184:Transplantation, Homologous; D017211:Treatment Failure; D016896:Treatment Outcome",
"nlm_unique_id": "8708728",
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"title": "Basiliximab induced non-cardiogenic pulmonary edema in two pediatric renal transplant recipients.",
"title_normalized": "basiliximab induced non cardiogenic pulmonary edema in two pediatric renal transplant recipients"
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"companynumb": "IE-ROCHE-2549571",
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"druga... |
{
"abstract": "Unresectable locally advanced or metastatic triple-negative (hormone-receptor-negative and human epidermal growth factor receptor 2 [HER2]-negative) breast cancer is an aggressive disease with poor outcomes. Nanoparticle albumin-bound (nab)-paclitaxel may enhance the anticancer activity of atezolizumab.\n\n\n\nIn this phase 3 trial, we randomly assigned (in a 1:1 ratio) patients with untreated metastatic triple-negative breast cancer to receive atezolizumab plus nab-paclitaxel or placebo plus nab-paclitaxel; patients continued the intervention until disease progression or an unacceptable level of toxic effects occurred. Stratification factors were the receipt or nonreceipt of neoadjuvant or adjuvant taxane therapy, the presence or absence of liver metastases at baseline, and programmed death ligand 1 (PD-L1) expression at baseline (positive vs. negative). The two primary end points were progression-free survival (in the intention-to-treat population and PD-L1-positive subgroup) and overall survival (tested in the intention-to-treat population; if the finding was significant, then it would be tested in the PD-L1-positive subgroup).\n\n\n\nEach group included 451 patients (median follow-up, 12.9 months). In the intention-to-treat analysis, the median progression-free survival was 7.2 months with atezolizumab plus nab-paclitaxel, as compared with 5.5 months with placebo plus nab-paclitaxel (hazard ratio for progression or death, 0.80; 95% confidence interval [CI], 0.69 to 0.92; P=0.002); among patients with PD-L1-positive tumors, the median progression-free survival was 7.5 months and 5.0 months, respectively (hazard ratio, 0.62; 95% CI, 0.49 to 0.78; P<0.001). In the intention-to-treat analysis, the median overall survival was 21.3 months with atezolizumab plus nab-paclitaxel and 17.6 months with placebo plus nab-paclitaxel (hazard ratio for death, 0.84; 95% CI, 0.69 to 1.02; P=0.08); among patients with PD-L1-positive tumors, the median overall survival was 25.0 months and 15.5 months, respectively (hazard ratio, 0.62; 95% CI, 0.45 to 0.86). No new adverse effects were identified. Adverse events that led to the discontinuation of any agent occurred in 15.9% of the patients who received atezolizumab plus nab-paclitaxel and in 8.2% of those who received placebo plus nab-paclitaxel.\n\n\n\nAtezolizumab plus nab-paclitaxel prolonged progression-free survival among patients with metastatic triple-negative breast cancer in both the intention-to-treat population and the PD-L1-positive subgroup. Adverse events were consistent with the known safety profiles of each agent. (Funded by F. Hoffmann-La Roche/Genentech; IMpassion130 ClinicalTrials.gov number, NCT02425891 .).",
"affiliations": "From the Barts Cancer Institute, Queen Mary University of London, London (P.S.); Perlmutter Cancer Center, New York University School of Medicine, New York (S.A.); the Department of Medicine, University of California, San Francisco, San Francisco (H.S.R.), and Genentech, South San Francisco (L.M., S.Y.C., R.F.) - both in California; University Hospital Heidelberg, Heidelberg, Germany (A.S.); Centro de Pesquisa em Oncologia, Hospital São Lucas, Pontifical Catholic University of Rio Grande do Sul, Porto Alegre (C.H.B.), and the University of São Paulo, São Paulo (R.H.) - both in Brazil; Aichi Cancer Center Hospital, Nagoya, Japan (H.I.); the Department of Medical Oncology, Institut Curie, Paris (V.D.); Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea (S.-A.I.); Florida Cancer Specialists and Research Institute, New Port Richey (G.S.W.); Roche, Basel, Switzerland (V.H., A.H.); Dana-Farber Cancer Institute, Boston (E.P.W.); Peter MacCallum Cancer Centre, University of Melbourne, Melbourne, VIC, Australia (S.L.); and the Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore (L.A.E.).;From the Barts Cancer Institute, Queen Mary University of London, London (P.S.); Perlmutter Cancer Center, New York University School of Medicine, New York (S.A.); the Department of Medicine, University of California, San Francisco, San Francisco (H.S.R.), and Genentech, South San Francisco (L.M., S.Y.C., R.F.) - both in California; University Hospital Heidelberg, Heidelberg, Germany (A.S.); Centro de Pesquisa em Oncologia, Hospital São Lucas, Pontifical Catholic University of Rio Grande do Sul, Porto Alegre (C.H.B.), and the University of São Paulo, São Paulo (R.H.) - both in Brazil; Aichi Cancer Center Hospital, Nagoya, Japan (H.I.); the Department of Medical Oncology, Institut Curie, Paris (V.D.); Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea (S.-A.I.); Florida Cancer Specialists and Research Institute, New Port Richey (G.S.W.); Roche, Basel, Switzerland (V.H., A.H.); Dana-Farber Cancer Institute, Boston (E.P.W.); Peter MacCallum Cancer Centre, University of Melbourne, Melbourne, VIC, Australia (S.L.); and the Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore (L.A.E.).;From the Barts Cancer Institute, Queen Mary University of London, London (P.S.); Perlmutter Cancer Center, New York University School of Medicine, New York (S.A.); the Department of Medicine, University of California, San Francisco, San Francisco (H.S.R.), and Genentech, South San Francisco (L.M., S.Y.C., R.F.) - both in California; University Hospital Heidelberg, Heidelberg, Germany (A.S.); Centro de Pesquisa em Oncologia, Hospital São Lucas, Pontifical Catholic University of Rio Grande do Sul, Porto Alegre (C.H.B.), and the University of São Paulo, São Paulo (R.H.) - both in Brazil; Aichi Cancer Center Hospital, Nagoya, Japan (H.I.); the Department of Medical Oncology, Institut Curie, Paris (V.D.); Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea (S.-A.I.); Florida Cancer Specialists and Research Institute, New Port Richey (G.S.W.); Roche, Basel, Switzerland (V.H., A.H.); Dana-Farber Cancer Institute, Boston (E.P.W.); Peter MacCallum Cancer Centre, University of Melbourne, Melbourne, VIC, Australia (S.L.); and the Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore (L.A.E.).;From the Barts Cancer Institute, Queen Mary University of London, London (P.S.); Perlmutter Cancer Center, New York University School of Medicine, New York (S.A.); the Department of Medicine, University of California, San Francisco, San Francisco (H.S.R.), and Genentech, South San Francisco (L.M., S.Y.C., R.F.) - both in California; University Hospital Heidelberg, Heidelberg, Germany (A.S.); Centro de Pesquisa em Oncologia, Hospital São Lucas, Pontifical Catholic University of Rio Grande do Sul, Porto Alegre (C.H.B.), and the University of São Paulo, São Paulo (R.H.) - both in Brazil; Aichi Cancer Center Hospital, Nagoya, Japan (H.I.); the Department of Medical Oncology, Institut Curie, Paris (V.D.); Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea (S.-A.I.); Florida Cancer Specialists and Research Institute, New Port Richey (G.S.W.); Roche, Basel, Switzerland (V.H., A.H.); Dana-Farber Cancer Institute, Boston (E.P.W.); Peter MacCallum Cancer Centre, University of Melbourne, Melbourne, VIC, Australia (S.L.); and the Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore (L.A.E.).;From the Barts Cancer Institute, Queen Mary University of London, London (P.S.); Perlmutter Cancer Center, New York University School of Medicine, New York (S.A.); the Department of Medicine, University of California, San Francisco, San Francisco (H.S.R.), and Genentech, South San Francisco (L.M., S.Y.C., R.F.) - both in California; University Hospital Heidelberg, Heidelberg, Germany (A.S.); Centro de Pesquisa em Oncologia, Hospital São Lucas, Pontifical Catholic University of Rio Grande do Sul, Porto Alegre (C.H.B.), and the University of São Paulo, São Paulo (R.H.) - both in Brazil; Aichi Cancer Center Hospital, Nagoya, Japan (H.I.); the Department of Medical Oncology, Institut Curie, Paris (V.D.); Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea (S.-A.I.); Florida Cancer Specialists and Research Institute, New Port Richey (G.S.W.); Roche, Basel, Switzerland (V.H., A.H.); Dana-Farber Cancer Institute, Boston (E.P.W.); Peter MacCallum Cancer Centre, University of Melbourne, Melbourne, VIC, Australia (S.L.); and the Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore (L.A.E.).;From the Barts Cancer Institute, Queen Mary University of London, London (P.S.); Perlmutter Cancer Center, New York University School of Medicine, New York (S.A.); the Department of Medicine, University of California, San Francisco, San Francisco (H.S.R.), and Genentech, South San Francisco (L.M., S.Y.C., R.F.) - both in California; University Hospital Heidelberg, Heidelberg, Germany (A.S.); Centro de Pesquisa em Oncologia, Hospital São Lucas, Pontifical Catholic University of Rio Grande do Sul, Porto Alegre (C.H.B.), and the University of São Paulo, São Paulo (R.H.) - both in Brazil; Aichi Cancer Center Hospital, Nagoya, Japan (H.I.); the Department of Medical Oncology, Institut Curie, Paris (V.D.); Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea (S.-A.I.); Florida Cancer Specialists and Research Institute, New Port Richey (G.S.W.); Roche, Basel, Switzerland (V.H., A.H.); Dana-Farber Cancer Institute, Boston (E.P.W.); Peter MacCallum Cancer Centre, University of Melbourne, Melbourne, VIC, Australia (S.L.); and the Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore (L.A.E.).;From the Barts Cancer Institute, Queen Mary University of London, London (P.S.); Perlmutter Cancer Center, New York University School of Medicine, New York (S.A.); the Department of Medicine, University of California, San Francisco, San Francisco (H.S.R.), and Genentech, South San Francisco (L.M., S.Y.C., R.F.) - both in California; University Hospital Heidelberg, Heidelberg, Germany (A.S.); Centro de Pesquisa em Oncologia, Hospital São Lucas, Pontifical Catholic University of Rio Grande do Sul, Porto Alegre (C.H.B.), and the University of São Paulo, São Paulo (R.H.) - both in Brazil; Aichi Cancer Center Hospital, Nagoya, Japan (H.I.); the Department of Medical Oncology, Institut Curie, Paris (V.D.); Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea (S.-A.I.); Florida Cancer Specialists and Research Institute, New Port Richey (G.S.W.); Roche, Basel, Switzerland (V.H., A.H.); Dana-Farber Cancer Institute, Boston (E.P.W.); Peter MacCallum Cancer Centre, University of Melbourne, Melbourne, VIC, Australia (S.L.); and the Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore (L.A.E.).;From the Barts Cancer Institute, Queen Mary University of London, London (P.S.); Perlmutter Cancer Center, New York University School of Medicine, New York (S.A.); the Department of Medicine, University of California, San Francisco, San Francisco (H.S.R.), and Genentech, South San Francisco (L.M., S.Y.C., R.F.) - both in California; University Hospital Heidelberg, Heidelberg, Germany (A.S.); Centro de Pesquisa em Oncologia, Hospital São Lucas, Pontifical Catholic University of Rio Grande do Sul, Porto Alegre (C.H.B.), and the University of São Paulo, São Paulo (R.H.) - both in Brazil; Aichi Cancer Center Hospital, Nagoya, Japan (H.I.); the Department of Medical Oncology, Institut Curie, Paris (V.D.); Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea (S.-A.I.); Florida Cancer Specialists and Research Institute, New Port Richey (G.S.W.); Roche, Basel, Switzerland (V.H., A.H.); Dana-Farber Cancer Institute, Boston (E.P.W.); Peter MacCallum Cancer Centre, University of Melbourne, Melbourne, VIC, Australia (S.L.); and the Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore (L.A.E.).;From the Barts Cancer Institute, Queen Mary University of London, London (P.S.); Perlmutter Cancer Center, New York University School of Medicine, New York (S.A.); the Department of Medicine, University of California, San Francisco, San Francisco (H.S.R.), and Genentech, South San Francisco (L.M., S.Y.C., R.F.) - both in California; University Hospital Heidelberg, Heidelberg, Germany (A.S.); Centro de Pesquisa em Oncologia, Hospital São Lucas, Pontifical Catholic University of Rio Grande do Sul, Porto Alegre (C.H.B.), and the University of São Paulo, São Paulo (R.H.) - both in Brazil; Aichi Cancer Center Hospital, Nagoya, Japan (H.I.); the Department of Medical Oncology, Institut Curie, Paris (V.D.); Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea (S.-A.I.); Florida Cancer Specialists and Research Institute, New Port Richey (G.S.W.); Roche, Basel, Switzerland (V.H., A.H.); Dana-Farber Cancer Institute, Boston (E.P.W.); Peter MacCallum Cancer Centre, University of Melbourne, Melbourne, VIC, Australia (S.L.); and the Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore (L.A.E.).;From the Barts Cancer Institute, Queen Mary University of London, London (P.S.); Perlmutter Cancer Center, New York University School of Medicine, New York (S.A.); the Department of Medicine, University of California, San Francisco, San Francisco (H.S.R.), and Genentech, South San Francisco (L.M., S.Y.C., R.F.) - both in California; University Hospital Heidelberg, Heidelberg, Germany (A.S.); Centro de Pesquisa em Oncologia, Hospital São Lucas, Pontifical Catholic University of Rio Grande do Sul, Porto Alegre (C.H.B.), and the University of São Paulo, São Paulo (R.H.) - both in Brazil; Aichi Cancer Center Hospital, Nagoya, Japan (H.I.); the Department of Medical Oncology, Institut Curie, Paris (V.D.); Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea (S.-A.I.); Florida Cancer Specialists and Research Institute, New Port Richey (G.S.W.); Roche, Basel, Switzerland (V.H., A.H.); Dana-Farber Cancer Institute, Boston (E.P.W.); Peter MacCallum Cancer Centre, University of Melbourne, Melbourne, VIC, Australia (S.L.); and the Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore (L.A.E.).;From the Barts Cancer Institute, Queen Mary University of London, London (P.S.); Perlmutter Cancer Center, New York University School of Medicine, New York (S.A.); the Department of Medicine, University of California, San Francisco, San Francisco (H.S.R.), and Genentech, South San Francisco (L.M., S.Y.C., R.F.) - both in California; University Hospital Heidelberg, Heidelberg, Germany (A.S.); Centro de Pesquisa em Oncologia, Hospital São Lucas, Pontifical Catholic University of Rio Grande do Sul, Porto Alegre (C.H.B.), and the University of São Paulo, São Paulo (R.H.) - both in Brazil; Aichi Cancer Center Hospital, Nagoya, Japan (H.I.); the Department of Medical Oncology, Institut Curie, Paris (V.D.); Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea (S.-A.I.); Florida Cancer Specialists and Research Institute, New Port Richey (G.S.W.); Roche, Basel, Switzerland (V.H., A.H.); Dana-Farber Cancer Institute, Boston (E.P.W.); Peter MacCallum Cancer Centre, University of Melbourne, Melbourne, VIC, Australia (S.L.); and the Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore (L.A.E.).;From the Barts Cancer Institute, Queen Mary University of London, London (P.S.); Perlmutter Cancer Center, New York University School of Medicine, New York (S.A.); the Department of Medicine, University of California, San Francisco, San Francisco (H.S.R.), and Genentech, South San Francisco (L.M., S.Y.C., R.F.) - both in California; University Hospital Heidelberg, Heidelberg, Germany (A.S.); Centro de Pesquisa em Oncologia, Hospital São Lucas, Pontifical Catholic University of Rio Grande do Sul, Porto Alegre (C.H.B.), and the University of São Paulo, São Paulo (R.H.) - both in Brazil; Aichi Cancer Center Hospital, Nagoya, Japan (H.I.); the Department of Medical Oncology, Institut Curie, Paris (V.D.); Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea (S.-A.I.); Florida Cancer Specialists and Research Institute, New Port Richey (G.S.W.); Roche, Basel, Switzerland (V.H., A.H.); Dana-Farber Cancer Institute, Boston (E.P.W.); Peter MacCallum Cancer Centre, University of Melbourne, Melbourne, VIC, Australia (S.L.); and the Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore (L.A.E.).;From the Barts Cancer Institute, Queen Mary University of London, London (P.S.); Perlmutter Cancer Center, New York University School of Medicine, New York (S.A.); the Department of Medicine, University of California, San Francisco, San Francisco (H.S.R.), and Genentech, South San Francisco (L.M., S.Y.C., R.F.) - both in California; University Hospital Heidelberg, Heidelberg, Germany (A.S.); Centro de Pesquisa em Oncologia, Hospital São Lucas, Pontifical Catholic University of Rio Grande do Sul, Porto Alegre (C.H.B.), and the University of São Paulo, São Paulo (R.H.) - both in Brazil; Aichi Cancer Center Hospital, Nagoya, Japan (H.I.); the Department of Medical Oncology, Institut Curie, Paris (V.D.); Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea (S.-A.I.); Florida Cancer Specialists and Research Institute, New Port Richey (G.S.W.); Roche, Basel, Switzerland (V.H., A.H.); Dana-Farber Cancer Institute, Boston (E.P.W.); Peter MacCallum Cancer Centre, University of Melbourne, Melbourne, VIC, Australia (S.L.); and the Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore (L.A.E.).;From the Barts Cancer Institute, Queen Mary University of London, London (P.S.); Perlmutter Cancer Center, New York University School of Medicine, New York (S.A.); the Department of Medicine, University of California, San Francisco, San Francisco (H.S.R.), and Genentech, South San Francisco (L.M., S.Y.C., R.F.) - both in California; University Hospital Heidelberg, Heidelberg, Germany (A.S.); Centro de Pesquisa em Oncologia, Hospital São Lucas, Pontifical Catholic University of Rio Grande do Sul, Porto Alegre (C.H.B.), and the University of São Paulo, São Paulo (R.H.) - both in Brazil; Aichi Cancer Center Hospital, Nagoya, Japan (H.I.); the Department of Medical Oncology, Institut Curie, Paris (V.D.); Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea (S.-A.I.); Florida Cancer Specialists and Research Institute, New Port Richey (G.S.W.); Roche, Basel, Switzerland (V.H., A.H.); Dana-Farber Cancer Institute, Boston (E.P.W.); Peter MacCallum Cancer Centre, University of Melbourne, Melbourne, VIC, Australia (S.L.); and the Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore (L.A.E.).;From the Barts Cancer Institute, Queen Mary University of London, London (P.S.); Perlmutter Cancer Center, New York University School of Medicine, New York (S.A.); the Department of Medicine, University of California, San Francisco, San Francisco (H.S.R.), and Genentech, South San Francisco (L.M., S.Y.C., R.F.) - both in California; University Hospital Heidelberg, Heidelberg, Germany (A.S.); Centro de Pesquisa em Oncologia, Hospital São Lucas, Pontifical Catholic University of Rio Grande do Sul, Porto Alegre (C.H.B.), and the University of São Paulo, São Paulo (R.H.) - both in Brazil; Aichi Cancer Center Hospital, Nagoya, Japan (H.I.); the Department of Medical Oncology, Institut Curie, Paris (V.D.); Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea (S.-A.I.); Florida Cancer Specialists and Research Institute, New Port Richey (G.S.W.); Roche, Basel, Switzerland (V.H., A.H.); Dana-Farber Cancer Institute, Boston (E.P.W.); Peter MacCallum Cancer Centre, University of Melbourne, Melbourne, VIC, Australia (S.L.); and the Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore (L.A.E.).;From the Barts Cancer Institute, Queen Mary University of London, London (P.S.); Perlmutter Cancer Center, New York University School of Medicine, New York (S.A.); the Department of Medicine, University of California, San Francisco, San Francisco (H.S.R.), and Genentech, South San Francisco (L.M., S.Y.C., R.F.) - both in California; University Hospital Heidelberg, Heidelberg, Germany (A.S.); Centro de Pesquisa em Oncologia, Hospital São Lucas, Pontifical Catholic University of Rio Grande do Sul, Porto Alegre (C.H.B.), and the University of São Paulo, São Paulo (R.H.) - both in Brazil; Aichi Cancer Center Hospital, Nagoya, Japan (H.I.); the Department of Medical Oncology, Institut Curie, Paris (V.D.); Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea (S.-A.I.); Florida Cancer Specialists and Research Institute, New Port Richey (G.S.W.); Roche, Basel, Switzerland (V.H., A.H.); Dana-Farber Cancer Institute, Boston (E.P.W.); Peter MacCallum Cancer Centre, University of Melbourne, Melbourne, VIC, Australia (S.L.); and the Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore (L.A.E.).;From the Barts Cancer Institute, Queen Mary University of London, London (P.S.); Perlmutter Cancer Center, New York University School of Medicine, New York (S.A.); the Department of Medicine, University of California, San Francisco, San Francisco (H.S.R.), and Genentech, South San Francisco (L.M., S.Y.C., R.F.) - both in California; University Hospital Heidelberg, Heidelberg, Germany (A.S.); Centro de Pesquisa em Oncologia, Hospital São Lucas, Pontifical Catholic University of Rio Grande do Sul, Porto Alegre (C.H.B.), and the University of São Paulo, São Paulo (R.H.) - both in Brazil; Aichi Cancer Center Hospital, Nagoya, Japan (H.I.); the Department of Medical Oncology, Institut Curie, Paris (V.D.); Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea (S.-A.I.); Florida Cancer Specialists and Research Institute, New Port Richey (G.S.W.); Roche, Basel, Switzerland (V.H., A.H.); Dana-Farber Cancer Institute, Boston (E.P.W.); Peter MacCallum Cancer Centre, University of Melbourne, Melbourne, VIC, Australia (S.L.); and the Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore (L.A.E.).;From the Barts Cancer Institute, Queen Mary University of London, London (P.S.); Perlmutter Cancer Center, New York University School of Medicine, New York (S.A.); the Department of Medicine, University of California, San Francisco, San Francisco (H.S.R.), and Genentech, South San Francisco (L.M., S.Y.C., R.F.) - both in California; University Hospital Heidelberg, Heidelberg, Germany (A.S.); Centro de Pesquisa em Oncologia, Hospital São Lucas, Pontifical Catholic University of Rio Grande do Sul, Porto Alegre (C.H.B.), and the University of São Paulo, São Paulo (R.H.) - both in Brazil; Aichi Cancer Center Hospital, Nagoya, Japan (H.I.); the Department of Medical Oncology, Institut Curie, Paris (V.D.); Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea (S.-A.I.); Florida Cancer Specialists and Research Institute, New Port Richey (G.S.W.); Roche, Basel, Switzerland (V.H., A.H.); Dana-Farber Cancer Institute, Boston (E.P.W.); Peter MacCallum Cancer Centre, University of Melbourne, Melbourne, VIC, Australia (S.L.); and the Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore (L.A.E.).",
"authors": "Schmid|Peter|P|;Adams|Sylvia|S|;Rugo|Hope S|HS|;Schneeweiss|Andreas|A|;Barrios|Carlos H|CH|;Iwata|Hiroji|H|;Diéras|Véronique|V|;Hegg|Roberto|R|;Im|Seock-Ah|SA|;Shaw Wright|Gail|G|;Henschel|Volkmar|V|;Molinero|Luciana|L|;Chui|Stephen Y|SY|;Funke|Roel|R|;Husain|Amreen|A|;Winer|Eric P|EP|;Loi|Sherene|S|;Emens|Leisha A|LA|;|||",
"chemical_list": "C520255:130-nm albumin-bound paclitaxel; D000418:Albumins; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; C000594389:atezolizumab; D017239:Paclitaxel",
"country": "United States",
"delete": false,
"doi": "10.1056/NEJMoa1809615",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0028-4793",
"issue": "379(22)",
"journal": "The New England journal of medicine",
"keywords": null,
"medline_ta": "N Engl J Med",
"mesh_terms": "D000328:Adult; D000368:Aged; D000418:Albumins; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols; D005260:Female; D006801:Humans; D057194:Intention to Treat Analysis; D008875:Middle Aged; D017239:Paclitaxel; D000077982:Progression-Free Survival; D016019:Survival Analysis; D064726:Triple Negative Breast Neoplasms",
"nlm_unique_id": "0255562",
"other_id": null,
"pages": "2108-2121",
"pmc": null,
"pmid": "30345906",
"pubdate": "2018-11-29",
"publication_types": "D017428:Clinical Trial, Phase III; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Atezolizumab and Nab-Paclitaxel in Advanced Triple-Negative Breast Cancer.",
"title_normalized": "atezolizumab and nab paclitaxel in advanced triple negative breast cancer"
} | [
{
"companynumb": "US-CELGENEUS-USA-20181102668",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "PACLITAXEL"
},
"drugadditional": null,
... |
{
"abstract": "We present a case of a 20-year-old man who suffered from Kawasaki disease (KD) associated with a florid parvovirus infection, and who died suddenly from thrombotic occlusion of the coronary arteries. The autopsy revealed several aneurysms of the coronary arteries, a chronic vasculitis and a myofibroblast proliferation leading to focal luminal narrowing. The inflammatory response as well as the detection of the viral particles by PCR in blood and in the lesional tissue demonstrated a possible cause by Parvovirus infection. The expression of endoglin on endothelial cells of neoangiogenesis indicates the involvement of the TGF-beta pathway, necessary for maintaining chronic inflammation. In addition, a possible connection between the intake of methylphenidate, arteritis and a possible pre-existing heart disease must be discussed. Furthermore, KD must also be considered as a cause of sudden death in the adult population.",
"affiliations": "Medical Faculty, Institute of Legal Medicine, University of Cologne, Melatengürtel 60-62, 50823, Cologne, Germany. stefan.flossdorf@uk-koeln.de.;Medical Faculty, Institute of Legal Medicine, University of Cologne, Melatengürtel 60-62, 50823, Cologne, Germany.;Medical Faculty, Institute of Legal Medicine, University of Cologne, Melatengürtel 60-62, 50823, Cologne, Germany.;Medical Faculty, Institute of Pathology, University Hospital of Cologne, Kerpener Str. 63, 50937, Cologne, Germany.;Medical Faculty, Institute of Legal Medicine, University of Cologne, Melatengürtel 60-62, 50823, Cologne, Germany.",
"authors": "Flossdorf|Stefan|S|0000-0001-5557-9935;Schiwy-Bochat|Karl Heinz|KH|;Teifel|Daniela|D|;Fries|Jochen W U|JWU|;Rothschild|Markus A|MA|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1007/s12024-020-00263-y",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1547-769X",
"issue": "16(3)",
"journal": "Forensic science, medicine, and pathology",
"keywords": "Adult; Coronary artery aneurysm; Endoglin; Kawasaki disease; Methylphenidat; Parvovirus",
"medline_ta": "Forensic Sci Med Pathol",
"mesh_terms": "D001167:Arteritis; D003323:Coronary Aneurysm; D003328:Coronary Thrombosis; D003331:Coronary Vessels; D003645:Death, Sudden; D016731:Erythema Infectiosum; D006801:Humans; D008297:Male; D009080:Mucocutaneous Lymph Node Syndrome; D009203:Myocardial Infarction; D055815:Young Adult",
"nlm_unique_id": "101236111",
"other_id": null,
"pages": "498-503",
"pmc": null,
"pmid": "32495258",
"pubdate": "2020-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Sudden death of a young adult with coronary artery vasculitis, coronary aneurysms, parvovirus B19 infection and Kawasaki disease.",
"title_normalized": "sudden death of a young adult with coronary artery vasculitis coronary aneurysms parvovirus b19 infection and kawasaki disease"
} | [
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"abstract": "'Levodopa Phobia' is under-recognised in Parkinson's disease but can cause profound detrimental clinical complications if left to continue. Several types can be encountered in clinical practice and can be driven by a misplaced fear of levodopa-induced dyskinesias, other gastrointestinal side effects and also the theoretical notion that levodopa may be toxic to dopaminergic neurons in the brain. The condition can be underpinned by a sense of strong influence from the physicians or carers who are unwilling to prescribe or consider levodopa, and also high levels of anxiety or even impulsive compulsive traits in patients who have been influenced by available literature or social media-based information. If unrecognised, the clinical issue may lead to motor deterioration and related muscle contractures leading to social isolation as well as a range of non-motor symptoms. In some, there may be emergence of intrusive impulse control disorders because of reliance on only dopamine agonists related to the fear of taking levodopa. Four cases illustrate the different patterns of 'Levodopa Phobia' in this study. Management of levodopa phobia is complex and includes recognition and skilled neuropsychological interventions to break the misperceptions about the complications of levodopa therapy.",
"affiliations": "1Department of Neurology, Neurosurgery and Medical Genetics, Federal State Budgetary Educational Institution of Higher Education, \"N.I. Pirogov Russian National Research Medical University\" of the Ministry of Healthcare of the Russian Federation, Moscow, Russia.;Russian Medical Academy of Professional Continuous Education, Centre of Extrapyramidal Disorders, Moscow, Russia.;1Department of Neurology, Neurosurgery and Medical Genetics, Federal State Budgetary Educational Institution of Higher Education, \"N.I. Pirogov Russian National Research Medical University\" of the Ministry of Healthcare of the Russian Federation, Moscow, Russia.;3Institute of Psychiatry, Psychology and Neuroscience at King's College London, London, UK.",
"authors": "Titova|Nataliya|N|;Levin|Oleg|O|;Katunina|Elena|E|;Ray Chaudhuri|K|K|",
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"fulltext": "\n==== Front\nNPJ Parkinsons DisNPJ Parkinsons DisNPJ Parkinson's Disease2373-8057Nature Publishing Group UK London 6710.1038/s41531-018-0067-zPerspective‘Levodopa Phobia’: a review of a not uncommon and consequential phenomenon Titova Nataliya nattitova@yandex.ru 1Levin Oleg 2Katunina Elena 1Ray Chaudhuri K. 341 0000 0000 9216 2496grid.415738.cDepartment of Neurology, Neurosurgery and Medical Genetics, Federal State Budgetary Educational Institution of Higher Education, “N.I. Pirogov Russian National Research Medical University” of the Ministry of Healthcare of the Russian Federation, Moscow, Russia 2 Russian Medical Academy of Professional Continuous Education, Centre of Extrapyramidal Disorders, Moscow, Russia 3 0000 0001 2322 6764grid.13097.3cInstitute of Psychiatry, Psychology and Neuroscience at King’s College London, London, UK 4 0000 0004 0391 9020grid.46699.34Parkinson Foundation International Centre of Excellence at King’s College Hospital, Denmark Hill, London, SE5 9RS UK 2 10 2018 2 10 2018 2018 4 3118 2 2018 9 8 2018 29 8 2018 © The Author(s) 2018Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.‘Levodopa Phobia’ is under-recognised in Parkinson’s disease but can cause profound detrimental clinical complications if left to continue. Several types can be encountered in clinical practice and can be driven by a misplaced fear of levodopa-induced dyskinesias, other gastrointestinal side effects and also the theoretical notion that levodopa may be toxic to dopaminergic neurons in the brain. The condition can be underpinned by a sense of strong influence from the physicians or carers who are unwilling to prescribe or consider levodopa, and also high levels of anxiety or even impulsive compulsive traits in patients who have been influenced by available literature or social media-based information. If unrecognised, the clinical issue may lead to motor deterioration and related muscle contractures leading to social isolation as well as a range of non-motor symptoms. In some, there may be emergence of intrusive impulse control disorders because of reliance on only dopamine agonists related to the fear of taking levodopa. Four cases illustrate the different patterns of ‘Levodopa Phobia’ in this study. Management of levodopa phobia is complex and includes recognition and skilled neuropsychological interventions to break the misperceptions about the complications of levodopa therapy.\n\nissue-copyright-statement© The Author(s) 2018\n==== Body\nIntroduction\nLevodopa is the gold standard for treatment of Parkinson’s disease (PD). However, since the early 2000s, clinical guidelines for management of PD have recommended a preferential use of dopamine agonists over levodopa as initial therapy. This rationale is underpinned by several well publicised levodopa versus dopamine agonist comparative studies, which showed a delay in the development of motor complications in the dopamine agonist arm.1–5 In addition, dopamine agonists were favoured over levodopa because of data suggesting a ‘toxic’ effect of levodopa on nigral neuronal cell cultures, although clear evidence of levodopa toxicity in humans are lacking.6,7 Aggressive marketing of this concept by pharmaceutical companies, as well as neurologists and geriatricians, particularly in the early 2000 period, have led to many patients with PD to either reject the option of using levodopa even when it is clearly clinically indicated or develop a ‘fear’ about the use of levodopa. The problem was originally highlighted by Levin et al.8 in 2001, who described the condition of ‘Levodopa Phobia’ in PD in Russian language. His cases also highlighted rejection of levodopa intake because of problems of overemphasised fears of gastrointestinal side effects for some patients, whereas others rejected the therapy as they had an impulsive compulsive personality trait. Kurlan9 then reported two cases who had developed severe akinesia, because the treating neurologists were unwilling to prescribe levodopa consequent to a misplaced fear about the side effects (unacceptable and troublesome dyskinesias) and widespread publicity of the benefits of ‘levodopa sparing’ therapies. He alluded to this condition as ‘Levodopa Phobia’, a PD-specific pharmacophobia. However, recent long-term studies of levodopa versus dopamine agonist trials including the Parkinson's disease medicines trial (PDMED) study suggest otherwise and the current view is that there is little evidence to justify withholding levodopa when clinically indicated over dopamine agonists.1,10,11\n\n‘Levodopa Phobia’ case reports\nIn this article we review the problem of ‘Levodopa Phobia’ among physicians, carers and patients still prevalent in real-life clinical practice and support the observations by related case reports.\n\nCase 1\nA 45-year-old Brazilian gentleman presented to KRC at a movement disorders clinic with a potential diagnosis of ‘severe’ PD. Enquiry revealed that he developed late-onset hyposmia when aged about 35 years and also showed signs of unilateral bradykinesia about the same time. He had an introverted and anxious personality. He was seen in several clinics where initially a diagnosis of PD was considered and he was advised to take levodopa because of severe akinesia, rest tremor and a poor quality of life. However, the patient had severe anxiety about taking levodopa based on information provided by his father who also refused to allow him to try levodopa. When seen in 2016 in London, he had bilateral severe akinesia with an almost unintelligible speech, bradyphrenia, dribbling of saliva, paroxysmal rest tremor, high non-motor symptoms questionnaire score. He was ambulant on a wheelchair with upper limb contractures, although he could walk when asked. The patient and father were sceptical about dopamine loss and a Datscan was performed and confirmed severe presynaptic dopamine transporter loss with putamen-binding ratios being < 1 (right 0.64, left 0.5) (Fig. 1). ‘Levodopa Phobia’ was diagnosed and a neuropsychological ‘anti-phobia’ support programme was initiated. After several weeks the patient and the father agreed to the use of levodopa, which was started at a daily dose of 150 mg increasing to 300 mg with good motor and non-motor response. At 1-year follow-up the patient is able to perform many activities of daily living.Fig. 1 Datscan of patient (case report 1) showing bilateral loss of dopamine transporter uptake. Courtesy Nuclear Imaging Department, Kings College Hospital, London\n\n\n\nCase 2\nA 48-year-old female media journalist in the United Kingdom, who was extremely well read about PD developed right-sided slowness of movement noticed when using her laptop and general slowness that was commented upon by her boyfriend and media colleagues. She also had marked fatigue and herself considered a diagnosis of PD. She then self-referred herself to KRC for further advise and management. She was felt to need immediate dopamine replacement therapy and levodopa was likely to be the most suitable drug given her bradykinesia and postural instability. However, she had severe ‘Levodopa Phobia’ being afraid about dyskinesias, which she had seen in people with PD as reported in the media and also by being member of several PD patient groups. She had also read some papers that had suggested levodopa is toxic to brain cells in animal models. As such initiation with levodopa was impossible and she was started on a dopamine agonist along with rasagiline. After 1 year she presented to the clinic with recurring bradykinesia interfering with her media work. However, even inspite of the bradykinesia and related issues she was not convinced about the need for levodopa to be started and wanted to stay on the same dose of treatment she was on. She tried various forms of complimentary medicine (herbal therapy, acupuncture, swimming and nutritional supplements) with no beneficial effect. After several consultations, a decision to use a wearable wristwatch sensor was made to document her bradykinesia in an objective manner. The report confirmed severe bradykinesia and she finally agreed to take levodopa after seeing the extent of bradykinesia but refused to go beyond 300 mg of levodopa per day. As a result, after an initial response to levodopa, bradykinesia remained a major problem and there were continuing issues related to her work in the media world.\n\nCase 3\nA 65-year-old Armenian teacher presented with a tremor dominant pattern of PD for 8 years. Tremor was pronounced in the left upper limb with associated pain. According to her she had a personality that was obsessed with making hand-made jewellery as a hobby. She was started and maintained on pramipexole slow release (3 mg) and amantadine (300 mg) by her treating physician. The physician had noted that levodopa therapy was not possible, as she was convinced that ‘levodopa destroys the body, it is a harmful drug and I will never take it’ in her own words. Prolonged and sustained use of pramipexole had caused severe impulse control disorder (ICD) and she had developed binge eating with marked weight gain approaching obesity in 2015. She also spent a large sum of money on compulsive shopping spree. She was troubled by severe depression and anxiety; however, she did not consult a neurologist, as she was travelling between Armenia and Russia. In 2016, she read that ICD could be caused by dopamine agonists and stopped all dopamine replacement therapy herself. She developed severe worsening of tremor and bradykinesia, and dopamine agonist withdrawal syndrome. She was then seen by NT with persisting and severe ‘Levodopa Phobia’. A trial of rotigotine transdermal patch was suggested based on data that rotigotine might be less likely to cause severe ICD but she was unable to afford the treatment. Subsequently, she was convinced to take a small dose of ropinirole (8 mg) with re-introduction of amantadine (300 mg) and addition of escitalopram (10 mg). Her ICD resolved. However, she continued to be troubled by her tremor, which she described as ‘horrible’, although objective examination revealed a low amplitude tremor likely to be helped by levodopa therapy. Inspite, she now wants to consider gamma-knife treatment for her mild tremor rather than use levodopa.\n\nCase 4\nNT conducted a domestic consultation to review a Russian patient who was 80 years old with PD for 14 years. He was demented, with contractures and immobile with bed sores. He was not on any dopaminergic therapy as the decision to treat was dictated by his daughter, a non-practising medical graduate with a very strong personality. Her opinion was influenced by the outcome of a consultation with a neurologist in the past, who had advised not to initiate treatment with levodopa as the drug would inevitably cause ‘problems’. Subsequently, the patient had developed hallucinations as well as confusional episodes while on dopamine agonists following which the daughter stopped dopamine agonist therapy. The daughter also did not consider another neurological consultation, as she felt that none of the available therapies could help her father and, therefore, she elected to leave him untreated. At current consultation with NT, an offer of palliation with levodopa therapy was discussed but not accepted.\n\nDiscussion\nOur cases illustrate the phenomenon of ‘Levodopa Phobia’ also referred to as pharmacophobia and is an irrational belief with consequent deleterious clinical effects in PD. The cases also suggest that several specific types of ‘Levodopa Phobia’ exist and this is also reflected by our own personal clinical experience from running large-scale PD clinics (Table 1). We believe that ‘Levodopa Phobia’ can be broadly of two types, the first being patient driven and the second related to extrinsic factors such as being driven by physicians where the issue is more of ‘aversion’ to levodopa and is described in the reports of Kurlan in addition to carer influences.9 In the PD patient group, ‘Levodopa Phobia’ can also be classed as an anxiety disorder related to a specific phobia about taking levodopa preparations. Patient-based ‘Levodopa Phobia’ could be of several types and can range from complete aversion to taking levodopa containing medications to secretly being non-compliant or refusing to increase the dose is inspite of clinical advice. Some patients my be afraid of levodopa use because of a potential risk of development of skin melanoma, whereas in others fear of gastrointestinal side effect is dominant. Cases observed by OL also demonstrate the peculiar phenomenon of aversion to levodopa in favour of invasive stereotactic brain surgery in the form of deep brain stimulation of subthalamic nucleus and indeed our case 3 reported by NT had considered gamma-knife therapy for her PD tremor even before considering levodopa. From a neuropsychological perspective, magical thinking on the part of the patient with PD is another factor as some patients avoid transitioning to levodopa treatment as its use denotes a new chapter in their life with PD. This may represent a concession to the disease or stark evidence that they really do have a progressive neurodegenerative disorder. In addition, we have also proposed a carer-based ‘Levodopa Phobia’, which can severely affect the patients as shown in our cases 1 and 4.Table 1 Proposed patterns of ‘Levodopa Phobia’ in Parkinson’s disease\n\nType of subject and personality\tPattern of ‘Levodopa Phobia’\tEvidence base\t\nPrimary: patient based:\t\nTrue ‘Levodopa Phobia’ (type 1)\tOften associated with high anxiety states, misperception of medical data (media-based lay information on dyskinesias and side-effect profile of levodopa as provided in drug information leaflet) and complete aversion to levodopa use inspite of serious health-related consequences.\tCase reports 2 and 3\t\n‘Levodopa Phobia’ leading to poor compliance with prescribed levodopa (type 2)\tPatients usually can be persuaded to start on levodopa but discontinues treatment or refuses to escalate the dose beyond a certain limit inspite of advice otherwise. Some could refrain from use of levodopa in secret as well.\tCase report 2\t\nSecondary and extrinsic factors based:\t\nPhysician based\tUsually related to misperception of knowledge of the potential risk of levodopa -induced dyskinesias. In addition, some may be influenced by data from animal models about the toxic effect of levodopa.\t(Ref. 9), Case report 4\t\nThe tendency to avoid levodopa could be pronounced by local clinical guidelines espousing preferential use of ‘levodopa sparing’ therapies and peer group pressure.\t\nCarer based\tCarer attitude towards levodopa use is reflected by a negativity or complete aversion towards using levodopa in patients.\tCase reports 1 and 4\t\n\n\nClinical implications and observations\nThe true prevalence of ‘Levodopa Phobia’ either in specific countries where use of ‘levodopa sparing’ strategies are widespread or globally is unknown. Availability of conflicting information on the pros and cons of using levodopa in social media can also bias the patients’ perception of treatment and reinforce the pharmacophobia, as well as incorrect interpretation of the physicians’ recommendations. Although physician and carer-driven ‘Levodopa Phobia’ may be relatively uncommon, most patients tend to belong to type 1 and 2 variants (see Table 2). However, Type 1 with severe ‘Levodopa Phobia’ is less frequent and the one with potentially serious consequences if the condition is allowed to continue. A potential list of complications of ‘Levodopa Phobia’ compiled from our own clinical experience is listed in Table 2. In particular, intrusive ICD related to compensatory overuse of single or multiple dopamine agonists because of ‘Levodopa Phobia’ may be a particular problem as is the worsening motor state with varying non-motor features.Table 2 Types of ‘Levodopa Phobia’ types and possible motor and non-motor complications\n\nTypes of ‘Levodopa Phobia’\tPatterns of complications and clinical consequences\t\nComplete ‘Levodopa Phobia’\tSevere akinesia causing lack of mobility\t\nContractures\t\nRespiratory tract infections\t\nSevere nociceptive pain\t\nDepression and anhedonia\t\nSocial withdrawal and carer dependence\t\nPoor compliance and secret rejection of levodopa use\tReport of lack of any effect of levodopa inspite of apparent use\t\nPrecipitation of unnecessary investigations for atypical ‘levodopa-resistant’ parkinsonism\t\nA tendency to seek multiple medical consultations owing to ‘lack of effect’ of therapy\t\nPossibility of development of impulse control disorders because of potential overuse of other (e.g., dopamine agonist) therapies\t\n\n\nDiagnostic considerations\nDiagnosis of ‘Levodopa Phobia’ is clinical and there may be certain pointers but there are no clear guidelines. These include the presence of a high anxiety state and hypochondriasis, over-reliance on ‘alternative’ treatment strategies, self-declaration that ‘levodopa does not work or is causing side effects’ without any spousal, or partner-based corroboration. Awareness of the problem of ‘Levodopa Phobia’ among clinicians including specialists as well as carers is an unmet need. Cultural perceptions are also important as within some ethnic groups the diagnosis of PD is considered a taboo and, as such, the use of medical therapies is discouraged, while families may resort to unconventional ‘traditional’ therapies.\n\nManagement\nThere are no guidelines for management of ‘Levodopa Phobia’ inspite of it’s potential serious consequences. Levodopa could be beneficial from early to advanced stages of PD. A visual sense of the different possible management options is proposed in Fig. 2 based on our pragmatic clinical experience. A multidisciplinary input to the problem is essential as often there is underlying severe anxiety state. In levodopaphobic patients paradoxically, anxiety can also be specifically triggered if the physician can persuade the patient to start levodopa. In these cases, emphasis must be on strategies to reduce levodopa-induced non-motor fluctuations which itself could aggravate anxiety states.12–14 The latter strategy is one of the ‘personality enablers’ of the recently described ‘circle of personalised medicine’ for PD.13,14 In selected cases, use of objective measures such as digital monitoring (wearable devices highlighting bradykinesia, Case 2) or Datscan (as in Case 1) may be helpful in convincing unwilling phobic PD patients to realise the extent of parkinsonism and the need to start levodopa therapy. Input from an expert patient group is also useful for convincing the patient regarding the benefits of levodopa therapy as is the role of a skilled psychotherapist with expertise in treating anxiety phenomena. In cases where there is severe comorbid anxiety disorder relevant anxiolytic pharmacological therapies and/or cognitive behavioural therapy may be required. If there is manifest ICD, treatment needs to be multidisciplinary with engagement of neuropsychology and neuropsychiatry teams. If one is successful in initiating levodopa therapy, patients need close surveillance for any side effects and also to ensure compliance. Anecdotally some patients have been persuaded to take mucuna pruriens (levodopa containing plant product)15 and subsequently switched to commercial levodopa preparation, and this may be an option worth exploring.Fig. 2 A proposed management plan of the levodopaphobic patient. MDT multidisciplinary team, CBT ognitive behavioural therapy, DA dopamine agonist, ICD = impulse control disorder\n\n\n\nConclusions\nMany phobias exists in PD patients and can range from needlephobia (relevant to subcutaneous treatments), claustrophobia (relevant to brain magnetic resonance imaging) and aversion to surgical therapy involving the brain and here we focus on a specific levodopa related phobia. Physicians may also have dopamine agonist-phobia thus refusing to prescribe any dopamine agonists when in some circumstances they can be beneficial to the patient. ‘Levodopa Phobia’ is another poorly recognised phenomenon in clinical practice sometimes with profound detrimental clinical consequences. The condition may arise from misperceptions of the side effects of levodopa by the patient but also can be precipitated by physicians or misguided but well meaning relatives inspite of the fact that levodopa remains the most effective treatment option even in the late stages of PD.16 Patients may suffer from underlying high anxiety state and depression aggravated by information circulating in social media. Early recognition is crucial as treatment can be time consuming and has to be multidisciplinary. There could also be cultural and ethnic differences which may drive ‘Levodopa Phobia’ in PD and large-scale epidemiological data capture is required.\n\nPublisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAcknowledgements\nNT and KRC acknowledge previous reports of ‘Levodopa Phobia’ by Professor O Levin (co-author) and Professor R Kurlan, which precipitated this paper. For KRC, this paper represents independent research part funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health.’\n\nAuthor contributions\nNT and KRC discussed and developed the concept of this study. The cases described in the study are personal cases seen by NT and KRC in their respective Parkinson’s disease consultation clinics. NT and KRC were equally involved in preparing, writing and referencing the paper. The cases and discussions were developed and contributed to by OL and EK. NT, OL, EK and KRC were equally involved in preparing, writing and referencing the paper.\n\nCompeting interests\nThe authors declare no competing interests.\n==== Refs\nReferences\n1. Gray R Long-term effectiveness of dopamine agonists and monoamine oxidase B inhibitors compared with levodopa as initial treatment for Parkinson’s disease (PD MED): a large, open-label, pragmatic randomised trial Lancet 2014 384 9949 1196 1205 10.1016/S0140-6736(14)60683-8 24928805 \n2. Parkinson Study Group. Pramipexole vs levodopa as initial treatment for Parkinson disease: a randomized controlled trial JAMA 2000 284 1931 1938 10.1001/jama.284.15.1931 11035889 \n3. Rascol O A five-year study of the incidence of dyskinesia in patients with early Parkinson’s disease who were treated with ropinirole or levodopa N. Engl. J. Med. 2000 342 1484 1491 10.1056/NEJM200005183422004 10816186 \n4. Oertel WH Pergolide versus levodopa monotherapy in early Parkinson’s disease patients: The PELMOPET study Mov. Disord. 2006 21 343 353 10.1002/mds.20724 16211594 \n5. Rinne UK Early treatment of Parkinson’s disease with cabergoline delays the onset of motor complications. Results of a double-blind levodopa controlled trial. The PKDS009 Study Group Drugs 1998 55 23 30 10.2165/00003495-199855001-00004 9483167 \n6. Fahn S Levodopa-induced neurotoxicity: does it represent a problem for the treatment of Parkinson’s disease? CNS Drugs 1997 8 376 393 10.2165/00023210-199708050-00004 \n7. Fahn S Cohen G The oxidant stress hypothesis in Parkinson’s disease: evidence supporting it Ann. Neurol. 1992 32 804 812 10.1002/ana.410320616 1471873 \n8. Левин ОС Лечение болезни Паркинсона на ранней стадии В мире лекарств. 2001 1 41 47 \n9. Kurlan R “Levodopa phobia”: A new iatrogenic cause of disability in Parkinson disease Neurology 2005 64 923 924 10.1212/01.WNL.0000152880.77812.5B \n10. Katzenschlager R Parkinson’s Disease Research Group of the United Kingdom. 14-year final report of the randomized PDRG-UK trial comparing three initial treatments in PD Neurology 2008 71 474 480 10.1212/01.wnl.0000310812.43352.66 18579806 \n11. Parkinson Study Group CALM Cohort Investigators. Long-term effect of initiating pramipexole vs levodopa in early Parkinson disease Arch. Neurol. 2009 66 563 570 10.1001/archneurol.2009.32 19433655 \n12. Storch A Nonmotor fluctuations in Parkinson’s disease: severity and correlation with motor complications Neurology 2013 80 800 809 10.1212/WNL.0b013e318285c0ed 23365054 \n13. Titova N The future of Parkinsonas treatment - personalised and precision medicine European Neurological Review 2017 12 1 15 16 10.17925/ENR.2017.12.01.15 \n14. Titova N Chaudhuri KR Non-motor Parkinson disease: new concepts and personalised management Med J. Aust. 2018 208 9 404 409 10.5694/mja17.00993 29764353 \n15. Cassani E Mucuna pruriens for Parkinson’s disease: low-cost preparation method, laboratory measures and pharmacokinetics profile J. Neurol. Sci. 2016 365 175 180 10.1016/j.jns.2016.04.001 27206902 \n16. Rosqvist K Levodopa effect and motor function in late stage Parkinson’s disease J. Park. Dis. 2018 8 1 59 70 10.3233/JPD-171181\n\n",
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"title": "'Levodopa Phobia': a review of a not uncommon and consequential phenomenon.",
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"abstract": "Pheochromocytoma/paraganglioma (PPGL) are neuroendocrine tumors that can secrete catecholamines. The authors describe a challenging case who presented as stress cardiomyopathy and myocardial infarction (MI). A 76-year-old man, with a medical history of Parkinson's disease, type 2 diabetes mellitus, hypertension, dyslipidaemia and a previous inferior MI in 2001, presented to the emergency department due to chest pain, headaches and vomiting. He also reported worsening blood glucose levels and increasing constipation over the preceding weeks. BP was 185/89 mmHg (no other relevant findings). EKG had ST segment depression in leads V2-V6, T troponin was 600 ng/L (<14) and the echocardiogram showed left ventricular hypokinesia with mildly compromised systolic function. Nevertheless, he rapidly progressed to severe biventricular dysfunction. Coronary angiogram showed a 90% anterior descendent coronary artery occlusion (already present in 2001), which was treated with angioplasty/stenting. In the following days, a very labile BP profile and unexplained sinus tachycardia episodes were observed. Because of sustained severe constipation, the patient underwent an abdominal CT that revealed a retroperitoneal, heterogeneous, hypervascular mass on the right (62 × 35 mm), most likely a paraganglioma. Urinary metanephrines were increased several fold. 68Ga-DOTANOC PET-CT scan showed increased uptake in the abdominal mass (no evidence of disease elsewhere). He was started on a calcium-channel blocker and alpha blockade and underwent surgery with no major complications. Eight months after surgery, the patient has no evidence of disease. Genetic testing was negative for known germline mutations. This was a challenging diagnosis, but it was essential for adequate cardiovascular stabilization and to reduce further morbidity. Learning points: PPGL frequently produces catecholamines and can manifest with several cardiovascular syndromes, including stress cardiomyopathy and myocardial infarction. Even in the presence of coronary artery disease (CAD), PPGL should be suspected if signs or symptoms attributed to catecholamine excess are present (in this case, high blood pressure, worsening hyperglycaemia and constipation). Establishing the correct diagnosis is important for adequate treatment choice. Inodilators and mechanical support might be preferable options (if available) for cardiovascular stabilization prior to alpha blockade and surgery. Laboratory interference should be suspected irrespective of metanephrine levels, especially in the context of treated Parkinson's disease.",
"affiliations": "Endocrinology and Diabetes Department, Garcia de Orta Hospital, Almada, Portugal.;Endocrinology Department, Portuguese Institute of Oncology Francisco Gentil, Lisbon, Portugal.;Cardiology Department, Garcia de Orta Hospital, Almada, Portugal.;Endocrinology and Diabetes Department, Garcia de Orta Hospital, Almada, Portugal.;Endocrinology and Diabetes Department, Garcia de Orta Hospital, Almada, Portugal.",
"authors": "Ferreira|Ana Gonçalves|AG|;Nunes da Silva|Tiago|T|;Alegria|Sofia|S|;Cordeiro|Maria Carlos|MC|;Portugal|Jorge|J|",
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"fulltext": "\n==== Front\nEndocrinol Diabetes Metab Case RepEndocrinol Diabetes Metab Case RepEDMEndocrinology, Diabetes & Metabolism Case Reports2052-0573Bioscientifica Ltd Bristol 10.1530/EDM-19-0017EDM190017Unique/Unexpected Symptoms or Presentations of a DiseaseParaganglioma presenting as stress cardiomyopathy: case report and literature review A G Ferreira and othersStress cardiomyopathy and paragangliomaFerreira Ana Gonçalves 1Nunes da Silva Tiago 2Alegria Sofia 3Cordeiro Maria Carlos 1Portugal Jorge 11 Endocrinology and Diabetes Department, Garcia de Orta Hospital, Almada, Portugal2 Endocrinology Department, Portuguese Institute of Oncology Francisco Gentil, Lisbon, Portugal3 Cardiology Department, Garcia de Orta Hospital, Almada, PortugalCorrespondence should be addressed to A G Ferreira; Email: adgonfer@gmail.com16 4 2019 2019 2019 19-001719 3 2019 28 3 2019 © 2019 The authors2019The authors This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License..Summary\nPheochromocytoma/paraganglioma (PPGL) are neuroendocrine tumors that can secrete catecholamines. The authors describe a challenging case who presented as stress cardiomyopathy and myocardial infarction (MI). A 76-year-old man, with a medical history of Parkinson’s disease, type 2 diabetes mellitus, hypertension, dyslipidaemia and a previous inferior MI in 2001, presented to the emergency department due to chest pain, headaches and vomiting. He also reported worsening blood glucose levels and increasing constipation over the preceding weeks. BP was 185/89 mmHg (no other relevant findings). EKG had ST segment depression in leads V2-V6, T troponin was 600 ng/L (<14) and the echocardiogram showed left ventricular hypokinesia with mildly compromised systolic function. Nevertheless, he rapidly progressed to severe biventricular dysfunction. Coronary angiogram showed a 90% anterior descendent coronary artery occlusion (already present in 2001), which was treated with angioplasty/stenting. In the following days, a very labile BP profile and unexplained sinus tachycardia episodes were observed. Because of sustained severe constipation, the patient underwent an abdominal CT that revealed a retroperitoneal, heterogeneous, hypervascular mass on the right (62 × 35 mm), most likely a paraganglioma. Urinary metanephrines were increased several fold. 68Ga-DOTANOC PET-CT scan showed increased uptake in the abdominal mass (no evidence of disease elsewhere). He was started on a calcium-channel blocker and alpha blockade and underwent surgery with no major complications. Eight months after surgery, the patient has no evidence of disease. Genetic testing was negative for known germline mutations. This was a challenging diagnosis, but it was essential for adequate cardiovascular stabilization and to reduce further morbidity.\n\nLearning points:\nPPGL frequently produces catecholamines and can manifest with several cardiovascular syndromes, including stress cardiomyopathy and myocardial infarction. \n\nEven in the presence of coronary artery disease (CAD), PPGL should be suspected if signs or symptoms attributed to catecholamine excess are present (in this case, high blood pressure, worsening hyperglycaemia and constipation).\n\nEstablishing the correct diagnosis is important for adequate treatment choice. \n\nInodilators and mechanical support might be preferable options (if available) for cardiovascular stabilization prior to alpha blockade and surgery.\n\nLaboratory interference should be suspected irrespective of metanephrine levels, especially in the context of treated Parkinson’s disease.\n==== Body\nBackground\nPPGLs are rare neuroendocrine tumors that usually produce and secrete catecholamines. Presentation can be extremely variable (1). Cardiovascular manifestations include chronic hypertension and hypertensive crisis associated with headaches, diaphoresis, pallor, tremor, palpitations and anxiety. Less commonly, PPGL can present as acute or chronic cardiomyopathy, MI even in the absence of CAD, heart failure, cardiogenic shock, tachyarrhythmia and aortic dissection (1). The authors describe a challenging case that presented as MI and stress cardiomyopathy in a patient with established CAD, whose clinical picture could not be explained by the coronary artery findings.\n\nCase presentation\nWe present a 76-year-old man, with a past medical history of Parkinson’s disease, type 2 diabetes mellitus, hypertension, dyslipidemia and a previous inferior ST segment elevation MI (STEMI) in 2001 with right coronary artery angioplasty (the coronary angiogram also showed a 90% proximal left anterior descending (LAD) artery occlusion that was not treated invasively). Patient’s medication included metformin 500 mg bid, olmesartan 20 mg/day, acetylsalicylic acid 150 mg/day, rosuvastatin 10 mg/day, sublingual nitroglycerin (SOS), levodopa 300 mg/day with benserazide 75 mg/day and rasigiline 1 mg/day. There was no history of smoking/illicit drugs/alcohol abuse. There was no relevant family history. He presented to the emergency department in November 2017 with chest pain, headaches and vomiting. The patient also reported worsening of his blood glucose levels and increasing constipation over the preceding weeks. At presentation, high blood pressure was noted (BP 185/89 mmHg) and the patient was found to be euvolemic. Cardiovascular and respiratory examination did not identify an abnormality. No other relevant findings.\n\nInvestigation\nEKG showed ST segment depression (leads V2-V6). T troponin level was 600 ng/L (<14). The first transthoracic echocardiogram (TTE) showed left ventricular hypokinesia with mildly compromised systolic function. He was diagnosed a NSTEMI (Killip-KimbalI class I). In the following hours, he became hypotensive with signs of systemic hypoperfusion and performed another TTE that now documented severe biventricular dysfunction. In this setting, an emergency coronary angiography was performed and revealed the already known 90% LAD artery occlusion that was not treated in 2001 and now treated with angioplasty/stenting. After the procedure, he became more hypotensive (BP 90/64 mmHg) and tachycardic (HR: 122 bpm) with progression to pulmonary edema and cardiogenic shock. He was started on norepinephrine and admitted to the coronary intensive care unit (ICU). In the following days, his BP profile was labile, with hypertensive crisis associated with vomiting and headaches that led to norepinephrine suspension alternating with severe hypotension and restarting of vasoactive amines. He also had unexplained sinus tachycardia episodes even without norepinephrine. Due to prolonged and severe constipation, present before and during hospital stay, the patient underwent an abdominal CT, which revealed a retroperitoneal, heterogeneous, hypervascular mass on the right (62 × 35 mm) (Fig. 1). At this point, the patient was observed by an endocrinologist. Urinary metanephrines estimated 12 days after the last vasoactive amine administration were significantly increased (Table 1). Due to markedly elevated plasma 3-methoxytyramine levels, there was a significant concern for malignant disease, so a staging 68Ga-DOTANOC PET-CT scan was performed. It showed increased uptake in the abdominal mass only, with no evidence of disease elsewhere (Fig. 1).Figure 1 Left: Abdominal mass – paraganglioma (arrow); right: 68-Ga-DOTANOC PET-CT scan with increased uptake in the abdominal mass (arrows).\n\n\nTable 1 Pre and post-operative 24-h urinary metanephrines.\n\nLaboratory test\tPre-operative result\tPost-operative result (8 weeks)\tReference range\t\nTotal metanephrines, μg/24 h\t23,180\t10,163\t329–1263\t\nMetanephrine, μg/24 h\t10,094\t214\t64–302\t\nNormetanephrine, μg/24 h\t4496\t1179\t162–527\t\n3-Methoxytyramine, μg/24 h\t8590\t8770\t103–434\t\n24-h urinary volume, mL\t2330\t2000\t–\t\n\n\n\nTreatment\nWhile in the ICU, blood pressure was still elevated, so the patient was started on amlodipine 10 mg/day and alpha blockade. Alfuzosin was the only alpha-blocker available at the hospital, so he was started on 0.4 mg twice daily. Subsequent 24-h BP monitoring revealed high systolic BP, with a concomitant high diastolic BP, especially at night (average 24-h BP of 155/81 mmHg and nocturnal of 167/83 mmHg), so amlodipine was switched to nifedipine 30 mg/day, with improved BP control. As blood glucose levels had also deteriorated, metformin 500 mg bid was uptitrated to 1000 mg bid and vildagliptin 50 mg bid was added, improving diabetes control. He underwent laparoscopic surgery while under treatment with alfuzosin 0.4 mg twice daily and nifedipine 30 mg daily, with no major anesthetic complications. No hypertensive crisis occurred during surgery, so no extra medication was necessary for blood pressure control during the procedure.\n\nOutcome and follow-up\nHistopathology confirmed the diagnosis of paraganglioma, with no aggressive features or lymph node involvement. Genetic testing was negative for known germline mutations (next-generation sequencing panel –TruSight Cancer Gene Set, Illumina). The genes evaluated include RET, VHL, SDHAF 2, SDHB, SDHC, SDHD, TMEM127 and MAX.\n\nAfter surgery, BP normalized (with nifedipine 30 mg/day only) and blood glucose control improved (which allowed returning to previous medical therapy). The only abnormality that persisted in the TTE was left ventricle posterior/inferior wall hypokinesia, most likely related to previous inferior MI. Constipation disappeared. This was accompanied by a significant decrease in urinary metanephrines 2 months post-operatively, with normalization of metanephrine, a significant decrease in normetanephrine and no change in 3-methoxytyramine (Table 1). An abdominal MRI and 68Ga-DOTANOC PET-CT scan were performed, with no evidence of recurrent or metastatic disease. After careful down-titration of his anti-Parkinsonic interfering medication for 23 days (including 7 days with no treatment), 3-methoxytyramine was 437 µg/24 h (reference range: 103–434 µg/24 h), confirming pharmacological interference. \n\nDiscussion\nThe patient described had an unusual cardiovascular presentation of catecholamine excess. There are 2 types of PPGL-related cardiomyopathy – acute and chronic (2). Both are rare forms of presentation. Most cases of the acute form refer to a Takotsubo-like phenotype (with LV ballooning), unlike our patient, who had diffuse biventricular hypokinesia. Data about its prevalence in PPGL are scarce, but there have been a few series addressing this issue. In 2011, Park et al. (3) reported three cases of acute cardiomyopathy, two with Takotsubo-like features (and one with diffuse hypokinesia) among 36 patients with pheochromoytoma. Zelinka et al. (4) reported, in 2012, 2 cases of Takotsubo-like cardiomyopathy in a cohort of 145 pheochromocytoma patients (1.4%). More recently, Giavarini et al. (5) found a prevalence of 4.3% in 140 PPGL (n = 6). Riester et al. (6) in a multicentre retrospective study found a prevalence of 3% (n = 4) in a cohort of 135 PPGL (mostly pheochromocytoma) and Gagnon et al. (7) found a prevalence of 2.6% (n = 4) in 152 secretory PPGLs.\n\nUnderlying mechanisms causing catecholamine-related cardiomyopathy are not fully understood but include direct myocardial damage (calcium-mediated and associated with free radicals), coronary artery vasospasm, tachycardia with increased oxygen demand, increased afterload, alpha and beta receptor downregulation (after chronic exposure to high levels of catecholamines) with decreased number of myocardial contracting units (8, 9). \n\nIn our case, the diagnosis was particularly challenging because the patient already had established CAD and presented with a NSTEMI, which could be secondary to his atherosclerotic disease. However, sudden progression to biventricular failure not explained by the coronary angiogram raised the suspicion that some non-atherosclerotic coronary mechanism could be causing the acute cardiac failure. His progression to cardiogenic shock and pulmonary edema after the procedure was also not explained by coronary artery findings. Moreover, while in the coronary ICU, the labile BP profile and sudden sinus tachycardia episodes were also not explained by the known cardiac disease nor by norepinephrine treatment. As after laparoscopic surgery, cardiac function returned to normal, the clinical picture was most likely related to catecholamine-induced cardiomyopathy. Constipation ended up being an important complaint to establish the diagnosis and can also be explained by catecholamine excess (as the initial report of a recent worsening of diabetes control). Both improved significantly after surgery, which makes this relationship much more likely. \n\nGagnon et al. (7) reviewed 59 acute cardiomyopathy cases related to PPGL reported in literature, added 4 patients of their own, and characterized the secretory pattern in 33 pheochromocytoma and 4 paraganglioma. They found that the tumors most frequently had mixed epinephrine and norepinephrine dominant secretion. Our case is less typical because it is a paraganglioma with much higher epinephrine secretion than norepinephrine (reported only in one of the paraganglioma cases reviewed by Gagnon et al. (7)). 3-methoxytyramine was also very elevated pre and post-operatively. At first, although we admitted it could be due to medication, we could not rule out the possibility that the tumor was also secreting dopamine because very high levels were found. This raised suspicion for a more undifferentiated phenotype and led us to perform a more extensive evaluation (with PET-CT) at diagnosis. Its level did not change significantly after surgery and 68Ga-DOTANOC PET-CT showed no evidence of disease, so the most likely explanation for this was Parkinson’s medication, which we confirmed after interrupting this treatment for a few days, as described. This assumption is corroborated by the work of Eisenhofer et al. (10) and Davidson et al. (11) using different assays. The first authors found that 3-methoxytyramine was several fold elevated with levodopa treatment, measured by LC-MS/MS (56-fold for free and 22-fold for deconjugated 3-methoxytyramine), while the second authors found a 14-fold increase of homovanillic acid with levodopa measured by HPLC-ECD (as in the case described). Unlike Eisenhofer et al., these authors also found metanephrine and normetanephrine measurement to be raised with this method (2.2 and 4.8-fold, respectively, versus other patients with Parkinson’s disease). Acute cardiomyopathy management might be challenging, especially when patients progress to cardiogenic shock. Alpha blockade is standard therapy in PPGL crisis but cannot be initiated in a patient in cardiogenic shock because it would aggravate hypotension. Some authors argue that mechanical support (intra-aortic balloon, ECMO, CPB) might be preferred in these patients (when available) and allow for alpha blockade sooner with better outcomes (12). Hemiken et al. (13) report nine patients with pheochromocytoma-induced adrenergic crisis with cardiogenic shock treated with ECMO, with a mortality rate of 33% (three patients). The authors also performed a systematic review of 40 cases and report a lower mortality rate – 7%. They assume that publication bias might explain the difference. Whitelaw et al. (12) review 21 cases of pheochromocytoma-induced cardiogenic shock treated with intra-aortic balloon, with only 2 deaths. \n\nVasoactive amines should be avoided in the management of these patients because they already have high catecholamine levels causing myocardial dysfunction and they might be relatively insensitive to their action due to long-term exposure (as previously explained). Some argue that inodilators such as levosimendan and milrinone could be good alternatives because they act through non-adrenergic pathways, providing inotropic support and relieving afterload (12, 14). Levosimendan has been used successfully with few adverse events in small studies (14, 15), none of them included patients with PPGL. There are two case reports of patients with PPGLwho were treated with levosimendan with good results (one also with dobutamine and the other with vasopressin also) (16, 17). Most recent European Society of Cardiology guidelines (18) for the treatment of Takotsubo cardiomyopathy do not advise milrinone use for cardiogenic shock, but there are at least five cases of PPGL described with its successful use (one also with norepinephrine, one with mechanical support and the remaining with standard medical care for heart failure), including a pregnant woman (19, 20, 21, 22, 23). \n\nAlpha blockade is standard of care after cardiovascular stabilization. There is not a single consensual approach to begin this treatment. Generally accepted rule is to start with low dose and titrate slowly (adding beta-blockade if necessary, afterwards). Casey et al. (24) describe a possible approach to test for tolerance, which is a 2.5 mg single dose of IV phentolamine (with previous fluid boluses of 250–500 mL of crystalloid to correct hypovolemia), with a cardiac team on standby prepared to perform emergent mechanical support if needed. \n\nSurgical removal of the primary tumor is definite treatment for these patients. Ideally, it should be done after cardiovascular stabilization, although the perfect timing is still a matter of debate (12). Some argue that in extreme cases, when patients fail to achieve hemodynamic stabilization after adequate treatment (for example, in cases of tumor rupture or hemorrhage with a large catecholamine surge), emergent surgery might be an option (12, 25). Scholten et al. (25) in their review of 97 cases of patients with adrenergic crisis (between 1944 and 2011) found 33 emergent adrenalectomies, with an 18% mortality rate (6 patients). When considering only the most recent surgeries (to exclude technical-related complications), only 1 in 18 patients died (6%). There was no mortality in the elective surgery group. \n\nPrognosis depends on how long the catecholamine exposure was and how extensive is the myocardial damage (2, 8). If minimal myocardial damage, partial or full recovery is predictable (in a few weeks or months) (8, 26). Long-standing exposure to excess catecholamines with chronic extensive myocardial damage, including dilated cardiomyopathy, has a lower recovery rate (2, 8). Establishing the correct diagnosis in due time is essential for cardiovascular stabilization and to reduce further morbidity and mortality.\n\nDeclaration of interest\nThe authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.\n\nFunding\nThis research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.\n\nPatient consent\nWritten informed consent was obtained from the patient described in this article for publication of the submitted paper and images.\n\nAuthor contribution statement\nAna Gonçalves Ferreira: first author; Tiago N Silva: first author and patient’s endocrinologist. Both co-first authors oversaw the conception and design of this case report (article drafting, literature review, revising and approval of the final version to be published) with equal level of contribution. Sofia Alegria: article reviewer and patient’s Cardiologist; Maria C Cordeiro: - article reviewer; Jorge Portugal: article reviewer. This paper was written with permission and revision from the patient’s physicians (who are also authors, as stated above).\n==== Refs\nReferences\n1 Prejbisza A Lendersb JWM Eisenhoferc G Januszewicza A \nCardiovascular manifestations of phaeochromocytoma . Journal of Hypertension \n2011 \n29 \n2049 –2060 . (10.1097/HJH.0b013e32834a4ce9 )21826022 \n2 Batisse-Lignier M Pereira B Motreff P Pierrard R Burnot C Vorilhon C Maqdasy S Roche B Desbiez F Clerfond G , \nAcute and chronic pheochromocytoma-induced cardiomyopathies: different prognoses? A systematic analytical review . Medicine \n2015 \n94 \ne2198 (10.1097/MD.0000000000002198 )26683930 \n3 Park JH Kim KS Sul JY Shin SK Kim JH Lee JH Choi SW Jeong JO Seong IW \nPrevalence and patterns of left ventricular dysfunction in patients with pheochromocytoma . Journal of Cardiovascular Ultrasound \n2011 \n19 \n76 –82 . (10.4250/jcu.2011.19.2.76 )21860721 \n4 Zelinka T Petrák O Turková H Holaj R Strauch B Kršek M Vránková AB Musil Z Dušková J Kubinyi J , \nHigh incidence of cardiovascular complications in pheochromocytoma . Hormone and Metabolic Research \n2012 \n44 \n379 –384 . (10.1055/s-0032-1306294 )22517556 \n5 Giavarini A Chedid A Bobrie G Plouin PF Hagège A Amar L \nAcute catecholamine cardiomyopathy in patients with phaeochromocytoma or functional paraganglioma . Heart \n2013 \n99 \n1438 –1444 . (10.1136/heartjnl-2013-304073 )23837998 \n6 Riester A Weismann D Quinkler M Lichtenauer UD Sommerey S Halbritter R Penning R Spitzweg C Schopohl J Beuschlein F , \nLife-threatening events in patients with pheochromocytoma . European Journal of Endocrinology \n2015 \n173 \n757 –764 . (10.1530/EJE-15-0483 )26346138 \n7 Gagnon N Mansour S Bitton Y Bourdeau I \nTakotsubo-like cardiomyopathy in a large cohort of patients With pheochromocytoma and paraganglioma . Endocrine Practice \n2017 \n23 \n1178 –1192 . (10.4158/EP171930.OR )28704094 \n8 Kassim TA Clarke DD Mai VQ Clyde PW Mohamed Shakir KM \nCatecholamine-induced cardiomyopathy . Endocrine Practice \n2008 \n14 \n1137 –1149 . (10.4158/EP.14.9.1137 )19158054 \n9 Brouwers FM Eisenhofer G Lenders JW Pacak K \nEmergencies caused by pheochromocytoma, neuroblastoma, or ganglioneuroma . Endocrinology and Metabolism Clinics of North America \n2006 \n35 \n699 –724 . (10.1016/j.ecl.2006.09.014 )17127142 \n10 Eisenhofer G Brown S Peitzsch M Pelzel D Lattke P Glöckner S Stell A Prejbisz A Fassnacht M Beuschlein F , \nLevodopa therapy in Parkinson’s disease: influence on liquid chromatographic tandem mass spectrometric-based measurement of plasma and urinary normetanephrine, metanephrine and methoxytyramine . Annals of Clinical Biochemistry \n2014 \n51 \n38 –46 . (10.1177/0004563213487894 )23873873 \n11 Davidson DF Grosset K Grosset D \nParkinson’s disease: the effect of L-dopa therapy on urinary free catecholamines and metabolites . Annals of Clinical Biochemistry \n2007 \n44 \n364 –368 . (10.1258/000456307780945705 )17594783 \n12 Whitelaw BC Prague JK Mustafa OG Schulte KM Schulte KM Hopkins PA Gilbert JA McGregor AM Aylwin SJ \nPhaeochromocytoma crisis . Clinical Endocrinology \n2014 \n80 \n13 –22 . (10.1111/cen.12324 )24102156 \n13 Hekimian G Kharcha F Bréchot N Schmidt M Ghander C Lebreton G Girerd X Tresallet C Trouillet JL Leprince P , \nExtracorporeal membrane oxygenation for pheochromocytoma-induced cardiogenic shock . Annals of Intensive Care \n2016 \n6 \n117 (10.1186/s13613-016-0219-4 )27896787 \n14 Yaman M Arslan U Kaya A Akyol A Ozturk F Okudan YE Bayramoglu A Bektas O \nLevosimendan accelerates recovery in patients with takotsubo cardiomyopathy . Cardiology Journal \n2016 \n23 \n610 –615 . (10.5603/CJ.a2016.0100 )27910084 \n15 Santoro F Ieva R Ferraretti A Ienco V Carpagnano G Lodispoto M Di Biase L Di Biase M Brunetti ND \nSafety and feasibility of Levosimendan Administration in Takotsubo Cardiomyopathy: a case series . Cardiovascular Therapeutics \n2013 \n31 \ne133 –e137 . (10.1111/1755-5922.12047 )24119220 \n16 Johnston PC Silversides JA Wallace H Farling PA Hutchinson A Hunter SJ Eatock F Mullan KR \nPhaeochromocytoma crisis: two cases of undiagnosed phaeochromocytoma presenting after elective nonrelated surgical procedures . Case Reports in Anesthesiology \n2013 \n2013 \n514714 (10.1155/2013/514714 )24288628 \n17 Westaby S Shahir A Sadler G Flynn F Ormerod O \nMechanical bridge to recovery in pheochromocytoma myocarditis . Nature Reviews: Cardiology \n2009 \n6 \n482 –487 . (10.1038/nrcardio.2009.58 )\n18 Ghadri JR Wittstein IS Prasad A Sharkey S Dote K Akashi YJ Cammann VL Crea F Galiuto L Desmet W , \nInternational expert consensus document on takotsubo syndrome (Part II): diagnostic workup, outcome, and management . European Heart Journal \n2018 \n39 \n2047 –2062 . (10.1093/eurheartj/ehy077 )29850820 \n19 Tagawa M Nanba H Suzuki H Nakamura Y Uchiyama H Ochiai S Terunuma M Yahata K Minamino T \nVentricular rhythm and hypotension in a patient with pheochromocytoma-induced myocardial damage and reverse takotsubo cardiomyopathy . Internal Medicine \n2015 \n54 \n2343 –2349 . (10.2169/internalmedicine.54.4732 )26370859 \n20 Berger J Chabot J Pun S Pelletier JP Vautour L Giannetti N \nAn unexpected post-partum fulminant heart failure . International Journal of Cardiology \n2014 \n177 \ne47 –e48 . (10.1016/j.ijcard.2014.09.082 )25304073 \n21 Mulla CM Marik PE \nUnusual association of diseases/symptoms pheochromocytoma presenting as acute decompensated heart failure reversed with medical therapy . BMJ Case Reports \n2012 (10.1136/bcr-2012-006319 )\n22 Kim J Reutrakul S Davis DB Kaplan EL Refetoff S \nMultiple endocrine neoplasia 2A syndrome presenting as peripartum cardiomyopathy due to catecholamine excess . European Journal of Endocrinology \n2004 \n151 \n771 –777 . (10.1530/eje.0.1510771 )15588245 \n23 Varghese RT John AM Paul TV \nCatecholamine induced cardiomyopathy in pheochromocytoma . Indian Journal of Endocrinology and Metabolism \n2013 \n17 \n733 –735 . (10.4103/2230-8210.113771 )23961496 \n24 Casey RT Challis BG Pitfield D Mahroof RM Jamieson N Bhagra CJ Vuylsteke A Pettit SJ Chatterjee KC \nManagement of an acute catecholamine-induced cardiomyopathy and circulatory collapse: a multidisciplinary approach . Endocrinology, Diabetes and Metabolism Case Reports \n2017 \n2017 Article ID: 17-0122. (10.1530/EDM-17-0122 )\n25 Scholten A Cisco RM Vriens MR Cohen JK Mitmaker EJ Liu C Tyrrell JB Shen WT Duh QY \nPheochromocytoma crisis is not a surgical emergency . Journal of Clinical Endocrinology and Metabolism \n2013 \n98 \n581 –591 . (10.1210/jc.2012-3020 )23284003 \n26 Lin PC Hsu JT Chung CM Chang ST \nPheochromocytoma underlying hypertension, stroke, and dilated cardiomyopathy . Texas Heart Institute Journal \n2007 \n34 \n244 –246 .17622380\n\n",
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"journal": "Endocrinology, diabetes & metabolism case reports",
"keywords": "2019; Adrenal; Alpha-blockers; Amlodipine; Angiography; April; Blood pressure; CT scan; Cardiogenic shock; Cardiomyopathy; Chest pain; Constipation; DPP4 inhibitors; Diabetes mellitus type 2; Echocardiogram; Electrocardiogram; Gallium scan; Geriatric; Glucose (blood); Headache; Histopathology; Hypertension; Hypotension; Laparoscopy; Levodopa; MRI; Male; Metanephrines; Metanephrines (urinary); Metformin; Methoxytyramine; Molecular genetic analysis; Myocardial infarction; Neuroendocrine tumour; Nifedipine; Norepinephrine; Normetanephrine; Oedema; PET scan; Paraganglioma; Portugal; Pulmonary oedema; Resection of tumour; Tachycardia; Troponin; Unique/unexpected symptoms or presentations of a disease; Urine 24-hour volume; Vildagliptin; Vomiting; White",
"medline_ta": "Endocrinol Diabetes Metab Case Rep",
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"pmid": "30991354",
"pubdate": "2019-04-16",
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"title": "Paraganglioma presenting as stress cardiomyopathy: case report and literature review.",
"title_normalized": "paraganglioma presenting as stress cardiomyopathy case report and literature review"
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"abstract": "BACKGROUND\nValproate-induced Fanconi syndrome is a rare adverse effect of valproate. Severely disabled patients who require tube feeding are reported to be susceptible to valproate-induced Fanconi syndrome. Although most patients with valproate-induced Fanconi syndrome are asymptomatic and detected incidentally with findings such as hypophosphatemia, hypouricemia, increased urinary β2-microglobulin, and generalized hyperaminoaciduria, clinical symptoms such as bone fracture, fever, tachypnea, and edema have been reported.\n\n\nMETHODS\nThis 15-year-old, severely disabled, tube-fed, male patient with cytochrome oxidase deficiency had taken valproate for 3 years when he developed fever for 3 weeks. Hypophosphatemia, hypouricemia, hypokalemia, increased urinary β2-microglobulin, and generalized hyperaminoaciduria, as well as hypocarnitinemia, were found, indicating that he had Fanconi syndrome. Valproate was the most likely cause of Fanconi syndrome in this patient. After discontinuation of valproate, the fever resolved immediately, and the laboratory findings normalized.\n\n\nCONCLUSIONS\nValproate-induced Fanconi syndrome should be considered when individuals taking valproate develop fever of unknown origin.",
"affiliations": "Department of Pediatrics, Shiga Medical Center for Children, Moriyama-shi, Shiga, Japan. Electronic address: nozaki-kgw@umin.ac.jp.;Department of Pediatrics, Shiga Medical Center for Children, Moriyama-shi, Shiga, Japan.;Department of Pediatrics, Shiga Medical Center for Children, Moriyama-shi, Shiga, Japan.;Department of Pediatrics, Shiga Medical Center for Children, Moriyama-shi, Shiga, Japan.;Department of Metabolism, Chiba Children's Hospital, Midori, Chiba, Japan.;Faculty of Medicine, Department of Pediatrics, Saitama Medical University, Saitama, Japan.",
"authors": "Nozaki|Fumihito|F|;Kumada|Tomohiro|T|;Kusunoki|Takashi|T|;Fujii|Tatsuya|T|;Murayama|Kei|K|;Ohtake|Akira|A|",
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"journal": "Pediatric neurology",
"keywords": "Fanconi syndrome; fever of unknown origin; side effects; valproate; valproate-induced Fanconi syndrome",
"medline_ta": "Pediatr Neurol",
"mesh_terms": "D000293:Adolescent; D030401:Cytochrome-c Oxidase Deficiency; D004791:Enzyme Inhibitors; D005198:Fanconi Syndrome; D005335:Fever of Unknown Origin; D006801:Humans; D008297:Male; D014635:Valproic Acid",
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"references": null,
"title": "Fever of unknown origin as the initial manifestation of valproate-induced Fanconi syndrome.",
"title_normalized": "fever of unknown origin as the initial manifestation of valproate induced fanconi syndrome"
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"abstract": "BACKGROUND\nSince the introduction of tyrosine kinase inhibitors (TKIs), the profile of pediatric relapse of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) has changed. However, the management of pediatric Ph+ ALL relapses is not currently standardized.\n\n\nMETHODS\nWe retrospectively analyzed the therapeutic strategies and outcomes of pediatric Ph+ ALL patients in first relapse who were initially treated with a TKI-containing regimen in one of the French pediatric hematology centers from 2004 to 2019.\n\n\nRESULTS\nTwenty-seven children experienced a Ph+ ALL relapse: 24 (89%) had an overt relapse and three a molecular relapse. Eight involved the central nervous system. A second complete remission (CR2) was obtained for 26 patients (96%). Induction consisted of nonintensive chemotherapy for 13 patients (48%) and intensive chemotherapy for 14 (52%). Thirteen patients (48%) received consolidation. Allogenic hematopoietic stem cell transplantation (alloHSCT) was performed for 21 patients (78%). The TKI was changed for 23 patients (88%), mainly with dasatinib (n = 15). T315I was the most common mutation at relapse (4/7). The 4-year event-free survival and survival rates were 60.9% and 76.1%, respectively. Survival was positively associated with alloHSCT in CR2.\n\n\nCONCLUSIONS\nWe show that pediatric first-relapse Ph+ ALL reinduces well with a second course of TKI exposure, despite the use of different therapeutic approaches. The main prognostic factor for survival was alloHSCT in CR2. Because of the small size of the cohort, we could not draw any conclusions about the respective impact of TKIs, but the predominance of the T315I mutation should encourage careful consideration of the TKI choice.",
"affiliations": "Department of Pediatric Hemato-Oncology, University Hospital of Rennes, Rennes, France.;Pediatric Hematology and Oncology Department, Armand Trousseau Hospital, APHP, Paris, France.;Department of the Institute of Pediatric Hematology and Oncology, University Hospital of Lyon, Lyon, France.;Department of Pediatric Hematology, Robert Debre Hospital, APHP, Paris, France.;Pediatric Hematology Oncology Department, University Hospital of Bordeaux, Bordeaux, France.;Department of Pediatric Onco-Hematology, University Hospital of Reims, Reims, France.;Department of Hematological Oncology and Cell Therapy, University Hospital of Poitiers, Poitiers, France.;Pediatric Hematology and Oncology Department, La Timone Children's Hospital, AP-HM, Marseille, France.;Pediatric Hematology Oncology Unity, University Hospital of Besançon, Besançon, France.;Pediatric Hematology and Oncology Immunology Department, University Hospital of Angers, Angers, France.;Pediatric Immuno-Hemato-Oncology Department, University Hospital of Grenoble, Grenoble, France.;Department of Pediatric Onco-Hematology, University Hospital of Montpellier, Montpellier, France.;Department of Pediatric Onco-Hematology, University Hospital of Saint-Etienne, Saint-Etienne, France.;Pediatric Oncology and Hematology Department, University Hospital of Nancy (CHRU Nancy), Nancy, France.;Department of Pediatric Hemato-Oncology, University Hospital of Toulouse, Toulouse, France.;Department of Pediatric Onco-Hematology, University Hospital of Nantes, Nantes, France.;Cytogenetic and Cell Biology Department, University Hospital of Rennes, Rennes, France.;Rennes University, University Hospital of Rennes, Inserm, CIC 1414 (Centre d'Investigation Clinique de Rennes), Rennes, France.;Department of Pediatric Hemato-Oncology, University Hospital of Rennes, Rennes, France.",
"authors": "Aubert|Lucie|L|https://orcid.org/0000-0002-3095-568X;Petit|Arnaud|A|;Bertrand|Yves|Y|;Ray-Lunven|Anne-France|AF|;Angoso|Marie|M|;Pluchart|Claire|C|;Millot|Frédéric|F|;Saultier|Paul|P|;Cheikh|Nathalie|N|;Pellier|Isabelle|I|;Plantaz|Dominique|D|;Sirvent|Anne|A|;Thouvenin-Doublet|Sandrine|S|;Valduga|Julie|J|;Plat|Geneviève|G|;Rialland|Fanny|F|;Henry|Catherine|C|https://orcid.org/0000-0002-8457-4487;Esvan|Maxime|M|;Gandemer|Virginie|V|https://orcid.org/0000-0002-4991-233X",
"chemical_list": null,
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"issue": null,
"journal": "Pediatric blood & cancer",
"keywords": "Philadelphia chromosome-positive acute lymphoblastic leukemia; children; relapse; tyrosine kinase inhibitors",
"medline_ta": "Pediatr Blood Cancer",
"mesh_terms": null,
"nlm_unique_id": "101186624",
"other_id": null,
"pages": "e29441",
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"pubdate": "2021-12-02",
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"title": "Therapeutic approach and outcome of children with Philadelphia chromosome-positive acute lymphoblastic leukemia at first relapse in the era of tyrosine kinase inhibitors: An SFCE retrospective study.",
"title_normalized": "therapeutic approach and outcome of children with philadelphia chromosome positive acute lymphoblastic leukemia at first relapse in the era of tyrosine kinase inhibitors an sfce retrospective study"
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"abstract": "Following local and systemic treatment of gliomas, the differentiation between glioma relapse and treatment-related changes such as pseudoprogression or radiation necrosis using conventional MRI is limited. To overcome this limitation, various amino acid PET tracers such as O-[2-(18F)-fluoroethyl]-L-tyrosine (FET) are increasingly used and provide valuable additional clinical information. We here report neuroimaging findings in a clincally symptomatic 53-year-old woman with a recurrent anaplastic oligodendroglioma with MRI findings highly suspicious for tumor progression. In contrast, FET PET imaging suggested treatment-related changes considerably earlier than the regression of contrast enhancement on MRI. In patients with oligodendroglioma, the phenomenon of symptomatic treatment-related changes is not well described, making these imaging findings unique and important for clinical decision-making.",
"affiliations": "Department of Neurology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.;Department of Neurology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.;Department of Neurology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.;Institute of Neuroscience and Medicine (INM-3, -4), Research Center Juelich, Juelich, Germany.;Department of Neurology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.",
"authors": "Bauer|Elena Katharina|EK|;Werner|Jan-Michael|JM|;Fink|Gereon R|GR|;Langen|Karl-Josef|KJ|;Galldiks|Norbert|N|",
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"doi": "10.3389/fonc.2021.735388",
"fulltext": "\n==== Front\nFront Oncol\nFront Oncol\nFront. Oncol.\nFrontiers in Oncology\n2234-943X\nFrontiers Media S.A.\n\n10.3389/fonc.2021.735388\nOncology\nCase Report\nCase Report: Detection of Symptomatic Treatment-Related Changes in a Patient With Anaplastic Oligodendroglioma Using FET PET\nBauer Elena Katharina 1\n\nWerner Jan-Michael 1\nFink Gereon R. 1 2\nLangen Karl-Josef 2 3 4\n\nGalldiks Norbert 1 2 4 *\n\n1 Department of Neurology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany\n2 Institute of Neuroscience and Medicine (INM-3, -4), Research Center Juelich, Juelich, Germany\n3 Department of Nuclear Medicine, University Hospital Aachen, Aachen, Germany\n4 Center of Integrated Oncology (CIO), Universities of Aachen, Bonn, Cologne, and Duesseldorf, Cologne, Germany\nEdited by: Alessandro Stecco, University of Eastern Piedmont, Italy\n\nReviewed by: Francesco Cicone, University of Catanzaro, Italy; Marco Riva, University of Milan, Italy; Jens Gempt, Technische Universität München, Germany\n\n*Correspondence: Norbert Galldiks, n.galldiks@fz-juelich.de\nThis article was submitted to Cancer Imaging and Image-directed Interventions, a section of the journal Frontiers in Oncology\n\n16 11 2021\n2021\n11 73538802 7 2021\n02 11 2021\nCopyright © 2021 Bauer, Werner, Fink, Langen and Galldiks\n2021\nBauer, Werner, Fink, Langen and Galldiks\nhttps://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.\nFollowing local and systemic treatment of gliomas, the differentiation between glioma relapse and treatment-related changes such as pseudoprogression or radiation necrosis using conventional MRI is limited. To overcome this limitation, various amino acid PET tracers such as O-[2-(18F)-fluoroethyl]-L-tyrosine (FET) are increasingly used and provide valuable additional clinical information. We here report neuroimaging findings in a clincally symptomatic 53-year-old woman with a recurrent anaplastic oligodendroglioma with MRI findings highly suspicious for tumor progression. In contrast, FET PET imaging suggested treatment-related changes considerably earlier than the regression of contrast enhancement on MRI. In patients with oligodendroglioma, the phenomenon of symptomatic treatment-related changes is not well described, making these imaging findings unique and important for clinical decision-making.\n\namino acid PET\npseudoprogression\nchemoradiation\noligodendroglioma\ndiagnostic challenge\nDeutsche Forschungsgemeinschaft 10.13039/501100001659 Deutsche Forschungsgemeinschaft 10.13039/501100001659\n==== Body\npmcIntroduction\n\nTreatment-related changes on conventional MRI are predominantly characterized by both an increase of contrast enhancement in the T1-weighted image and a hyperintensity in the fluid-attenuated inversion recovery (FLAIR) sequence, which either remain stable or even disappear over time without any change of anticancer treatment. Not infrequently, patients experience no clinical deterioration. Misinterpretation of these imaging findings may result in an unnecessary discontinuation of an effective treatment with a potentially negative impact on the patient’s survival. Due to the low specificity of conventional MRI, the differentiation of treatment-related changes from actual tumor progression in glioma patients following radiotherapy or chemoradiation using conventional MRI is challenging (1–4).\n\nThe additional use of amino acid PET using O-[2-(18F)-fluoroethyl]-L-tyrosine (FET) in the care of glioma patients is gaining more attention. In recent years, a high diagnostic accuracy for the differentiation between tumor progression and treatment-related changes using FET PET has repeatedly been shown predominantly in patients with astrocytic gliomas (1, 2, 5, 6). In these studies, either static parameters or the combination of static and dynamic parameters derived from FET PET seem to be of considerable clinical value for the for the differentiation of tumor progression from treatment-related changes (range of sensitivity, 91-99%; range of specificity, 94-100%) (1, 5, 6). Despite its clinical relevance, only a few studies described treatment-related changes in patients with oligodendrogliomas.\n\nOligodendroglial gliomas are characterized by the presence of an isocitrate dehydrogenase (IDH) gene mutation and a 1p/19q codeletion and are histologically corresponding to the grade II or III of the in 2016 revised World Health Organisation (WHO) classification of Tumors of the Central Nervous System (7). This rare tumor entity accounts for 5.3% of all tumors of the central nervous system.\n\nWe here report the phenomenon of symptomatic treatment-related changes in a patient with an anaplastic oligodendroglioma.\n\nCase Presentation\n\nA 53-year-old female patient with a recurrent anaplastic oligodendroglioma (IDH mutant, 1p/19q co-deleted) was diagnosed with the second local tumor recurrence 15 years after initial diagnosis. The first-line treatment included tumor resection and radiotherapy. Eleven years later, a first local tumor recurrence was treated with re-resection followed by adjuvant temozolomide chemotherapy. Four years later, the tumor recurred locally again. Following complete resection and re-irradiation, she underwent adjuvant nitrosourea-based chemotherapy with procarbazine and lomustine. After two cycles, the patient experienced a clinical deterioration with an expressive aphasia and a right-sided hemiparesis. According to current response assessment criteria (3), the findings of the first and second follow-up MRI were consistent with “Progressive Disease”, whereas the corresponding FET PET scans remained unchanged compared to baseline (see Figure 1 ). Without changing the treatment regimen, symptomatic therapy with dexamethasone prompted a rapid clinical improvement. During follow-up, dexamethasone could subsequently be tapered from 8 mg to 0.5 mg. The diagnosis of treatment-related changes was based on the MRI findings performed 26 weeks after baseline imaging, which showed especially an almost complete decrease of contrast enhancement, accompanied by a further improvement of the clinical condition.\n\nFigure 1 Neuroimages including contrast-enhanced MRI, FLAIR-weighted MRI, and FET PET of a patient with an anaplastic oligodendroglioma (IDH mutant, 1p/19q co-deleted). Compared to the baseline MRI (A), the follow-up MRI perfomed 9 weeks later (17 weeks after end of radiotherapy) (B) showed a substantial contrast enhancement and an extensive FLAIR signal hyperintensity in the area of the resection defect. In contrast, both the baseline and first follow-up FET PET (A, B) showed no pathologically increased tracer uptake (mean tumor-to-brain ratios in both scans, 1.8). The rationale for this is based on the fact that several FET PET studies suggested that especially in pretreated glioma patients a mean tumor-to-brain ratio of 2.0 separates best between tumor relapse and treatment-related changes (1, 6, 8). The second follow-up MRI (C) showed a further slight increase of the FLAIR signal alteration. Again, the corresponding follow-up FET PET showed no substantial change of metabolic activity compared to the previous examinations (A, B). Not earlier than 26 weeks, the third follow-up MRI (D) revealed an almost complete decrease of the contrast enhancement.\n\nDiscussion\n\nFollowing radiotherapy with or without alyklating chemotherapy, treatment-related changes such as pseudoprogression or radiation necrosis represent a major diagnostic challenge in patients with astrocytic glioma. In this group of brain tumors, the steadily increasing number of studies highlights the value of amino acid PET for the differentiation of treatment-related changes from actual tumor progression with a high diagnostic accuracy (1, 2, 4, 9).\n\nOn the other hand, oligodendrogliomas represent a small glioma subgroup and constitute only approximately 5% of primary intracranial tumors. Importantly, it has been demonstrated that in oligodendrogliomas the rate of treatment-related changes is significantly lower than in patients with gliomas without 1p/19q codeletion (i.e., astrocytoma, glioblastoma) (10, 11). For example, Lin and co-workers reported a pseudo-progression rate of 31% for tumors without codeletions, and only 3% for tumors with codeletions (11). Moreover, amino acid uptake in 1p/19q-codeleted oligodendroglial tumors is generally significantly increased, even higher when compared to IDH mutant astrocytic tumors (12, 13), and similar to glioblastoma (13). Thus, a considerably increased FET uptake can be expected in the case of oligodendroglioma relapse. Consequently, the absence of this uptake pattern in our case further supports the diagnosis of treatment-related changes.\n\nAnother important aspect of the present case is the extensive increase of the FLAIR signal hyperintensity, suggesting non-enhancing tumor progression. In contrast, FET PET showed in spatial correspondence no pathological increased tracer uptake. Thus, FET PET seems also to be of value to rule out this particular phenomenon. In summary, this case highlights the value of FET PET for the diagnosis of treatment-related changes in a glioma subtype characterized by a naturally increased amino acid uptake and a low rate of treatment-related changes.\n\nData Availability Statement\n\nThe original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.\n\nEthics Statement\n\nAll procedures performed in the studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.\n\nAuthor Contributions\n\nData acquisition, EB, NG, and J-MW. Writing of manuscript drafts, EB, NG, and J-MW. All authors contributed to the article and approved the submitted version.\n\nFunding\n\nSupported by the Deutsche Forschungsgemeinschaft (DFG), project number 428090865 (EB and NG), and the Cologne Clinician Scientist Program (CCSP)/Faculty of Medicine/University of Cologne, funded by the DFG, FI 773/15-1 (J-MW).\n\nConflict of Interest\n\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n\nPublisher’s Note\n\nAll claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.\n==== Refs\nReferences\n\n1 Galldiks N Dunkl V Stoffels G Hutterer M Rapp M Sabel M . Diagnosis of Pseudoprogression in Patients With Glioblastoma Using O-(2-[18F]Fluoroethyl)-L-Tyrosine PET. Eur J Nucl Med Mol Imaging (2015) 42 (5 ):685–95. doi: 10.1007/s00259-014-2959-4\n2 Langen KJ Galldiks N Hattingen E Shah NJ . Advances in Neuro-Oncology Imaging. Nat Rev Neurol (2017) 13 (5 ):279–89. doi: 10.1038/nrneurol.2017.44\n3 Wen PY Macdonald DR Reardon DA Cloughesy TF Sorensen AG Galanis E . Updated Response Assessment Criteria for High-Grade Gliomas: Response Assessment in Neuro-Oncology Working Group. J Clin Oncol (2010) 28 (11 ):1963–72. doi: 10.1200/JCO.2009.26.3541\n4 Albert NL Weller M Suchorska B Galldiks N Soffietti R Kim MM . Response Assessment in Neuro-Oncology Working Group and European Association for Neuro-Oncology Recommendations for the Clinical Use of PET Imaging in Gliomas. Neuro Oncol (2016) 18 (9 ):1199–208. doi: 10.1093/neuonc/now058\n5 Bashir A Mathilde Jacobsen S Molby Henriksen O Broholm H Urup T Grunnet K . Recurrent Glioblastoma Versus Late Posttreatment Changes: Diagnostic Accuracy of O-(2-[18F]Fluoroethyl)-L-Tyrosine Positron Emission Tomography (18F-FET PET). Neuro Oncol (2019) 21 (12 ):1595–606. doi: 10.1093/neuonc/noz166\n6 Galldiks N Stoffels G Filss C Rapp M Blau T Tscherpel C . The Use of Dynamic O-(2-18F-Fluoroethyl)-L-Tyrosine PET in the Diagnosis of Patients With Progressive and Recurrent Glioma. Neuro Oncol (2015) 17 (9 ):1293–300. doi: 10.1093/neuonc/nov088\n7 Louis DN Perry A Reifenberger G von Deimling A Figarella-Branger D Cavenee WK . The 2016 World Health Organization Classification of Tumors of the Central Nervous System: A Summary. Acta Neuropathol (2016) 131 (6 ):803–20. doi: 10.1007/s00401-016-1545-1\n8 Law I Albert NL Arbizu J Boellaard R Drzezga A Galldiks N . Joint EANM/EANO/RANO Practice Guidelines/SNMMI Procedure Standards for Imaging of Gliomas Using PET With Radiolabelled Amino Acids and [(18)F]FDG: Version 1.0. Eur J Nucl Med Mol Imaging (2019) 46 (3 ):540–57. doi: 10.1007/s00259-018-4207-9\n9 Werner JM Stoffels G Lichtenstein T Borggrefe J Lohmann P Ceccon G . Differentiation of Treatment-Related Changes From Tumour Progression: A Direct Comparison Between Dynamic FET PET and ADC Values Obtained From DWI MRI. Eur J Nucl Med Mol Imaging (2019) 46 (9 ):1889–901. doi: 10.1007/s00259-019-04384-7\n10 Lin AL White M Miller-Thomas MM Fulton RS Tsien CI Rich KM . Molecular and Histologic Characteristics of Pseudoprogression in Diffuse Gliomas. J Neurooncol (2016) 130 (3 ):529–33. doi: 10.1007/s11060-016-2247-1\n11 Lin AL Liu J Evans J Leuthardt EC Rich KM Dacey RG . Codeletions at 1p and 19q Predict a Lower Risk of Pseudoprogression in Oligodendrogliomas and Mixed Oligoastrocytomas. Neuro Oncol (2014) 16 (1 ):123–30. doi: 10.1093/neuonc/not142\n12 Takei H Shinoda J Ikuta S Maruyama T Muragaki Y Kawasaki T . Usefulness of Positron Emission Tomography for Differentiating Gliomas According to the 2016 World Health Organization Classification of Tumors of the Central Nervous System. J Neurosurg (2019) 1–10. doi: 10.3171/2019.5.JNS19780\n13 Kim D Chun JH Kim SH Moon JH Kang SG Chang JH . Re-Evaluation of the Diagnostic Performance of (11)C-Methionine PET/CT According to the 2016 WHO Classification of Cerebral Gliomas. Eur J Nucl Med Mol Imaging (2019) 46 (8 ):1678–84. doi: 10.1007/s00259-019-04337-0\n\n",
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"issue": "11()",
"journal": "Frontiers in oncology",
"keywords": "amino acid PET; chemoradiation; diagnostic challenge; oligodendroglioma; pseudoprogression",
"medline_ta": "Front Oncol",
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"title": "Case Report: Detection of Symptomatic Treatment-Related Changes in a Patient With Anaplastic Oligodendroglioma Using FET PET.",
"title_normalized": "case report detection of symptomatic treatment related changes in a patient with anaplastic oligodendroglioma using fet pet"
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"abstract": "BACKGROUND\nBoth diuretics and nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used, in particular among the elderly. The use of NSAIDs may decrease the efficacy of diuretics and induce congestive heart failure (CHF) in patients treated with diuretics.\n\n\nOBJECTIVE\nTo investigate the risk of CHF associated with combined use of diuretics and NSAIDs in patients older than 55 years.\n\n\nMETHODS\nWe conducted a study in a base cohort of 10,519 recipients of diuretics and NSAIDs identified in the PHARMO database during the period from 1986 through 1992. The incidence density of hospitalizations for CHF during exposure to both diuretics and NSAIDs (index) was compared with that during exposure to diuretics only (reference).\n\n\nRESULTS\nWe found an overall increased risk of hospitalization for CHF during periods of concomitant use of diuretics and NSAIDs compared with use of diuretics only (crude relative risk, 2.2; 95% confidence interval, 1.7-2.9). After adjusting for cofactors including age, sex, history of hospitalization, and drug use, a 2-fold increased risk remained (relative risk, 1.8; 95% confidence interval, 1.4-2.4).\n\n\nCONCLUSIONS\nUse of NSAIDs in elderly patients taking diuretics is associated with a 2-fold increased risk of hospitalization for CHF, especially in those with existing serious CHF.",
"affiliations": "Department of Pharmacoepidemiology and Pharmacotherapy, University of Utrecht, The Netherlands.",
"authors": "Heerdink|E R|ER|;Leufkens|H G|HG|;Herings|R M|RM|;Ottervanger|J P|JP|;Stricker|B H|BH|;Bakker|A|A|",
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"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000894:Anti-Inflammatory Agents, Non-Steroidal; D004232:Diuretics; D005260:Female; D006333:Heart Failure; D006760:Hospitalization; D006801:Humans; D008297:Male; D008875:Middle Aged; D012306:Risk; D012307:Risk Factors",
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"title": "NSAIDs associated with increased risk of congestive heart failure in elderly patients taking diuretics.",
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"abstract": "Herein we present a case of giant cell arteritis presenting with nodular posterior scleritis and exudative retinal detachment mimicking a choroidal mass.\nA 67-year-old man presented with sudden onset left-sided periorbital pain, blurry vision, and a choroidal lesion in the posterior pole. Despite treatment with high-dose oral prednisone for suspected nodular posterior scleritis mimicking a choroidal mass, the vision in his left eye did not recover, and he developed optic nerve pallor on exam. Further evaluation revealed an ESR of >140 mm/hr (Upper limit of normal = 20 mm/hr), a CRP of 113 mg/L (Upper limit of normal = 9 mg/L), and a temporal artery biopsy consistent with GCA. The patient was started on methotrexate and the oral steroids were slowly tapered.\nGiven the potential for GCA to present with scleritis and the potential for nodular posterior scleritis to mimic a choroidal mass, presence of a painful choroidal lesion with optic nerve swelling should prompt an evaluation for GCA to prevent permanent and bilateral vision loss.",
"affiliations": "Tennessee Retina, 345 23rd Ave N, Ste 350, Nashville, TN, 37203, USA.;Tennessee Retina, 345 23rd Ave N, Ste 350, Nashville, TN, 37203, USA.;Tennessee Retina, 345 23rd Ave N, Ste 350, Nashville, TN, 37203, USA.",
"authors": "Awh|Caroline|C|;Reichstein|David A|DA|;Thomas|Akshay S|AS|",
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"fulltext": "\n==== Front\nAm J Ophthalmol Case RepAm J Ophthalmol Case RepAmerican Journal of Ophthalmology Case Reports2451-9936Elsevier S2451-9936(19)30237-310.1016/j.ajoc.2019.100583100583Case ReportA case of giant cell arteritis presenting with nodular posterior scleritis mimicking a choroidal mass Awh Caroline Reichstein David A. Thomas Akshay S. akshaysthomas@gmail.com∗Tennessee Retina, 345 23rd Ave N, Ste 350, Nashville, TN, 37203, USA∗ Corresponding author. 345 23rd Ave N, Ste 350, Nashville, TN, 37203, USA. akshaysthomas@gmail.com01 1 2020 3 2020 01 1 2020 17 10058321 9 2019 15 12 2019 31 12 2019 © 2019 The Author(s)2019This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Purpose\nHerein we present a case of giant cell arteritis presenting with nodular posterior scleritis and exudative retinal detachment mimicking a choroidal mass.\n\nObservations\nA 67-year-old man presented with sudden onset left-sided periorbital pain, blurry vision, and a choroidal lesion in the posterior pole. Despite treatment with high-dose oral prednisone for suspected nodular posterior scleritis mimicking a choroidal mass, the vision in his left eye did not recover, and he developed optic nerve pallor on exam. Further evaluation revealed an ESR of >140 mm/hr (Upper limit of normal = 20 mm/hr), a CRP of 113 mg/L (Upper limit of normal = 9 mg/L), and a temporal artery biopsy consistent with GCA. The patient was started on methotrexate and the oral steroids were slowly tapered.\n\nConclusions\nGiven the potential for GCA to present with scleritis and the potential for nodular posterior scleritis to mimic a choroidal mass, presence of a painful choroidal lesion with optic nerve swelling should prompt an evaluation for GCA to prevent permanent and bilateral vision loss.\n\nKeywords\nGiant cell arteritisPosterior scleritisChoroidal mass\n==== Body\n1 Introduction\nGiant cell arteritis (GCA), also known as temporal arteritis, is a common systemic vasculitis of medium- and large-sized arteries in patients aged over 50 years with a wide spectrum of clinical manifestations. It is a true ophthalmic emergency—a delay in treatment may result in permanent and bilateral vision loss from ischemic complications. Ocular manifestations are often preceded by the most common systemic symptoms of the disease: new-onset headache, scalp tenderness, jaw claudication, and constitutional symptoms. Common ocular symptoms include visual loss, amaurosis fugax, diplopia, and eye pain. The most common ocular ischemic complication is arteritic anterior ischemic optic neuropathy with the classic sign of a pale and swollen optic disc. However, there are a variety of less common ocular manifestations of GCA, including anterior uveitis, ocular hypotony, scleritis, episcleritis, and, rarely, orbital pseudotumor.1 We report a rare presentation of GCA with nodular posterior scleritis mimicking a choroidal mass.\n\n2 Case report\nA 67-year-old male presented to an outside ophthalmologist with sudden onset left-sided periorbital pain and blurry vision. Ophthalmologic examination found a corrected visual acuity of 20/70 in the left eye and a choroidal lesion in the posterior pole. Given concern for a metastatic process to the left eye, he underwent an MRI of the brain and orbits and a CT of the chest, abdomen, and pelvis for systemic screening for malignancy. The MRI revealed a focal thickening in the posterior wall of the left globe with a posterior extraocular component. The CT found no masses.\n\nTwo weeks later, the patient presented to our clinic for further workup. By this time, vision in his left eye had further declined to 20/400 with continued periorbital pain. Dilation had been performed earlier that day and so evaluation for an afferent pupillary defect was not possible. Anterior segment evaluation of both eyes was unremarkable as was funduscopic evaluation of the right eye. Funduscopic examination of the left eye revealed an elevated amelanotic choroidal lesion in the macula measuring 10 mm × 7 mm, chorioretinal folds, exudative retinal detachment, and optic disc swelling (Fig. 1). Optical coherence tomography (OCT) revealed a dome-shaped choroidal “mass” with overlying subretinal fluid. Fluorescein angiography (FA) demonstrated punctate staining in the area of the lesion and leakage of the disc in the left eye. B-scan ultrasonography of the lesion revealed homogenous dense echogenicity with an apical height of 5.8 mm. Based on these findings, the patient was started on treatment with high-dose oral prednisone (60 mg daily) for suspected nodular posterior scleritis mimicking a choroidal mass.Fig. 1 Baseline imaging of the left eye is represented in photos A-E. Fundus photo (A) showing an amelanotic macular choroidal lesion and optic nerve swelling. Mid-phase (B) and late (C) fluorescein angiographic images showing punctate staining of the lesion and leakage of the disc. B-scan ultrasonography (D) revealed diffuse choroidal thickening as well as an area of nodular thickening with homogenous dense echogenicity. Optical coherence tomography (OCT) through the lesion (E) revealed choroidal thickening with overlying subretinal fluid and retinal folds. After 3 weeks of oral steroids, the choroidal lesion had resolved (F) but optic nerve swelling was still evident. OCT at that time showed improvement of choroidal thickening and subretinal fluid (G). After another 3 weeks of oral steroids, optic nerve pallor was evident (H) on funduscopy while OCT revealed resolution of choroidal thickening and subretinal fluid.\n\nFig. 1\n\nLaboratory workup for autoimmune markers (antinuclear antibodies, antineutrophil cytoplasmic antibodies, rheumatoid factor), infectious causes (syphilis, sarcoidosis, tuberculosis, Bartonella), angiotensin-converting enzyme and a chest X-Ray were all within the reference ranges. The patient's steroids were slowly tapered over several weeks to 20 mg daily with resolution of periorbital pain, choroidal thickening, exudative retinal detachment and optic nerve swelling. However, the vision in the left eye did not recover and stabilized at counting fingers (CF). Additionally, significant optic nerve pallor was noted at his 6-week follow-up while still on 20 mg of prednisone. Upon further questioning, the patient reported a slight headache with the taper of steroids. The degree of optic nerve pallor and headache raised concern for GCA, and the prednisone dosage was promptly increased to 60 mg daily. Further laboratory evaluation that day revealed an ESR of >140 mm/hr (Upper limit of normal = 20 mm/hr) and a CRP of 113 mg/L (Upper limit of normal = 9 mg/L). A temporal artery biopsy was consistent with GCA. The patient was started on methotrexate and the oral steroids were slowly tapered. No other systemic complications of GCA such as aortitis were found on further evaluation. Vision remained 20/20 in the right eye and CF in the left eye.\n\n3 Discussion\nScleritis is an ocular inflammatory disease that is often associated with systemic autoimmune conditions (e.g. rheumatoid arthritis, relapsing polychondritis, psoriatic arthritis) some of which feature a prominent vasculitic component (e.g. granulomatosis with polyangiitis, systemic lupus erythematosus).2 Given that GCA is a systemic immune-mediated vasculitis, which can involve any organ system,3 involvement of scleral blood vessels with resulting scleritis may occur. In our review of the literature, we found only 2 reported cases of GCA in association with posterior scleritis.4,5 This is, however, the first report of GCA presenting with nodular posterior scleritis mimicking a choroidal mass. GCA has, however, been reported to present mimicking a mass elsewhere including a submandibular mass6 and testicular mass.7\n\nPosterior scleritis classically presents with symptoms of decreased vision, ocular and periorbital pain, and headaches. Clinical signs include proptosis, ciliary and conjunctival injection, optic disc swelling, retinal striae, serous retinal detachment, and chorioretinal folds.4,5 However, it can pose a diagnostic challenge due to its low incidence and variety of clinical presentations. In the case of nodular posterior scleritis, patients may present with a lesion large enough to mimic a choroidal mass. Although rare, reports in the literature serve as a reminder to consider nodular posterior scleritis if a patient presents with a painful choroidal mass.8, 9, 10\n\nIn our case, there was a delay in diagnosis of posterior scleritis due to reasonable concerns for a metastatic process by the referring physician. Additionally, the optic nerve swelling noted during our initial evaluation was incorrectly attributed to the posterior scleritis and while oral steroids were immediately started, an earlier diagnosis of GCA would have led to a more gradual taper of steroids. Initial fluorescein angiography did not reveal patchy choroidal filling which may have raised greater concerns for GCA earlier on. The diagnosis of GCA was ultimately suspected based on the significant and rapid onset of optic nerve pallor which is not characteristic of an inflammatory papillitis. Methotrexate has documented efficacy in the treatment of GCA and was our initial choice for steroid-sparing immunosuppression.11 While tocilizumab is FDA-approved for the treatment of GCA, we reserve it for those who have failed a steroid taper while on methotrexate given tocilizumab's significant cost.\n\nGiven the potential for GCA to present with scleritis and the potential for nodular posterior scleritis to mimic a choroidal mass, presence of a painful choroidal lesion with optic nerve swelling should prompt an evaluation for GCA to prevent permanent and bilateral vision loss.\n\nPatient Consent\nConsent to publish the case report was not obtained. This report does not contain any personal information that could lead to the identification of the patient.\n\nFunding\nNo funding or grant support.\n\nAuthorship\nAll authors attest that they meet the current ICMJE criteria for Authorship.\n\nDeclaration of competing interest\nNo conflicting relationship exists for any author.\n\nAcknowledgments\nNone.\n==== Refs\nReferences\n1 Hayreh S.S. Podhajsky P.A. Zimmerman B. Ocular manifestations of giant cell arteritis Am J Ophthalmol 125 4 1998 509 520 9559737 \n2 Sainz de la maza M. Foster C.S. Jabbur N.S. Scleritis associated with systemic vasculitic diseases Ophthalmology 102 4 1995 687 692 7724185 \n3 Guevara M. Kollipara C.S. Recent advances in giant cell arteritis Curr Rheumatol Rep 20 5 2018 25 29611005 \n4 Erdogan M. Sayin N. Yıldız ekinci D. Bayramoglu S. Bilateral posterior scleritis associated with giant cell arteritis: a case report Ocul Immunol Inflamm 26 8 2018 1244 1247 28914559 \n5 Cavallini G.M. Volante V. Bigliardi M.C. Mascia M.T. Forlini M. Bilateral posterior scleritis as a presenting manifestation of giant cell arteritis: a case report Can J Ophthalmol 49 6 2014 e141 e143 25433749 \n6 Ruiz-masera J.J. Alamillos-granados F.J. Dean-ferrer A. Submandibular swelling as the first manifestation of giant cell arteritis. Report of a case J Cranio-Maxillo-Fac Surg 23 2 1995 119 121 \n7 Sundaram S. Smith D.H. Giant cell arteritis mimicking a testicular tumour Rheumatol Int 20 5 2001 215 216 11518043 \n8 Shukla D. Kim R. Giant nodular posterior scleritis simulating choroidal melanoma Indian J Ophthalmol 54 2 2006 120 122 16770031 \n9 Hage R. Jean-charles A. Guyomarch J. Rahimian O. Donnio A. Merle H. Nodular posterior scleritis mimicking choroidal metastasis: a report of two cases Clin Ophthalmol 5 2011 877 880 21760715 \n10 Liu A.T. Luk F.O. Chan C.K. A case of giant nodular posterior scleritis mimicking choroidal malignancy Indian J Ophthalmol 63 12 2015 919 921 26862098 \n11 Leon L. Rodriguez-rodriguez L. Morado I. Treatment with methotrexate and risk of relapses in patients with giant cell arteritis in clinical practice Clin Exp Rheumatol 36 2 2018 121 128\n\n",
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"abstract": "BACKGROUND\nIn 2010, over 220 000 people attempted suicide in France, in other words up to one suicide attempt every 85s. Numerous risk factors are involved, including iatrogenic factors. Data from previous retrospective studies indicate, on average, 5.7 % of people treated with corticosteroids develop severe steroid-induced psychiatric disorders. Steroid-induced suicidal behavior is not explicitly specified in these studies, except for one recent descriptive study. Its prevalence remains unclear and is probably underestimated.\n\n\nMETHODS\nWe report the case of a 50-year-old woman treated by intravenous methylprednisolone for a relapsing-remitting multiple sclerosis relapse. Two weeks following a five-day intravenous treatment, she attempted suicide by prescription drug overdose at home. In the two months leading up to this event, she described symptoms of major depressive disorder which were left untreated. In retrospect, high doses of corticosteroids seem to have played a significant role in the occurrence of transient acute suicidal behavior. The patient improved significantly under antidepressant treatment and was discharged after three weeks of hospitalization.\n\n\nCONCLUSIONS\nThis clinical case points out that corticosteroids are likely to precipitate suicidal behavior in a patient with a premorbid undiagnosed depressive disorder. Early detection of psychiatric disorders before starting corticotherapy seems to be essential. However, management strategies are not explicit enough in the literature to be recommended. Treatment discontinuation should not be done systematically, but tapering should be considered in combination with an antidepressant drug. A recent longitudinal study by Fardet et al. on oral corticotherapy suggests a positive correlation between steroids treatment and suicidal behavior. These results may support our clinical observation. In addition, the neurobiologic correlates may give credit to the underlying pathophysiology proposed as a potential explanation to the patient's sudden suicidal behavior after corticotherapy. Physicians and patients must be aware of possible risks of increased suicidality when undergoing corticosteroid treatment in order to prevent fatal outcomes for the patient.",
"affiliations": "Département de psychiatrie, psychotraumatisme et addictions, CHU Tenon, 4, rue de la Chine, 75020 Paris, France; Université Pierre-et-Marie-Curie, 15, rue de l'École-de-médecine, 75006 Paris, France. Electronic address: guilhemcarle@gmail.com.;Département de psychiatrie, psychotraumatisme et addictions, CHU Tenon, 4, rue de la Chine, 75020 Paris, France; Université Pierre-et-Marie-Curie, 15, rue de l'École-de-médecine, 75006 Paris, France.",
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"keywords": "Corticosteroid; Corticoïdes; Dépression; Intoxication médicamenteuse; Multiple sclerosis; Sclérose en plaques; Side effect; Steroid-induced psychiatric disorders; Suicide attempt; Tentative de suicide",
"medline_ta": "Encephale",
"mesh_terms": "D000305:Adrenal Cortex Hormones; D000893:Anti-Inflammatory Agents; D003865:Depressive Disorder, Major; D005260:Female; D006801:Humans; D007275:Injections, Intravenous; D008775:Methylprednisolone; D008875:Middle Aged; D020529:Multiple Sclerosis, Relapsing-Remitting; D059020:Suicidal Ideation; D013406:Suicide, Attempted",
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"title": "Corticotherapy and suicidal behavior: A case report.",
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"abstract": "Drug-resistant epilepsy (DRE) occurs in 20-30% of all patients who develop epilepsy and can occur from diverse causes. Cyclosporine-A (CSA) is an immunosuppressive drug utilized to prevent graft-versus-host disease (GvHD) in transplant patients and is known to cause neurotoxicity, including seizures. In some cases, however, patients can develop DRE. Only a limited number of cases have been reported in which DRE has developed after CSA exposure - all in children. Here we present a rare case of an adult developing DRE after post-transplant CSA neurotoxicity. In addition, we provide a comprehensive review and analysis of all reported cases in the literature.\nA 29-year-old man with Non-Hodgkin's Lymphoma underwent an allogenic hematopoietic stem cell transplant and experienced a CSA-induced seizure at 7.5 months' post-transplant. The patient was discontinued on CSA and began a low dose tacrolimus regimen. At 33 months' post-transplant, he had seizure recurrence and developed DRE. Imaging revealed right mesial temporal sclerosis (MTS) and video EEG localized ictal activity to the right anterior temporal lobe. He was successfully treated with a right anterior temporal lobectomy and amygdalohippocampectomy.\nSeven peer-reviewed studies described 15 patients who underwent transplantation with post-transplant CSA administration and subsequently developed DRE following an initial CSA-induced seizure. All 15 patients were children suggesting that young age is a risk factor for DRE after CSA-induced seizures. Initial CSA-induced seizures occurred at an average of 1.6 ± 1.1 months after transplant and seizure recurrence 9.2 ± 8.0 months after transplant. All reported CSA routes of administration (n = 6) were intravenous and 7 of 9 (78%) reported CSA blood levels above the therapeutic range. The incidence of MTS (40%) in these 15 patients was significantly higher than the incidence in the general DRE population (24%) and was most effectively treated via epilepsy surgery.\nThe use of cyclosporine for GvHD prophylaxis and treatment following transplantation may cause seizures and be associated with DRE. Although discontinuation and dose decrease of CSA often reverse adverse neurological events, initial CSA-induced seizures may be associated with MTS that and subsequent greater risk of DRE development.",
"affiliations": "University of Iowa Carver College of Medicine, Iowa City, IA, USA.;Department of Neurosurgery, University of Iowa Hospitals and Clinics, Iowa City, IA, USA.;Department of Neurology, University of Iowa Hospitals and Clinics, Iowa City, IA, USA.;University of Iowa Carver College of Medicine, Iowa City, IA, USA.;Department of Neurosurgery, University of Iowa Hospitals and Clinics, Iowa City, IA, USA.;University of Iowa Carver College of Medicine, Iowa City, IA, USA.",
"authors": "Vesole|Adam S|AS|;Nagahama|Yasunori|Y|;Granner|Mark A|MA|;Howard|Matthew A|MA|;Kawasaki|Hiroto|H|;Dlouhy|Brian J|BJ|",
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"fulltext": "\n==== Front\nEpilepsy Behav Case RepEpilepsy Behav Case RepEpilepsy & Behavior Case Reports2213-3232Elsevier S2213-3232(18)30003-310.1016/j.ebcr.2018.01.002ArticleDrug-resistant epilepsy development following stem cell transplant and cyclosporine neurotoxicity induced seizures: Case report in an adult and analysis of reported cases in the literature Vesole Adam S. aNagahama Yasunori bGranner Mark A. cHoward Matthew A. abdKawasaki Hiroto bDlouhy Brian J. brian-dlouhy@uiowa.eduabd⁎a University of Iowa Carver College of Medicine, Iowa City, IA, USAb Department of Neurosurgery, University of Iowa Hospitals and Clinics, Iowa City, IA, USAc Department of Neurology, University of Iowa Hospitals and Clinics, Iowa City, IA, USAd Pappajohn Biomedical Institute, University of Iowa Carver College of Medicine, Iowa City, IA, USA⁎ Corresponding author at: Department of Neurosurgery, University of Iowa Children's Hospital, University of Iowa Hospitals and Clinics, 200 Hawkins Drive, Iowa City, IA 52242, USA. brian-dlouhy@uiowa.edu08 2 2018 2018 08 2 2018 10 8 13 7 1 2018 19 1 2018 27 1 2018 This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Introduction\nDrug-resistant epilepsy (DRE) occurs in 20–30% of all patients who develop epilepsy and can occur from diverse causes. Cyclosporine-A (CSA) is an immunosuppressive drug utilized to prevent graft-versus-host disease (GvHD) in transplant patients and is known to cause neurotoxicity, including seizures. In some cases, however, patients can develop DRE. Only a limited number of cases have been reported in which DRE has developed after CSA exposure — all in children. Here we present a rare case of an adult developing DRE after post-transplant CSA neurotoxicity. In addition, we provide a comprehensive review and analysis of all reported cases in the literature.\n\nCase report\nA 29-year-old man with Non-Hodgkin's Lymphoma underwent an allogenic hematopoietic stem cell transplant and experienced a CSA-induced seizure at 7.5 months' post-transplant. The patient was discontinued on CSA and began a low dose tacrolimus regimen. At 33 months' post-transplant, he had seizure recurrence and developed DRE. Imaging revealed right mesial temporal sclerosis (MTS) and video EEG localized ictal activity to the right anterior temporal lobe. He was successfully treated with a right anterior temporal lobectomy and amygdalohippocampectomy.\n\nLiterature review\nSeven peer-reviewed studies described 15 patients who underwent transplantation with post-transplant CSA administration and subsequently developed DRE following an initial CSA-induced seizure. All 15 patients were children suggesting that young age is a risk factor for DRE after CSA-induced seizures. Initial CSA-induced seizures occurred at an average of 1.6 ± 1.1 months after transplant and seizure recurrence 9.2 ± 8.0 months after transplant. All reported CSA routes of administration (n = 6) were intravenous and 7 of 9 (78%) reported CSA blood levels above the therapeutic range. The incidence of MTS (40%) in these 15 patients was significantly higher than the incidence in the general DRE population (24%) and was most effectively treated via epilepsy surgery.\n\nConclusions\nThe use of cyclosporine for GvHD prophylaxis and treatment following transplantation may cause seizures and be associated with DRE. Although discontinuation and dose decrease of CSA often reverse adverse neurological events, initial CSA-induced seizures may be associated with MTS that and subsequent greater risk of DRE development.\n\nKeywords\nDrug-resistant epilepsyMedically intractable epilepsyAntiseizure drugsSeizuresCyclosporine-ACyclosporine neurotoxicityTransplantMesial temporal sclerosis\n==== Body\n1 Introduction\nDrug-resistant epilepsy (DRE) occurs in 20–30% of all patients who develop epilepsy and can occur from diverse causes. Cyclosporine-A (CSA) is a common immunosuppressant drug utilized to prevent graft-versus-host disease (GvHD) in patients who undergo solid organ or bone marrow transplantation. Twenty to 40% of transplant patients experience a central nervous system (CNS) complication due to CSA, most commonly in the first few months post-transplant [1], [2].\n\nAcute CSA-induced neurotoxic effects include headache, encephalopathy, mental status changes, visual disturbances, akinetic mutism, stroke and seizures [3], [4], [5], [6], [7], [8], [9]. Seizures, the second most common of CSA-induced neurotoxic events, have been reported in 2.5–8.4% of pediatric and 1.5–5.5% of adult post-transplant patients [2], [10], [11], [12]. The neurotoxic effects of CSA often resolve after discontinuing CSA, switching to a different immunosuppressant drug such as tacrolimus, or administering antiseizure drugs in the case of seizures [2]. However, in some cases of CSA-induced seizures, patients can develop DRE — the majority of them reported in pediatric patients.\n\nHere we discuss a rare reported case of an adult developing DRE after transplant CSA neurotoxicity. Due to its rare occurrence, few studies have characterized the onset and course of DRE following CSA-induced seizures, including discussion and effectiveness of surgical treatment [4], [5], [10], [11], [13], [14]. Therefore, we provide a comprehensive literature review and analysis of all reported cases of the development of DRE following CSA-induced seizures in transplant patients. Understanding risk factors and pathogenesis for the development of drug-resistant epilepsy after CSA-neurotoxicity will be useful in limiting and treating this complication.\n\n2 Case report\n2.1 Initial presentation and development of T-cell lymphoma (Non-Hodgkin's lymphoma)\nA 28-year-old man with a history of common variable immunodeficiency (CVID) and panhypogammaglobulinemia was found to have liver lesions and adenopathy near the aortic arch. A liver biopsy revealed T-cell lymphoma, and he was subsequently treated with four cycles of CHOP chemotherapy (cyclophosphamide, hydroxydaunorubicin, Oncovin and prednisone) and two cycles of DHAP chemotherapy (dexamethasone, high dose cytarabine and cisplatin). Chemotherapy had no significant effect on T-cell lymphoma (Non-Hodgkin's lymphoma, NHL) progression, and therefore, the patient underwent bone marrow transplant.\n\n2.2 Allogenic bone marrow transplant\nThe patient began an immunosuppressive conditioning regimen of cyclophosphamide and total body irradiation (TBI) prior to an allogenic HLA-matched related bone marrow transplant from his sister and engrafted by day 20. Post-transplant, he received monthly intravenous immunoglobulin (IVIG) infusions and 550 mg of cyclosporine daily. The patient developed graft-versus-host disease (GvHD) of the liver, and the patient was started on prednisone and continued cyclosporine. While tapering prednisone, the patient was hospitalized for herpes simplex I of the mouth and nose and bacterial sinusitis, treated successfully with acyclovir and cefepime, respectively — both suspected to have occurred due to a weakened immune system from prednisone and cyclosporine.\n\n2.3 Cyclosporine toxicity, neurological effects, and initial seizure\nDays after his hospitalization for herpes simplex and sinusitis, at 7.5 months' post-transplant, the patient was readmitted due to cyclosporine toxicity with a blood level of 1467 ng/ml (therapeutic range: 100–200 ng/ml). He experienced cortical blindness and a single focal impaired awareness seizure and MRI showed increased occipital/parietal signal intensity consistent with posterior reversible encephalopathy syndrome (PRES). There was no evidence of any pre-existing epileptogenic lesions on MRI. Symptoms improved upon immediate replacement of cyclosporine with tacrolimus and administration of phenytoin. Besides cyclosporine neurotoxicity, he did not have any preexisting risk factors for epilepsy development such as febrile seizures, family history of seizures/epilepsy or childhood seizures/epilepsy.\n\n2.4 Seizure recurrence\nThe next two years following cyclosporine toxicity, the patient was seizure-free although this was complicated with acute GvHD of the liver and chronic GvHD of the skin. At 33 months' post-transplant, he experienced a generalized tonic–clonic (GTC) seizure and remained in non-convulsive status epilepticus until treated with phenytoin. MRI at the time of seizure recurrence (Fig. 1) showed a subtle signal intensity increase in the right insular cortex and hippocampus and atrophy in the right parietal lobe. An EEG was abnormal with frequent spike–wave discharges with occasional delta slow waves in the right temporal region. His medical history, EEG and neuroimaging were consistent of a focal seizure tendency. Lumbar puncture was clear and negative for adenovirus, herpes and varicella making an encephalitis etiology unlikely. PCR confirmed the negative herpes culture.Fig. 1 Axial T2 MRI of MTS progression and post-operative outcome. A) Axial FLAIR MRI following cyclosporine-induced seizure showing diffuse occipital and parietal signal intensity increase consistent with posterior reversible encephalopathy syndrome (PRES). No preexisting mesial temporal sclerosis present. B) Axial FLAIR MRI after first seizure recurrence showing subtle signal intensity increase in right insular cortex and hippocampus with volume loss. C) Axial FLAIR MRI 10 months post-seizure recurrence showing slight right hippocampal signal intensity and volume loss indicative of right mesial temporal sclerosis (MTS). D) Coronal FLAIR MRI 2 years post-seizure recurrence showing marked right hippocampal signal intensity and volume loss. E) Axial FLAIR MRI showing post-operative resection of hippocampus and amygdala.\n\nFig. 1\n\n2.5 Development of epilepsy, epilepsy surgery and postoperative outcome\nThe patient continued to have drug-resistant seizures. His seizures were mostly focal with impaired awareness and progressively increased in frequency to 4–5 times per week. Antiseizure drug trials of lamotrigine, levetiracetam, phenytoin and oxcarbazepine were largely unsuccessful in controlling his seizures. No autoantibody titers were tested to rule in an autoimmune etiology. MRI (Fig. 1) and PET imaging at 2 years' post-seizure recurrence revealed right mesial temporal sclerosis (MTS) and right temporal hypometabolism, respectively. Seizure semiology consisted of focal aware seizures of odd smell and taste, most consistent with medial temporal localization. Ictal EEG localized to the right anterior temporal lobe and interictal EEG showed right temporal slowing with occasional right anterior temporal sharp waves. Wada testing of visual and verbal memory and language all lateralized to the left hemisphere. A neuropsychological cognitive assessment revealed bilateral mesial temporal dysfunction and moderate anterograde memory deficits. Presurgical workup (Table 1) and discussion at our multidisciplinary epilepsy conference indicated the patient for a right anterior temporal lobectomy and amygdalohippocampectomy without intracranial electrode monitoring at eight years' post-transplant. Pathology showed subpial gliosis in the right anterior temporal lobe with dentate cell dispersion and right hippocampal sclerosis. The surgery was uncomplicated, and the patient developed no cognitive deficits. A 3-month postoperative neuropsychological cognitive assessment indicated stable or improved functioning in most cognitive domains with a less severe anterograde memory deficit compared to the preoperative assessment. At the eight-year follow-up, with the exception of two episodes concerning for focal aware seizures at the two-year follow-up, the patient was seizure free since surgery (Engel Score Class Ib) and remains in NHL remission 16 years' post-transplant.Table 1 Presurgical workup for drug-resistant epilepsy patient post-bone-marrow-transplantation.\n\nTable 1\tType\tCharacteristics\tFrequency\t\nSeizure semiology\tFocal aware seizures\tNumbness/tingles of LUE, odd smell/taste\tSeveral/day\t\nFocal impaired awareness seizures\tNumbness/tingles of LUE, odd smell/taste, left eye blink, giggle, left hand claw, unaware, unresponsive\t4–5/week\t\nGTCS\tNumbness/tingles of LUE, odd smell/taste, generalized convulsions, LOC\t3 lifetime\t\n\n\n\t\n\tTime of surgery\tFailed\t\nAntiseizure drugs\tLevetiracetam, lamotrigine\tPhenytoin, levetiracetam, oxcarbazepine\t\n\n\n\t\n\tIctal\tInterictal\t\n\t\nEEG\tLocalized to right anterior temporal lobe\tRight temporal slowing, occasional right anterior temporal sharp waves\t\n\n\n\t\n\tMRI\tPET\t\n\t\nNeuroimaging\tRight mesiotemporal sclerosis\tRight temporal hypometabolism\t\nNeuropsychology cognitive assessment\tBilateral mesial temporal lobe dysfunction, moderate anterograde memory impairments\t\n\n\n\t\n\tVisual memory\tVerbal memory\tLanguage\t\nWada testing\tLeft lateralizing\tLeft lateralizing\tLeft lateralizing\t\nGTCS = generalized tonic–clonic seizure; LUE = left upper extremity; LOC = loss of consciousness; MRI = magnetic resonance imaging; PET = positron emission tomography.\n\n\n\n3 Discussion\nSeizures, the second most common adverse neurological effect in CSA toxicity, have been well documented in post-transplant patients. However, CSA-induced seizures and the development of DRE are uncommon. Here we report a rare case of an adult developing DRE after CSA neurotoxicity post-transplant. In addition, we provide a comprehensive characterization of all reported patients who have developed DRE after CSA neurotoxicity.\n\n3.1 Incidence of CSA neurotoxicity — seizures and DRE\nStratifying CSA neurotoxicity by age, about 82% of adults (over age 18) will have a single, reversible event, while about half of children (under age 18) will experience recurrent seizures [15], [16]. Of all the patients that experience a CSA-induced seizure, 32–50% will have an independent seizure recurrence, and about half of seizure recurrent patients will develop DRE [10], [11], [17]. Based upon work from Gaggero et al. and Gleeson et al., we calculated the incidence of DRE development after administration of post-transplant CSA at approximately 0.4–0.5%, assuming no preexisting neurological conditions [10], [11]. We identified a total of 15 patients (not including ours) from the literature that developed DRE after CSA-neurotoxicity. These were all pediatric patients with a mean age of 5.5 years at transplant (range: 2.3–15 years). All but three patients had no history of prior seizures (three patients had history of febrile seizures). Nine of fifteen patients (60%) had a hematopoietic stem cell transplant (HSCT), and the remaining (40%) had solid organ transplants. Initial CSA-induced seizures occurred an average of 1.6 ± 1.1 months after transplant and seizure recurrence 9.2 ± 8.0 months after transplant (recurrence time N/A for 9 patients). All reported CSA routes of administration (n = 6) were intravenous and 7 of 9 (78%) reported CSA blood levels above the therapeutic range. MTS on neuroimaging was observed in 40% (n = 6) with one confirmed by pathology. Only 13% (n = 2) underwent a temporal lobectomy and amygdalohippocampectomy. Latest follow-ups of an average 6.9 years' post-transplant reveal that 80% (n = 12) continued to have seizures while the two patients with anterior temporal lobectomies were seizure-free. One patient died five months' post-transplant due to deteriorating neurological status.\n\n3.2 Risk factors for the development of DRE\nPatients that undergo transplantation for any cause and require a post-transplant immunosuppressant regimen should be assessed for risk factors associated with the development of DRE. Significant risk factors for intractable epilepsy development include prior febrile or neonatal seizures, earlier age of seizure onset, family history of intractable epilepsy, neuroimaging abnormality such as MTS, persistent EEG abnormalities, developmental delay, motor or mental deficiencies, and traumatic brain injury [11], [18], [19], [20]. These risks factors are increased if the patient has had more than 10 seizures before receiving antiseizure treatment or has a seizure frequency of greater than one per month [18], [21]. Intrathecal chemotherapy, intensive pre-transplant chemotherapy or total body irradiation may contribute to these risk factors [2], [22]. If the patient presents with these significant pre-transplant risk factors, pursuing an alternative to cyclosporine for GvHD prevention could be considered. In addition to these pre-transplant risk factors, post-transplant risk factors for intractable epilepsy development include CSA neurotoxicity, young age, GvHD, herpes simplex 1 infection, persistent EEG abnormalities, and MTS on MRI [4], [23], [24], [25]. Another significant risk factor to consider in the context of our patient is a preexisting autoimmune disease, such as CVID. Positive autoantibody titers for voltage-gated potassium channels, GAD, AMPA receptors and GABA receptors have been shown to be associated with DRE [26].\n\n3.3 Age and CSA-induced DRE\nAll 15 patients reported in the literature that have developed CSA-induced DRE (Table 2) were pediatric patients (less than 18 years old) at the time of transplantation and CSA administration. Interestingly, the patient described here in our report is an adult known to have developed DRE following post-transplant CSA-induced neurotoxicity — a presentation uncommonly found in adults. In the general population, DRE in adults is much less common compared to in children [27]. Additionally, most adults that go on to develop DRE have had medically-controlled epilepsy since age 12 or younger (about 80%) [18]. Although drug-resistance etiology in epilepsy is multifactorial and not well understood, some have hypothesized that DRE pathogenesis is thought to arise from antiseizure drugs not reaching their target (predominately voltage-gated ion channels and GABA receptors), an alteration of the antiseizure drug targets, and/or antiseizure drugs binding incorrect targets [28], [29]. Why children are more susceptible to these antiseizure drug resistance mechanisms and DRE development remains unclear, but this may explain why DRE development in those with CSA-induced seizures are mostly children [28]. However, our adult patient appeared to have been at a higher risk of developing DRE compared to an average adult with CSA-induced seizures due to his complex immunological history and degree of CSA neurotoxicity (second highest CSA blood level out of all patients in literature review).Table 2 Literature review of a CSA-induced seizure followed by development of drug-resistant epilepsy — transplant and first seizure.\n\nTable 2Patient #\tAuthor\tYear\tPatient transplant\tFirst CSA-induced seizure\t\nAge at transplant/Gender\tUnderlying disease\tTransplant type\tProphylactic GvHD regimen\tCSA dose (mg/kg/day), administration\tTime (months) PT\tSeizure type/neurological events\tCSA blood levels (ng/ml)b\tLong-term CSA discontinuation?\t\n1\tGleeson et al.\t1998\t15/M\tPolymyositis\tHeart\tCSA\tNA\t0 (1 day)\tFIAS, clonic jerks\t342\tNA\t\n2\tGleeson et al.\t1998\t6/M\tGN\tRenal\tCSA\tNA\t0.7\tGTCS, visual disturbance, occipital HA\t350\tNA\t\n3\tGleeson et al.\t1998\t4/M\tBiliary atresia\tLiver\tCSA\tNA\t3.0\tSE, listless\t550\tNA\t\n4\tFaraci et al.a\t2003\t2.9/M\tHLH\tHSCT\tCSA, ATG, MTX\t3, i.v.\t3.0\tGS, visual disturbance, HBP\tWNL\tN, discontinued after 4.3 years\t\n5\tFaraci et al.a\t2003\t3.9/M\tOsteopetrosis\tHSCT\tCSA\t1, i.v.\t1.7\tGS, cortical blindness\t2410\tY, substituted other ISPs\t\n6\tFaraci et al.a\t2003\t3.3/M\tHLH\tHSCT\tCSA, Campath 1G,MTX\t3, i.v.\t2.0\tGS, coma (grade 2), HBP\t375\tN, reduced dose, discontinued after 1.8 years\t\n7\tGaggero et al.c\t2006\t6/M\tALL\tHSCT\tCSA\t1, i.v.\t2.5\tGS, visual disturbance, HBP\t377\tN, discontinued for 2 days, low dose reintroduced\t\n8\tAyas et al.\t2008\t11/F\tALL\tHSCT\tCSA,MTX\tNA\t0.4\tGS\tWNL\tY, switched to tacrolimus\t\n9\tEndo et al.\t2012\t6/F\tAplastic anemia\tHSCT\tCSA\t3, i.v.\t0.7\tGS, LOC, HBP\tNA\tY, later switched to tacrolimus\t\n10\tChen et al.\t2015\t3.2/NA\tNephrotic syndrome\tRenal\tCSA\tNA\t1.0\tSE, altered mental status\tNA\tNA\t\n11\tChen et al.\t2015\t2.3/NA\tNephrotic syndrome\tRenal\tCSA\tNA\t1.0\tSE, altered mental status, aggressive behavior\tNA\tNA\t\n12\tChen et al.\t2015\t5.2/NA\tAcute leukemia\tHSCT\tCSA\tNA\t2.8\tCluster sz, cortical blindness, altered mental status\tNA\tNA\t\n13\tChen et al.\t2015\t5.4/NA\tAcute leukemia\tHSCT\tCSA\tNA\t0.6\tSE, altered mental status\tNA\tNA\t\n14\tChen et al.\t2015\t5.5/NA\tThalassemia\tHSCT\tCSA\tNA\t2.7\tSE, altered mental status\tNA\tNA\t\n15\tDilena et al.\t2016\t3/F\tCirrhosis\tLiver\tCSA\t1.5, i.v.\t0.1\tFIAS, clonic jerks, HBP\t479\tY, switched to tacrolimus\t\nALL = acute lymphatic leukemia; ATG = anti-thymocyte globulin; FIAS = focal impaired awareness seizure; CSA = cyclosporine A; F = female; F/U = follow-up; GN = glomerulonephritis; GS = generalized seizure; GTCS = generalized tonic–clonic seizure; HA = headache; HLH = hemophagocytic lymphohistiocytosis; HBP = high blood pressure; HSCT = hematopoietic stem cell transplant; ISP = immunosuppressants; LOC = loss of consciousness; M = male; MTS = mesial temporal sclerosis; MTX = methotrexate; N = no; NA = data not available; PT = post-transplant; SE = status epilepticus; sz = seizures; WNL = within normal limits; Y = yes.\n\na History of febrile seizures prior to transplant.\n\nb Therapeutic range: 100–200 ng/ml.\n\nc Patient originally described in Faraci et al., 2003 and since updated in Gaggero et al., 2006.\n\n\n\n3.4 Oral vs. intravenous cyclosporine\nOf the six reported cyclosporine administrations that led to DRE in our review (Table 2), all experienced CSA neurotoxicity while on intravenous CSA. Whether intravenous CSA contributes to a higher incidence of neurotoxicity than oral CSA is unclear. However, past studies have found that microemulsion oral CSA (Neoral) causes fewer neurological complications than intravenous CSA with no difference in acute rejection occurrence [30], [31]. Although the adult patient we reported here was given oral CSA, the use of oral CSA instead of intravenous CSA may reduce the chance of CSA-induced seizures, especially in those patients presenting with existing risk factors for DRE.\n\n3.5 Cyclosporine discontinuation, reduction and substitution\nFour of the seven patients, in addition to the patient we presented here, were discontinued on CSA following their first CSA-induced seizure and placed on tacrolimus (or a milder immunosuppressant) (Table 2). Despite discontinuation of CSA, the time to seizure recurrence was not significantly different compared to those that remained on CSA (CSA discontinued: 11.0 ± 11.5 months vs. CSA continued: 7.5 ± 4.4 months) nor was seizure frequency following recurrence. In fact, a systematic review has shown that tacrolimus has a significantly higher relative risk ratio for neurological complications when compared to cyclosporine [32]. The standard of care for CSA or tacrolimus-induced neurotoxicity is to initially discontinue CSA or tacrolimus followed by readministration at a reduced dose. Often this is effective in reversing neurological symptoms, although ineffective in patients that may have experienced irreversible brain damage due to their initial CSA-induced seizure. The long-term neurotoxic effects of continuing CSA or tacrolimus beyond the early posttransplant period (one month) are unclear [33]. Potential alternatives to high dose calcineurin inhibitors, shown to exhibit lower permanent neurological side effects, are mycophenolate mofetil (either as a monotherapy or in combination with low dose CSA/tacrolimus) and mTOR inhibitors, such as everolimus [34]. However, these therapies may not achieve adequate immunosuppression for GvHD prevention in comparison to CSA and tacrolimus [35].\n\n3.6 Incidence of MTS in CSA-induced drug-resistant epilepsy\nFollowing CSA neurotoxicity, six of the fifteen (40%) patients reviewed had MTS on neuroimaging while five (33%) showed parietal cerebral atrophy (Table 3). Of the six MTS patients, two (33%) underwent epilepsy surgery and one received a pathologic confirmation of MTS (the other had no pathology described). Similarly, our patient showed right MTS on MRI and confirmed by pathology after right temporal lobectomy and amygdalohippocampectomy.Table 3 Literature review of a CSA-induced seizure followed by development of drug-resistant epilepsy — epilepsy and outcomes.\n\nTable 3Patient #\tEpilepsy characteristics\tOutcomes\t\nTime (months) PT of seizure recurrence\tSeizure type\tSeizure frequency per month\tIntractable?\tNeuroimaging findings\tEEG results\tEpilepsy surgery?\tPathology\tTime (months) PT of last F/U\tF/U outcome\t\n1\tNA\tGS\tNA\tY\tAsymmetric ventricular enlargement\tFocal left temporal slowing\tN\tNA\t42\tContinued GS\t\n2\tNA\tGS, severe\tNA\tY\tModerate atrophy\tMultifocal epileptiform discharges with posterior slowing\tN\tNA\t72\tContinued GS\t\n3\tNA\tFIAS\tNA\tY\tNormal\tNA\tN\tNA\t96\tContinued FIAS\t\n4\t9\tFIAS\tSeveral\tY\tLeft MTS\tBilateral occipital slowing, left hemisphere paroxysmal activity\tN\tNA\t72\tContinued FIAS\t\n5\t6.7\tFocal motor sz\tNA\tY\tRight MTS, slight ipsilateral temporal neocortical atrophy\tMild, slow abnormalities\tN\tNA\t108\tContinued FIAS\t\n6\t2.5\tFocal motor sz, secondary generalized\tSeveral\tY\tRight MTS\tDiffuse epileptiform discharges, focal central occipital paroxysmal activity\tN\tNA\t60\tContinued focal motor sz\t\n7\t11\tFIAS w/ left laterality\t1\tY\tRight MTS\tBilateral central-occipital slowing, right central-temporal paroxysmal activity\tY (120 months PT)\tNA\t126\tSeizure-free\t\n8\t2.2\tFocal seizure\tSeveral\tY\tGlobal extensive white matter changes suggestive of CSA/tacrolimus toxicity\tNA\tN\tNA\t≈ 5\tDied from deteriorating neurological status\t\n9\tNA\tNA\tNA\tY\tBilateral high-intensity in parietal\tNA\tN\tNA\t60\tContinued sz, severe cognitive impairments\t\n10\tNA\tNA\tNA\tY\tGlobal cerebral atrophy\tNA\tN\tNA\t10\tContinued sz, tremors\t\n11\tNA\tNA\tNA\tY\tParietal-occipital cerebral atrophy, right basal ganglion gliosis\tNA\tN\tNA\t108\tContinued sz, severe cognitive impairments, autism\t\n12\tNA\tNA\tNA\tY\tBilateral parietal cerebral atrophy\tNA\tN\tNA\t11\tContinued sz, dysmetria\t\n13\tNA\tNA\tNA\tY\tBilateral parietal cerebral atrophy\tNA\tN\tNA\t48\tContinued sz\t\n14\tNA\tNA\tNA\tY\tLeft MTS, bilateral parietal cerebral atrophy\tNA\tN\tNA\t144\tContinued sz, HA, ADHD\t\n15\t24.0\tFIAS, sometimes GTCS\t30–60\tY\tLeft MTS\tFocal left temporal slowing with sharp waves\tY (144 months PT)\tLeft MTS\t204\tSeizure-free\t\n\n\nBased on a 2002 Icelandic epidemiological study, a patient experiencing a single seizure has a predicted 6% chance of eventually developing temporal lobe epilepsy with MTS as indicated by MRI [25]. Furthermore, MTS appears to be a significant risk factor for developing drug-resistant epilepsy. Semah et al. found that 11% of epilepsy patients with MTS on antiseizure drugs were seizure-free compared to 31% of those with temporal lobe epilepsy without MTS and 45% of all epilepsy patients. Of the 55% of all epilepsy patients that did not respond to antiseizure drugs (DRE), 24% had MTS [36]. Comparing this to the population of CSA-induced intractable epilepsy patients, 40% had MTS. The difference found between the population incidence of MTS in intractable epilepsy and MTS in CSA-induced intractable epilepsy may be due to the increased risk for developing MTS following an initial precipitating incident such as febrile seizures, trauma, infection, hypoxia or CSA neurotoxicity.\n\nPathogenesis of MTS following an initial precipitating event is not well understood but potential mechanisms could be neuronal death due to mitochondrial dysfunction, glutamate neurotoxicity, excessive immune response, or genetic predisposition [25].\n\n4 Conclusion\nThe use of cyclosporine following a solid organ or bone marrow transplant for GvHD prophylaxis and treatment may cause neurotoxicity and result in seizures that lead to DRE. Risk factors for CSA-induced seizures and subsequent epilepsy development should be considered before and after administration of post-transplant CSA to best avoid neurotoxicity. Although temporary discontinuation and long-term dose decrease of CSA often reverse adverse neurological events that could lead to seizure recurrence, initial CSA-induced seizures status epilepticus may be associated with MTS that and subsequent greater risk of epilepsy development via MTS pathogenesis. In these cases, epilepsy surgery is the most effective means for treating DRE.\n\nDisclosures\nThe authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper. The patient gave signed consent for the release of his health information in the context of this case study. He is a subject of our research protocol that has been reviewed and accepted by the University of Iowa's Institutional Review Board (IRB).\n==== Refs\nReferences\n1 Kahan B.D. Cyclosporine N Engl J Med 321 25 1989 1725 1738 2687689 \n2 Gijtenbeek J.M. van den Bent M.J. Vecht C.J. Cyclosporine neurotoxicity: a review J Neurol 246 5 1999 339 346 10399863 \n3 Saner F.H. Severe neurological events following liver transplantation Arch Med Res 38 1 2007 75 79 17174727 \n4 Faraci M. Mesial temporal sclerosis—a late complication in four allogeneic pediatric recipients with persistent seizures after an acute episode of cyclosporine-A neurotoxicity Bone Marrow Transplant 31 10 2003 919 922 12748669 \n5 Dilena R. Epilepsy surgery in a liver-transplanted girl with temporal lobe epilepsy and hippocampal sclerosis following PRES with status epilepticus Eur J Paediatr Neurol 20 4 2016 652 656 27133780 \n6 Reece D.E. Neurologic complications in allogeneic bone marrow transplant patients receiving cyclosporin Bone Marrow Transplant 8 5 1991 393 401 1768975 \n7 Trullemans F. Clinical findings and magnetic resonance imaging in severe cyclosporine-related neurotoxicity after allogeneic bone marrow transplantation Eur J Haematol 67 2 2001 94 99 11722596 \n8 Bird G.L. Cyclosporin-associated akinetic mutism and extrapyramidal syndrome after liver transplantation J Neurol Neurosurg Psychiatry 53 12 1990 1068 1071 2292700 \n9 Cyclosporine neurotoxicity N Engl J Med 324 24 1991 1744 1745 2034256 \n10 Gaggero R. Intractable epilepsy secondary to cyclosporine toxicity in children undergoing allogeneic hematopoietic bone marrow transplantation J Child Neurol 21 10 2006 861 866 17005102 \n11 Gleeson J.G. Cyclosporin A acute encephalopathy and seizure syndrome in childhood: clinical features and risk of seizure recurrence J Child Neurol 13 7 1998 336 344 9701483 \n12 O'Sullivan D.P. Convulsions associated with cyclosporin A Br Med J (Clin Res Ed) 290 6471 1985 858 \n13 Endo A. Posterior reversible encephalopathy syndrome in childhood: report of four cases and review of the literature Pediatr Emerg Care 28 2 2012 153 157 22307182 \n14 Ayas M. Al-Jefri A. Al-Seraihi A. In cyclosporine induced neurotoxicity, is tacrolimus an appropriate substitute or is it out of the frying pan and into the fire? Pediatr Blood Cancer 50 2 2008 426 [author reply 427] 17427233 \n15 Chen L.W. Age-dependent vulnerability of cyclosporine-associated encephalopathy in children Eur J Paediatr Neurol 19 4 2015 464 471 25769225 \n16 Hauben M. Cyclosporine neurotoxicity Pharmacotherapy 16 4 1996 576 583 8840363 \n17 Zhong Z.D. Analysis of seizure risk factors after allogeneic hematopoietic stem cell transplantation: a 8 case report and literature review J Huazhong Univ Sci Technolog Med Sci 33 5 2013 656 660 24142716 \n18 Voll A. Predicting drug resistance in adult patients with generalized epilepsy: a case–control study Epilepsy Behav 53 2015 126 130 26561950 \n19 Wirrell E. Predictors and course of medically intractable epilepsy in young children presenting before 36 months of age: a retrospective, population-based study Epilepsia 53 9 2012 1563 1569 22738069 \n20 Seker Yilmaz B. Okuyaz C. Komur M. Predictors of intractable childhood epilepsy Pediatr Neurol 48 1 2013 52 55 23290021 \n21 Camfield C. Does the number of seizures before treatment influence ease of control or remission of childhood epilepsy? Not if the number is 10 or less Neurology 46 1 1996 41 44 8559418 \n22 Kasai-Yoshida E. Temporal lobe epilepsy with hippocampal sclerosis in acute lymphoblastic leukemia Pediatrics 132 1 2013 e252 6 23776122 \n23 Laohathai C. Chronic herpes simplex type-1 encephalitis with intractable epilepsy in an immunosuppressed patient Infection 44 1 2016 121 125 26187268 \n24 Zhang X.H. Epileptic seizures in patients following allogeneic hematopoietic stem cell transplantation: a retrospective analysis of incidence, risk factors, and survival rates Clin Transpl 27 1 2013 80 89 \n25 Wieser H.G. ILAE commission report. Mesial temporal lobe epilepsy with hippocampal sclerosis Epilepsia 45 6 2004 695 714 15144438 \n26 Bien C.G. Scheffer I.E. Autoantibodies and epilepsy Epilepsia 52 Suppl. 3 2011 18 22 21542841 \n27 Giussani G. A population-based study of active and drug-resistant epilepsies in Northern Italy Epilepsy Behav 55 2016 30 37 26731716 \n28 Kwan P. Schachter S.C. Brodie M.J. Drug-resistant epilepsy N Engl J Med 365 10 2011 919 926 21899452 \n29 Meldrum B.S. Rogawski M.A. Molecular targets for antiepileptic drug development Neurotherapeutics 4 1 2007 18 61 17199015 \n30 Levy G.A. Neoral in de novo liver transplantation: adequate immunosuppression without intravenous cyclosporine Liver Transpl Surg 3 6 1997 571 577 9404955 \n31 Hemming A.W. A microemulsion of cyclosporine without intravenous cyclosporine in liver transplantation Transplantation 62 12 1996 1798 1802 8990366 \n32 Webster A. Tacrolimus versus cyclosporin as primary immunosuppression for kidney transplant recipients Cochrane Database Syst Rev 4 2005 Cd003961 \n33 Bechstein W.O. Neurotoxicity of calcineurin inhibitors: impact and clinical management Transpl Int 13 5 2000 313 326 11052266 \n34 Vogelsang G.B. Arai S. Mycophenolate mofetil for the prevention and treatment of graft-versus-host disease following stem cell transplantation: preliminary findings Bone Marrow Transplant 27 12 2001 1255 1262 11548843 \n35 Jimenez-Perez M. Everolimus plus mycophenolate mofetil as initial immunosuppression in liver transplantation Transplant Proc 47 1 2015 90 92 25645779 \n36 Semah F. Is the underlying cause of epilepsy a major prognostic factor for recurrence? Neurology 51 5 1998 1256 1262 9818842\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2213-3232",
"issue": "10()",
"journal": "Epilepsy & behavior case reports",
"keywords": "Antiseizure drugs; Cyclosporine neurotoxicity; Cyclosporine-A; Drug-resistant epilepsy; Medically intractable epilepsy; Mesial temporal sclerosis; Seizures; Transplant",
"medline_ta": "Epilepsy Behav Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101614202",
"other_id": null,
"pages": "8-13",
"pmc": null,
"pmid": "30062084",
"pubdate": "2018",
"publication_types": "D002363:Case Reports",
"references": "26731716;16235347;11548843;24142716;22738069;22938074;10399863;15144438;21899452;27133780;8840363;25645779;23290021;11722596;17174727;9404955;26187268;22307182;11052266;25769225;17427233;2292700;2687689;21542841;26561950;3919822;17005102;8559418;9818842;9701483;17199015;8990366;2034256;1768975;23776122;12748669",
"title": "Drug-resistant epilepsy development following stem cell transplant and cyclosporine neurotoxicity induced seizures: Case report in an adult and analysis of reported cases in the literature.",
"title_normalized": "drug resistant epilepsy development following stem cell transplant and cyclosporine neurotoxicity induced seizures case report in an adult and analysis of reported cases in the literature"
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"companynumb": "US-TEVA-2018-US-918937",
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"occurcountry": "US",
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"abstract": "This retrospective study was to compare the efficacy of intravitreal injection of ranibizumab and aflibercept for patients with pachychoroid neovasculopathy. 54 eyes were initially treated with 3 monthly loading injections of ranibizumab or aflibercept. Treatment switching from ranibizumab to aflibercept, and aflibercept to photodynamic therapy was done at 3 months in case of incomplete fluid absorption. At 3 months, the rate of complete fluid absorption was significantly higher in the aflibercept-treated group than in the ranibizumab-treated group (82.6% vs 51.6%, p = 0.018). The mean reduction of subfoveal choroidal thickness was significantly greater in the aflibercept group than in the ranibizumab group (-35 µm vs -9 µm, p = 0.013). There was no significant difference between the two groups in terms of visual improvement or decrease in central macular thickness. Complete fluid absorption was achieved after switching from ranibizumab to aflibercept in 13 of 15 eyes (86.7%). Adjunctive photodynamic therapy was required in 6 eyes. In conclusion, treatment mainly with anti-vascular endothelial growth factor effectively improved visual acuity within 12 months (from 20/56 to 20/44 at 3 months and to 20/36 at 12 months). Aflibercept was superior to ranibizumab in achieving dry macula and reducing choroidal thickness at 3 months.",
"affiliations": "Department of Ophthalmology and Visual Science, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, 505 Banpo-dong, Seocho-ku, Seoul, 137-701, Korea.;Department of Ophthalmology and Visual Science, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, 505 Banpo-dong, Seocho-ku, Seoul, 137-701, Korea.;Department of Ophthalmology and Visual Science, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, 505 Banpo-dong, Seocho-ku, Seoul, 137-701, Korea. jhletter22@gmail.com.;Department of Ophthalmology and Visual Science, Bucheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.;Department of Ophthalmology and Visual Science, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, 505 Banpo-dong, Seocho-ku, Seoul, 137-701, Korea.;Department of Ophthalmology and Visual Science, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, 505 Banpo-dong, Seocho-ku, Seoul, 137-701, Korea.",
"authors": "Jung|Byung Ju|BJ|0000-0003-4043-5407;Kim|Joo Young|JY|;Lee|Jae Hyung|JH|;Baek|Jiwon|J|;Lee|Kook|K|;Lee|Won Ki|WK|",
"chemical_list": "D020533:Angiogenesis Inhibitors; D011993:Recombinant Fusion Proteins; D042461:Vascular Endothelial Growth Factor A; C533178:aflibercept; D040262:Receptors, Vascular Endothelial Growth Factor; D000069579:Ranibizumab",
"country": "England",
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"doi": "10.1038/s41598-019-38504-y",
"fulltext": "\n==== Front\nSci RepSci RepScientific Reports2045-2322Nature Publishing Group UK London 3850410.1038/s41598-019-38504-yArticleIntravitreal aflibercept and ranibizumab for pachychoroid neovasculopathy http://orcid.org/0000-0003-4043-5407Jung Byung Ju 1Kim Joo Young 1Lee Jae Hyung jhletter22@gmail.com 1Baek Jiwon 2Lee Kook 1Lee Won Ki 11 0000 0004 0470 4224grid.411947.eDepartment of Ophthalmology and Visual Science, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, 505 Banpo-dong, Seocho-ku, Seoul, 137-701 Korea 2 0000 0004 0470 4224grid.411947.eDepartment of Ophthalmology and Visual Science, Bucheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea 14 2 2019 14 2 2019 2019 9 20559 8 2018 21 12 2018 © The Author(s) 2019Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.This retrospective study was to compare the efficacy of intravitreal injection of ranibizumab and aflibercept for patients with pachychoroid neovasculopathy. 54 eyes were initially treated with 3 monthly loading injections of ranibizumab or aflibercept. Treatment switching from ranibizumab to aflibercept, and aflibercept to photodynamic therapy was done at 3 months in case of incomplete fluid absorption. At 3 months, the rate of complete fluid absorption was significantly higher in the aflibercept-treated group than in the ranibizumab-treated group (82.6% vs 51.6%, p = 0.018). The mean reduction of subfoveal choroidal thickness was significantly greater in the aflibercept group than in the ranibizumab group (−35 µm vs −9 µm, p = 0.013). There was no significant difference between the two groups in terms of visual improvement or decrease in central macular thickness. Complete fluid absorption was achieved after switching from ranibizumab to aflibercept in 13 of 15 eyes (86.7%). Adjunctive photodynamic therapy was required in 6 eyes. In conclusion, treatment mainly with anti-vascular endothelial growth factor effectively improved visual acuity within 12 months (from 20/56 to 20/44 at 3 months and to 20/36 at 12 months). Aflibercept was superior to ranibizumab in achieving dry macula and reducing choroidal thickness at 3 months.\n\nissue-copyright-statement© The Author(s) 2019\n==== Body\nIntroduction\nThe term “pachychoroid neovasculopathy” has been introduced to describe Type 1 neovascularization associated with choroidal thickening and/or dilated Haller vessels in the absence of characteristic age-related macular degeneration features1,2. It is a newly recognized clinical entity of choroidal neovascularization (CNV) that is thought to be induced by pachychoroid phenotype–driven pathophysiological mechanisms3. This disease entity has been suggested to be in the spectrum between central serous chorioretinopathy (CSC) and polypoidal choroidal vasculopathy (PCV). Pang and Freund reported that pachychoroid neovasculopathy can develop after long-standing CSC and may eventually progress to PCV in some cases2.\n\nHowever, pachychoroid neovasculopathy still remains a subjective term with no clear definition. Moreover, in some reports, type 1 neovascularization with polypoidal lesions was included in the inclusion criteria of pachychoroid neovasculopathy, causing confusion in the classification of diseases4–6. The polypoidal lesion is a hallmark of PCV, and based on the diagnostic criteria to date, Type 1 neovascularization that accompanies polypoidal lesions shown by indocyanine green angiography (ICGA) should be classified as PCV and not otherwise7. Based on the original description, pachychoroid neovasculopathy should be designated in neovascular lesions with pachychoroid features but without polypoidal lesions. In the current study, we tried to apply finer and more detailed criteria in defining pachychoroid neovasculopathy, although no criteria have been established for this new disease entity.\n\nThe emergence of anti-vascular endothelial growth factor (VEGF) agents has led to a significant reduction in visual impairment from neovascular age-related macular degeneration (nAMD)8, and ranibizumab and aflibercept are the two approved drugs. Results from randomized clinical trials indicated that monthly doses of ranibizumab produced similar efficacy and safety outcomes as aflibercept (dosed either monthly or every 2 months, following 3 initial monthly loading doses) in nAMD9. However, ranibizumab and aflibercept differ with respect to their molecular structure, and may produce different efficacy in specific diseases10. The response of pachychoroid neovasculopathy to anti–VEGF drugs has not been fully understood yet. A few studies recently reported efficacy of anti-VEGF therapy in pachychoroid neovasculopathy similar to that in nAMD6,11. However, enrolled cases were relatively small and PCV lesions were included in both groups, making their results inconclusive. Moreover, there have been no reports specifically focusing on the differences between the two anti-VEGF agents in the treatment of pachychoroid neovasculopathy.\n\nThe purpose of this study was to evaluate 1-year vision improvement and morphological changes with the use of mainly anti-VEGF drugs for pachychoroid neovasculopathy. Also we tried to determine the differences between aflibercept and ranibizumab in terms of short-term therapeutic efficacy in the treatment of this disease.\n\nResults\nBaseline characteristics\nA total of 54 eyes (52 patients) were diagnosed with pachychoroid neovasculopathy according to our inclusion criteria. The mean age of the entire study group was 64.0 ± 7.6 years. The mean subfoveal choroidal thickness (SFCT) was 436 ± 83 µm (range: 307–599 µm) at baseline, and the choroidal vascularity index (CVI) was 65.0 + 2.7%. On ICGA, 34 eyes (64.1%) demonstrated choroidal vascular hyperpermeability (CVH), and 7 eyes (12.7%) had retinal pigment epithelium (RPE) atrophic tracks on fluorescein angiography (FAG) or fundus autofluorescence (FAF). The intraclass correlation coefficients for inter-observer reproducibility about CVI showed almost perfect agreement with the level of 0.93 (95%CI: 0.87–0.96, P < 0.001). The Fleiss’ kappa test also demonstrated substantial agreement with the level of 0.77 (P < 0.001) in the analysis of CVH. Fellow eye findings of 50 patients were pachychoroid pigment epitheliopathy in 17 eyes, chronic CSC without choroidal neovascularization in 2 eyes, and PCV in 1 eye. The baseline characteristics of the study eyes are listed in Table 1. At baseline, there were no significant differences between the aflibercept-group (23 eyes) and the ranibizumab-group (31 eyes) with regard to best-corrected visual acuity (BCVA), central macular thickness (CMT), SFCT, greatest linear dimension, CVI, and incidence of CVH.Table 1 Baseline characteristics of the patients with pachychoroid neovasculopathy enrolled in this study.\n\n\tTotal (n = 55)\tRanibizumab (n = 31)\tAflibercept (n = 23)\tP value\t\nAge, years\t64.0 ± 7.6\t64.6 ± 8.4\t63.1 ± 6.2\t0.672a\t\nGender, male/female\t35/20\t19/12\t16/7\t0.859b\t\nRPE tract, n (%)\t7 (12.7)\t4 (12.9)\t3 (13.0)\t0.844b\t\nGreatest linear diameter of CNV, µm\t2782 ± 775\t2837 ± 850\t2697 ± 660\t0.747a\t\nChoroidal vascular hyperpermeability, n (%)\t34 (64.1)\t18 (58.1)\t16 (69.5)\t0.543b\t\nCentral macular thickness, µm\t337 ± 53\t332 ± 54\t345 ± 52\t0.456a\t\nSubfoveal choroidal thickness, µm\t436 ± 83\t438 ± 78\t433 ± 93\t0.877a\t\nChoroidal vascularity index, %\t65.0 + 2.7\t65.1 ± 2.5\t64.9 ± 3.1\t0.687a\t\nBCVA, logMAR\t0.45 ± 0.26\t0.46 ± 0.24\t0.43 ± 0.26\t0.614a\t\nRPE = retinal pigment epithelium; CNV = choroidal neovascularization; BCVA = best-corrected visual acuity; logMAR = logarithm of the minimal angle of resolution.\n\naMann-Whitney test.\n\nbChi-square test.\n\n\n\nAnatomical and functional outcomes at 3 months\nTable 2 summarizes the anatomical and visual outcomes of the two groups. The proportion of patients with complete fluid absorption was significantly higher in the aflibercept group (19 of 23 eyes, 82.6%) than in the ranibizumab group (16 of 31 eyes, 51.6%, P = 0.018).Table 2 Clinical outcomes after ranibizumab and aflibercept injections at 3 months.\n\n\tRanibizumab (n = 31)\tAflibercept\n(n = 23)\tP value\t\nComplete resolution of fluid, n (%)\t16(51.6)\t19(82.6)\t0.018b\t\nBCVA, logMAR\t\nbaseline\t0.46 ± 0.24\t0.43 ± 0.26\t0.614a\t\n3 months\t0.38 ± 0.31(0.002)c\t0.27 ± 0.21(0.013)c\t0.287a\t\nCentral macular thickness, μm\t\nbaseline\t332 ± 54\t345 ± 52\t0.456a\t\n3 months\t276 ± 60(<0.001)c\t264 ± 83(0.004)c\t0.258a\t\nSubfoveal choroidal thickness, μm\t\nbaseline\t438 ± 78\t433 ± 93\t0.877a\t\n3 months\t429 ± 75(0.042)c\t399 ± 96(<0.001)c\t0.371a\t\nBCVA = best-corrected visual acuity; logMAR = logarithm of the minimal angle of resolution.\n\naMann-Whitney test.\n\nbChi-square test.\n\ncWilcoxon signed rank test.\n\n\n\nThe mean SFCT decreased significantly from 433 ± 93 µm to 399 ± 96 µm in the aflibercept group, and from 438 ± 78 µm to 429 ± 75 µm in the ranibizumab group (P < 0.001, P = 0.042, respectively). The mean reduction was significantly greater in the aflibercept group than in the ranibizumab group (−35 ± 34 µm vs. −9 ± 22 µm, P = 0.013). The mean CMT decreased significantly from 345 ± 52 µm to 264 ± 83 µm in the aflibercept group, and from 332 ± 54 µm to 276 ± 60 µm in the ranibizumab group (P = 0.004, P < 0.001, respectively). The mean CMT at 3 months did not differ significantly between the two groups (P = 0.258).\n\nSignificant visual improvement was seen in both groups. The mean the logarithm of the minimal angle of resolution (logMAR) BCVA was 0.43 ± 0.26 logMAR (Snellen equivalent, 20/54) at baseline and 0.27 ± 0.21 logMAR (Snellen equivalent, 20/37) at 3 months in the aflibercept group (P = 0.013) and 0.46 ± 0.24 logMAR (Snellen equivalent, 20/58) at baseline and 0.38 ± 0.31 logMAR (Snellen equivalent, 20/50) at 3 months in the ranibizumab group (P = 0.002). At 3 months, no statistically significant difference was noted between the two groups regarding logMAR BCVA (P = 0.287) or CMT (P = 0.258).\n\nTreatment switch and clinical outcomes at 12 months\nIn 35 eyes that showed complete fluid absorption at 3 months (19 eyes in the aflibercept group, 16 eyes in the ranibizumab group), 7 eyes (36.8%) in the aflibercept group and 9 eyes (56.2%) in the ranibizumab group showed recurrent fluid accumulation on spectral-domain optical coherence tomography (SD OCT) within 12 months (P = 0.163). The favorable response to initial anti-VEGF drugs was maintained in these eyes, and treatment switch was not required until 12 months. The mean number of injections was 3.5 (range: 3 to 6, median: 3) in the aflibercept group and 4.6 (range: 3 to 8, median: 3) in the ranibizumab group until 12 months (P = 0.114).\n\nIn 13 of 15 eyes (86.7%) that did not respond to ranibizumab initially, complete fluid absorption was achieved after switching to 3 loading aflibercept injections (Fig. 1). Photodynamic therapy (PDT) was applied in the other 2 eyes and 4 eyes which did not respond to aflibercept initially, and dry macula was noted at 3 months after the PDTs in all 6 eyes. Recurrent fluid accumulation was not noted in these 6 eyes by the end of a 1-year follow-up period.Figure 1 The case of a 69-year-old male who was switched to aflibercept injections due to the poor response to ranibizumab. (Top left) Color fundus photograph shows reduced background fundus tessellation without drusen. (Top second) Fluorescein angiography demonstrates ill-defined late leakage. (Top third) Late-phase indocyanine green angiography exhibits focal hyperfluorescent spots and choroidal vascular hyperpermeability within the posterior pole. (Top right) Fundus autofluorescence image shows hyperfluorescence in the area inferior to the fovea. (Bottom left) Spectral-domain optical coherence tomography (OCT) at baseline reveals Type 1 neovascularization, which was confirmed on swept-source OCT angiography (inlet). Multiple dilated Haller vessels with attenuation of choriocapillaris are seen beneath the lesion. Best-corrected visual acuity (BCVA) of the right eye was 20/63 at baseline. (Bottom middle) After three loading injections of ranibizumab, subretinal fluid remained and BCVA decreased to 20/80. (Bottom right) Treatment was switched to aflibercept, and after three consecutive injections, complete fluid absorption was achieved and BCVA improved to 20/40. The subfoveal choroidal thickness decreased from 354 µm at baseline, to 341 µm after ranibizumab injections, and 293 µm after aflibercept injections.\n\n\n\nIncluding the treatment switch, the total mean BCVA of 54 eyes gradually improved from 0.45 ± 0.25 logMAR at baseline to 0.34 ± 0.27 logMAR at 3 months and to 0.26 ± 0.25 logMAR at 12 months (P < 0.001, P < 0.001, respectively). The mean CMT showed similar improvement from baseline (337 ± 53 µm) to 3 months (271 ± 69 µm, P < 0.001) and 12 months (251 ± 68 µm, P < 0.001). Figure 2 shows the BCVA and CMT changes at a 12-month follow-up.Figure 2 Changes in best-corrected visual acuity (BCVA) and central macular thickness (CMT) during the 12-month follow-up period. The mean BCVA and CMT improved at 3 months after three loading anti-vascular endothelial growth factor injections, and after the treatment switch, those outcomes further improved at 12 months.\n\n\n\nDiscussion\nIn the current study, we first demonstrated that aflibercept was more effective in inducing fluid absorption in pachychoroid neovasculopathy at least in the short term. Reduction in SFCT was significantly higher in the aflibercept group at 3 months. Although visual outcome did not differ significantly between the two groups after 3 loading injections, the aflibercept-treated eyes showed a higher incidence of dry macula at 3 months. Switching to aflibercept also resulted in complete fluid absorption in 86.7% of poor responders to ranibizumab. Because the switching was done immediately after 3 loading injections, we can assume that this may have resulted from the difference in drug efficacy rather than from the development of tachyphylaxis to ranibizumab12.\n\nTo date, no randomized trials have compared aflibercept with ranibizumab for nAMD, apart from the pivotal phase III randomized controlled trials of aflibercept9. The proportion with dry retina at 1 year was similar between the two drugs in the VIEW 1 trial; however, it was higher in the aflibercept group (80.3%) than in the ranibizumab group (60.4%) in the VIEW 2 trial in which one fourth of enrolled patients were not Caucasian. Also, a subgroup analysis of those trials showed that the proportion of dry macula at 3 months was greater for intravitreal aflibercept than for ranibizumab (75.7% versus 53.3%) in Asian patients13. These results may reflect that aflibercept can be superior to ranibizumab in eyes with thick choroid and CVH, which are prevalent characteristics in Asian populations14. In the current study, about two thirds of enrolled eyes demonstrated CVH on ICGA, which was observed in 44.4% to 53.8% of pachychoroid neovasculopathy in previous reports4,5. Several studies have reported that aflibercept was superior to ranibizumab in reducing choroidal thickness and achieving remission of exudation in eyes with thick choroid and/or CVH15,16. The reduction of SFCT was significantly greater in the aflibercept group, which may represent further reduction in CVH and disease activity.\n\nThe etiology of CNV development in pachychoroid neovasculopathy remains elusive and may be different from that in typical nAMD. Based on the observation of choriocapillaris attenuation at the disease’s focus in pachychoroid phenotypes17,18, it has been suggested that the neovascular process may be triggered by focal RPE disturbances and inner choroid attenuation overlying pachyvessels, which leads to up-regulation of VEGF. Others have proposed that chronic inflammation involving the choriocapillaris may also play a role in angiogenesis19. Hata et al. reported lower intraocular VEGF level in pachychoroid neovasculopathy than in nAMD5. Nevertheless, the authors reported that pachychoroid neovasculopathy responded favorably to anti-VEGF therapy, which was also demonstrated by the results of this study. In the current study, almost 90% of patients responded well to anti-VEGF drugs initially, and only a few patients (6 of 54 eyes, 11.1%) needed adjunctive PDT for complete fluid absorption. The favorable response to PDT in these eyes is in line with our previous report that showed the efficacy of adjunctive PDT in pachychoroid neovasculopathy refractory to anti-VEGF monotherapy20. In PCV, the primary treatment of choice is shifting from PDT to anti-VEGF injections due to the inherent risks associated with repeated PDT, including cumulative damage to normal choroidal vasculature and RPE7. To minimize the deteriorating effects, applying PDT as a deferred or rescue option is being attempted in PCV21,22, and the same strategy might be appropriate in pachychoroid neovasculopathy.\n\nThe concept of pachychoroid has evolved from the increase in choroidal thickness to the presence of characteristic morphologic changes (pachychoroid phenotype) that implicate structural and functional choroidal alteration. These include dilated choroidal vessels in Haller’s layer (pachyvessels), accompanied by thinning of the choriocapillaris and Sattler’s layer with or without RPE abnormalities overlying the pachyvessels. Eyes with pachychoroid disease may have normal SFCT if the luminal volume increase in the outer choroidal vessel is offset by a reduction in inner choroidal volume3. Indeed, our group previously reported that the SFCT of PCV exhibited a bimodal distribution, with peaks at 170 μm and 390 μm18. To date, however, there is no consensus on whether type 1 neovascularization in thin/normal choroid with dilated Haller vessels should be classified as pachychoroid neovasculopathy or nAMD in Asians. To investigate whether the two anti-VEGF agents may yield different treatment responses in pachychoroid neovasculopathy, we narrowed the inclusion criteria and minimized the gray zone. Thus, we only enrolled eyes with pachychoroid features and thick choroid (SFCT of 300 μm or more)17 in the current study.\n\nThe current study has several limitations, including its retrospective and nonrandomized nature. However, we collected a relatively large number of cases with strict inclusion criteria, and there was no significant difference in baseline characteristics between the two groups. All treatment decisions were made by a single retinal specialist (WKL) with a certain strategy. Because treatment switch was made after 3 loading injections, we cannot compare the efficacy of the two drugs in the long term. It is interesting that initial responders to both drugs showed favorable response and did not require treatment switch until 12 months later. Therefore, the treatment strategy of pachychoroid neovasculopathy needs to be individualized, and further studies should be focused on identifying possible prognostic factors predicting favorable treatment responses.\n\nDespite the absence of clear consensus in defining pachychoroid neovasculopathy, we enrolled eyes exhibiting pachychoroid phenotypes with thick choroid to adhere to the original description of this specific disease. Based on our results, intravitreal aflibercept was superior to ranibizumab in reducing choroidal thickness and achieving dry macula at 3 months, and was also effective to initial poor responders to ranibizumab. The exudation from pachychoroid neovasculopathy was successfully managed with either of the two anti-VEGF drugs in most eyes over a 1-year treatment period. However, further research with longer follow-up periods and comparing treatment regimens are still needed.\n\nMethods\nWe conducted a retrospective review of the medical records of treatment-naïve patients with pachychoroid neovasculopathy treated at the Seoul St. Mary’s Hospital of the Catholic University of Korea between January 2014 and October 2016. This study was approved by the Institutional Review Board of the Seoul St. Mary’s Hospital College of Medicine, which waived the written informed consent because of the study’s retrospective design and was conducted in accordance with the tenets of the Declaration of Helsinki.\n\nInclusion and exclusion criteria\nThe diagnosis of pachychoroid neovasculopathy was based on the presence of Type 1 neovascularization in patients older than 50 years old without any features of AMD or other degenerative changes. The presence of Type 1 neovascularization was confirmed on swept-source OCT angiography (SS OCTA) at least once from baseline throughout the 12 months of follow-up. We enrolled cases that exhibited localized areas of choroidal thickening directly below the neovascular tissue and/or pachyvessels with attenuation of overlying choriocapillaris. Minimum cutoff value of SFCT was 300 µm. The enrolled patients were followed for at least 12 months after initial treatment. The exclusion criteria were presence of polyps on ICGA, drusen greater than Category 1 criteria used in the Age-Related Eye Disease Study23, presence of RPE tears or subretinal fibrosis, and the presence of any other ocular disease that may have affected visual acuity. Patients with serosanguinous changes associated with large pigment epithelial detachment, which is a frequent presenting feature of PCV even in cases without definitive polyps, were also excluded24. The representative cases are shown in Fig. 3.Figure 3 Multimodal imaging features of pachychoroid neovasculopathy. (Top row) Images of the eye of a 52-year-old female. Fluorescein angiography (FAG) shows minimal leakage, and indocyanine green angiography (ICGA) images show a small neovascular network on the early phase (arrow) and choroidal vascular hyperpermeability (CVH) in the mid-to-late phase. Spectral-domain optical coherence tomography (SD OCT) through the lesion demonstrates Type 1 neovascularization, which is apparent on swept-source OCT angiography (SS OCTA, inlet). The arrow indicates the presume site of feeder vessel ingrowth. The subfoveal choroidal thickness is 311 µm. (Middle row) Images of the eye of a 65-year-old male. FAG shows leakage at the fovea, while neovascular network is not evident on early-phase ICGA. Late-phase ICGA shows CVH at the posterior pole. A small pigment epithelial detachment is noted on SD OCT, which is revealed as choroidal neovascularization on SS OCTA (inlet). The subfoveal choroidal thickness was 520 µm while dilated Haller vessel is not apparent. (Bottom row) Images of the eye of a 68-year-old male. Late-phase FAG reveals ill-defined leakage. Abnormal choroidal vessels without polypoidal lesions are noted in the early-phase ICGA and CVH in the mid-to-late phase. SD OCT shows Type 1 neovascularization and the is 509 µm. Dilated Haller vessels (asterisks) are noted with loss of overlying choriocapillaris and Sattler layers below the area in and around the Type 1 neovascularization lesion. Choroidal neovascular network is evident on SS OCTA (inlet).\n\n\n\nTreatment and assessment schedule\nAll patients initially received 3 monthly intravitreal anti-VEGF injections, using 0.5 mg of ranibizumab (Lucentis®; Genentech, Inc., South San Francisco, CA, USA) or 2 mg of aflibercept (Eylea; Bayer HealthCare, Berlin, Germany). Each patient was scheduled for a follow-up examination at 3 months, and complete fluid absorption was assessed at that time. Patients who showed complete fluid absorption at 3 months (initial responder) were followed regularly at 1- to 2-month intervals, depending on lesion activity. Retreatment was administered with initial anti-VEGF drugs in these patients whenever evidence of recurrent/ persistent fluid involving the fovea was detected on follow-up OCT (as needed). In patients with persistent intraretinal or subretinal fluid at 3 months (initial non-responder), the treatment switch was made at that time point. In patients who received ranibizumab, the treatment was changed to 3 monthly intravitreal aflibercept injections. In patients who received aflibercept initially, full-dose PDT was administered adjunctively. For PDT, patients were administered 6 mg of verteporfin per square meter of body surface area intravenously over 10 minutes. Fifteen minutes after the start of the infusion, PDT at standard fluence (light dose, 50 J/cm2; dose rate, 600 mW/cm2; wavelength, 689 nm) was applied for 83 seconds. The laser spot size was determined by adding 1 mm to the margin of the lesion detected on ICGA. Thereafter, all initial non-responders were followed up at 1- to 2-month intervals based on disease activity, and retreatment was given with aflibercept.\n\nOutcome measurement\nPatient charts were reviewed until 12 months after the initial treatment. BCVA was measured using a standardized Snellen chart, and comprehensive ocular examination and SD OCT imaging with enhanced depth-imaging (EDI) mode was performed using Spectralis OCT (Heidelberg Engineering, Heidelberg, Germany) for both eyes at baseline and for the affected eye at each follow-up visit. A 25-line horizontal raster scan covering 30° × 20° centering at the fovea was obtained for each eye, and an individual B-scan was 240 µm apart from the next B-scan. CMT was designated as the average thickness of the 1-mm central area of the SD OCT map. SFCT was measured using EDI OCT at baseline and 3 months. We used the entire length of an EDI OCT scan for image binarization and measured the CVI by using the protocol described in previous studies25,26. The average of the two independent graders’ (JHL, JYK) measurements was used for analysis. The intra-class correlation coefficients for inter-observer variability about CVI were used to assess the reliability of the agreements. FAG, ICGA, and FAF (Heidelberg Retina Angiograph; Heidelberg Engineering) were performed at baseline in all patients. For the FAF image, a 30° × 30° area centered at the fovea was scanned using excitation with a 488-nm argon laser and 500-nm filter. CVH was defined as multifocal areas of hyperfluorescence with blurred margins within the choroid evaluated in the late phase of ICGA. Two retinal specialists (JHL, BJJ), who were blinded to all the other medical information, evaluated CVH and, in cases of discrepancy, another retinal specialist (WKL) made the final decision. For the inter-observer agreement evaluation about CVH, Fleiss’ kappa test was used. SS OCTA images were acquired using the DRI OCT Triton machine version 10.11 (Topcon Corporation, Tokyo, Japan). Acquisition protocol in the macular region consisted of a 3 × 3 mm2 area centered on the fovea for maximum resolution of the lesion examined. Whenever the lesion extended beyond the image border, a 4.5 × 4.5 mm2 or 6 × 6 mm2 area was used to include the entire extent of the lesion.\n\nThe main outcomes measured included the rate of complete fluid absorption at 3 months between the two groups and comparisons of visual and tomographic outcomes between baseline and 12 months in all enrolled cases. The recurrence rate and number of retreatments until 12 months was also evaluated within initial responders.\n\nStatistical analysis\nFor statistical analysis, Snellen visual acuity was converted to logMAR. The Mann-Whitney test was used for analysis of continuous variables, and the chi-square test was used for categorical variables. For comparison of BCVA and CMT at 3 months and 12 months with baseline values, the paired t-test with Bonferroni correction was used. Statistical analyses were performed using SPSS software (version 21.0; IBM Corp., Armonk, NY, USA). A P value of <0.05 was considered to indicate statistical significance.\n\nPublisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nJoo Young Kim, Jiwon Baek, Kook Lee and Won Ki Lee contributed equally.\n\nAuthor Contributions\nContributions were as follows: J.H.L., W.K.L.: conception and design; B.J.J., J.Y.K., K.L., J.B.: collection and assembly of data; B.J.J.: data analysis and interpretation; and B.J.J., J.H.L., W.K.L.: writing manuscript text and preparing figures. All authors reviewed the manuscript.\n\nData Availability\nAll authors agree to make materials, data and associated protocols promptly available to readers.\n\nCompeting Interests\nThe authors declare no competing interests.\n==== Refs\nReferences\n1. Warrow DJ Hoang QV Freund KB Pachychoroid Pigment Epitheliopathy Retina-J Ret Vit Dis 2013 33 1659 1672 10.1097/IAE.0b013e3182953df4 \n2. 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Cheung CMG Polypoidal Choroidal Vasculopathy: Definition, Pathogenesis, Diagnosis, and Management Ophthalmology 2018 125 708 724 10.1016/j.ophtha.2017.11.019 29331556 \n8. Johnston RL UK Age-Related Macular Degeneration Electronic Medical Record System (AMD EMR) Users Group Report IV: Incidence of Blindness and Sight Impairment in Ranibizumab-Treated Patients Ophthalmology 2016 123 2386 2392 10.1016/j.ophtha.2016.07.037 27615601 \n9. Heier JS Intravitreal aflibercept (VEGF trap-eye) in wet age-related macular degeneration Ophthalmology 2012 119 2537 2548 10.1016/j.ophtha.2012.09.006 23084240 \n10. Yang J Comparison of binding characteristics and in vitro activities of three inhibitors of vascular endothelial growth factor A Mol Pharm 2014 11 3421 3430 10.1021/mp500160v 25162961 \n11. Padron-Perez N Changes in Choroidal Thickness After Intravitreal Injection of Anti-Vascular Endothelial Growth Factor in Pachychoroid Neovasculopathy Invest Ophthalmol Vis Sci 2018 59 1119 1124 10.1167/iovs.17-22144 29490349 \n12. Mantel, I., Gillies, M. C. & Souied, E. H. Switching between ranibizumab and aflibercept for the treatment of neovascular age-related macular degeneration. Surv Ophthalmol, 10.1016/j.survophthal.2018.02.004 (2018).\n13. Wong, T. Y. et al. Efficacy and Safety of Intravitreal Aflibercept and Ranibizumab in Asian Patients with Neovascular Age-Related Macular Degeneration: Subgroup Analyses From the View Trials. Retina, 10.1097/IAE.0000000000001986 (2017).\n14. Yanagi Y Prevalence and Risk Factors for Nonexudative Neovascularization in Fellow Eyes of Patients With Unilateral Age-Related Macular Degeneration and Polypoidal Choroidal Vasculopathy Invest Ophthalmol Vis Sci 2017 58 3488 3495 10.1167/iovs.16-21167 28702676 \n15. Hata M Efficacy of intravitreal injection of aflibercept in neovascular age-related macular degeneration with or without choroidal vascular hyperpermeability Invest Ophthalmol Vis Sci 2014 55 7874 7880 10.1167/iovs.14-14610 25395483 \n16. Koizumi H Short-term changes in choroidal thickness after aflibercept therapy for neovascular age-related macular degeneration Am J Ophthalmol 2015 159 627 633 10.1016/j.ajo.2014.12.025 25555799 \n17. Dansingani KK Balaratnasingam C Naysan J Freund KB En Face Imaging of Pachychoroid Spectrum Disorders with Swept-Source Optical Coherence Tomography Retina 2016 36 499 516 10.1097/IAE.0000000000000742 26335436 \n18. Lee WK Baek J Dansingani KK Lee JH Freund KB Choroidal Morphology in Eyes with Polypoidal Choroidal Vasculopathy and Normal or Subnormal Subfoveal Choroidal Thickness Retina 2016 36 1 S73 S82 10.1097/IAE.0000000000001346 28005665 \n19. Kitaya N Features of abnormal choroidal circulation in central serous chorioretinopathy Br J Ophthalmol 2003 87 709 712 10.1136/bjo.87.6.709 12770966 \n20. Lee JH Lee WK One-Year Results of Adjunctive Photodynamic Therapy for Type 1 Neovascularization Associated with Thickened Choroid Retina 2016 36 889 895 10.1097/IAE.0000000000000809 27115853 \n21. Gomi F Initial Versus Delayed Photodynamic Therapy in Combination with Ranibizumab for Treatment of Polypoidal Choroidal Vasculopathy: The Fujisan Study Retina 2015 35 1569 1576 10.1097/IAE.0000000000000526 25830698 \n22. Lee WK Efficacy and Safety of Intravitreal Aflibercept for Polypoidal Choroidal Vasculopathy in the PLANET Study: A Randomized Clinical Trial JAMA Ophthalmol 2018 136 786 793 10.1001/jamaophthalmol.2018.1804 29801063 \n23. Age-Related Eye Disease Study Research, G The Age-Related Eye Disease Study system for classifying age-related macular degeneration from stereoscopic color fundus photographs: the Age-Related Eye Disease Study Report Number 6 Am J Ophthalmol 2001 132 668 681 10.1016/S0002-9394(01)01218-1 11704028 \n24. Sho K Polypoidal choroidal vasculopathy: incidence, demographic features, and clinical characteristics Arch Ophthalmol 2003 121 1392 1396 10.1001/archopht.121.10.1392 14557174 \n25. Sonoda S Choroidal structure in normal eyes and after photodynamic therapy determined by binarization of optical coherence tomographic images Invest Ophthalmol Vis Sci 2014 55 3893 3899 10.1167/iovs.14-14447 24894395 \n26. Ting DSW Choroidal Remodeling in Age-related Macular Degeneration and Polypoidal Choroidal Vasculopathy: A 12-month Prospective Study Sci Rep 2017 7 7868 10.1038/s41598-017-08276-4 28801615\n\n",
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"title": "Intravitreal aflibercept and ranibizumab for pachychoroid neovasculopathy.",
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"abstract": "We report a case of unruptured fungal internal carotid artery (ICA) aneurysm and review the pertinent literature. A 79-year-old man presented with decreased visual acuity on the right side, and he was diagnosed with retrobulbar optic neuritis. Medical treatment with steroids resulted in Aspergillus meningoencephalitis spreading to the bottom of bilateral frontal lobes, caused by an intracranial extension of sphenoid sinusitis. Magnetic resonance imaging (MRI) performed 26 days after the start of antifungal therapy showed a denovo right ICA aneurysm projecting anteriorly into the sphenoid sinus. As the aneurysm grew rapidly, it was trapped surgically after establishing a high-flow bypass from the external carotid artery to the middle cerebral artery. The patient's postoperative course was uneventful. Anti-fungal medication was continued until plasma concentrations of beta-D-glucan decreased to within normal limits. Although fungal ICA aneurysm carries a high mortality rate, early detection and prompt treatment by trapping and high-flow bypass can lead to good clinical outcome.",
"affiliations": "Department of Neurosurgery, Nagoya Daini Red Cross Hospital.",
"authors": "Yamaguchi|Junya|J|;Kawabata|Teppei|T|;Motomura|Ayako|A|;Hatano|Norikazu|N|;Seki|Yukio|Y|",
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"fulltext": "\n==== Front\nNeurol Med Chir (Tokyo)Neurol. Med. Chir. (Tokyo)NMCNeurologia medico-chirurgica0470-81051349-8029The Japan Neurosurgical Society 2680418910.2176/nmc.cr.2015-0206nmc-56-89Case ReportFungal Internal Carotid Artery Aneurysm Treated by Trapping and High-Flow Bypass: A Case Report and Literature Review YAMAGUCHI Junya 1KAWABATA Teppei 1MOTOMURA Ayako 2HATANO Norikazu 1SEKI Yukio 11 Department of Neurosurgery, Nagoya Daini Red Cross Hospital, Nagoya, Aichi2 Department of Neurosurgery, Daido Hospital, Nagoya, AichiConflicts of Interest Disclosure\n\nThe authors have no personal, financial, or institutional interest in any of the drugs, materials, or devices presented in this article. All authors who are members of The Japan Neurosurgical Society (JNS) have registered online Self-reported COI Disclosure Statement Forms through the website for JNS members.\n\nAddress reprint requests to: Junya Yamaguchi, MD, Department of Neurosurgery, Nagoya Daini Red Cross Hospital, 2–9 Myouken, Showa-Ku, Nagoya 466-8650, Japan. e-mail:jyamaguchi@nagoya2.jrc.or.jp2 2016 22 1 2016 56 2 89 94 05 8 2015 26 10 2015 © 2016 The Japan Neurosurgical Society2016This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/We report a case of unruptured fungal internal carotid artery (ICA) aneurysm and review the pertinent literature. A 79-year-old man presented with decreased visual acuity on the right side, and he was diagnosed with retrobulbar optic neuritis. Medical treatment with steroids resulted in Aspergillus meningoencephalitis spreading to the bottom of bilateral frontal lobes, caused by an intracranial extension of sphenoid sinusitis. Magnetic resonance imaging (MRI) performed 26 days after the start of antifungal therapy showed a denovo right ICA aneurysm projecting anteriorly into the sphenoid sinus. As the aneurysm grew rapidly, it was trapped surgically after establishing a high-flow bypass from the external carotid artery to the middle cerebral artery. The patient’s postoperative course was uneventful. Anti-fungal medication was continued until plasma concentrations of beta-D-glucan decreased to within normal limits. Although fungal ICA aneurysm carries a high mortality rate, early detection and prompt treatment by trapping and high-flow bypass can lead to good clinical outcome.\n\nfungal aneurysmAspergillustrappinghigh-flow bypass\n==== Body\nIntroduction\nIt has been reported that fungal internal carotid artery (ICA) aneurysm is very rare, and its mortality rate is very high.1) Owing to the increase in the number of immunocompromised patients resulting from the widespread use of steroidal, chemotherapy, and immunosuppressive agents, the incidence of fungal ICA aneurysm is expected to increase.2) Recently, there have been several case reports of fungal ICA aneurysms in which performance of endovascular surgery tended to be associated with increased survival rates.1,3–6) Here we report a case of unruptured fungal ICA aneurysm that was treated successfully by surgical trapping and high-flow bypass and present a review of the pertinent literature.\n\nCase Description\nA 79-year-old man with a past history of diabetes mellitus and tuberculosis presented with decreased visual acuity on the right side and was diagnosed with retrobulbar optic neuritis. Medical treatment with a steroid (prednisolone 40 mg/day) was initiated and continued for 2 months but provided no symptom relief and subsequently resulted in a recurrence of tuberculosis. The steroid was discontinued, antituberculosis therapy was initiated. As the patient’s cognitive function began to decline 2 weeks later, cerebrospinal fluid (CSF) examination and MRI were performed. A CSF examination showed an elevated cell count and the protein level (cell count: 139/dL, glucose: 72 mg/dL, protein: 101 mg/dL) and was positive for the Aspergillus antigen. Fluid attenuated inversion recovery (FLAIR) imaging revealed an isointense lesion in the right side of the sphenoid sinus and a high-intensity lesion spreading at the bottom of the bilateral frontal lobes (Fig. 1A, B). Based on these findings, a diagnosis of fungal meningoencephalitis due to intracranial extension of Aspergillus sinusitis was made.\n\nAntifungal therapy with amphotericin B was started, but it was subsequently changed to micafungin because of an adverse effect on renal function. Follow-up CSF examination and MRI performed 26 days after starting of antifungal therapy showed decreased CSF cell counts (cell count: 6/dL, glucose: 71 mg/dL, protein: 130 mg/dL), some shrinkage of the sphenoid sinus lesion, and a de novo right ICA aneurysm projecting anteriorly into the sphenoid sinus at the C3 portion (Fig. 1C). It was noted that bilateral anterior cerebral arteries (ACAs) distal to the anterior communicating artery (AcoA) were pooly visualized, suggesting the presence of arterial stenosis caused by frontal base meningoencephalitis. Because a three-dimensional computed tomography (3D-CT) angiogram taken 5 days later showed rapid growth of this fungal aneurysm (from 9 mm × 3 mm to 11 mm × 10 mm) (Fig. 1D), we planned an emergency operation to prevent the aneurysm rupturing, which might have resulted in fatal epistaxis. Pre-operative single photon emission computed tomogram (SPECT) showed presence of a hypoperfusion area in the anterior cerebral artery distribution (Fig. 1E).\n\nUnder endotracheal general anesthesia, a high-flow bypass from the external carotid artery to the M2 portion of the middle cerebral artery (MCA) was established on the right side using a radial artery graft following a superficial temporal artery (STA) - MCA assist bypass to the M4 portion distal to the anastomosis site of the high-flow bypass. Subsequently, the right ICA was trapped between its origin in the neck and the C2 portion of the ICA. A marked granulomatous change was seen in the dura mater in the frontal base. The right ophthalmic artery was involved in the trapping, as the patient’s right visual acuity consisting of only light perception just before the operation. We believed that performing anterior clinoidectomy to expose the ophthalmic artery might further accelerate the intracranial invasion of Aspergillus species. Finally, we anastomosed the frontal branch of the STA to the cortical branch of the right ACA to increase perfusion in its territory.\n\nThe patient’s postoperative course was uneventful. MRI taken 4 days after the operation showed patency of both the radial artery graft and the frontal branch of the right STA (Fig. 2A). There was no new cerebral infarction. The right ICA had been obliterated and the aneurysm was not visualized. Post-operative SPECT taken 2 weeks after the operation showed improved perfusion in the right anterior cerebral artery distribution (Fig. 2B). Antifungal treatment was continued with itraconazole until plasma concentrations of beta-D-glucan had decreased to within normal limits. Fifty-five days after the operation, the patient was transferred to a rehabilitation hospital because of persisting cognitive function impairment.\n\nDiscussion\nIntracranial fungal infection is a rare condition, accounting for 0.8% of all intracranial infections.7) There are three routes through which a fungus invades the intracranial space.8) The first route is hematogenous dissemination from a remote extracranial site, such as the lung. The second route is through direct invasion from a contiguous cranial focus, as in fungal paranasal sinusitis. The third route is through contamination caused by improper neurosurgical procedures. In cases of hematogenous dissemination, fungal aneurysms tend to develop at distal sites of the ACA, MCA, or posterior cerebral artery (PCA) rather than the ICA, as is the case for mycotic aneurysms that result from infectious endocarditis.8) In contrast, when the fungus invades from the paranasal sinus, intracavernous and supraclinoid portions of the ICA are frequently affected like the present case. Owing to the recent increase in the number of immunocompromised patients, it is expected that the incidence of fungal ICA aneurysms will likewise increase, just as the number of patients with fungal paranasal sinusitis is increasing.2) However, it is often difficult to diagnose a fungal aneurysm before it ruptures because its presentation is insidious (e.g., the fungal sinusitis presents with vague symptoms, such as headache, rhinorrhea, disorder of the sense of smell, or facial discomfort).6) Among 18 cases of fungal ICA aneurysms described below, just 5 patients were diagnosed before its rupture. Thus, it is important to have a high index of suspicion of a fungal ICA aneurysm in patients with fungal paranasal sinusitis, especially when orbital apex syndrome is present.8) In the present case, the patient’s cognitive function impairment triggered a thorough study of the brain, including MRI, and therefore, a rapidly developing ICA aneurysm could be detected before its rupture.\n\nAspergillus is the most common cause of fungal aneurysms. This is because Aspergillus is most frequently found in deep mycosis and has the characteristic of vasocentric tropism. The key molecule that leads to aneurysm formation is the elastase produced by Aspergillus. Elastase decomposes elastine, a major component of the vascular wall, and induces inflammation in all layers of the vascular wall.9)\n\nBy searching the English-language medical literature, we were able to collect 18 case reports of fungal ICA aneurysms (Table 1). Among these 18 cases, 11 of the patients had died. Of 9 cases in which surgical or endovascular intervention was performed, 7 patients survived. Among the 9 cases, endovascular surgery was selected in 6 cases and open surgery in 3 cases. In contrast, in the 9 cases in which aneurysms were treated conservatively, all the patients died. These data demonstrate that early intervention is warranted to obliterate fungal ICA aneurysms and prevent patient deaths. In endovascular surgery for fungal ICA aneurysms, parent artery occlusion with a detachable coil or balloon was the main procedure selected. It is less invasive and has merit to provide immediate hemostasis against a background of ongoing epistaxis. Recently Kim et al. reported a case of a patient who presented with severe epistaxis due to rupture of a fungal cavernous ICA aneurysm. The aneurysm was successfully treated with a graft stent. However, two aneurysms developed later, downstream of the affected ICA, and the authors suspected that these aneurysms were mycotic and had developed owing to a graft stent infection.6) As no such a complication was reported in other patients who received endovascular parent artery occlusion, preservation of blood flow through a bioprosthesis in the setting of an active infection may result in colonization with the circulating fungus. Hurst et al. reported a case in which a fungal ICA aneurysm extended intradurally and caused a fatal subarachnoid hemorrhage after parent artery occulusion with a coil.3) These reports suggest that treating fungal ICA aneurysms with foreign bodies, such as a stent or coil, might not be a promising approach.\n\nIn the context of surgical cases, Bowers et al. reported a case of a patient with ruptured fusiform paraclinoid ICA aneurysm caused by Aspergillus invasion. Although clip-wrapping of the aneurysm was performed, the patient died owing to occlusion of the affected ICA and a complete infarct in its distribution.10) Loeys et al. reported a case of fungal ICA aneurysm in a child with familial chronic mucocutaneous candidiasis. In this patient, clipping the aneurysm after 3 months of antimycotic treatment led to a favorable outcome.12) Several issues need to be considered when planning surgery for fungal ICA aneurysms. First, fungal aneurysms are prone to rupture and therefore require prompt obliteration. Second, surgical manipulation of the skull base, such as anterior clinoidectomy, carries the potential risk of disseminating the fungus to the central nervous system. Third, considering the pathological changes to the affected arterial wall, neck clipping the aneurysm in the acute stage may not be reliable. In the present case, we performed trapping of the ICA aneurysm with an extracranial-intracranial high-flow bypass. This procedure precluded the risk of rupture, thereby avoiding ischemia and procedure-related dissemination of the fungal infection. There may be an arguement about the necessity of trapping the aneurysm. Another option of surgical procedure is affected ICA ligation at the neck with a high-flow bypass. However, in this setting the risk of rupture could not be precluded until the aneurysm becomes completely thrombosed and is isolated from the established collateral circulation. As for the high-flow bypass in this case, we believed it was mandatory because 3D-CT angiogram did not show the AcoA and bilateral distal ACAs. Probably collateral flow through the leptomeningeal anastomosis was supplying their territories. In such a setting, a low-flow bypass may not be enough to avoid ischemia in the ICA territory after its occlusion.\n\nIn conclusion, in cases of invasive paranasal sinus aspergillosis, early detection of a fungal ICA aneurysm is paramount. Prompt trapping of the aneurysm with an appropriate bypass combined with antifungal medications is a reliable treatment regimen for particular group of patients.\n\nFig. 1 A: Axial FLAIR image showing an isointense lesion (arrow) in the right side of the sphenoid sinus extending to the orbital apex and the cavernous portion of the ICA. B: Axial FLAIR image showing a high-intensity lesion (arrow) at the base of the bilateral frontal lobes, suggesting meningoencephalitis due to intracranial extension of sphenoid sinusitis. C: MRA image, right anterior oblique view, showing an aneurysm (arrow) projecting anteriorly at the C3 portion of the right ICA. D: 3D-CT angiography, right anterior oblique view, showing rapid growth of the aneurysm (arrow). Note that bilateral anterior cerebral arteries distal to the anterior communicating artery are not opacified, suggesting the presence of a stenosis caused by frontal base meningoencephalitis. E: Pre-operative single photon emission computed tomography showing a hypoperfusion area in the anterior cerebral artery distribution. FLAIR: fluid attenuated inversion recovery, ICA: internal carotid artery, MRA: magnetic resonance angiogram, 3D-CT: three-dimensional computed tomography.\n\nFig. 2 A: MRI image taken 4 days after the operation showing patency of both the radial artery graft and the frontal branch of the right superficial temporal artery. The right ICA has been obliterated, and the aneurysm is not visualized. B: Post-operative single photon emission computed tomogram showing improved perfusion in the right anterior cerebral artery distribution. ICA: internal carotid artery, MRI: magnetic resonance imaging.\n\nTable 1 Summary of reported cases of fungal internal carotid artery aneurysm\n\nAuthor (year)\tAge (years)/Sex\tUnderlying diseases and use of immunosuppressant\tFungus\tSite of aneurysm\tCondition of aneurysm\tProcedure\tOutcome\t\nMahaley and Spick (1968)\n13)\t27/F\tAcute leukemia\t\nAspergillus\n\tIntracranial ICA\tUnruptured\tNone\tDied\t\nMorriss and Spock (1970)\n14)\t11/M\tMaxiallary tooth extraction\t\nPenicillium\n\tIntracranial ICA\tUA\tNone\tDied\t\nAhuja et al. (1978)\n15)\t18/M\tUA\t\nAspergillus\n\tIntracranial ICA\tRuptured\tNone\tDied\t\nSaff et al. (1989)\n16)\t76/M\tDM\t\nMucor\n\tCavernous CA\tUnruptured\tNone\tDied\t\nIihara et al. (1990)\n17)\t78/M\tCLL\t\nAspergillus\n\tCavernous CA\tRuptured\tNone\tDied\t\nKomatsu et al. (1991)\n18)\t61/F\tTranssphenoidal resection of Rathke cleft cyst\t\nAspergillus\n\tICA\tRuptured\tNone\tDied\t\nOkada et al. (1998)\n8)\t62/M\tSteroid\t\nAspergillus\n\tIC-PC\tRuptured\tNone\tDied\t\nLoeys et al. (1999)\n12)\t5/M\tChronic cutaneous candiasis\t\nCandida albicans\n\tC2 segment\tUnruptured\tClipping\tSurvive\t\nHurst et al. (2001)\n3)\t73/M\tIdiopathic thrombocytopenic purpura/CLL\t\nAspergillus\n\tCavernous CA\tRuptured\tPAO (coil+balloon)\tDied\t\nThajeb et al. (2004)\n19)\t62/F\tDM\t\nMucor\n\tCavernous CA\tRuptured\tNone\tDied\t\nHot et al. (2007)\n1)\t61/M\tHairly cell leukemia\t\nAspergillus\n\tExtracranial ICA\tRuptured\tPAO (coil+balloon)\tSurvive\t\nWatanabe et al. (2009)\n11)\t15/M\tPost allogeneic bone marrow transplantation\t\nAspergillus\n\tExtracranial ICA\tRuptured\tCoil trapping\tSurvive\t\nAlvernia et al. (2009)\n4)\t38/M\tDM\t\nMucor\n\tPetrous CA\tUnruptured\tPAO (coil)\tSurvive\t\nLim et al. (2010)\n20)\t63/M\tDM\t\nAspergillus\n\tSupraclinoid CA\tRuptured\tNone\tDied\t\nJao et al. (2011)\n5)\t76/M\tDM\t\nAspergillus\n\tCavernous CA\tRuptured\tPAO (coil+n-BCA)\tSurvive\t\nKim et al. (2012)\n6)\t46/F\tSteroid, Cyclophosphamide\t\nAspergillus\n\tCavernous CA\tRuptured\tGraft stent\tSurvive\t\nBowers (2015)\n10)\t76/F\tSteroid, Methotrexate\t\nAspergillus\n\tSupraclinoid CA\tRuptured\tClip-wrapping\tDied\t\nPresent case\t76/M\tDM, steroid\t\nAspergillus\n\tInfraclinoid CA\tUnruptured\tHigh-flow bypass & trapping\tSurvive\t\nCA: carotid artery, CLL: chronic lymphoid leukemia, DM: diabetes mellitus, F: female, ICA: internal carotid artery, IC-PC: internal carotid-posterior communicating, M: male, n-BCA: n-butyl cyanoacrylate, PAO: parent artery occlusion, UA: unavailable.\n==== Refs\nReferences\n1) \nHot A Mazighi M Lecuit M Poirée S Viard JP Loulergue P Suarez F Dupont B Merland JJ Lortholary O : \nFungal internal carotid artery aneurysms: successful embolization of an Aspergillus-associated case and review . \nClin Infect Dis \n45 : \ne156 –\ne161 , \n2007 \n18190310 \n2) \nArnold TM Sears CR Hage CA : \nInvasive fungal infections in the era of biologics . \nClin Chest Med \n30 : \n279 –\n286 , \nvi , \n2009 \n19375634 \n3) \nHurst RW Judkins A Bolger W Chu A Loevner LA : \nMycotic aneurysm and cerebral infarction resulting from fungal sinusitis: imaging and pathologic correlation . \nAJNR Am J Neuroradiol \n22 : \n858 –\n863 , \n2001 \n11337328 \n4) \nAlvernia JE Patel RN Cai DZ Dang N Anderson DW Melgar M : \nA successful combined endovascular and surgical treatment of a cranial base mucormycosis with an associated internal carotid artery pseudoaneurysm . \nNeurosurgery \n65 : \n733 –\n740 ; \ndiscussion 740 , \n2009 \n19834379 \n5) \nJao SY Weng HH Wong HF Wang WH Tsai YH : \nSuccessful endovascular treatment of intractable epistaxis due to ruptured internal carotid artery pseudoaneurysm secondary to invasive fungal sinusitis . \nHead Neck \n33 : \n437 –\n440 , \n2011 \n19953634 \n6) \nKim YC Lee H Ryu HH Beom SH Yang Y Kim S Chin HJ : \nAspergillus-associated cerebral aneurysm successfully treated by endovascular and surgical intervention with voriconazole in lupus nephritis patient . \nJ Korean Med Sci \n27 : \n317 –\n320 , \n2012 \n22379345 \n7) \nKamei S Takasu T : \nNationwide survey of the annual prevalence of viral and other neurological infections in Japanese inpatients . \nIntern Med \n39 : \n894 –\n900 , \n2000 \n11065239 \n8) \nOkada Y Shima T Nishida M Yamane K Yoshida A : \nSubarachnoid hemorrhage caused by Aspergillus aneurysm as a complication of transcranial biopsy of an orbital apex lesion—case report . \nNeurol Med Chir (Tokyo) \n38 : \n432 –\n437 , \n1998 \n9745252 \n9) \nKothary MH Chase T Macmillan JD : \nCorrelation of elastase production by some strains of Aspergillus fumigatus with ability to cause pulmonary invasive aspergillosis in mice . \nInfect Immun \n43 : \n320 –\n325 , \n1984 \n6360904 \n10) \nBowers CA Saad D Clegg DO Ng P Clayton F Haydoura S Schmidt RH : \nRapidly fatal internal carotid artery mycotic aneurysm rupture in a rheumatoid patient taking a tnf-α inhibitor: case report and literature review . \nJ Neurol Surg A Cent Eur Neurosurg \n76 : \n249 –\n254 , \n2015 \n25045858 \n11) \nWatanabe T Okada T Okada C Onishi T Watanabe H Okamoto Y Kitamura Y Manabe S Matsubara S Kageji T Iwai A : \nAn aspergillotic aneurysm of the internal carotid artery following allogeneic bone marrow transplantation: successful management with catheter coil embolization and long-term antifungal agents . \nTranspl Infect Dis \n11 : \n49 –\n53 , \n2009 \n18713137 \n12) \nLoeys BL Van Coster RN Defreyne LR Leroy JG : \nFungal intracranial aneurysm in a child with familial chronic mucocutaneous candidiasis . \nEur J Pediatr \n158 : \n650 –\n652 , \n1999 \n10445344 \n13) \nMahaley M Spick A : \nAn unusual case of intracranial aneurysm , in\nSmith J (ed): \nNeuro-Ophthalmology . \nSt. Louis , \nMosby , \n1968 , pp \n158 –\n166 \n\n14) \nMorriss FH Spock A : \nIntracranial aneurysm secondary to mycotic orbital and sinus infection. Report of a case implicating penicillium as an opportunistic fungus . \nAm J Dis Child \n119 : \n357 –\n362 , \n1970 \n5467227 \n15) \nAhuja GK Jain N Vijayaraghavan M Roy S : \nCerebral mycotic aneurysm of fungal origin. Case report . \nJ Neurosurg \n49 : \n107 –\n110 , \n1978 \n580788 \n16) \nSaff G Frau M Murtagh FR Silbiger ML : \nMucormycosis associated with carotid cavernous fistula and cavernous carotid mycotic aneurysm . \nJ Fla Med Assoc \n76 : \n863 –\n865 , \n1989 \n2809556 \n17) \nIihara K Makita Y Nabeshima S Tei T Keyaki A Nioka H : \nAspergillosis of the central nervous system causing subarachnoid hemorrhage from mycotic aneurysm of the basilar artery—case report . \nNeurol Med Chir (Tokyo) \n30 : \n618 –\n623 , \n1990 \n1703641 \n18) \nKomatsu Y Narushima K Kobayashi E Tomono Y Nose T : \nAspergillus mycotic aneurysm—case report . \nNeurol Med Chir (Tokyo) \n31 : \n346 –\n350 , \n1991 \n1724300 \n19) \nThajeb P Thajeb T Dai D : \nFatal strokes in patients with rhino-orbito-cerebral mucormycosis and associated vasculopathy . \nScand J Infect Dis \n36 : \n643 –\n648 , \n2004 \n15370650 \n20) \nLim SC Choi JU Bae SH : \nRapid development of an infectious aneurysm of the internal carotid artery from orbital apex syndrome . \nOtolaryngol Head Neck Surg \n142 : \n294 –\n295 , \n2010 \n20115995\n\n",
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"mesh_terms": "D000368:Aged; D001228:Aspergillosis; D002340:Carotid Artery Diseases; D002343:Carotid Artery, Internal; D006801:Humans; D002532:Intracranial Aneurysm; D008279:Magnetic Resonance Imaging; D008297:Male; D008590:Meningoencephalitis; D019635:Neurosurgical Procedures",
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"title": "Fungal Internal Carotid Artery Aneurysm Treated by Trapping and High-Flow Bypass: A Case Report and Literature Review.",
"title_normalized": "fungal internal carotid artery aneurysm treated by trapping and high flow bypass a case report and literature review"
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"abstract": "OBJECTIVE\nThis case report describes two cases of high-dose methotrexate-induced nephrotoxicity: death in the case of conventional supportive care and successful renal function recovery in a patient treated with glucarpidase and continuous dialysis.\n\n\nMETHODS\nHigh dose methotrexate is widely used for management of adult and pediatric malignancies. However, high-dose methotrexate-induced renal nephrotoxicity may cause severe, even lethal complications. Here we present examples of such outcomes.\n\n\nRESULTS\nWe present one case of lethal high-dose methotrexate nephrotoxicity in a patient treated with conventional rescue therapy. We contrast this outcome with another patient with high-dose methotrexate-induced anuric acute kidney injury, who has recovered renal function following therapy with glucarpidase and continuous dialysis.\n\n\nCONCLUSIONS\nThis is only the second reported case of high-dose methotrexate-induced anuric acute kidney injury, and the only one with a reported clinical outcome. This first report of recovery from high-dose methotrexate-induced anuric acute kidney injury after glucarpidase administration supports available evidence pointing to the effectiveness of this therapy.",
"affiliations": "Nephrology Research and Training Center, Division of Nephrology, Department of Medicine, The University of Alabama at Birmingham, Birmingham, AL, USA.;Department of Neurology, The University of Alabama at Birmingham, Birmingham, AL, USA.;Nephrology Research and Training Center, Division of Nephrology, Department of Medicine, The University of Alabama at Birmingham, Birmingham, AL, USA.;Department of Neurology, The University of Alabama at Birmingham, Birmingham, AL, USA.;Nephrology Research and Training Center, Division of Nephrology, Department of Medicine, The University of Alabama at Birmingham, Birmingham, AL, USA.",
"authors": "Harms|James|J|;Khawaja|Ayaz|A|;Taylor|Maria|M|;Han|Xiaosi|X|;Mrug|Michal|M|",
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"fulltext": "\n==== Front\nSAGE Open Med Case RepSAGE Open Med Case RepSCOspscoSAGE Open Medical Case Reports2050-313XSAGE Publications Sage UK: London, England 10.1177/2050313X1770505010.1177_2050313X17705050Case ReportRecovery of methotrexate-induced anuric acute kidney injury after glucarpidase therapy Harms James 1Khawaja Ayaz 2Taylor Maria 1Han Xiaosi 2Mrug Michal 131 Nephrology Research and Training Center, Division of Nephrology, Department of Medicine, The University of Alabama at Birmingham, Birmingham, AL, USA2 Department of Neurology, The University of Alabama at Birmingham, Birmingham, AL, USA3 Department of Veterans Affairs Medical Center, Birmingham, AL, USAMichal Mrug, Nephrology Research and Training Center, Division of Nephrology, Department of Medicine, The University of Alabama at Birmingham, Tinsley Harrison Tower 611J, 1900 University Blvd, Birmingham, AL 35294, USA. Email: mmrug@uab.edu21 4 2017 2017 5 2050313X177050507 6 2016 16 3 2017 © The Author(s) 20172017SAGE PublicationsThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 3.0 License (http://www.creativecommons.org/licenses/by-nc/3.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access page(https://us.sagepub.com/en-us/nam/open-access-at-sage).Objectives:\nThis case report describes two cases of high-dose methotrexate–induced nephrotoxicity: death in the case of conventional supportive care and successful renal function recovery in a patient treated with glucarpidase and continuous dialysis.\n\nMethods:\nHigh dose methotrexate is widely used for management of adult and pediatric malignancies. However, high-dose methotrexate–induced renal nephrotoxicity may cause severe, even lethal complications. Here we present examples of such outcomes.\n\nResults:\nWe present one case of lethal high-dose methotrexate nephrotoxicity in a patient treated with conventional rescue therapy. We contrast this outcome with another patient with high-dose methotrexate–induced anuric acute kidney injury, who has recovered renal function following therapy with glucarpidase and continuous dialysis.\n\nConclusions:\nThis is only the second reported case of high-dose methotrexate–induced anuric acute kidney injury, and the only one with a reported clinical outcome. This first report of recovery from high-dose methotrexate–induced anuric acute kidney injury after glucarpidase administration supports available evidence pointing to the effectiveness of this therapy.\n\nHigh-dose methotrexatemethotrexateacute kidney injurycontinuous renal replacement therapycover-dateJanuary-December 2017\n==== Body\nIntroduction\nMethotrexate (MTX) is a dihydrofolate reductase inhibitor that blocks de novo nucleotide synthesis. It is used in the treatment of many conditions ranging from autoimmune disease to malignancies, with doses ranging from 20 mg/m2 per week to 1000–33,000 mg/m2 depending on indication.1 The latter dose range is known as high-dose methotrexate (HDMTX), which is often used as the first-line treatment of central nervous system (CNS) lymphoma and acute lymphoblastic leukemia, among other indications.1–3 However, HDMTX therapy may be nephrotoxic in up to 12% of patients.1,3 It is believed that MTX induces renal injury either by precipitation in, or a direct toxic effect on, the renal tubules.1 MTX and its metabolites are poorly soluble when in acidic environments, promoting potential precipitation in acidic urine.1 Strategies for prevention of the HDMTX nephrotoxic effects include adequate hydration, urine alkalinization, and leucovorin rescue.3\n\nSince over 90% of MTX is cleared by kidneys,1 HDMTX-induced kidney injury is central in the development of other HDMTX toxicities including myelosuppression and mucositis.1 The threshold MTX levels triggering such toxicity are 5–10, 1, and 0.1 µM at 24, 48, and 72 h, respectively.1,3\n\nOnce HDMTX-induced renal dysfunction is manifested by oliguria, rising creatinine, or elevated MTX levels, management options include high-dose leucovorin rescue, extracorporeal methods of MTX removal (e.g. hemodialysis (HD)), or administration of glucarpidase.1,3 The recently developed therapy glucarpidase, a recombinant bacterial enzyme that hydrolyzes MTX to inactive metabolites, rapidly lowers plasma MTX concentrations (by over 98% within 15 min of administration) and is relatively well tolerated.1\n\nHere, we contrast outcomes of two cases of HDMTX nephrotoxicity: death in the case of conventional supportive care and successful renal function recovery in a patient treated with glucarpidase and continuous dialysis.\n\nPatient A\nA 54-year-old white male with Waldenstrom’s macroglobulinemia was scheduled for treatment with autologous stem cell transplant. Due to rising immunoglobulin M level to 1600 mg/dL, he received chemo-mobilization with cyclophosphamide. This therapy was complicated by acute kidney injury (AKI; serum creatinine rising to 1.8 mg/dL); however, his kidney function recovered with intravenous hydration (serum creatinine returned to baseline of 0.9 mg/dL). This episode of AKI was closely associated with receiving cyclophosphamide and attributed to pre-renal injury because of its improvement with intravenous fluids. Three months after chemo-mobilization with cyclophosphamide, he was diagnosed with CNS lymphoma and, instead of the stem cell transplant, was scheduled to receive HDMTX therapy.\n\nHis physical examination on the day of HDMTX was unremarkable with the exception of class 2 obesity (body weight 128.6 kg; body mass index (BMI) of 38.5). Therefore, his MTX dose was reduced to intravenous 6 g/m2 from a standard 8 g/m2 (total 14 g), and it was given with leucovorin rescue and prophylactic maintenance intravenous fluids.\n\nAfter administration of MTX, the patient became anuric and encephalopathic with only 65 mL of urine output over 24 h after the HDMTX. His creatinine rose from 1.3 to 3.1 mg/dL during this time period and potassium to 5.7 from normal baseline. Urinalysis reported 2+ blood and protein, but manual urine microscopy was bland (no crystals or active sediment) and there was no evidence of obstruction on renal ultrasound. His MTX level at 24 h post-HDMTX was 201.2 µM (Figure 1, left panel). The proximity of AKI to MTX administration, elevated serum MTX levels, and lack of other obvious causes lead to the suspected diagnosis of HDMTX nephrotoxicity.\n\nFigure 1. High-dose methotrexate (HDMTX) therapy outcomes. Patient A (left panel) has developed anuric acute kidney injury after HDMTX. However, he has recovered renal function with supportive care that included glucarpidase administration and continuous renal replacement therapy (CRRT). Patient B (right panel) has developed HDMTX-induced AKI that was milder and non-oliguric; however, later died due to complications of severe sepsis.\n\nIntermittent HD was performed 1 day after the HDMTX to facilitate MTX clearance as well as management of emerging AKI complications and the patient was transferred to the intensive care unit for close monitoring. However, a standard 4-h intermittent HD treatment decreased MTX levels to 139.4 µM/L (a 30.73% reduction), and 60 µM by day 3 post-HDMTX. At that time, continuous renal replacement therapy (CRRT) was initiated and glucarpidase (BTG International, Inc.) was administered intravenously at the recommended dose of 50 U/kg. The decision was made to use CRRT based on the patient developing relative hypotension and our institutional practices for care of patients in the intensive care unit. Post-glucarpidase MTX levels were 9.92 µM (an 83.5% reduction). CRRT was held for 3 days after glucarpidase administration, but was restarted and continued from day 6 to day 17 post-HDMTX to aid management of AKI complications. However, his urine output subsequently improved and renal function recovered to a serum creatinine of 1.6 on day 27 post-HDMTX (MTX level at that time was 0.07 µM). Similarly, he recovered from additional HDMTX complications that included myelosuppression, urinary tract infection, pulmonary edema, and mildly increased liver function tests.\n\nCase B\nA 55-year-old white male with newly diagnosed large B-cell lymphoma, otherwise unremarkable history and physical examination with the exception of borderline class 1 obesity (weight of 96 kg; BMI, 30.3). His baseline renal function was normal with a serum creatinine of 0.7 mg/dL. He received HDMTX at intravenous dose 8 g/m2 (total 17 g) without any additional chemotherapy. Standard supportive HDMTX care included prophylactic intravenous fluids pre- and post-HDMTX administration and timely leucovorin rescue. However, his serum creatinine increased to 1.7 mg/dL on day 1 post-HDMTX. On day 2 post-HDMTX, the MTX level was 286.5 µM, intravenous fluids were continued, and leucovorin dose increased from 25 to 100 mg every 6 h. His creatinine peaked at 3.6 mg/dL on day 5 post-HDMTX and declined to 2.5 mg/dL by day 7 post-HDMTX. A renal ultrasound demonstrated normal-appearing kidneys without obstruction. However, he also developed HDMTX-induced myelotoxicity complicated by severe pancytopenia; for example, 9 days post-HDMTX white blood cell count declined to 370 per cubic millimeter (cmm), hemoglobin to 8.8 g/dL, and platelet count to 27,500 per cmm). In addition, on day 7 post-HDMTX, he developed septic shock with severe persistent hypotension and eventually become unresponsive to intravenous fluids or vasopressors. His AKI was thought to be secondary to HDMTX initially, with contribution of acute tubular necrosis from septic shock later in his clinical course. Due to the progressively worsening septic shock complications, intensive supportive care was discontinued on day 12 post-HDMTX and the patient died later that day.\n\nDiscussion\nThis case report demonstrates the importance of quickly identifying and treating the MTX toxicity. In addition, consistent with previous report,4 it points to potential beneficial adjuvant effects of glucarpidase and high-flux HD therapy.\n\nRisk factors predisposing to nephrotoxic complication of HDMTX are incompletely understood. Obesity, seen in both Patient A and Patient B, is among such risk factors since it delays MTX clearance.5 Consequently, an alternative dosing regimen of HDMTX was suggested for obese patients.5,6–8 However, even 25% MTX dose reduction did not protect Patient A from developing HDMTX-induced anuric AKI.\n\nThe severity of AKI seen in Patient A represents an extremely rare example of severe HDMTX nephrotoxicity. This is only the second reported case of anuric AKI induced by HDMTX,9 and the only case with a reported clinical outcome. For example, in a case series of patients with CNS lymphoma that were treated with HDMTX, nobody developed severe nephrotoxicity.10 While the exact etiology of anuric AKI in Patient A is unknown, it is likely that it included obesity complications and reduction of renal reserve due to history of previous AKI, and Waldenstrom’s macroglobulinemia, a potential cause of renal insufficiency. Waldenstrom’s macroglobulinemia has been reported to cause AKI by IgM deposition in the glomerular basement membrane, as well as lymphoid cell infiltration of the interstitium.11 He had no other easily identifiable HDMTX risk factors.5\n\nThe limitations of this study include the MTX measurement method. Specifically, MTX levels were measured by automated fluorescence polarization immunoassay (FPI) and not by the more accurate high-performance liquid chromatography. Inactive metabolites of glucarpidase-mediated MTX degradation can cross-react with MTX when using FPI and likely led to falsely elevated post-glucarpidase MTX levels. Also, without biopsy confirmation, the cause of AKI is not definitive in both cases and could have been significantly impacted by factors unique to each of their hospital courses.\n\nIn summary, this case report points to the danger of HDMTX-induced nephrotoxicity, importance of its early recognition and initiation of effective therapy. We report the second case of HDMTX-induced anuric AKI, and this case is the first one with a reported clinical outcome. This report points to administration of glucarpidase as rapid effective treatment of HDMTX toxicity and supports the use of adjuvant therapy with extracorporeal removal such as high-flux HD and CRRT to improve MTX clearance in patients with severe AKI.\n\nDeclaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.\n\nEthical approval: Our institution does not require ethical approval for reporting individual cases or case series.\n\nFunding: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: M.M. was supported in part by R01 DK097423; Hepato/Renal Fibrocystic Disease Core Center P30 DK074038, UAB-UCSD O’Brien Center 1P30 DK079337, and 1 I01 BX002985 from the Office of Research and Development, Medical Research Service, Department of Veterans Affairs. M.M. received research funding from Otsuka Pharmaceuticals and Genzyme.\n\nInformed consent: Informed consent for patient information to be published in this article was not obtained because it was not possible for us to obtain consent for this case report from the two patients because they died 2 or 3 years ago. However, this case report meets all conditions for protection of individual data as specified by the Committee on Publication Ethics’ (COPE) Code of Conduct (see the Compliance with ethical standards section).\n==== Refs\nReferences\n1 \nWidemann BC \nUnderstanding and managing methotrexate nephrotoxicity . Oncologist \n2006 ; 11 (6 ): 694 –703 .16794248 \n2 \nWidemann BC Balis FM Kim A \nGlucarpidase, leucovorin, and thymidine for high-dose methotrexate-induced renal dysfunction: clinical and pharmacologic factors affecting outcome . J Clin Oncol \n2010 ; 28 (25 ): 3979 –3986 .20679598 \n3 \nAlbushra Y \nPrevention and management of high-dose methotrexate toxicity . J Cancer Sci Therapy \n2013 ; 5 (3 ), https://www.omicsonline.org/1948-5956/JCST-05-106.digital/fscommand/JCST-05-106.pdf\n4 \nSaland J Leavey P Bash R \nEffective removal of methotrexate by high-flux hemodialysis . Pediatr Nephrol \n2002 ; 17 (10 ): 825 –829 .12376811 \n5 \nSchwartz S Borner K Muller K \nGlucarpidase (carboxypeptidase G2) intervention in adult and elderly cancer patients with renal dysfunction and delayed methotrexate elimination after high-dose methotrexate therapy . Oncologist \n2007 ; 12 (11 ): 1299 –1308 .18055849 \n6 \nFleming RA Eldridge RM Johnson CE \nDisposition of high-dose methotrexate in an obese cancer patient . Cancer \n1991 ; 68 (6 ): 1247 –1250 .1714790 \n7 \nVilay A Mary Bruce A \nTreatment of methotrexate intoxication with various modalities of continuous extracorporeal therapy and glucarpidase . Pharmacotherapy \n2010 ; 30 (1 ): 111 .20030480 \n8 \nGurney H \nDose calculation of anticancer drugs: a review of the current practice and introduction of an alternative . J Clin Oncol \n1996 ; 14 : 2590 –2611 .8823340 \n9 \nThierry FX Vernier I Dueymes JM \nAcute renal failure after high-dose methotrexate therapy . Nephron \n1989 ; 51 (3 ): 416 –417 .2918955 \n10 \nZhu J-J Gerstner ER Engler DA \nHigh-dose methotrexate for elderly patients with primary CNS lymphoma . Neuro Oncol \n2008 ; 11 (2 ): 211 –215 .18757775 \n11 \nVeltman G Van Veen S Kluin-Nelemans J \nRenal disease in Waldenstrom’s macroglobulinaemia . Nephrol Dial Transpl \n1997 ; 12 (6 ): 1256 –1259 .\n\n",
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"title": "Recovery of methotrexate-induced anuric acute kidney injury after glucarpidase therapy.",
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"abstract": "Spontaneous rupture of the inferior vena cava (IVC) is a rare entity. We report a case of a spontaneous IVC rupture associated with IVC filter thrombosis in a patient presenting with severe atraumatic back pain. Computed tomography (CT) identified a retroperitoneal hematoma and suggested IVC thrombosis. Magnetic resonance (MR) imaging confirmed the presence of IVC filter thrombosis and demonstrated a large defect in the infrarenal IVC, with the vessel lumen in free communication with the adjacent hematoma. The patient was managed conservatively and discharged in stable condition. MR imaging played an important role in characterizing the CT findings, which were unclear.",
"affiliations": "Mallinckrodt Institute of Radiology Washington University School of Medicine Saint Louis, MO, USA.;Mallinckrodt Institute of Radiology Washington University School of Medicine Saint Louis, MO, USA.;Mallinckrodt Institute of Radiology Washington University School of Medicine Saint Louis, MO, USA.;Mallinckrodt Institute of Radiology Washington University School of Medicine Saint Louis, MO, USA.",
"authors": "Ludwig|Daniel R|DR|;Fraum|Tyler J|TJ|;White|G Lance|GL|;Narra|Vamsi R|VR|",
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"keywords": "Retroperitoneal hematoma; case report; inferior vena cava filter; inferior vena cava rupture; inferior vena cava thrombosis; spontaneous",
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"mesh_terms": "D000072700:Conservative Treatment; D006406:Hematoma; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D012187:Retroperitoneal Space; D012422:Rupture, Spontaneous; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome; D016306:Vena Cava Filters; D014682:Vena Cava, Inferior; D020246:Venous Thrombosis",
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"title": "Spontaneous rupture of the inferior vena cava (IVC) in the setting of IVC filter thrombosis: case report.",
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"drugadditional": nu... |
{
"abstract": "OBJECTIVE\nTo test the transferability of the Helsinki stroke thrombolysis model that achieved a median 20-minute door-to-needle time (DNT) to an Australian health care setting.\n\n\nMETHODS\nThe existing \"code stroke\" model at the Royal Melbourne Hospital was evaluated and restructured to include key components of the Helsinki model: 1) ambulance prenotification with patient details alerting the stroke team to meet the patient on arrival; 2) patients transferred directly from triage onto the CT table on the ambulance stretcher; and 3) tissue plasminogen activator (tPA) delivered in CT immediately after imaging. We analyzed our prospective, consecutive tPA registry for effects of these protocol changes on our DNT after implementation during business hours (8 am to 5 pm Monday-Friday) from May 2012.\n\n\nRESULTS\nThere were 48 patients treated with tPA in the 8 months after the protocol change. Compared with 85 patients treated in 2011, the median (interquartile range) DNT was reduced from 61 (43-75) minutes to 46 (24-79) minutes (p = 0.040). All of the effect came from the change in the in-hours DNT, down from 43 (33-59) to 25 (19-48) minutes (p = 0.009), whereas the out-of-hours delays remain unchanged, from 67 (55-82) to 62 (44-95) minutes (p = 0.835).\n\n\nCONCLUSIONS\nWe demonstrated rapid transferability of an optimized tPA protocol to a different health care setting. With the cooperation of ambulance, emergency, and stroke teams, we succeeded in the absence of a dedicated neurologic emergency department or electronic patient records, which are features of the Finnish system. The next challenge is providing the same service out-of-hours.",
"affiliations": "From the Departments of Neurology and Medicine (A.M., L.W., M.U., N.Y., B.Y., P.H., S.M.D., B.C.V.C), Nursing (L.W.), and Emergency Department (M.T.), The Royal Melbourne Hospital, University of Melbourne, Parkville, Australia; and Department of Neurology (A.M.), Helsinki University Central Hospital, Finland.",
"authors": "Meretoja|Atte|A|;Weir|Louise|L|;Ugalde|Melissa|M|;Yassi|Nawaf|N|;Yan|Bernard|B|;Hand|Peter|P|;Truesdale|Melinda|M|;Davis|Stephen M|SM|;Campbell|Bruce C V|BC|",
"chemical_list": "D005343:Fibrinolytic Agents; D010959:Tissue Plasminogen Activator",
"country": "United States",
"delete": false,
"doi": "10.1212/WNL.0b013e3182a4a4d2",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0028-3878",
"issue": "81(12)",
"journal": "Neurology",
"keywords": null,
"medline_ta": "Neurology",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D001315:Australia; D004636:Emergency Service, Hospital; D005260:Female; D005343:Fibrinolytic Agents; D006801:Humans; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D020521:Stroke; D015912:Thrombolytic Therapy; D013997:Time Factors; D010959:Tissue Plasminogen Activator; D016896:Treatment Outcome; D014218:Triage",
"nlm_unique_id": "0401060",
"other_id": null,
"pages": "1071-6",
"pmc": null,
"pmid": "23946303",
"pubdate": "2013-09-17",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Helsinki model cut stroke thrombolysis delays to 25 minutes in Melbourne in only 4 months.",
"title_normalized": "helsinki model cut stroke thrombolysis delays to 25 minutes in melbourne in only 4 months"
} | [
{
"companynumb": "AU-ROCHE-1684593",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ALTEPLASE"
},
"drugadditional": null,
"druga... |
{
"abstract": "OBJECTIVE\nParitaprevir/ritonavir/ombitasvir+dasabuvir (PrOD) is a direct-acting antiviral (DAA) approved for the treatment of chronic hepatitis C virus. We report on a probable interaction between PrOD with ribavirin and warfarin.\n\n\nMETHODS\nTwo weeks after the start of PrOD with ribavirin, the patient's international normalized ratio (INR) became subtherapeutic. Eleven weeks into therapy and following a 125% total increase in the weekly warfarin dose, therapeutic INR was achieved. Thirteen days after DAA therapy was completed and discontinued, the patient's INR became critically supratherapeutic.\n\n\nCONCLUSIONS\nPatients on PrOD plus ribavirin with warfarin should have INR followed closely upon initiation and discontinuation of therapy due to a probable drug interaction.",
"affiliations": "PGY2 Pharmacy Resident, Ambulatory Care, VA Maine Healthcare System, Augusta, ME, USA.;Clinical Pharmacy Specialist, Pharmacy Service, VA Maine Healthcare System, Augusta, ME, USA.;Gastroenterology Section, Medical Service, VA Maine Healthcare System, Augusta, ME, USA.;Department of Pharmaceutical Sciences, St. John's University, Queens, NY, USA.;Clinical Pharmacy Specialist, Pharmacy Service, VA North Texas Health Care System, Dallas, TX, USA.",
"authors": "Puglisi|G M|GM|http://orcid.org/0000-0001-7749-0683;Smith|S M|SM|;Jankovich|R D|RD|;Ashby|C R|CR|;Jodlowski|T Z|TZ|",
"chemical_list": "D000813:Anilides; D000925:Anticoagulants; D000998:Antiviral Agents; D002219:Carbamates; D003521:Cyclopropanes; D047029:Lactams, Macrocyclic; D047028:Macrocyclic Compounds; D013449:Sulfonamides; C586094:ombitasvir; D012254:Ribavirin; D014498:Uracil; D014859:Warfarin; D011392:Proline; D015081:2-Naphthylamine; C588260:dasabuvir; D014633:Valine; D019438:Ritonavir; C585405:paritaprevir",
"country": "England",
"delete": false,
"doi": "10.1111/jcpt.12475",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0269-4727",
"issue": "42(1)",
"journal": "Journal of clinical pharmacy and therapeutics",
"keywords": "anticoagulation; drug interaction; paritaprevir/ritonavir/ombitasvir+dasabuvir; ribavirin; vitamin K antagonist; warfarin",
"medline_ta": "J Clin Pharm Ther",
"mesh_terms": "D015081:2-Naphthylamine; D000813:Anilides; D000925:Anticoagulants; D000998:Antiviral Agents; D002219:Carbamates; D003521:Cyclopropanes; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D019698:Hepatitis C, Chronic; D006801:Humans; D047029:Lactams, Macrocyclic; D047028:Macrocyclic Compounds; D008297:Male; D008875:Middle Aged; D011392:Proline; D012254:Ribavirin; D019438:Ritonavir; D013449:Sulfonamides; D014498:Uracil; D014633:Valine; D014859:Warfarin",
"nlm_unique_id": "8704308",
"other_id": null,
"pages": "115-118",
"pmc": null,
"pmid": "27813106",
"pubdate": "2017-02",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Paritaprevir/ritonavir/ombitasvir+dasabuvir plus ribavirin therapy and inhibition of the anticoagulant effect of warfarin: a case report.",
"title_normalized": "paritaprevir ritonavir ombitasvir dasabuvir plus ribavirin therapy and inhibition of the anticoagulant effect of warfarin a case report"
} | [
{
"companynumb": "US-TARO PHARMACEUTICALS USA.,INC-2017SUN00053",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "RIBAVIRIN"
},
"drugadditi... |
{
"abstract": "BACKGROUND\nOcular toxoplasmosis may present in atypical fashion, particularly in immunosuppressed patients, and PCR is an important diagnostic tool especially when differentiating from other infectious causes.\n\n\nMETHODS\nA descriptive case-series demonstrating the use of a novel real-time PCR protocol targeting 529 bp repeat element, a multicopy and highly conserved fragment, in Toxoplasma gondii genome. This was designed and established by our microbiology service following independent, external validation.\n\n\nRESULTS\nThree immunosuppressed patients presenting to a tertiary uveitis referral centre with unilateral, severe, sight-threatening uveitis are described. One patient presented with a large focus of sight-threatening retinitis and occlusive vasculitis while on systemic immunosuppression with azathioprine and adalimumab for Crohn's disease. One patient with chronic lymphocytic leukaemia presented with severe posterior uveitis and total retinal detachment. Finally, the third patient presented with severe retinitis adjacent to the optic nerve and vitritis causing acute vision loss. HIV infection was subsequently identified. In all three cases, the cause of inflammation was not clear from clinical examination alone and prompt treatment was required to prevent permanent vision loss. Intraocular sampling and PCR testing was performed including testing for toxoplasmosis, herpesviruses and syphilis.\n\n\nCONCLUSIONS\nThe novel real-time PCR assay described is more sensitive than those targeting the Toxoplasma B1 gene owing to the higher number of repeats and highly conserved sequence level. This technique can be applied in clinical practice and provides a valuable tool for the rapid diagnosis of ocular toxoplasmosis.",
"affiliations": "Manchester Royal Eye Hospital, Manchester, UK.;Public Health England, Public Health Laboratory, Manchester Medical Microbiology Partnership, Manchester Royal Infirmary, Manchester, UK.;Manchester Royal Eye Hospital, Manchester, UK.",
"authors": "Steeples|Laura R|LR|;Guiver|Malcolm|M|;Jones|Nicholas P|NP|",
"chemical_list": "D017931:DNA Primers; D015342:DNA Probes; D016054:DNA, Protozoan; D004338:Drug Combinations; D007166:Immunosuppressive Agents; D015662:Trimethoprim, Sulfamethoxazole Drug Combination; D017963:Azithromycin; D011239:Prednisolone",
"country": "England",
"delete": false,
"doi": "10.1136/bjophthalmol-2015-306801",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0007-1161",
"issue": "100(2)",
"journal": "The British journal of ophthalmology",
"keywords": "Diagnostic tests/Investigation; Infection; Inflammation; Microbiology",
"medline_ta": "Br J Ophthalmol",
"mesh_terms": "D000368:Aged; D017963:Azithromycin; D020029:Base Pairing; D017931:DNA Primers; D015342:DNA Probes; D016054:DNA, Protozoan; D004338:Drug Combinations; D015822:Eye Infections, Parasitic; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D008297:Male; D008875:Middle Aged; D011239:Prednisolone; D060888:Real-Time Polymerase Chain Reaction; D012091:Repetitive Sequences, Nucleic Acid; D014122:Toxoplasma; D014126:Toxoplasmosis, Ocular; D015662:Trimethoprim, Sulfamethoxazole Drug Combination; D014605:Uveitis; D014822:Vitreous Body",
"nlm_unique_id": "0421041",
"other_id": null,
"pages": "200-3",
"pmc": null,
"pmid": "26174811",
"pubdate": "2016-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Real-time PCR using the 529 bp repeat element for the diagnosis of atypical ocular toxoplasmosis.",
"title_normalized": "real time pcr using the 529 bp repeat element for the diagnosis of atypical ocular toxoplasmosis"
} | [
{
"companynumb": "GB-ABBVIE-16P-167-1559615-00",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "AZATHIOPRINE"
},
"drugadditional": null,
... |
{
"abstract": "Although HIV infection can mimic the manifestations of various autoimmune disorders, the coexistence of HIV and systemic lupus erythematosus (SLE) has been rarely reported. The exact impact of HIV on SLE and vice versa is unclear. We report an HIV-seropositive female on highly active antiretroviral therapy presenting with features of SLE. Herein, an attempt has been made to discuss the various complex clinical and therapeutic implications along with the influence on disease course and prognosis.",
"affiliations": "Department of Skin and VD, BJGMC, Pune, Maharashtra, India.;Department of Skin and VD, BJGMC, Pune, Maharashtra, India.;Department of Skin and VD, BJGMC, Pune, Maharashtra, India.;Department of Skin and VD, BJGMC, Pune, Maharashtra, India.;Department of Skin and VD, BJGMC, Pune, Maharashtra, India.;Department of Skin and VD, BJGMC, Pune, Maharashtra, India.",
"authors": "Belgaumkar|Vasudha A|VA|;Chavan|Ravindranath B|RB|;Suryataley|Prernaa R|PR|;Salunke|Aarti S|AS|;Patil|Pallavi P|PP|;Borade|Sandhya M|SM|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.4103/ijstd.IJSTD_26_18",
"fulltext": "\n==== Front\nIndian J Sex Transm Dis AIDSIndian J Sex Transm Dis AIDSIJSTDIndian Journal of Sexually Transmitted Diseases and AIDS2589-05572589-0565Medknow Publications & Media Pvt Ltd India IJSTD-40-6410.4103/ijstd.IJSTD_26_18Case ReportSystemic lupus erythematosus in HIV: An insight into clinical implications and management Belgaumkar Vasudha A. Chavan Ravindranath B. Suryataley Prernaa R. Salunke Aarti S. Patil Pallavi P. Borade Sandhya M. Department of Skin and VD, BJGMC, Pune, Maharashtra, IndiaAddress for correspondence: Dr. Ravindranath B. Chavan, Department of Skin and VD, BJGMC, Pune, Maharashtra, India. E-mail: drravindranathchavan@gmail.comJan-Jun 2019 40 1 64 66 Copyright: © 2019 Indian Journal of Sexually Transmitted Diseases and AIDS2019This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.Although HIV infection can mimic the manifestations of various autoimmune disorders, the coexistence of HIV and systemic lupus erythematosus (SLE) has been rarely reported. The exact impact of HIV on SLE and vice versa is unclear. We report an HIV-seropositive female on highly active antiretroviral therapy presenting with features of SLE. Herein, an attempt has been made to discuss the various complex clinical and therapeutic implications along with the influence on disease course and prognosis.\n\nKey words:\nAIDSautoimmune diseasesimmune reconstitution inflammatory syndromelupus erythematosus\n==== Body\nINTRODUCTION\nSystemic lupus erythematosus (SLE) can affect persons irrespective of age or gender with predilection for females of child-bearing age.[1] It is an autoimmune multisystem disorder causing microvascular inflammation with generation of numerous antinuclear autoantibodies (ANA).[2] The occurrence of a particular autoimmune disease in an HIV-seropositive individual depends on the degree of immunosuppression.[3] There is limited literature elaborating the coexistence and interaction of HIV and SLE.\n\nCASE REPORT\nA 47-year-old female presented with erythematous-violaceous scaly plaques on the malar and other photoexposed areas [Figures 1 and 2] with bulla over the left arm [Figure 3] and buccal erosions for 1 month with fatigue, anorexia, and weight loss. She was a known HIV seropositive (baseline CD4 706) on TLE (tenofovir 300 mg, lamivudine 300 mg, and efavirenz [600 mg])-based antiretroviral therapy (ART) for 6 months. General examination revealed pallor. Systemic and musculoskeletal examination was unremarkable. Differential diagnoses of photoallergic dermatitis, drug-induced lichenoid eruption, polymorphic light eruption, lupus erythematosus, and immune reconstitution inflammatory syndrome (IRIS) were considered. She was anemic (hemoglobin – 7.8 g%) with leukopenia (3400 cells/ml) and thrombocytopenia, elevated erythrocyte sedimentation rate, and CD4 count 309 cells/dl. 24-h urinary protein was normal. Venereal Disease Research Laboratory titer was negative. Radiological investigations were noncontributory. ANA was positive (titer: 3.08). Skin histopathology was consistent with lupus erythematosus [Figure 4]. A final diagnosis of SLE was reached on fulfillment of Systemic Lupus International Collaborating Clinics Criteria (two clinical, one laboratory, and immunological with characteristic histopathology).\n\nFigure 1 Clinical picture showing malar rash\n\nFigure 2 Clinical picture showing hyperpigmented atrophic plaques over extensors aspect of the upper limb\n\nFigure 3 Bullous lesion over the left arm\n\nFigure 4 Histopathology showing hyperkeratosis, irregular acanthosis, focal hydropic degeneration in the basal layer. Dermal perivascular mononuclear cell infiltrate with fibrinoid deposits\n\nShe was restarted on highly active ART (HAART) and prednisolone 1 mg/kg (tapered over 6 weeks) with hydroxychloroquine 400 mg/day. Strict photoprotection was advised with sunscreen lotion (SPF 50) and fluocinolone acetonide cream. The patient responded with complete resolution of all cutaneous lesions within 6–8 weeks with maintenance on tablet 200 mg/day and sunscreen. She is currently under stringent monitoring.\n\nDISCUSSION\nAlthough HIV infection is often associated with several autoimmune diseases, its coexistence with SLE is uncommon.[4] Retroviral infections including HIV have been proposed as etiologies in SLE and Sjogren's syndrome due to antibodies to retroviral proteins or viable/dead organisms. HIV causes a state of immunodeficiency and is responsible for several serum abnormalities. The resultant immune dysregulation facilitates the development of autoimmune diseases.[5]\n\nAutoimmunity in HIV patients may present as IRIS or late manifestations of HIV. ART initiation leads to the recovery of CD4+ T-cells with restoration of protective immunity and reduced occurrence of opportunistic infections. However, in a subset of patients, dysregulated immune response leads to the phenomenon of IRIS.[6] Although our patient developed inflammatory rash within 5 months of starting ART, evidence of immune restoration was lacking. Thus, only one major criterion was fulfilled, thereby precluding IRIS.\n\nDiagnosis of SLE in HIV may pose difficulty as they share common features such as photosensitivity, oral ulceration, sicca syndrome, arthritis, fever, hypergammaglobulinemia, cytopenias, neuropathies, and ANA positivity.[7] It is still uncertain whether autoimmunity in HIV-positive patients has any bearing on course or prognosis. Although generally HIV-related immunosuppression improves LE symptoms,[8] ART may trigger flares subsequent to increase in CD4 count.\n\nWhile some authors have paradoxically suggested that the presence of autoimmune diseases like SLE may be protective for HIV,[6] others believe that like HIV, SLE also affects the immune system, compromising the ability to combat infection.[7] Consequently, the coexistence may predispose to opportunistic infections.\n\nTreatment of SLE in an HIV-infected individual is more challenging, as the usual armamentarium may potentially worsen immunosuppression. HAART should be resumed or continued unless ART toxicity is the main differential. Hydroxychloroquine/chloroquine has immunomodulatory and anti-inflammatory properties useful in T-cell-mediated immune diseases such as SLE and steroid-resistant graft versus host disease. These antimalarials interfere with cell activation pathways (major histocompatibility complex Class II antigen presentation and T-cell receptor-mediated intracellular calcium signaling). They demonstrate anti-HIV properties (in vitro and in vivo) by inhibiting posttranslational modification of gp120. Hydroxychloroquine is a safe, cost-effective oral once-daily treatment option for HIV–SLE coexistence.[9]\n\nThis case emphasizes the importance of serological screening for LE in HIV patients with a photosensitive rash. HIV has now probably replaced syphilis as the great imitator which justifies screening for HIV while evaluating suspected autoimmune diseases.[5]\n\nDeclaration of patient consent\nThe authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given her consent for her images and other clinical information to be reported in the journal. The patient understands that names and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n==== Refs\nREFERENCES\n1 D'Cruz DP Khamashta MA Hughes GR Systemic lupus erythematosus Lancet 2007 369 587 96 17307106 \n2 Cojocaru M Cojocaru IM Silosi I Vrabie CD Manifestations of systemic lupus erythematosus Maedica (Buchar) 2011 6 330 6 22879850 \n3 Roszkiewicz J Smolewska E Kaleidoscope of autoimmune diseases in HIV infection Rheumatol Int 2016 36 1481 91 27544391 \n4 Calza L Manfredi R Colangeli V D'Antuono A Passarini B Chiodo F Systemic and discoid lupus erythematosus in HIV-infected patients treated with highly active antiretroviral therapy Int J STD AIDS 2003 14 356 9 12803945 \n5 Kaliyadan F HIV and lupus erythematosus: A diagnostic dilemma Indian J Dermatol 2008 53 80 2 19881993 \n6 Sharma SK Soneja M HIV and immune reconstitution inflammatory syndrome (IRIS) Indian J Med Res 2011 134 866 77 22310819 \n7 Virot E Duclos A Adelaide L Miailhes P Hot A Ferry T Autoimmune diseases and HIV infection: A cross-sectional study Medicine (Baltimore) 2017 96 e5769 28121924 \n8 Zandman-Goddard G Shoefield Y HIV and autoimmunity review article Autoimmune Rev 2002 1 329 37 \n9 Paton NI Goodall RL Dunn DT Franzen S Collaco-Moraes Y Gazzard BG Effects of hydroxychloroquine on immune activation and disease progression among HIV-infected patients not receiving antiretroviral therapy: A randomized controlled trial JAMA 2012 308 353 61 22820788\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "2589-0557",
"issue": "40(1)",
"journal": "Indian journal of sexually transmitted diseases and AIDS",
"keywords": "AIDS; autoimmune diseases; immune reconstitution inflammatory syndrome; lupus erythematosus",
"medline_ta": "Indian J Sex Transm Dis AIDS",
"mesh_terms": null,
"nlm_unique_id": "101730896",
"other_id": null,
"pages": "64-66",
"pmc": null,
"pmid": "31143863",
"pubdate": "2019",
"publication_types": "D002363:Case Reports",
"references": "12803945;12848988;17307106;19881993;22310819;22820788;22879850;27544391;28121924",
"title": "Systemic lupus erythematosus in HIV: An insight into clinical implications and management.",
"title_normalized": "systemic lupus erythematosus in hiv an insight into clinical implications and management"
} | [
{
"companynumb": "IN-APPCO PHARMA LLC-2118328",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LAMIVUDINE"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nA delay of 4 to 6 weeks after a suspected anaphylactic reaction has commonly been recommended before performing skin testing. However, sometimes surgery cannot be delayed, and investigation must be done earlier. Recent recommendations suggest that skin testing can be performed immediately after a reaction.\n\n\nMETHODS\nWe describe three cases in which skin testing was performed within 3 weeks after the suspected anaphylactic reaction. A literature review was undertaken to evaluate cases where skin testing was performed within 3 weeks of a suspected anaphylactic reaction during anaesthesia.\n\n\nRESULTS\nReview of the literature did not give a definite answer to the optimal timing of skin testing after a suspected anaphylactic reaction during anaesthesia.\n\n\nCONCLUSIONS\nOnly positive skin tests can be taken into account, and there is little safety data to provide confidence in early skin testing. A protocol of how to act if urgent surgery is necessary is suggested.",
"affiliations": "Department of Anaesthesia, AZ Turnhout, Campus Sint-Elisabeth, Belgium. filiep.soetens@skynet.be",
"authors": "Soetens|F|F|;Rose|M|M|;Fisher|M|M|",
"chemical_list": "D000777:Anesthetics; D003473:Neuromuscular Nondepolarizing Agents",
"country": "England",
"delete": false,
"doi": "10.1111/j.1399-6576.2011.02643.x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0001-5172",
"issue": "56(8)",
"journal": "Acta anaesthesiologica Scandinavica",
"keywords": null,
"medline_ta": "Acta Anaesthesiol Scand",
"mesh_terms": "D000368:Aged; D000707:Anaphylaxis; D000758:Anesthesia; D000777:Anesthetics; D019645:Arthroplasty, Replacement, Knee; D002277:Carcinoma; D002408:Catheters, Indwelling; D003082:Colectomy; D004342:Drug Hypersensitivity; D006801:Humans; D010535:Laparoscopy; D008297:Male; D008479:Mediastinal Neoplasms; D003473:Neuromuscular Nondepolarizing Agents; D011237:Predictive Value of Tests; D012086:Reoperation; D012882:Skin Tests; D013997:Time Factors",
"nlm_unique_id": "0370270",
"other_id": null,
"pages": "1042-6",
"pmc": null,
"pmid": "22313451",
"pubdate": "2012-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Timing of skin testing after a suspected anaphylactic reaction during anaesthesia.",
"title_normalized": "timing of skin testing after a suspected anaphylactic reaction during anaesthesia"
} | [
{
"companynumb": "BE-RANBAXY-2012R1-61200",
"fulfillexpeditecriteria": "1",
"occurcountry": "BE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ROCURONIUM BROMIDE"
},
"drugadditional": null,
... |
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