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"abstract": "BACKGROUND\nTumoral calcinosis is a disorder of phosphate metabolism characterized by ectopic calcification around major joints. Surgery is the current treatment of choice, but a suboptimal choice in recurrent and multicentric lesions.\n\n\nOBJECTIVE\nTo evaluate the efficacy of bisphosphonates for the management of tumoral calcinosis on optimized medical treatment.\n\n\nMETHODS\nThe study was done in the endocrine department of a tertiary care hospital in South India. We prospectively studied two patients with recurrent tumoral calcinosis who had failed therapy with phosphate lowering measures.\n\n\nMETHODS\nAfter informed consent, we treated both patients with standard age adjusted doses of bisphosphonates for 18 months. The response was assessed by X ray and whole body 99mTc-methylene diphosphonate bone scan at the beginning of therapy and at the end of 1 year. We also estimated serum phosphate levels and urinary phosphate to document serial changes.\n\n\nRESULTS\nTwo patients (aged 19 and 5 years) with recurrent idiopathic hyperphosphatemic tumoral calcinosis, following surgery were studied. Both patients had failed therapy with conventional medical management - low phosphate diet and phosphate binders. They had restriction of joint mobility. Both were given standard doses of oral alendronate and parenteral pamidronate respectively for more than a year, along with phosphate lowering measures. At the end of 1 year, one of the patients had more than 95% and 90% reduction in the size of the lesions in right and left shoulder joints respectively with total improvement in range of motion. In contrast, the other patient (5-year-old) had shown no improvement, despite continuing to maintain normophosphatemia following treatment.\n\n\nCONCLUSIONS\nBisphosphonate therapy in tumoral calcinosis is associated with lesion resolution and may be used as a viable alternative to surgery, especially in cases with multicentric recurrence or treatment failure to other drugs.",
"affiliations": "Department of Endocrinology, Jawaharlal Institute of Post Graduate Medical Education and Research, Puducherry, India.;Department of Endocrinology, Jawaharlal Institute of Post Graduate Medical Education and Research, Puducherry, India.;Department of Endocrinology, Jawaharlal Institute of Post Graduate Medical Education and Research, Puducherry, India.;Department of Endocrinology, Jawaharlal Institute of Post Graduate Medical Education and Research, Puducherry, India.;Department of Nuclear Medicine, Jawaharlal Institute of Post Graduate Medical Education and Research, Puducherry, India.",
"authors": "Balachandran|Karthik|K|;Kamalanathan|Sadishkumar|S|;Sahoo|Jaya Prakash|JP|;Das|Ashok Kumar|AK|;Halanaik|Dhanapathi|D|",
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"doi": "10.4103/2230-8210.137511",
"fulltext": "\n==== Front\nIndian J Endocrinol MetabIndian J Endocrinol MetabIJEMIndian Journal of Endocrinology and Metabolism2230-82102230-9500Medknow Publications & Media Pvt Ltd India IJEM-18-52110.4103/2230-8210.137511Original ArticleDifferential response of idiopathic sporadic tumoral calcinosis to bisphosphonates Balachandran Karthik Kamalanathan Sadishkumar Sahoo Jaya Prakash Das Ashok Kumar Halanaik Dhanapathi 1Department of Endocrinology, Jawaharlal Institute of Post Graduate Medical Education and Research, Puducherry, India1 Department of Nuclear Medicine, Jawaharlal Institute of Post Graduate Medical Education and Research, Puducherry, IndiaCorresponding Author: Dr. Sadishkumar Kamalanathan, Endocrinology, 557, Fourth floor, Inpatient Division, Superspecialty Block, Dhanvantri Nagar, Jawaharlal Institute of Post-graduate Medical Education and Research, Puducherry - 605 006, India. E-mail: sadishkk@gmail.comJul-Aug 2014 18 4 521 525 Copyright: © Indian Journal of Endocrinology and Metabolism2014This 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.Context:\nTumoral calcinosis is a disorder of phosphate metabolism characterized by ectopic calcification around major joints. Surgery is the current treatment of choice, but a suboptimal choice in recurrent and multicentric lesions.\n\nAims:\nTo evaluate the efficacy of bisphosphonates for the management of tumoral calcinosis on optimized medical treatment.\n\nSettings and Design:\nThe study was done in the endocrine department of a tertiary care hospital in South India. We prospectively studied two patients with recurrent tumoral calcinosis who had failed therapy with phosphate lowering measures.\n\nMaterials and Methods:\nAfter informed consent, we treated both patients with standard age adjusted doses of bisphosphonates for 18 months. The response was assessed by X ray and whole body 99mTc-methylene diphosphonate bone scan at the beginning of therapy and at the end of 1 year. We also estimated serum phosphate levels and urinary phosphate to document serial changes.\n\nResults:\nTwo patients (aged 19 and 5 years) with recurrent idiopathic hyperphosphatemic tumoral calcinosis, following surgery were studied. Both patients had failed therapy with conventional medical management − low phosphate diet and phosphate binders. They had restriction of joint mobility. Both were given standard doses of oral alendronate and parenteral pamidronate respectively for more than a year, along with phosphate lowering measures. At the end of 1 year, one of the patients had more than 95% and 90% reduction in the size of the lesions in right and left shoulder joints respectively with total improvement in range of motion. In contrast, the other patient (5-year-old) had shown no improvement, despite continuing to maintain normophosphatemia following treatment.\n\nConclusions:\nBisphosphonate therapy in tumoral calcinosis is associated with lesion resolution and may be used as a viable alternative to surgery, especially in cases with multicentric recurrence or treatment failure to other drugs.\n\nBisphosphonatesfibroblast growth factor 23hyperphosphatemiatumoral calcinosis\n==== Body\nINTRODUCTION\nTumoral calcinosis is a rare genetic disorder of phosphate homeostasis characterized by metastatic calcification in the subcutaneous tissue. The common sites include elbow, shoulder, hip and ankles. Pain is unusual, but large masses can lead to restriction of range of motion of the concerned joint. The primary driving force for calcification is hyperphosphatemia, which, in the setting of normal calcium levels, leads to deposition of amorphous hydroxyapatite. The hyperphosphatemia is attributed to reduced bioactive fibroblast growth factor23 (FGF23) causing increased phosphate reabsorption. Standard management includes dietary restriction of phosphate and surgical resection of the calcified mass. However, recurrence of the tumor is the rule rather than exception.\n\nMedical therapy of tumoral calcinosis has largely focused on control of hyperphosphatemia. Several agents like phosphate binders, acetazolamide, and calcitonin have been tried with varied results. Bisphosphonates show promise as a therapeutic modality in the management of this rare disorder as it has been shown to induce remission even in normophosphatemic variants. We wondered if medical management of the recurrent lesions with bisphosphonates would lead to resolution of the lesion. Our current lacuna in understanding the pathogenesis of tumoral calcinosis limits designing of an effective therapeutic regimen.\n\nMATERIALS AND METHODS\nTwo cases of sporadic tumoral calcinosis which recurred after surgical therapy were tried on medical treatment with bisphosphonates in the absence of better alternative and for logistic reasons.\n\nCase 1\nA 19-year-old male presented with swelling in the left thigh for 3 months. The swelling was large and had shown relatively rapid growth. It had variegated consistency and the skin over the swelling was stretched. On evaluation, he had shown hyperphosphatemia as the sole metabolic abnormality which was missed by the treating surgeon. The swelling was subsequently excised and its biopsy showed tumoral calcinosis. The patient was lost to follow-up. One year later, the patient presented to our department with swelling involving bilateral shoulders with decreased range of motion and discomfort. On examination, he had globular swellings involving bilateral shoulders with winging of right scapula and drooping of the corresponding shoulder. Fluffy calcification in bilateral shoulder joints was seen in X ray examination. Computed tomography (CT) brain revealed calcified lesion of right temporal lobe. CT shoulder was done for further delineation of the lesion which showed infiltration into the joint space. Biochemical evaluation showed a normal calcium level, increased serum phosphate, and normal alkaline phosphatase. Parathormone was suppressed and calcitriol was inappropriately normal. C-terminal FGF23 level was grossly elevated [Table 1]. Bone scan done showed increased tracer activity associated with areas of bilateral shoulder lesions [Figure 1a and c]. In view of the above features, a diagnosis of tumoral calcinosis was made.\n\nTable 1 Laboratory and clinical values of patients at the time of presentation and after 1 year of bisphosphonate therapy\n\nFigure 1 99mTc-methylene diphosphonate whole body bone scan (a and b with anterior and posterior views) and their respective single-photon emission computed tomography (SPECT). Computed tomography (CT) fused (c and d) images before and after treatment. a and c are pre treatment images shows intense uptake in bilateral shoulder joints with evidence of shoulder joints infiltration on SPECT. CT fused images. b and d are posttreatment images showing significant reduction of activity from both shoulder joints\n\nSince the patient had presented with recurrence and the calcified mass had breached joint capsule, the risk of poor surgical outcome was deemed high. Hence, medical management was considered. He was initially prescribed low phosphate diet with phosphate binder, lanthanum carbonate 250 mg thrice daily for 6 months. Unfortunately, he had poor response to the above regimen. Hence, it was decided to try bisphosphonate therapy in this patient. He was started on alendronate 70 mg weekly.\n\nCase 2\nA 5-year-old female child presented to us with recurrent swelling in the right gluteal region after surgery for a similar swelling in the same site 1 year back. The swelling had increased in size over the past few months [Figure 2a and c] and now was causing severe pain and restriction of movement of the hip joint. She also had loss of appetite and loss of weight. She had been found to have hyperphosphatemia during evaluation of previous swelling prior to surgery.\n\nFigure 2 99mTc- methylene diphosphonate whole body bone scan (a and b with anterior and posterior views) and their respective single-photon emission computed tomography (SPECT). Computed tomography (CT) fused (c and d) images before and after treatment. a and c are pretreatment images shows intense uptake in right gluteal with large calcified soft tissue mass on SPECT. CT. b and d are posttreatment images showing significant increase in size of calcified soft tissue mass with increased tracer uptake in right gluteal region\n\nThe biopsy was reported as tumoral calcinosis and the patient was lost to follow-up. During the current admission, the patient was noted to have hyperphosphatemia and normal calcium levels with suppressed parathyroid hormone (PTH) [Table 1]. Calcitriol levels were inappropriately normal. Considering the age and size of the lesion, she was initiated on intravenous pamidronate therapy. Like the previous patient, she was also on regular medication with lanthanum carbonate 250 mg thrice daily and low phosphate diet. After a transient initial improvement, the lesion increased in size. Acetazolamide was added to her regimen, but it had no benefit.\n\nRESULTS\nCase 1\nOn follow-up after 1 year, the patient had shown marked improvement with reduction in size of the lesion by 95% on the right side and 90% on the left side [Figure 1b and d]. The range of movements in shoulder joint was normal. The patient continues to improve on this regimen and is currently continuing bisphosphonates with low phosphate diet.\n\nCase 2\nDuring follow-up, her lesion had increased in size [Figure 2b and d], resulting in pain and severe restriction of movement in the hip joint. Surgical option was ruled out as the removal of the entire lesion would compromise muscle mass so much that the patient would not be able to walk postoperatively. Following failure of intravenous pamidronate, she was considered for more potent intravenous bisphosphonate, zoledronic acid. After informed consent, she was given injection zoledronic acid 1 mg intravenous. Similar to the first attempt, she had a mild initial regression in size after which there is no change in size of swelling. The patient is on regular follow-up and she is on therapy with low phosphate diet, lanthanum, and acetazolamide.\n\nDISCUSSION\nIdiopathic tumoral calcinosis is a rare genetically heterogeneous disorder of phosphate metabolism, resulting in ectopic calcification around the joints or in blood vessels. It is diagnosed after ruling out family history of tumoral calcinosis and secondary causes for the same like chronic kidney disease, hyperparathyroidism, and hypervitaminosis D as was done in our cases. The disorder can be hyperphosphatemic or normophosphatemic. The deranged phosphate metabolism is due reduced FGF23 bioactivity, leading to increased renal resorption of phosphate. This can occur due to mutation of FGF23 itself, GALNT3 (an enzyme involved in O-glycosylation and stabilization of wild type FGF23), or α klotho (the cofactor for FGF23 action).[1]\n\nSlavin et al., proposed the following theory for the pathogenesis of this disorder. Tumoral calcinosis is initiated by periarticular microtrauma in the setting of hyperphosphatemia. The first line of defence involves infiltration by histiocytes, attempting an adventitious bursa formation. The purpose is to shield the joint from further trauma. However, the continuing hyperphosphatemia leads to apoptosis of the histiocytes, causing release of hydroxyapatite. Thus, the reparative response is ineffective, as the compartments are obliterated by continued deposition of hydroxyapatite. The next line of defense involves multinucleate giant cells which try to resorb the calcified lesion. As the lesion lacks the normal bony scaffolding necessary for the action of these “osteoclast- like” giant cells, resorption of calcification fails. Furthermore, the calcific crystals are coated with chymotrypsin and the extrusion of bicarbonate by the giant cells creates an alkaline milieu, inhibiting resolution of lesion. This leads to continued growth of the lesion.[2] Therefore, tumoral calcinosis does not follow the regular schema of metastatic or dystrophic calcification.\n\nThe treatment of tumoral calcinosis has traditionally been complete surgical excision. However, recurrence is the rule rather than exception.[3] The option for medical treatment of this disorder has never been formally evaluated in any clinical trial due to the rarity and heterogeneity of this disorder. Indeed, the definition of successful therapeutic outcome itself is not clear.\n\nCurrently, used medical therapy focuses on the reduction in phosphate levels with the hope that resolution of hyperphosphatemia will lead to reduction in size of the lesion or at least eliminate the cardiovascular risk associated with hyperphosphatemia, as it can lead to vascular calcification. However, the response is variable and this approach does not address the normophosphatemic variant of tumoral calcinosis. The approach to medical management of hyperphosphatemia is twofold-limiting absorption (phosphate-restricted diet,[4] phosphate binders-lanthanum, sevelamer[5]) and increasing renal clearance (acetazolamide,[6] calcitonin[7]). Dialysis with low phosphate containing dialysate and parathyroidectomy for severe secondary hyperparathyroidism has also been tried.[8] Bisphosphonates have recently been reported to be helpful in management. Sodium thiosulphate is another topical option.[9]\n\nFor any drug to be useful in tumoral calcinosis, it must not only inhibit formation of new hydroxyapatite crystals, but also dissolve the existing ones. Bisphosphonates act on the osteoclasts and osteoclast-like cells, which are implicated in the pathogenesis of tumoral calcinosis. This results in the alteration of biochemical and cellular milieu leading to reduced crystal formation and aggregation.[10] The ability of bisphosphonates to promote dissolution of existing crystals[11] makes them an attractive option in management of tumoral calcinosis.\n\nInitial use of bisphosphonates (as long as 3 decades back) was met with failure in cases of familial or idiopathic tumoral calcinosis.[1213] The first successful use of bisphosphonates in idiopathic tumoral calcinosis was shown by Jubbin et al.,[10] who reported complete resolution of the lesion in a patient treated with oral alendronate for 18 months. However, the patient did not have hyperphosphatemia and the size of the lesion was small, unlike our cases where the lesion was very large. Both of our patients had recurrent tumoral calcinosis with poor response to conventional therapy. The two cases differ only in age, gender, and size of the recurrent lesion. Their biochemical profiles were identical except for the degree of serum C-terminal FGF23 level elevation. Both of our cases have decreased serum PTH levels and inappropriately normal calcitriol levels. Albeit atypical, this has been reported in literature before.[14]\n\nC-terminal FGF23 levels can be elevated in tumoral calcinosis due to mutations in FGF23, GALNT3, or α klotho. The elevation of C terminal FGF23 is the common denominator of all three mutations. Elevated C-terminal fragments with low intact FGF23 is seen in FGF23 and GALNT3 mutation, while both intact FGF23 and C-terminal fragments are increased in α klotho mutation, which leads to FGF23 resistance.[15] As we could not estimate intact FGF23 level, it was not possible to hypothesize the causative mutation behind our cases.\n\nBoth had raised C-terminal FGF23 levels demonstrating the presence in circulation of inactive fragments. This possibly reflects a compensatory attempt at increasing production of FGF23 as a response to raised phosphate levels.[3] The fact that control of hyperphosphatemia was achieved in both cases indicates that phosphate (and hence calcium phosphate product) is not the only driver of ectopic calcification and that additional mechanisms probably exist. The difference in size is unlikely to be an explanation for the lack of response as very large lesions have been noted to undergo remission with oral therapy and reduction in phosphate levels.[5]\n\nThe reasons for lack of response could be the short duration of therapy, the possibility of some patients being “slow responders.” Since we could not do genetic analysis of these patients, the possibility of a mutation resulting in a more severe phenotype cannot be excluded. This is more likely due to the fact that the patient who did not respond presented at a much younger age than what is typical for tumoral calcinosis. However, this does not explain the apparent “uncoupling” of phosphate metabolism and therapeutic response. This also questions the assumption that calcium phosphate product is the principal determinant in cases of ectopic calcification.\n\nThe singular advantage of bisphosphonate therapy over the other methods is its possible use in normophosphatemic variant of tumoral calcinosis.[10] The use of parenteral bisphosphonates would lead to better compliance and obviate the need for daily treatment. Unfortunately, the biochemical heterogeneity and rarity of the disorder precludes the possibility of well-designed clinical trials which can throw light on this question. The wider availability and utilization of molecular techniques would likely result in better design of treatment regimens in future. Until recombinant FGF23 or its agonist is available, a prudent therapeutic regimen would include a multipronged approach for correction of hyperphosphatemia and concomitant use of bisphosphonates. This is especially important in patients with recurrence, to whom, it will provide a much needed alternative to surgery.\n\nSource of Support: Nil\n\nConflict of Interest: None declared\n==== Refs\nREFERENCES\n1 Fukumoto S Physiological regulation and disorders of phosphate metabolism--pivotal role of fibroblast growth factor 23 Intern Med 2008 47 337 43 18310961 \n2 Slavin RE Wen J Barmada A Tumoral calcinosis--a pathogenetic overview: A histological and ultrastructural study with a report of two new cases, one in infancy Int J Surg Pathol 2012 20 462 73 22614164 \n3 Farrow EG Imel EA White KE Miscellaneous non-inflammatory musculoskeletal conditions. Hyperphosphatemic familial tumoral calcinosis (FGF23, GALNT3 and αKlotho) Best Pract Res Clin Rheumatol 2011 25 735 47 22142751 \n4 Alkhooly AZ Medical treatment for tumoral calcinosis with eight years of follow-up: A report of four cases J Orthop Surg (Hong Kong) 2009 17 379 82 20065385 \n5 Garringer HJ Fisher C Larsson TE Davis SI Koller DL Cullen MJ The role of mutant UDP-N-acetyl-alpha-D-galactosamine-polypeptide N-acetylgalactosaminyltransferase 3 in regulating serum intact fibroblast growth factor 23 and matrix extracellular phosphoglycoprotein in heritable tumoral calcinosis J Clin Endocrinol Metab 2006 91 4037 42 16868048 \n6 Yamaguchi T Sugimoto T Imai Y Fukase M Fujita T Chihara K Successful treatment of hyperphosphatemic tumoral calcinosis with long-term acetazolamide Bone 1995 16 4 Suppl 247 50S 7756054 \n7 Candrina R Cerudelli B Braga V Salvi A Effects of the acute subcutaneous administration of synthetic salmon calcitonin in tumoral calcinosis J Endocrinol Invest 1989 12 55 7 2745932 \n8 Thakur A Hines OJ Thakur V Gordon HE Tumoral calcinosis regression after subtotal parathyroidectomy: A case presentation and review of the literature Surgery 1999 126 95 8 10418601 \n9 Ratsimbazafy V Bahans C Guigonis V Dramatic diminution of a large calcification treated with topical sodium thiosulfate Arthritis Rheum 2012 64 3826 22806424 \n10 Jacob JJ Mathew K Thomas N Idiopathic sporadic tumoral calcinosis of the hip: Successful oral bisphosphonate therapy Endocrine Pract 2007 13 182 6 \n11 Russell RG Bisphosphonates: The first 40 years Bone 2011 49 2 19 21555003 \n12 Hug I Gunçaga J Tumoral calcinosis with sedimentation sign Br J Radiol 1974 47 734 6 4433987 \n13 Leicht E Tkocz HJ Seeliger H Lauffenburger T Haas HG Tumoral calcinosis. Observations during six years Horm Metab Res 1980 12 269 73 6773868 \n14 Feldman D Vitamin D, parathyroid hormone, and calcium: A complex regulatory network Am J Med 1999 107 637 9 10625035 \n15 Ichikawa S Imel EA Sorenson AH Severe R Knudson P Harris GJ Tumoral calcinosis presenting with eyelid calcifications due to novel missense mutations in the glycosyl transferase domain of the GALNT3 gene J Clin Endocrinol Metabol 2006 91 4472 5\n\n",
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"keywords": "Bisphosphonates; fibroblast growth factor 23; hyperphosphatemia; tumoral calcinosis",
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"title": "Differential response of idiopathic sporadic tumoral calcinosis to bisphosphonates.",
"title_normalized": "differential response of idiopathic sporadic tumoral calcinosis to bisphosphonates"
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"abstract": "We report the case of a 76-year-old male patient with a history of coronary artery bypass graft surgery presented with a large pseudoaneurysm emerging from a previously occluded saphenous bypass graft (SVG). A largely contained hematoma is seen in the mediastinum on computed tomography angiography (CTA) of the chest. Flow was seen from the ascending aorta into the pseudoaneurysm through the aorto-ostial opening of the bypass graft. Closure of the aorto-ostial origin of the graft was performed using the AMPLATZER muscular ventricular septal defect (VSD) occluder (St Jude's Medical, St. Paul, MN) with immediate interruption of flow into the graft and the pseudoaneurysm. A repeat CTA of the ascending aorta at 6 months postprocedure continued to confirm an optimal positioning of the occluder with no flow into the pseudoaneurysm. This case offers an endovascular alternative to close the aorto-ostial opening of a saphenous bypass graft in the setting of a rare but potentially life-threatening SVG pseudoaneurysm.",
"affiliations": "Midwest Cardiovascular Research Foundation, Davenport, IA.;American University of Beirut, Beirut, Lebanon.;Cardiovascular Medicine, PC, Davenport, IA.;Genesis Medical Center, Davenport, IA.",
"authors": "Shammas|Nicolas W|NW|;Chammas|Majid Z|MZ|;Robken|Jon|J|;Geiss|Dale|D|",
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"journal": "The International journal of angiology : official publication of the International College of Angiology, Inc",
"keywords": "AMPLATZER occluder; aneurysm; ascending aorta; pseudoaneurysm; saphenous bypass graft",
"medline_ta": "Int J Angiol",
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"title": "Percutaneous Closure of the Aorto-Ostial Origin of a Coronary Artery Saphenous Bypass Graft with a Large Pseudoaneurysm Using the AMPLATZER Muscular Ventricular Septal Defect Occluder.",
"title_normalized": "percutaneous closure of the aorto ostial origin of a coronary artery saphenous bypass graft with a large pseudoaneurysm using the amplatzer muscular ventricular septal defect occluder"
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"abstract": "This Japanese, multicenter, randomized, double-blind trial, evaluating the efficacy and safety of blonanserin compared with haloperidol in patients with schizophrenia, was previously published by Murasaki in the Japanese language. In this article, we present the results of the trial based on full analysis dataset instead of per protocol dataset formerly reported and discuss the findings in light of the latest knowledge of pharmacological treatment for schizophrenia.\n\n\n\nA total of 265 patients were randomized to receive blonanserin (8 to 24 mg/d) or haloperidol (4 to 12 mg/d) twice daily for 8 weeks. Efficacy assessments included the Clinical Global Impressions-Improvement (CGI-I) and the Positive and Negative Syndrome Scale (PANSS).\n\n\n\nBlonanserin was not inferior to haloperidol with a margin of 10% with respect to the improvement rate on CGI-I at end of study (60.5% vs 50.0%, P < 0.001). The decrease in the PANSS total score did not differ between the drugs (-10.3 vs -7.1). For the PANSS negative symptom score, the decrease was significantly greater with blonanserin than with haloperidol (P = 0.006). Blonanserin was well tolerated. The incidence of adverse events was similar for the two drugs. Extrapyramidal adverse events, sedation, hypotension, and prolactin increase were rarer with blonanserin than with haloperidol. No clinically important weight gain was observed.\n\n\n\nBlonanserin is as effective as haloperidol for the treatment of schizophrenia. Blonanserin is more effective for negative symptoms with a lower risk of extrapyramidal symptoms compared with haloperidol.",
"affiliations": "Leonard M. Miller Professor of Psychiatry and Behavioral Sciences, University of Miami Miller School of Medicine, Miami, Florida.;Medical Affairs, Sumitomo Dainippon Pharma Co., Ltd, Tokyo, Japan.;Institute of CNS Pharmacology, Kanagawa, Japan.",
"authors": "Harvey|Philip D|PD|0000-0002-9501-9366;Nakamura|Hiroshi|H|;Murasaki|Mitsukuni|M|",
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"doi": "10.1002/npr2.12057",
"fulltext": "\n==== Front\nNeuropsychopharmacol Rep\nNeuropsychopharmacol Rep\n10.1002/(ISSN)2574-173X\nNPR2\nNeuropsychopharmacology Reports\n2574-173X John Wiley and Sons Inc. Hoboken \n\n10.1002/npr2.12057\nNPR212057\nOriginal Article\nOriginal Articles\nBlonanserin versus haloperidol in Japanese patients with schizophrenia: A phase 3, 8‐week, double‐blind, multicenter, randomized controlled study\nHARVEY et al.Harvey Philip D. https://orcid.org/0000-0002-9501-9366\n1\npharvey@miami.edu Nakamura Hiroshi \n2\n Murasaki Mitsukuni \n3\n \n1 \nLeonard M. Miller Professor of Psychiatry and Behavioral Sciences\nUniversity of Miami Miller School of Medicine\nMiami\nFlorida\n\n\n2 \nMedical Affairs\nSumitomo Dainippon Pharma Co., Ltd\nTokyo\nJapan\n\n\n3 \nInstitute of CNS Pharmacology\nKanagawa\nJapan\n\n* Correspondence\n\nPhilip D. Harvey, Psychiatry and Behavioral Sciences, 1120 NW 14th ST Suite 1450, Miami, FL 33136.\n\nEmail: pharvey@miami.edu\n\n30 4 2019 \n9 2019 \n39 3 10.1002/npr2.v39.3173 182\n19 11 2018 24 1 2019 02 4 2019 © 2019 The Authors. Neuropsychopharmacology Reports published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Society of NeuropsychopharmacologyThis is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.Abstract\nObjective\nThis Japanese, multicenter, randomized, double‐blind trial, evaluating the efficacy and safety of blonanserin compared with haloperidol in patients with schizophrenia, was previously published by Murasaki in the Japanese language. In this article, we present the results of the trial based on full analysis dataset instead of per protocol dataset formerly reported and discuss the findings in light of the latest knowledge of pharmacological treatment for schizophrenia.\n\nMethods\nA total of 265 patients were randomized to receive blonanserin (8 to 24 mg/d) or haloperidol (4 to 12 mg/d) twice daily for 8 weeks. Efficacy assessments included the Clinical Global Impressions—Improvement (CGI‐I) and the Positive and Negative Syndrome Scale (PANSS).\n\nResults\nBlonanserin was not inferior to haloperidol with a margin of 10% with respect to the improvement rate on CGI‐I at end of study (60.5% vs 50.0%, P < 0.001). The decrease in the PANSS total score did not differ between the drugs (−10.3 vs −7.1). For the PANSS negative symptom score, the decrease was significantly greater with blonanserin than with haloperidol (P = 0.006). Blonanserin was well tolerated. The incidence of adverse events was similar for the two drugs. Extrapyramidal adverse events, sedation, hypotension, and prolactin increase were rarer with blonanserin than with haloperidol. No clinically important weight gain was observed.\n\nConclusions\nBlonanserin is as effective as haloperidol for the treatment of schizophrenia. Blonanserin is more effective for negative symptoms with a lower risk of extrapyramidal symptoms compared with haloperidol.\n\nBlonanserin is as effective as haloperidol for the treatment of schizophrenia. Blonanserin is more effective for negative symptoms with a lower risk of extrapyramidal symptoms compared with haloperidol. Blonanserin is considered an appropriate antipsychotic drug to combine with cognitive remediation therapy.\n\n\nantipsychotic agentsblonanserinhaloperidolrandomized controlled trialschizophreniaSumitomo Dainippon Pharma Co, Ltd 10.13039/501100002975 source-schema-version-number2.0cover-dateSeptember 2019details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:5.8.4 mode:remove_FC converted:11.06.2020\n\n\nHarvey \nPD \n, \nNakamura \nH \n, \nMurasaki \nM \n. Blonanserin versus haloperidol in Japanese patients with schizophrenia: A phase 3, 8‐week, double‐blind, multicenter, randomized controlled study\n. Neuropsychopharmacol Rep . 2019 ;39 :173 –182\n. 10.1002/npr2.12057 \n31041855 \n\n\n\nFunding information\n\n\nThe study was sponsored by Sumitomo Dainippon Pharma Co, Ltd.\n\nInstitutions at which the work was carried out: The study was conducted at 83 medical institutions in Japan.\n==== Body\n1 INTRODUCTION\nSchizophrenia is a psychiatric disorder characterized by various psychotic symptoms including positive symptoms (eg, hallucinations and delusions) and negative symptoms (eg, affective flattening, alogia, and avolition). In addition, cognitive impairment is commonly observed in patients with schizophrenia, with deficits in processing speed, sustained attention, verbal memory, and executive function.1\n\n\nThe most popular etiological theory of schizophrenia is a neurodegenerative hypothesis, which claims that the disorder is caused by the degeneration of the brain and follows a chronic downhill course.2 Positive symptoms are usually episodic with rapid onset and manageable with dopamine D2 receptor blockade by first‐ and second‐generation antipsychotics (FGAs and SGAs) in most cases. In contrast, negative symptoms typically remain stable across the course of schizophrenia along with cognitive impairment,3 although some studies have suggested that some newer‐generation antipsychotic medications have higher efficacy than FGAs against negative symptoms.4 Increased negative symptoms and cognitive impairment are longitudinal predictors of poor social functioning in schizophrenia.5, 6 In addition, suboptimal medication adherence often seen in the treatment of schizophrenia is considered to be a primary cause of relapse, necessitating the development of formulations expected to improve the adherence to provide stable blood drug concentrations. A recently recognized treatment goal of schizophrenia is not only clinical recovery such as the control of psychiatric symptoms and functional recovery but also personal recovery, as represented by subjective well‐being, employment status, social relationships, and hope for the future.7 To facilitate personal recovery, management of negative symptoms, and cognitive impairment that still remain after remission in chronic patients should be necessary, leading to various pharmacological, nonpharmacological, or combined clinical approaches to date, although sufficient evidence is still to be established.\n\nBlonanserin is a relatively new antipsychotic agent that received the first regulatory approval in Japan in 2008, followed by Korea, and most recently in China in 2017, with an indication for schizophrenia. Blonanserin has high receptor selectivity not only with SGA characteristics of potent dopamine D2 and serotonin 5‐HT2A receptor binding affinities, but also with potent affinity for the D3 receptor, and low affinity for the dopamine D1, serotonin 5‐HT2C, adrenaline α1, histamine H1, and muscarinic M1 receptors.8 The superiority of blonanserin over placebo with regard to the primary efficacy endpoint has been demonstrated in Japanese and non‐Japanese randomized control studies using the transdermal patch formulation (being filed for approval in Japan) and the tablet formulation, respectively, in patients with schizophrenia.9, 10\n\n\nMurasaki reported the results of a phase 3, double‐blind, multicenter, randomized controlled study comparing the efficacy and safety of blonanserin with those of haloperidol in Japanese patients with schizophrenia based on per protocol set (PPS).8 In his report on PPS, noninferiority in efficacy of blonanserin against haloperidol was demonstrated along with its favorable safety profile. The efficacy finding was also supported by other intergroup comparisons. For evaluation of intergroup differences in a randomized controlled study, on the other hand, analysis based on full analysis set (FAS) is recommended to maintain random assignment. FAS analysis also allows clinicians to generalize the results to actual practice in a clinical setting. In this article, we report the results of the study based on FAS analysis, which is completely new in this version of the report. In addition, we discuss our findings in light of the latest knowledge of pharmacological treatment for schizophrenia especially focusing on the importance of management of negative symptoms and cognitive impairment to achieve recovery of social function and behavior. The trial was conducted based on the regulatory submission requirement and included as a pivotal study in the application package for approval of blonanserin in Japan.\n\n2 METHODS\nMost of the methods used in the study were previously described,8 however, since the previous study was published in the Japanese language, the details of the methods for entire the study are shown below.\n\n2.1 Design\nThis multicenter, randomized, double‐blind, active‐controlled study were conducted at 83 medical institutions in Japan from March 1997 through September 2000. The study duration was extended during the study by 2 years to achieve the planned sample size. The study was conducted in accordance with the Good Clinical Practice and local regulatory requirements. The study protocol was approved by the institutional review board of each study site. Before the initiation of any study procedures, all patients (and/or their legal representatives if patients were unable to give consent or younger than 20 years old) provided written‐informed consent.\n\n2.2 Patients\nPatients were eligible if they were between 16 and 64 years of age and met the F20 schizophrenia criteria of the International Classification of Diseases (ICD) 10, Diagnostic Criteria for Research. Patients were excluded if they had a prominent state of excitement or stupor; had personality disintegration or treatment resistance; used any prior long‐acting antipsychotic drug; had a history of neuroleptic malignant syndrome or water intoxication; or met the guidance of contraindication or careful administration of haloperidol.\n\n2.3 Study procedures\nEligible patients were randomized to blonanserin or haloperidol in a 1:1 ratio with the use of computer‐generated block randomization (four patients per block) and received the study drugs orally twice daily for 8 weeks. Blinding of the treatment assignment was ensured by the supply of the active drugs and matching placebos in identical, masked packaging (each tablet manufactured by Sumitomo Dainippon Pharma Co, Ltd). The initial dose was 8 mg/d for blonanserin and 4 mg/d for haloperidol. Dose adjustment was allowed within the range of 8 to 24 mg/d for blonanserin and 4 to 12 mg/d for haloperidol, in increments of 4 mg/d for blonanserin and 2 mg/d for haloperidol, according to the treatment response and tolerability. The dose was escalated when the Clinical Global Impressions—Improvement (CGI‐I, see Section 3.2.2) at the study visit was minimally improved, no change, or worse from baseline and no major safety concern was found. If any safety concern was found, a dose reduction was allowed. Any prior antipsychotics were discontinued before the start of study treatment, and patients were then switched to the study drug. Concomitant use of antipsychotics, epinephrine, terfenadine, and astemizole was prohibited. Prophylactic antiparkinsonian medication was prohibited. Prior antiparkinsonian drugs were discontinued by 2 weeks after the initiation of study treatment, but its concomitant use was allowed if extrapyramidal symptoms worsened or emerged. Prior hypnotic drugs could be continued during the study, and the addition of the drugs was allowed if insomnia worsened or newly emerged. Concomitant use of other drugs (eg, antidepressant medications) was allowed without changing the drug or dosage.\n\n2.4 Endpoints\nThe primary efficacy endpoint was the CGI‐I rating at the end of study. The CGI‐I is a physician‐rating scale to assess the general change from baseline in the patient's condition. The change is rated on a 7‐rank scale of very much improved, much improved, minimally improved, no change, minimally worse, much worse, and very much worse compared with baseline, or otherwise reported as not assessable. For patients with prior antipsychotics, the rating on CGI‐I was adjusted according to the guidelines presented in Table 1 to exclude the effect of the prior drugs on the efficacy evaluation for this study. The other efficacy variables were the Positive and Negative Syndrome Scale (PANSS)11 Japanese edition and the Brief Psychiatric Rating Scale (BPRS)12 Japanese edition. The PANSS was assessed at baseline and after 8 weeks of study treatment (ie, week 8) or at study discontinuation, and the CGI‐I and BPRS were assessed at baseline (CGI‐I was assessed for on‐treatment patients only), weeks 1, 2, 3, 4, 6, and 8 or at study discontinuation.\n\nTable 1 Adjustment guideline for postbaseline rating on CGI‐I for patients with prior antipsychotics\n\nUnadjusted postbaseline rating on CGI‐I\tAdjusted postbaseline rating on CGI‐I\t\nSimilar to baseline rating\tSame as unadjusted postbaseline rating\t\nHigher rank than baseline rating\tHigher rank than unadjusted postbaseline rating\t\nLower rank than baseline rating\tLower rank than unadjusted postbaseline rating\t\nNote\nBaseline CGI‐I ratings reflected baseline improvement associated with prior antipsychotics. Adapted from Murasaki M. 2007, table 2.\n\nAbbreviation: CGI‐I, Clinical Global Impressions—Improvement.\n\nJohn Wiley & Sons, LtdSafety assessments included treatment‐emergent adverse events, adverse drug reactions, the Drug‐Induced Extra‐Pyramidal Symptoms Scale (DIEPSS) scores,13 laboratory data (hematology, blood chemistry, and urinalysis), vital signs (blood pressure, pulse rate, and body temperature), weight, 12‐lead electrocardiography at rest, and electroencephalography. Adverse events were coded and classified according to the Japanese Adverse Reaction Terminology 1996 and translated into English. A relationship with the study drug was classified as definitely related, probably related, probably not related, and not related. An adverse drug reaction was defined as an event considered definitely or probably related to the study drug or for which a relationship was unknown. The DIEPSS is a physician‐rating scale to assess the severity of extrapyramidal symptoms induced by antipsychotics on a 5‐rank scale of 0 (normal) to 4 (severe) for each of 8 symptom categories (gait, bradykinesia, sialorrhea, muscle rigidity, tremor, akathisia, dystonia, and dyskinesia) and one global assessment (overall severity). Although the study protocol defined the primary safety endpoint as the incidence of extrapyramidal side effects, we have reported the incidence of extrapyramidal adverse events instead, to exclude potential subjectivity of causality assessment.\n\n2.5 Statistical analysis\nSAS version 6.12 (SAS Institute Japan Ltd.) was used for statistical analyses. In the previous report by Murasaki, results of statistical analyses based on PPS were presented. In this article, on the other hand, results based on FAS are described. The efficacy analysis population in the previous report included patients who were judged eligible for PPS by the controller committee prior to key code breaking. The safety analysis population in the previous report and the efficacy and safety analysis population in this article, that is, FAS, comprised all patients with schizophrenia who were randomized and treated with at least one dose of the study drug and had at least one postbaseline data point. Analyses of the change from baseline were based on those who had both baseline and postbaseline evaluable data. The Mantel‐Haenszel method was used to test noninferiority of blonanserin to haloperidol for the improvement rate (the percentage of patients rated as very much or much improved) on the final CGI‐I rating, with a margin of 10% at a one‐sided significance level of 0.025. Intergroup comparisons of changes from baseline at end of study were performed with the Wilcoxon rank sum test at a significance level of 0.05 (two‐sided). The tests were not adjusted for multiplicity. Missing data at week 8 were imputed with last observation carried forward. The incidence of adverse events and abnormal changes in laboratory data, vital signs, weight, and electrocardiography and electroencephalography parameters was calculated for each group. To provide a power of 80% to establish noninferiority with regard to the improvement rate with a margin of 10% at a one‐sided significance level of 0.05 (Note: The significance level was initially 0.05 and then revised for the noninferiority analysis to 0.025 before unblinding according to the ICH E9.) and to provide a power of 70% to detect treatment difference with regard to the incidence of drug‐related extrapyramidal symptoms at a two‐sided significance level of 0.05, a sample size of 220 patients (110 per group) were required.\n\n3 RESULTS\nThe results shown here are based on FAS which is newly presented in this article instead of PPS previously reported by Murasaki.8\n\n\n3.1 Patient characteristics\nPatients were enrolled in the study at Japanese medical institutions, and 265 patients were randomized to receive blonanserin or haloperidol (Figure 1). Of these patients, 263 received at least one dose of the study drug. Seventy patients discontinued study treatment, and the withdrawal rate was similar in the two groups: 24.0% in the blonanserin group and 29.1% in the haloperidol group. Of the 263 treated patients, two had a GCP violation, and the remaining 261 (129 in the blonanserin group, 132 in the haloperidol group) were included in the efficacy and safety analyses.\n\nFigure 1 \nCONSORT diagram for study flow. Patients who discontinued the study for more than one reasons were counted for each category\n\nBaseline characteristics were comparable across treatment groups (Table 2). The mean age was 41.9 years in the blonanserin group and 42.9 years in the haloperidol group. In each group, nearly 60% of patients were male. Duration of schizophrenia was 3 years or longer in more than 75% of the patients. The most prominent schizophrenia subtypes were hebephrenic, paranoid, and residual schizophrenia according to the ICD‐10. The mean baseline PANSS total score was approximately 80, and the negative symptoms were prominent in almost 80% of patients. Most patients were treated with prior antipsychotics at baseline. More than 75% of the patients were receiving antiparkinsonian medication.\n\nTable 2 Baseline patient characteristics\n\nCategory\tBlonanserin (N = 129)\tHaloperidol (N = 132)\t\nSex, n (%)\t\nMale\t75 (58.1)\t78 (59.1)\t\nAge (years), mean ± SD\t41.9 ± 12.7\t42.9 ± 13.2\t\nWeight (kg), mean ± SD\t61.5 ± 12.9\t61.7 ± 14.2\t\nDuration of disease (years), n (%)\t\n<1\t7 (5.4)\t11 (8.3)\t\n≥1, <2\t13 (10.1)\t4 (3.0)\t\n≥2, <3\t8 (6.2)\t4 (3.0)\t\n≥3, <5\t13 (10.1)\t10 (7.6)\t\n≥5, <10\t20 (15.5)\t21 (15.9)\t\n≥10\t65 (50.4)\t81 (61.4)\t\nUnknown\t3 (2.3)\t1 (0.8)\t\nDisease type by ICD‐10, n (%)\t\nHebephrenic\t36 (27.9)\t48 (36.4)\t\nParanoid\t36 (27.9)\t45 (34.1)\t\nResidual\t32 (24.8)\t25 (18.9)\t\nUndifferentiated\t17 (13.2)\t8 (6.1)\t\nCatatonic\t6 (4.7)\t4 (3.0)\t\nSimplified\t1 (0.8)\t1 (0.8)\t\nUnspecified\t1 (0.8)\t0\t\nPostschizophrenic depression\t0\t1 (0.8)\t\nDisease type by DSM‐IV, n (%)\t\nParanoid\t36 (27.9)\t45 (34.1)\t\nResidual\t35 (27.1)\t25 (18.9)\t\nDisorganized\t33 (25.6)\t44 (33.3)\t\nUndifferentiated\t19 (14.7)\t13 (9.8)\t\nCatatonic\t6 (4.7)\t4 (3.0)\t\nOthers\t0 (0.0)\t1 (0.8)\t\nUse of prior antipsychotics, n (%)\t\nYes\t116 (89.9)\t123 (93.2)\t\nUse of antiparkinsonian drugs, n (%)\t\nYes\t98 (76.0)\t108 (81.8)\t\nPANSS total score, mean ± SD\t81.5 ± 21.6\t82.3 ± 21.7\t\nDominance in PANSS, n (%)a\n\t\nNegative symptoms\t103 (79.8)\t102 (77.3)\t\nPositive symptoms\t18 (14.0)\t23 (17.4)\t\nComparable\t8 (6.2)\t7 (5.3)\t\nAbbreviations: DSM‐IV, Diagnostic and Statistical Manual of Mental Disorders, 4th edition; ICD‐10, International Classification of Diseases 10; PANSS, Positive and Negative Syndrome Scale; SD, standard deviation.\n\na Positive symptoms are dominant when the total score on PANSS positive symptom scale is higher than the total score on PANSS negative symptom scale, and vice versa.\n\nJohn Wiley & Sons, Ltd3.2 Efficacy\nEfficacy results based on FAS were quite similar to those on PPS.\n\n3.2.1 Final global improvement rating\nThe final improvement rate on CGI‐I demonstrated the noninferiority of blonanserin to haloperidol with a margin of 10% (P < 0.001), although the rate was higher for blonanserin by about 10% (Table 3). During the study, the improvement rate gradually increased for both blonanserin and haloperidol, and the rate was higher for blonanserin than for haloperidol at each evaluation point (Table S1 and Figure 2).\n\nTable 3 Comparisons of CGI‐I rating at end of study\n\nCategory\tBlonanserin (N = 129), n (%)\tHaloperidol (N = 132), n (%)\t\nVery much improved\t17 (13.2)\t15 (11.4)\t\nMuch improved\t61 (47.3)\t51 (38.6)\t\nMinimally improved\t26 (20.2)\t33 (25.0)\t\nNo change\t8 (6.2)\t14 (10.6)\t\nMinimally worse\t8 (6.2)\t5 (3.8)\t\nMuch worse\t9 (7.0)\t8 (6.1)\t\nVery much worse\t0\t6 (4.5)\t\nImprovement ratea\n\t60.5%\t50.0%\t\n95% CI of intergroup difference (%)\t−1.5, 22.5\t\n\nP valueb\n\t<0.001\t\nAbbreviations: CGI‐I, Clinical Global Impressions—Improvement; CI, confidence interval.\n\na The improvement rate was defined as the percentage of patients rated as very much or much improved on the CGI‐I.\n\nb The Mantel‐Haenszel method was used to test noninferiority of blonanserin to haloperidol with a margin of 10% at a one‐sided significance level of 0.025.\n\nJohn Wiley & Sons, LtdFigure 2 Abbreviations: LOCF, last observation carried forward. Time course of change in improvement rate, that is, the percentage of patients rated as very much or much improved from baseline on the Clinical Global Impressions—Improvement rating, during the study for blonanserin (n = 129, 124, 115, 112, 104, and 129 at week 1, 2, 3, 4, 6, and 8 [LOCF], respectively) and haloperidol (n = 130, 125, 116, 110, 100, and 132 at week 1, 2, 3, 4, 6, and 8 [LOCF], respectively). Noninferiority of blonanserin to haloperidol was demonstrated with a margin of 10% at end of study (P < 0.001)\n\n3.2.2 PANSS\nThe mean PANSS total score at end of study was lower than baseline in each group (Table 4 and Figure S1). No statistically significant difference was found in the decrease between blonanserin and haloperidol. Of the PANSS subscales, the negative subscale score decreased significantly more with blonanserin than with haloperidol (P = 0.006).\n\nTable 4 Comparisons of change from baseline in PANSS scores at end of study\n\nCategory\tGroup\tN\tBaseline, mean ± SD\tChange from baseline, mean ± SD\t\nP valuea\n\t\nTotal\tBlonanserin\t127\t82.5 ± 21.9\t−10.3 ± 18.7\t0.096\t\nHaloperidol\t128\t82.2 ± 22.3\t−7.1 ± 18.3\t\nPositive\tBlonanserin\t127\t16.6 ± 6.0\t−2.0 ± 6.1\t0.762\t\nHaloperidol\t128\t17.2 ± 6.3\t−1.6 ± 5.7\t\nNegative\tBlonanserin\t127\t24.2 ± 7.7\t−3.5 ± 4.8\t0.006\t\nHaloperidol\t128\t23.7 ± 7.5\t−2.2 ± 5.1\t\nGeneral psychopathology\tBlonanserin\t127\t41.8 ± 11.6\t−4.8 ± 9.8\t0.149\t\nHaloperidol\t128\t41.3 ± 12.5\t−3.4 ± 9.5\t\nAbbreviations: PANSS, Positive and Negative Syndrome Scale; SD, standard deviation.\n\na The Wilcoxon rank sum test was used for a comparison of the change from baseline at a significance level of 0.05. Missing data were imputed with last observation carried forward.\n\nJohn Wiley & Sons, Ltd3.2.3 BPRS\nSimilar results were obtained for the BPRS. The mean BPRS total score at end of study was lower than baseline in each group (Table S2). No significant difference was found in the decrease at end of study between the groups. Of the BPRS clusters, the cluster scores of anergia and anxiety/depression decreased more largely with blonanserin than with haloperidol (anxiety/depression showed no statistical significance in the previous report based on PPS). During the study, the decrease in BPRS total score from baseline was greater for blonanserin at each evaluation point (Table S3 and Figure S2).\n\n3.3 Safety\nSafety results based on FAS were exactly the same as those reported by Murasaki8 for safety analysis population in his report corresponded to FAS.\n\nThe mean daily dose at end of study was 15.7 mg/d (standard deviation [SD], 6.0) for blonanserin and 7.9 mg/d (SD, 3.0) for haloperidol (Table S4).\n\n3.3.1 Adverse events\nNo obvious difference was found in the incidence of adverse events between blonanserin and haloperidol (93.0% vs 95.5%, Table 5). One death was reported in the study; a patient in the haloperidol group died 14 days after the completion of study treatment (completed suicide). Other serious adverse events occurred in three patients receiving blonanserin (blood sodium decreased, blood urea increased, insomnia, irritability/anxiety, and excitability in one patient each) and four patients receiving haloperidol (suicide attempt in two patients, neuroleptic malignant syndrome, hypokinesia, gait abnormal, musculoskeletal stiffness, bradykinesia, and dystonia in one patient each). The neuroleptic malignant syndrome, hypokinesia, gait abnormal, musculoskeletal stiffness, bradykinesia, and dystonia were considered related to haloperidol, and none of the serious adverse events were considered related to blonanserin. While adverse drug reactions were commonly reported in both groups with similar frequency, the incidence of those leading to medical intervention, dose reduction, and study discontinuation in the blonanserin group was generally lower than those in the haloperidol group. Of the adverse events commonly reported in the study, tremor, akathisia, bradykinesia, and somnolence occurred less frequently (ie, treatment difference in incidence >10%) with blonanserin than with haloperidol (Table 6). The other adverse events were reported in a similar incidence across groups. Most adverse events were mild or moderate in severity.\n\nTable 5 Summary of adverse events\n\n \tBlonanserin (N = 129), n (%)\tHaloperidol (N = 132), n (%)\t\nAdverse events\t120 (93.0)\t126 (95.5)\t\nDeath\t0\t1 (0.8)\t\nSerious adverse events\t3 (2.3)\t4 (3.0)\t\nAdverse drug reactions\t106 (82.2)\t110 (83.3)\t\nAdverse drug reactions leading to medical interventiona\n\t45 (34.9)\t59 (45.0)\t\nAdverse drug reactions leading to dose reductiona\n\t18 (14.0)\t22 (16.8)\t\nAdverse drug reactions leading to discontinuationa\n\t13 (10.1)\t22 (16.8)\t\nPatients with extrapyramidal adverse events\t73 (56.6)\t102 (77.3)\t\na One patient in the haloperidol group who discontinued the study but did not undergo the discontinuation visit was excluded from the analysis. This patient did not experience adverse drug reactions during the study. Adapted from and added to Murasaki M. 2007, table 10.\n\nJohn Wiley & Sons, LtdTable 6 Incidence of adverse events (≥5% in either group)\n\nSystem organ class\tBlonanserin (N = 129), n (%)\tHaloperidol (N = 132), n (%)\t\nPreferred term\t\nExtrapyramidal system\t\nTremor\t39 (30.2)\t59 (44.7)\t\nAkathisia\t35 (27.1)\t55 (41.7)\t\nBradykinesia\t29 (22.5)\t49 (37.1)\t\nGait abnormal\t26 (20.2)\t36 (27.3)\t\nMusculoskeletal stiffness\t26 (20.2)\t35 (26.5)\t\nSalivary hypersecretion\t25 (19.4)\t35 (26.5)\t\nDyslalia\t20 (15.5)\t20 (15.2)\t\nHypokinesia\t19 (14.7)\t27 (20.5)\t\nDyskinesia\t12 (9.3)\t10 (7.6)\t\nDystonia\t11 (8.5)\t16 (12.1)\t\nPsychophysiologic system\t\nInsomnia\t53 (41.1)\t62 (47.0)\t\nIrritability/anxiety\t38 (29.5)\t38 (28.8)\t\nExcitability\t26 (20.2)\t26 (19.7)\t\nSomnolence\t20 (15.5)\t34 (25.8)\t\nDepression\t16 (12.4)\t12 (9.1)\t\nHeadache/head discomfort\t15 (11.6)\t22 (16.7)\t\nSedation\t7 (5.4)\t14 (10.6)\t\nGeneral symptom\t\nMalaise\t23 (17.8)\t35 (26.5)\t\nDizziness/dizziness postural\t10 (7.8)\t20 (15.2)\t\nAsthenia\t10 (7.8)\t16 (12.1)\t\nFeeling hot\t8 (6.2)\t8 (6.1)\t\nCirculatory system\t\nTachycardia\t7 (5.4)\t6 (4.5)\t\nBlood pressure decreased\t4 (3.1)\t9 (6.8)\t\nDigestive system\t\nAnorexia\t29 (22.5)\t22 (16.7)\t\nConstipation\t20 (15.5)\t31 (23.5)\t\nThirst\t20 (15.5)\t20 (15.2)\t\nNausea/vomiting\t17 (13.2)\t14 (10.6)\t\nDiarrhea\t5 (3.9)\t17 (12.9)\t\nEndocrine system\t\nMenstrual disordera\n\t6 (11.1)\t2 (3.7)\t\nVital signs\t\nWeight decreased\t11 (8.5)\t10 (7.6)\t\nBody temperature increased\t9 (7.0)\t10 (7.6)\t\nHematology test\t\nWhite blood cell count increased\t3 (2.3)\t7 (5.3)\t\nProlactin\t\nBlood prolactin increased\t11 (8.5)\t20 (15.2)\t\nBiochemical examination of blood\t\nBlood creatine phosphokinase increased\t10 (7.8)\t17 (12.9)\t\nALT (GPT) increased\t9 (7.0)\t7 (5.3)\t\nBlood triglycerides increased\t8 (6.2)\t6 (4.5)\t\nAST (GOT) increased\t8 (6.2)\t4 (3.0)\t\nGamma‐glutamyltransferase increased\t3 (2.3)\t7 (5.3)\t\nOthers\t\nNasopharyngitis\t10 (7.8)\t10 (7.6)\t\nVisual acuity reduced\t8 (6.2)\t9 (6.8)\t\nDysuria\t3 (2.3)\t12 (9.1)\t\na Menstruation abnormal was aggregated for female patients (54 patients each in the blonanserin and haloperidol groups). Adapted from Murasaki M. 2007, table 11.\n\nJohn Wiley & Sons, Ltd3.3.2 Extrapyramidal symptoms\nThe incidence of extrapyramidal adverse events was lower in the blonanserin group than in the haloperidol group (56.6% vs 77.3%, Table 5). The mean (SD) DIEPSS total score was comparable in the two groups at baseline: 2.1 (2.9) in the blonanserin group and 2.3 (2.9) in the haloperidol group. During the study, the DIEPSS total score remained unchanged in the blonanserin group and increased in the haloperidol group; the intergroup difference in the change from baseline was significant (P = 0.024, Table 7).\n\nTable 7 Comparisons of change from baseline in DIEPSS total score\n\nGroup\tN\tBaseline, mean ± SD\tChange from baseline, mean ± SD\t\nP valuea\n\t\nBlonanserin\t129\t2.1 ± 2.9\t0.3 ± 2.9\t0.024\t\nHaloperidol\t131\t2.3 ± 2.9\t1.3 ± 3.7\t\nAbbreviations: DIEPSS, Drug‐Induced Extra‐Pyramidal Symptoms Scale; SD, standard deviation.\n\na The Wilcoxon rank sum test was used for a comparison of the change from baseline at a significance level of 0.05. Missing data were imputed with last observation carried forward. Adapted from Murasaki M. 2007, table 13.\n\nJohn Wiley & Sons, Ltd3.3.3 Laboratory data\nOf the laboratory parameters tested, those with the incidence of abnormal changes higher than 5% in either group were prolactin (11.0% for blonanserin and 19.4% for haloperidol), CPK (7.8% vs 13.4%), triglyceride (6.9% vs 3.3%), ALT (6.8% vs 5.7%), AST (5.9% vs 3.3%), and WBC (3.4% vs 6.6%). The incidence of abnormal change in prolactin was slightly higher in the haloperidol group. Mean (SD) prolactin levels decreased during the study in each group: 25.2 (25.1) ng/mL at baseline and 17.1 (19.4) ng/mL at end of study in the blonanserin group and 29.5 (30.7) ng/mL at baseline and 22.7 (21.5) ng/mL at end of study in the haloperidol group.\n\n3.3.4 Others\nWeight did not change notably during the study in either group; mean (SD) weight was 61.8 (13.0) kg at baseline and 61.1 (12.6) kg at end of study in the blonanserin group and 61.4 (13.5) kg at baseline and 60.7 (13.5) kg at end of study in the haloperidol group. Weight gain was reported as an adverse event in as low as 2.3% of patients receiving blonanserin and none receiving haloperidol. Drug‐related electrocardiographic abnormalities were reported in two patients receiving blonanserin, and two patients receiving haloperidol: ventricular extrasystoles/ventricular tachycardia (moderate) in one patient receiving blonanserin and mild sinus bradycardia in the remaining three patients. Drug‐related electroencephalographic abnormalities were not reported in the blonanserin group and reported in two patients of the haloperidol group. No obvious change from baseline was found in mean vital signs in either group.\n\n4 DISCUSSION\nThe study by Murasaki8 was the first randomized controlled trial to investigate the safety and efficacy of blonanserin comparing with haloperidol. The daily dose administered to FAS population was 8‐24 mg (mean, 15.7 mg at end of study) for blonanserin, which is the same as those instructed in the current local package insert; and 4‐12 mg (mean, 7.9 mg at end of study) for haloperidol, being in agreement with its recommended optimal dose.14, 15 Very few of the enrolled patients were treatment‐naïve or in the acute phase of the disease; the majority of patients had treatment experience with antipsychotics, indicating the chronic course of disease.\n\nMurasaki previously reported the results of the trial based on PPS, showing favorable efficacy and safety of blonanserin in patients with schizophrenia.8 PPS analysis well represents the efficacy and safety of a study drug in patients without major protocol deviations. From a modern statistical point of view, on the other hand, FAS analysis is recommended to evaluate intergroup difference for a randomized controlled study because it can maintain prognostic balance of the random allocation. In addition, in examination of noninferiority as well, analyses based on FAS along with PPS are considered relevant for robust interpretation of the data. We discuss the findings of the study on the basis of both the analyses and in the context of the most recent knowledge of pharmacological treatment in schizophrenia.\n\nIn the present FAS analysis, consistent results were obtained which confirm the previous findings based on PPS,8 demonstrating that blonanserin was not inferior to haloperidol with respect to the improvement rate on CGI‐I after 8 weeks of treatment. The result was, in both PPS and FAS, supported by the other efficacy endpoint data; decrease in the PANSS total score from baseline did not differ between the drugs. When analyzed according to symptom type, improvement was significantly greater with blonanserin than with haloperidol in PANSS negative symptom scores in both PPS and FAS. With regard to efficacy of blonanserin, previous findings by Murasaki8 were wholly sustained by the present FAS analysis. Those findings are consistent with the results obtained in another study that also compared blonanserin with haloperidol, where 5‐10 mg/d of blonanserin was as effective as 10 mg/d of haloperidol with respect to reduction in PANSS total score, and showed greater efficacy than haloperidol against negative symptoms in non‐Japanese patients with schizophrenia.9\n\n\nAs described by Murasaki,8 blonanserin was well tolerated. The incidence of treatment‐emergent adverse events was similar for blonanserin and haloperidol. None of the serious adverse events were related to blonanserin. Incidence of adverse drug reactions leading to study discontinuation was lower for blonanserin than for haloperidol. Extrapyramidal symptoms, sedation, and hypotension, which are clinically significant side effects of FGAs, were fewer with blonanserin. Prolactin increase, which often occurs in FGAs and some SGAs, was generally fewer with blonanserin. Weight gain is also one of the significant side effects of SGAs, but was observed in a small percentage of blonanserin‐treated patients during the study. These safety findings are in agreement with the above‐mentioned haloperidol‐controlled study that demonstrated the tolerability of blonanserin with lower incidences of extrapyramidal symptoms and prolactin increase than haloperidol and a low frequency of weight gain.9\n\n\nThe efficacy of blonanserin for schizophrenia is comparable with that of other SGAs, as shown in a meta‐analysis of randomized controlled trials comparing blonanserin with other antipsychotics.16 Of the SGAs other than blonanserin, however, only aripiprazole and olanzapine have data showing a significantly higher efficacy than haloperidol against negative symptoms in Japanese patients.17, 18\n\n\nThe blonanserin‐induced significant improvement of negative symptoms compared with haloperidol in the present study might be attributed to the selective dopamine D3 antagonism of blonanserin as well as serotonin 5‐HT2A antagonism. Unlike other SGAs, blonanserin acts as a full antagonist of D3 receptor, showing the binding affinity for human D3 receptors higher than risperidone, olanzapine, and aripiprazole, and comparable to cariprazine (dopamine D2/D3 receptor partial agonist) in vitro, and high D3 receptor occupancy in vivo in rats.19, 20 In healthy subjects, a clinical dose of blonanserin occupied D3 receptor as much as D2 receptor.21 The dopamine D3 receptor predominantly localizes in the ventral striatum, a region relevant to emotion, reward, and motivation, and the other limbic area in human brain, and modulates dopamine release.22 Animal studies suggest that D3 receptor antagonism might have beneficial effects on functions of the frontal cortex, such as the negative symptoms and cognitive deficits associated with schizophrenia, and might act on the reward system to enhance motivation.22, 23 Improvement of negative symptoms relates to improvement of social function, which is associated with intrinsic motivation enhancement or activation of the reward system. Therefore, the selective D3 receptor antagonism of blonanserin might improve social function by enhancing motivation and by reducing negative symptoms, and consequently contribute to the personal recovery.\n\nEfficacy of psychosocial intervention against negative symptoms is currently limited, while moderate improvements in cognitive performance have been shown in cognitive remediation therapy in schizophrenia.24 An important approach to enhance the effect of cognitive rehabilitation is to improve motivation; therefore, the combination of a drug that could enhance motivation with psychosocial therapy is considered promising.25 Since D3 receptor antagonists may improve motivation through the dopamine‐mediated reward system, those compounds may synergistically improve the procognitive effects when combined with cognitive remediation therapy. Since the present study showed that blonanserin is effective for negative symptoms and recent studies suggested potential procognitive effects of blonanserin in animal models26, 27 and in patients with schizophrenia,28, 29 blonanserin is considered an appropriate antipsychotic drug to combine with cognitive remediation therapy.\n\nThere are several methodological limitations to this study. First, prior antipsychotics were not tapered off with the use of placebo and were switched to a low dose of the study drug alone in all patients regardless of the dose of the prior drug. Patients receiving a high dose of prior antipsychotics at baseline might have experienced aggravation of symptoms after initiation of study treatment. Placebo run‐in was not included in the study because placebo use in psychiatry was commonly considered unethical at the time of the study in Japan. Second, the CGI‐I, which measured the primary efficacy endpoint of this study, is not fully standardized since it does not define an anchor point to assess treatment effects. However, CGI‐I was commonly used, at the time of the study, in Japanese clinical studies of psychiatry, and using CGI‐I as a primary efficacy endpoint for the present study was the requirement from the local regulatory authority. This was also the case for previously approved antipsychotics, which obtained regulatory approval in Japan for the indication of schizophrenia based on studies that used CGI‐I as a primary endpoint.\n\nThe remaining unmet medical need in schizophrenia, suboptimal medication adherence, could be expectedly dealt with a transdermal patch formulation of blonanserin now being filed for approval in Japan. The current tablet and upcoming patch formulations of blonanserin have shown efficacy for the positive and negative symptoms of schizophrenia and are expected to synergistically provide beneficial effects when combined with psychosocial therapy.\n\nCONFLICT OF INTEREST\nPhilip D. Harvey has received lecture honoraria from Sumitomo Dainippon Pharma Co, Ltd within the last 3 years. Hiroshi Nakamura is the employee of Sumitomo Dainippon Pharma Co., Ltd. Additional details are to be described, once all COI disclosure forms are collected.\n\nDATA REPOSITORY\nThere are no data listings publicly available for this study, because information about public data sharing was not included in the informed consent form of this study.\n\nAPPROVAL OF THE RESEARCH PROTOCOL BY AN INSTITUTIONAL REVIEWER BOARD\nThe study protocol was approved by the institutional review board of each study site.\n\nINFORMED CONSENT\nAll subjects (and/or their legal representatives if patients were unable to give consent or younger than 20 years old) provided written‐informed consent.\n\nREGISTRY AND THE REGISTRATION NO. OF THE STUDY/TRIAL\nThe study has not been registered in any publicly accessible database since the study was started before November 1st, 2013, when the study registration became mandatory.\n\nAUTHOR CONTRIBUTIONS\nMM took responsibility for the design, data collection, case handling, and interpretation of data as a chief investigator for the study. HN wrote the first draft of the manuscript including literature searches. PH finalized the manuscript. All authors had full access to all study data, had final responsibility for the decision to submit for publication, took part in either drafting or revising the manuscript, and approved the final version of the manuscript.\n\nSupporting information\n \n\nClick here for additional data file.\n\n ACKNOWLEDGMENTS\nThe study was sponsored by Sumitomo Dainippon Pharma Co, Ltd.\n==== Refs\nREFERENCES\n1 \n\nBowie \nCR \n, \nHarvey \nPD \n. Cognition in schizophrenia: impairments, determinants, and functional importance\n. Psychiatr Clin North Am . 2005 ;28 (3 ):613 –33\n, 26.16122570 \n2 \n\nGupta \nS \n, \nKulhara \nP \n. What is schizophrenia: a neurodevelopmental or neurodegenerative disorder or a combination of both? A critical analysis\n. Indian J Psychiatry . 2010 ;52 (1 ):21 –7\n.20174514 \n3 \n\nSommer \nIE \n, \nBearden \nCE \n, \nVan Dellen \nE \n, \nBreetvelt \nEJ \n, \nDuijff \nSN \n, \nMaijer \nK \n, et al. Early interventions in risk groups for schizophrenia: what are we waiting for?\n\nNPJ Schizophr . 2016 ;2 :16003 .27336054 \n4 \n\nNémeth \nG \n, \nLaszlovszky \nI \n, \nCzobor \nP \n, \nSzalai \nE \n, \nSzatmári \nB \n, \nHarsányi \nJ \n, et al. Cariprazine versus risperidone monotherapy for treatment of predominant negative symptoms in patients with schizophrenia: a randomised, double‐blind, controlled trial\n. Lancet . 2017 ;389 (10074 ):1103 –13\n.28185672 \n5 \n\nHodgekins \nJ \n, \nBirchwood \nM \n, \nChristopher \nR \n, \nMarshall \nM \n, \nCoker \nS \n, \nEverard \nL \n, et al. Investigating trajectories of social recovery in individuals with first‐episode psychosis: a latent class growth analysis\n. Br J Psychiatry . 2015 ;207 (6 ):536 –43\n.26294371 \n6 \n\nMilev \nP \n, \nHo \nBC \n, \nArndt \nS \n, \nAndreasen \nNC \n. Predictive values of neurocognition and negative symptoms on functional outcome in schizophrenia: a longitudinal first‐episode study with 7‐year follow‐up\n. Am J Psychiatry . 2005 ;162 (3 ):495 –506\n.15741466 \n7 \n\nHarvey \nPD \n, \nBellack \nAS \n. Toward a terminology for functional recovery in schizophrenia: is functional remission a viable concept?\n\nSchizophr Bull . 2009 ;35 (2 ):300 –6\n.19126634 \n8 \n\nMurasaki \nM \n. Clinical evaluation of blonanserin for schizophrenia–a double‐blind trial comparing blonanserin with haloperidol\n. Jpn J Clin Psychopharmacol . 2007 ;10 :2059 –79\n.\n9 \n\nGarcia \nE \n, \nRobert \nM \n, \nPeris \nF \n, \nNakamura \nH \n, \nSato \nN \n, \nTerazawa \nY \n. The efficacy and safety of blonanserin compared with haloperidol in acute‐phase schizophrenia\n. CNS Drugs . 2009 ;23 (7 ):615 –25\n.19552488 \n10 \nSumitomo Dainippon Pharma Co, Ltd \n. Sumitomo Dainippon Pharma and Nitto announce positive topline results from phase 3 study evaluating transdermal patch formulation of atypical antipsychotic LONASEN\n. 2018 Available from: https://www.ds-pharma.com/ir/news/2018/20180214-2.html Accessed January 23, 2019.\n11 \n\nKay \nSR \n, \nFiszbein \nA \n, \nOpler \nLA \n. The positive and negative syndrome scale (PANSS) for schizophrenia\n. Schizophr Bull . 1987 ;13 (2 ):261 –76\n.3616518 \n12 \n\nOverall \nJE \n, \nGorham \nDR \n. The brief psychiatric rating scale (BPRS): recent developments in ascertainment and scaling\n. Psychopharmacol Bull . 1988 ;24 (1 ):97 –99\n.\n13 \n\nInada \nT \n. A second‐generation rating scale for antipsychotic‐induced extrapyramidal symptoms: drug‐induced extrapyramidal symptoms scale . Tokyo : Seiwa Shoten Publishers ; 2009 .\n14 \nJapanese package insert of LONASEN® 2 mg tablet, 4 mg tablet, 8 mg tablet, and 2% powder\n. Sumitomo Dainippon Pharma Co, Ltd.\n15 \n\nGeddes \nJ \n, \nFreemantle \nN \n, \nHarrison \nP \n, \nBebbington \nP \n. Atypical antipsychotics in the treatment of schizophrenia: systematic overview and meta‐regression analysis\n. BMJ . 2000 ;321 (7273 ):1371 –6\n.11099280 \n16 \n\nKishi \nT \n, \nMatsui \nY \n, \nMatsuda \nY \n, \nKatsuki \nA \n, \nHori \nH \n, \nYanagimoto \nH \n, et al. Efficacy, tolerability, and safety of blonanserin in schizophrenia: an updated and extended systematic review and meta‐analysis of randomized controlled trials\n. Pharmacopsychiatry . 2019 ;52 (2 ):52 –62\n.29514360 \n17 \n\nIshigooka \nJ \n, \nMiura \nS \n, \nKoyama \nT \n, \nToru \nM \n, \nMurasaki \nM \n, \nYagi \nG \n. Clinical evaluation of aripiprazole in schizophrenic patients: a comparative double‐blind study with haloperidol [in Japanese]\n. Jpn J Clin Psychopharmacol . 2006 ;9 (2 ):295 –329\n.\n18 \n\nIshigooka \nJ \n, \nInada \nT \n, \nMiura \nS \n. Olanzapine versus haloperidol in the treatment of patients with chronic schizophrenia: results of the Japan multicenter, double‐blind olanzapine trial\n. Psychiatry Clin Neurosci . 2001 ;55 (4 ):403 –14\n.11442893 \n19 \n\nBaba \nS \n, \nEnomoto \nT \n, \nHorisawa \nT \n, \nHashimoto \nT \n, \nOno \nM \n. Blonanserin extensively occupies rat dopamine D3 receptors at antipsychotic dose range\n. J Pharmacol Sci . 2015 ;127 (3 ):326 –31\n.25837930 \n20 \n\nCitrome \nL \n. Cariprazine in bipolar disorder: clinical efficacy, tolerability, and place in therapy\n. Adv Ther . 2013 ;30 (2 ):102 –13\n.23361832 \n21 \n\nTateno \nA \n, \nSakayori \nT \n, \nKim \nWC \n, \nHonjo \nK \n, \nNakayama \nH \n, \nArakawa \nR \n, et al. Comparison of dopamine D3 and D2 receptor occupancies by a single dose of blonanserin in healthy subjects: a positron emission tomography study with [11C]‐(+)‐PHNO\n. Int J Neuropsychopharmacol . 2018 ;21 (6 ):522 –7\n.29346639 \n22 \n\nGross \nG \n, \nDrescher \nK \n. The role of dopamine D(3) receptors in antipsychotic activity and cognitive functions\n. Handb Exp Pharmacol . 2012 ;213 :167 –210\n.\n23 \n\nSimpson \nEH \n, \nWiniger \nV \n, \nBiezonski \nDK \n, \nHaq \nI \n, \nKandel \nER \n, \nKellendonk \nC \n. Selective overexpression of dopamine D3 receptors in the striatum disrupts motivation but not cognition\n. Biol Psychiatry . 2014 ;76 (10 ):823 –31\n.24387821 \n24 \n\nMcGurk \nSR \n, \nTwamley \nEW \n, \nSitzer \nDI \n, \nMcHugo \nGJ \n, \nMueser \nKT \n. A meta‐analysis of cognitive remediation in schizophrenia\n. Am J Psychiatry . 2007 ;164 (12 ):1791 –802\n.18056233 \n25 \n\nHarvey \nPD \n, \nSand \nM \n. Pharmacological augmentation of psychosocial and remediation training efforts in schizophrenia\n. Front Psychiatry . 2017 ;8 :177 .28993740 \n26 \n\nHida \nH \n, \nMouri \nA \n, \nMori \nK \n, \nMatsumoto \nY \n, \nSeki \nT \n, \nTaniguchi \nM \n, et al. Blonanserin ameliorates phencyclidine‐induced visual‐recognition memory deficits: the complex mechanism of blonanserin action involving D(3)‐5‐HT(2)A and D(1)‐NMDA receptors in the mPFC\n. Neuropsychopharmacology . 2015 ;40 (3 ):601 –13\n.25120077 \n27 \n\nHuang \nM \n, \nKwon \nS \n, \nOyamada \nY \n, \nRajagopal \nL \n, \nMiyauchi \nM \n, \nMeltzer \nHY \n. Dopamine D3 receptor antagonism contributes to blonanserin‐induced cortical dopamine and acetylcholine efflux and cognitive improvement\n. Pharmacol Biochem Behav . 2015 ;138 :49 –57\n.26383990 \n28 \n\nHashimoto \nN \n, \nToyomaki \nA \n, \nMiyamoto \nT \n, \nMiyazaki \nA \n, \nKuksumi \nI \n. Olanzapine, blonanserin, and aripiprazole associated with different frontostriatal reward system activation in patients with schizophrenia\n. Schizophr Res . 2017 \n10.1016/j.schres.2017.11.035 [Epub ahead of print].\n29 \n\nHori \nH \n, \nYamada \nK \n, \nKamada \nD \n, \nShibata \nY \n, \nKatsuki \nA \n, \nYoshimura \nR \n, et al. Effect of blonanserin on cognitive and social function in acute phase Japanese schizophrenia compared with risperidone\n. Neuropsychiatr Dis Treat . 2014 ;10 :527 –33\n.24707178\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2574-173X",
"issue": "39(3)",
"journal": "Neuropsychopharmacology reports",
"keywords": "antipsychotic agents; blonanserin; haloperidol; randomized controlled trial; schizophrenia",
"medline_ta": "Neuropsychopharmacol Rep",
"mesh_terms": "D000328:Adult; D014150:Antipsychotic Agents; D004311:Double-Blind Method; D004361:Drug Tolerance; D005260:Female; D006220:Haloperidol; D006801:Humans; D008297:Male; D008875:Middle Aged; D010879:Piperazines; D010880:Piperidines; D012559:Schizophrenia; D015430:Weight Gain",
"nlm_unique_id": "101719700",
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"pages": "173-182",
"pmc": null,
"pmid": "31041855",
"pubdate": "2019-09",
"publication_types": "D017428:Clinical Trial, Phase III; D003160:Comparative Study; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": "26383990;23027416;3616518;28185672;23361832;19126634;29223323;26294371;25120077;16122570;29514360;31041855;11442893;29346639;28993740;24387821;19552488;24707178;25837930;27336054;18056233;11099280;20174514;15741466",
"title": "Blonanserin versus haloperidol in Japanese patients with schizophrenia: A phase 3, 8-week, double-blind, multicenter, randomized controlled study.",
"title_normalized": "blonanserin versus haloperidol in japanese patients with schizophrenia a phase 3 8 week double blind multicenter randomized controlled study"
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"activesubstancename": "HALOPERIDOL"
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{
"abstract": "Secondary hemophagocytic lymphohistiocytosis (HLH) is a rare and potentially fatal immune-deficiency disorder that develops in response to diseases that produce strong immunologic activation, such as infection and malignancy. Although secondary HLH is reported to occur in association with various malignancies, there is no report of its association with thyroid cancer. We evaluated a 19-year-old man who presented with HLH. During investigation for an underlying cause of his HLH computed tomographic scan of the neck discovered thyroid nodules that were confirmed with biopsy to be papillary thyroid carcinoma. He was treated with surgery followed by radioactive iodine therapy and remains without any recurrence of malignancy or his secondary HLH. This report documents the first observation of HLH associated with thyroid cancer, and illustrates the need to include imaging of the neck while evaluating patients with secondary HLH for an underlying malignancy.",
"affiliations": "Division of Bone Marrow Transplantation and Immune Deficiency.;Division of Bone Marrow Transplantation and Immune Deficiency.;Division of Endocrinology.;Division of Oncology.;Division of Radiology, Cincinnati Children's Hospital.;Division of Hematology/Oncology, University of Cincinnati Medical Center, Cincinnati, OH.;Division of Bone Marrow Transplantation and Immune Deficiency.",
"authors": "Wakefield|Connor|C|;Mehta|Parinda A|PA|;Corathers|Sarah|S|;Geller|James|J|;Gelfand|Michael|M|;Olowokure|Olugbenga|O|;Marsh|Rebecca A|RA|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/MPH.0000000000000991",
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"issn_linking": "1077-4114",
"issue": "40(2)",
"journal": "Journal of pediatric hematology/oncology",
"keywords": null,
"medline_ta": "J Pediatr Hematol Oncol",
"mesh_terms": "D006801:Humans; D051359:Lymphohistiocytosis, Hemophagocytic; D008297:Male; D000077273:Thyroid Cancer, Papillary; D013964:Thyroid Neoplasms; D055815:Young Adult",
"nlm_unique_id": "9505928",
"other_id": null,
"pages": "e97-e98",
"pmc": null,
"pmid": "29087969",
"pubdate": "2018-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A First Report of Secondary Hemophagocytic Lymphohistiocytosis Associated With Papillary Thyroid Carcinoma.",
"title_normalized": "a first report of secondary hemophagocytic lymphohistiocytosis associated with papillary thyroid carcinoma"
} | [
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"companynumb": "US-BAUSCH-BL-2018-012369",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
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"activesubstancename": "DEXAMETHASONE"
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... |
{
"abstract": "Neuroendocrine Carcinoma of the Prostate (NECP) is rare and only few cases have been reported, constituting less than 0.5% of prostatic malignancies. We report a rare case of large bowel obstruction from NECP posing a further challenge in management due to resistant hypokalaemia. A 70-year-old man presented with clinical signs of large bowel obstruction who was known to have prostatic carcinoma three years ago, treated initially with hormone therapy then chemoradiation. The blood profile showed a severe hypokalaemia and CT scan revealed liver and lung metastases apart from confirming large bowel obstruction from local invasion of NECP. Severe hypokalaemia was believed to be caused by paraneoplastic syndrome from tumor burden or by recent administration of Etoposide. Intensive potassium correction through a central venous access in maximal doses of 150 mmol/24 hours under cardiac monitoring finally raised serum potassium to 3.8 mmol/L. This safe period allowed us to perform a trephine colostomy at the left iliac fossa. The postoperative period was relatively uneventful. This first case report is presenting a rare cause of large bowel obstruction from a neuroendocrine carcinoma of prostate and highlights the importance of an early, intensive correction of electrolytes in patients with large tumor burden from NECP.",
"affiliations": "Department of Hepatobiliary Surgery, Royal Free Hospital, Pond Street, London NW3 2QG, UK.;Department of Paediatrics, Eastbourne District General Hospital, Eastbourne BN21 2UD, UK.;Department of Transplantation, Leicester General Hospital, Leicester LE5 4PW, UK.;Department of General Surgery, St Helier Hospital, Carshalton SM5 1AA, UK.",
"authors": "Mathuram Thiyagarajan|Umasankar|U|0000-0001-7272-5252;Ponnuswamy|A|A|0000-0002-6704-1347;Bagul|A|A|;Gupta|A|A|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1155/2017/2394365",
"fulltext": "\n==== Front\nCase Rep SurgCase Rep SurgCRISCase Reports in Surgery2090-69002090-6919Hindawi 10.1155/2017/2394365Case ReportAn Unusual Case of Resistant Hypokalaemia in a Patient with Large Bowel Obstruction Secondary to Neuroendocrine Carcinoma of the Prostate http://orcid.org/0000-0001-7272-5252Mathuram Thiyagarajan Umasankar \n1\n\n*\nhttp://orcid.org/0000-0002-6704-1347Ponnuswamy A. \n2\nBagul A. \n3\nGupta A. \n4\n1Department of Hepatobiliary Surgery, Royal Free Hospital, Pond Street, London NW3 2QG, UK2Department of Paediatrics, Eastbourne District General Hospital, Eastbourne BN21 2UD, UK3Department of Transplantation, Leicester General Hospital, Leicester LE5 4PW, UK4Department of General Surgery, St Helier Hospital, Carshalton SM5 1AA, UK*Umasankar Mathuram Thiyagarajan: umasurgeon@gmail.comAcademic Editor: Makoto Ohori\n\n2017 13 3 2017 2017 239436529 7 2016 14 2 2017 20 2 2017 Copyright © 2017 Umasankar Mathuram Thiyagarajan et al.2017This 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.Neuroendocrine Carcinoma of the Prostate (NECP) is rare and only few cases have been reported, constituting less than 0.5% of prostatic malignancies. We report a rare case of large bowel obstruction from NECP posing a further challenge in management due to resistant hypokalaemia. A 70-year-old man presented with clinical signs of large bowel obstruction who was known to have prostatic carcinoma three years ago, treated initially with hormone therapy then chemoradiation. The blood profile showed a severe hypokalaemia and CT scan revealed liver and lung metastases apart from confirming large bowel obstruction from local invasion of NECP. Severe hypokalaemia was believed to be caused by paraneoplastic syndrome from tumor burden or by recent administration of Etoposide. Intensive potassium correction through a central venous access in maximal doses of 150 mmol/24 hours under cardiac monitoring finally raised serum potassium to 3.8 mmol/L. This safe period allowed us to perform a trephine colostomy at the left iliac fossa. The postoperative period was relatively uneventful. This first case report is presenting a rare cause of large bowel obstruction from a neuroendocrine carcinoma of prostate and highlights the importance of an early, intensive correction of electrolytes in patients with large tumor burden from NECP.\n==== Body\n1. Introduction\nNeuroendocrine Carcinoma of the Prostate (NEC) is rare and only few cases have been reported constituting less than 0.5% of prostatic malignancies [1]. Epstein et al. classified the NEC into (i) usual prostatic carcinoma with NE differentiation; (ii) prostatic carcinoma with Paneth cell NE differentiation; (iii) carcinoid tumor; (iv) small cell carcinoma (SmCC); (v) large cell neuroendocrine carcinoma (LCNEC); and (vi) mixed NE carcinoma (SmCC or LCNEC), acinar adenocarcinoma [2].\n\nRectal involvement in prostatic only occurs in about 4% of patients [3–6]. The rectal infiltration can present as an anterior rectal mass (52%), an annular stricture (45%), and separate metastasis (3%) [7]. To the best of our knowledge this is a first case of LCNEC with rectal involvement; more importantly it presented with resistant hypokalaemia in our patient which posed a challenge before trephine colostomy. This electrolyte abnormality may have been caused by a paraneoplastic syndrome of NEC due to a large tumor volume and might have also contributed by the use of Etoposide based chemotherapy.\n\nHence, we feel that it is a unique and rare presentation of prostatic malignancy in a surgical patient; thus this report will be useful on managing challenges in patients with large bowel obstruction caused by NEC.\n\n2. Case Presentation\nA 70-year-old man presented with abdominal distension, gurgling, and poor appetite for past three weeks. He has also experienced intermittent abdominal discomfort and nausea with reduction in stool volume. There was no history of vomiting but his stools were watery recently. He was diagnosed to have prostatic carcinoma three years ago, treated initially with androgen ablation for 1 year followed by chemoradiation as a part of clinical trial. Full details were not available as his prostate cancer treatment was performed in a tertiary oncology centre in another hospital. Figure 1 shows an advanced prostatic cancer involving rectum.\n\nHe is hypertensive but suffered no other systemic illnesses. Due to the bladder outlet obstruction, he had had suprapubic catheter insertion two years back. He was retired 5 years back and lives with his wife.\n\n3. Investigations\nPreliminary investigations including full blood count (FBC), renal function tests (RFT), liver function (LFT), and clotting profile were performed. His blood tests showed a severe hypokalaemia (of 2.5 mmol/L) and remaining tests were within normal limits. Urine dipstick test was also normal.\n\nAbdominal X-rays showed a dilated small, large bowel loops; a further abdominal computed tomography (CT scan) confirmed a large bowel obstruction possibly from local invasion of NEC. The transition point was noted in the pelvis just proximal to the soft tissue pelvis disease which encompassed the rectum resulting in significant narrowing. There were multiple liver and lung metastases with a single lytic lesion in the left femur noted.\n\n4. Treatment\nPatient was cannulated and intravenous morphine was given with cyclizine; intravenous saline (0.9%) was also commenced immediately for rehydration. As patient was suffering from hypokalaemia, intravenous potassium replacement is given with saline infusion through the peripheral line. In line with the CT findings, it was deemed that a trial conservative management with electrolytes correction would be the best choice. He was later reviewed by the palliative oncology team and has agreed with our plan.\n\nPatient was kept nil by mouth and nasogastric tube; urinary catheter was inserted. The patient received trial phosphate enema but responded minimally. Later, patient was assessed by the anaesthetist team in the next day and central line was placed for rigorous intravenous potassium correction.\n\nDaily FBC, RFT, and liver function tests were performed; but patient's hypokalaemia was failed to respond to a maximal dose (10 mmol/hour) ward based parenteral potassium infusion after 48 hrs. Patient symptoms also did not improve with conservative management. More importantly, he was pyrexial (39 degrees centigrade) and Tazocin® [(Piperacillin and Tazobactam) Pfizer Limited, Kent, United Kingdom] was started after consultation with the microbiologist. Due to the worsening of clinical picture, trial conservative management was abandoned and planned for emergency trephine colostomy.\n\nUnfortunately patient's hypokalaemia (2.5 to 1.9 mmol/L) has got worse with new onset of hypomagnesaemia (0.55 mmol/L and hypophosphatemia (0.37 mmol/L)). As the ward based electrolyte correction did not improve, patient was transferred to surgical high dependency unit for intensive electrolyte correction with continuous cardiac monitoring.\n\nWithin 12 hrs, the potassium, other electrolytes have improved and we have taken this opportunity to perform a trephine colostomy. The ACTH level was measured postoperatively which was found to be elevated 100 pg/mL but unfortunately patient did not wish to proceed with any further investigation. Hence we cannot explain the source of high ACTH level with dexamethasone suppression test. Postoperative period was uneventful and patient was discharged in day 4 to attend his son's wedding. Now, it is three months after surgery, doing well with no problems with colostomy.\n\n5. Discussion\nThe least common manifestation of neuroendocrine (NE) differentiation in prostate cancer is the development of NE tumors, with either pure or admixed conventional adenocarcinoma [1]. NEC is a distinct clinicopathologic entity that typically manifests after long-term hormonal therapy for prostatic adenocarcinoma [1].\n\nNeuroendocrine (NE) cells represent a third type of epithelial cell in benign prostatic glands and are a distinctly minor component after basal cells and secretory luminal cells. They are considered to be terminally differentiated, postmitotic cells that arise from a putative stem cell with a basal cell phenotype [8]. They lack androgen receptor expression and are thought to play a regulatory role in proliferative and secretory activity of prostatic glandular epithelium [9, 10].\n\nLarge cell neuroendocrine carcinoma (LCNEC) of prostate subtype is exceptionally rare [11]. It is a high-grade tumor that consists of large nests and ribbons of cells with abundant pale to amphiphilic cytoplasm, large nuclei, and prominent nucleoli along with high mitotic activity and foci of necrosis [12, 13]. LCNEC is strongly positive for CD56, CD57, Chromogranin A, synaptophysin, and P504S/alpha methylacyl CoA racemase. Unfortunately as previous investigations and treatment for his prostate cancer were performed in another tertiary oncology unit, we could not get histological images for this publication.\n\nPatients with NEC of prostate may present with haematuria, burning nocturia, urinary frequency, oliguria, or symptoms of urinary retention [1]. On the other hand, patients with “carcinoid-like” tumors are usually asymptomatic, although some cases of Cushing's syndrome induced by the production of adrenocorticotropic hormone have been reported [14].\n\nLCNEC were most commonly an incidental finding at the time of palliative transurethral resection of prostate (TURP) for urinary obstruction in the setting of androgen-independent disease [1]. These tumors manifested as androgen-resistant disease and pursued an aggressive clinical course characterized by widespread metastases, a generally poor response to platinum-based chemotherapy, and a mean survival of 7 months after the presence of LCNEC was recognized [1].\n\nRecent report on LCNEC showed a short survival which is likely reflecting the fact that the LCNEC was incidentally detected late in the course of the disease [1]. These patients nonetheless had a generally poor response to standard NEC chemotherapy protocols [1] as in our patient.\n\nHere, our patient developed the large bowel obstruction long after the diagnosis of LCNEC. As we are aware of the metastatic peritoneal, liver, lung spread we have attempted a conservative management. Unfortunately this plan has failed with worsening of hypokalaemia which was a challenge before the surgical management.\n\nInitial ward based intensive hypokalaemia correction attempt (up to 150 mmol/L per day) has failed. But, interestingly hypokalaemia has worsened with new onset of hypomagnesaemia and hypophosphatemia. Paraneoplastic Cushing's syndrome in which adrenocorticotropic hormone (ACTH), or corticotrophin-releasing factor, is produced by nonendocrine tumors is mostly associated with SCC of the lung [15]. It is not surprising that the syndrome has also been described in SCC of the prostate [16]. Small cell variant of NEC is known to cause electrolyte abnormalities, but LNEC has never been reported to have any similar presentations [17]. The above electrolytes abnormalities and high ACTH level are likely caused by LNEC but recent use of Etoposide might have also contributed for worsening of hypokalaemia. As patient did not wish to be investigated further due to the advanced prostatic malignancy, we could not confirm the aetiology of his resistant hypokalaemia.\n\nThe main lesson here was that electrolytes correction in these difficult patients has to be planned early and needs an intensive correction in the high dependency unit with continuous cardiac monitoring. Failure to recognize these potential challenges ahead could significantly increase the morbidity and mortality.\n\nWe believe that our case report will make clinicians, surgeons, urologists, anaesthetist, and intensivist aware of rarity and our experience could be translated into treating similar patients with large bowel obstruction.\n\nConflicts of Interest\nThe authors declare that they have no conflicts of interest.\n\nFigure 1 A sagittal and coronal view showing an advanced prostatic cancer involving rectum.\n==== Refs\n1 Evans A. J. Humphrey P. A. Belani J. Van Der Kwast T. H. Srigley J. R. Large cell neuroendocrine carcinoma of prostate: a clinicopathologic summary of 7 cases of a rare manifestation of advanced prostate cancer American Journal of Surgical Pathology 2006 30 6 684 693 10.1097/00000478-200606000-00003 2-s2.0-33745895892 16723845 \n2 Epstein J. I. Amin M. B. Beltran H. Proposed morphologic classification of prostate cancer with neuroendocrine differentiation The American Journal of Surgical Pathology 2014 38 6 756 767 10.1097/pas.0000000000000208 2-s2.0-84900836746 24705311 \n3 Graves R. C. Millitzer R. E. Carcinoma of the prostate with metastases The Journal of Urology 1935 33 235 251 \n4 Kickham C. J. Carcinoma of prostate simulating primary rectal malignancy The Journal of Urology 1936 35, article 342 \n5 Arnheim F. K. Carcinoma of the prostate: a study of the postmortem findings in one hundred and seventy-six cases The Journal of Urology 1948 50 599 603 \n6 Franks L. M. The spread of prostatic cancer The Journal of Pathology and Bacteriology 1956 72 2 603 611 10.1002/path.1700720227 \n7 Bowrey D. J. Otter M. I. Billings P. J. Rectal infiltration by prostatic adenocarcinoma: report on six patients and review of the literature Annals of the Royal College of Surgeons of England 2003 85 6 382 385 10.1308/003588403322520726 2-s2.0-0242720470 14629877 \n8 Bonkhoff H. Neuroendocrine differentiation in human prostate cancer. Morphogenesis, proliferation and androgen receptor status Annals of Oncology 2001 12 supplement 2 S141 S144 10.1093/annonc/12.suppl_2.s141 2-s2.0-0035170776 11762342 \n9 Bonkhoff H. Stein U. Remberger K. Androgen receptor status in endocrine-paracrine cell types of the normal, hyperplastic, and neoplastic human prostate Virchows Archiv A Pathological Anatomy and Histopathology 1993 423 4 291 294 10.1007/BF01606893 2-s2.0-0027438929 7694424 \n10 Krijnen J. L. M. Bogdanowicz J. F. A. T. Seldenrijk C. A. Mulder P. G. H. Van Der Kwast T. H. The prognostic value of neuroendocrine differentiation in adenocarcinoma of the prostate in relation to progression of disease after endocrine therapy Journal of Urology 1997 158 1 171 174 10.1097/00005392-199707000-00054 2-s2.0-0030947224 9186347 \n11 Mackey J. R. Au H.-J. Hugh J. Venner P. Genitourinary small cell carcinoma: determination of clinical and therapeutic factors associated with survival Journal of Urology 1998 159 5 1624 1629 10.1097/00005392-199805000-00058 2-s2.0-0032460558 9554367 \n12 Chiaverotti T. Couto S. S. Donjacour A. Dissociation of epithelial and neuroendocrine carcinoma lineages in the transgenic adenocarcinoma of mouse prostate model of prostate cancer American Journal of Pathology 2008 172 1 236 246 10.2353/ajpath.2008.070602 2-s2.0-38749142915 18156212 \n13 Mazzucchelli R. Morichetti D. Lopez-Beltran A. Neuroendocrine tumours of the urinary system and male genital organs: clinical significance BJU International 2009 103 11 1464 1470 10.1111/j.1464-410x.2009.08451.x 2-s2.0-65549100578 19254281 \n14 Ghali V. S. Garcia R. L. Prostatic adenocarcinoma with carcinoidal features producing adrenocorticotropic syndrome. Immunohistochemical study and review of the literature Cancer 1984 54 6 1043 1048 10.1002/1097-0142(19840915)54:6<1043::aid-cncr2820540619>3.0.co;2-u 2-s2.0-0021223493 6147188 \n15 Meador C. K. Liddle G. W. Island D. P. Cause of Cushing's syndrome in patients with tumors arising from “nonendocrine” tissue The Journal of Clinical Endocrinology and Metabolism 1962 22 693 703 10.1210/jcem-22-7-693 2-s2.0-0004939322 14471915 \n16 Vuitch M. F. Mendelsohn G. Relationship of ectopic ACTH production to tumor differentiation: a morphologic and immunohistochemical study of prostatic carcinoma with Cushing's syndrome Cancer 1981 47 2 296 299 10.1002/1097-0142(19810115)47:2<296::aid-cncr2820470215>3.0.co;2-n 2-s2.0-0019377110 6257375 \n17 Nimalasena S. Freeman A. Harland S. Paraneoplastic Cushing's syndrome in prostate cancer: a difficult management problem BJU International 2008 101 4 424 427 10.1111/j.1464-410x.2007.07294.x 2-s2.0-38549136410 18070179\n\n",
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"title": "An Unusual Case of Resistant Hypokalaemia in a Patient with Large Bowel Obstruction Secondary to Neuroendocrine Carcinoma of the Prostate.",
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"abstract": "We present 2 cases of elderly females presenting with atraumatic, near-vertical (Pauwells grade 3), intracapsular neck of femur fractures. Following diagnosis of osteoporosis on DEXA scans, they had received alendronic acid for 7 and 10 years respectively. Routine blood tests and serum estimations of calcium, vitamin-D and thyroid-stimulating hormone, done at admission, were within the normal ranges. These patients were managed with a hemiarthroplasty and a dynamic hip screw (DHS) respectively, following discontinuation of bisphosphonates. We present these 2 cases in light of emerging evidence that associates long-term bisphosphonate use with atypical low energy femoral fractures. Only subtrochanteric/diaphyseal fractures have been reported to date. We present a new variant of atypical femoral neck fractures in metaphyseal bone related to prolonged bisphosphonate therapy.",
"affiliations": "Orthopaedic Registrar, Northumbria Healthcare NHS Trust, Ashington, UK.;Upper Limb and Trauma Fellow, Sir Charles Gairdner Hospital, Perth, Australia.;Specialty Trainee in Obstetrics and Gynaecology, Wrightington, Wigan and Leigh NHS Foundation Trust, UK.;Consultant Histopathologist, North Cumbria University Hospitals, Carlisle, UK.;Consultant Geriatrician, North Cumbria University Hospitals, Carlisle, UK.;Consultant Orthopaedic Surgeon, North Cumbria University Hospitals, Carlisle, UK.",
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"title": "Atraumatic intracapsular neck of femur fractures after prolonged bisphosphonate treatment: a new atypical variant?",
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"abstract": "Recent studies have suggested an association between mutations in the IL-36RN gene and the onset of pustular generalized. In the literature, only one case of acute generalized exanthematous pustulosis (AGEP) induced by codeine in a patient with IL36RN mutation has been reported. Herein, we reported an unusual case of AGEP caused by codeine in a patient with a history of psoriasis and confirmed by an oral provocation test. In this case, we have shown that the IL36RN gene mutation is not a constant condition in drug-induced AGEP. Clinicians should be aware of this side effect of codeine especially, in patients with a history of psoriasis. More studies are needed to clarify the association between drug-induced AGEP and IL36RN gene mutations.",
"affiliations": "Pharmacology Department, Faculty of Medicine, University of Monastir, Tunisia.;Pharmacology Department, Faculty of Medicine, University of Monastir, Tunisia.;Pharmacology Department, Faculty of Medicine, University of Monastir, Tunisia.;Pharmacology Department, Faculty of Medicine, University of Monastir, Tunisia.;Pharmacology Department, Faculty of Medicine, University of Monastir, Tunisia.;Pharmacology Department, Faculty of Medicine, University of Monastir, Tunisia.;Pharmacology Department, Faculty of Medicine, University of Monastir, Tunisia.;Pharmacology Department, Faculty of Medicine, University of Monastir, Tunisia.",
"authors": "Chadli|Zohra|Z|;Ladhari|Chayma|C|;Kerkeni|Emna|E|;Djobbi|Amira|A|;Fredj|Nadia B|NB|;Chaabane|Amel|A|;Boughattas|Naceur A|NA|;Aouam|Karim|K|",
"chemical_list": "C122187:IL36RN protein, human; D007378:Interleukins; D003061:Codeine",
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"mesh_terms": "D056150:Acute Generalized Exanthematous Pustulosis; D000328:Adult; D003061:Codeine; D005260:Female; D006801:Humans; D007378:Interleukins; D009154:Mutation; D055815:Young Adult",
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"title": "Codeine-induced acute generalized exanthematous pustulosis without IL36RN mutations.",
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"abstract": "Undifferentiated embryonal sarcomas of the liver (UESL) are extremely rare and continue to pose a diagnostic and therapeutic challenge. The aim of the study was to present a multicenter experience of the German CWS and Polish PPSTG groups in the treatment of UESL in children.\n\n\n\nTwenty-five patients were treated according to the CWS-96, CWS-2002, and CYVADIC protocols. Distant metastases were observed in four cases (16%). In four cases, an initial disease presentation mimicked other entities. A pure cystic appearance of liver mass led to misdiagnosis of hydatid cyst in three cases. In one case, laparotomy was performed due to the signs of appendicitis, and bleeding from ruptured liver tumor was found. All these patients were finally diagnosed as UESL.\n\n\n\nThirteen patients received preoperative chemotherapy. Partial response was observed in 10 cases. Tumor resection was performed in 20 patients (primary resections, 12; delayed resections-, 8). In five patients, the primary tumor never became operable. The macroscopically complete resection rate was 95% (19/20). Postoperative chemotherapy was given to 20 children. Local radiotherapy was used in three children. After a median follow-up time of 136 months, 17 patients (68%) were alive with no evidence of disease. All children with unresectable tumor and three out of four patients with distant metastases died. The five-year overall survival (OS) rate was 72%.\n\n\n\nIn summary, a complete tumor excision plays the central role in the treatment of UESL. A cystic presentation of the liver lesion on imaging does not exclude the diagnosis of malignant tumor.",
"affiliations": "Deptartment of Surgery and Urology for Children and Adolescents, Medical University of Gdansk, Gdansk, Poland.;Department of Pediatric Hematology, Oncology and Immunology, Olgahospital, Klinikum Stuttgart, Germany.;Department of Pediatric Hematology, Oncology and Immunology, Olgahospital, Klinikum Stuttgart, Germany.;Department of Pediatrics, Hematology and Oncology, Medical University of Gdansk, Gdansk, Poland.;Department of Bone Marrow Transplantation, Children Oncology and Haematology, Medical University of Wroclaw, Wroclaw, Poland.;Department of Pediatric Oncology, Children's Memorial Health Institute, Warsaw, Poland.;Department of Pediatric Surgery and Organ Transplantation, Children's Memorial Health Institute, Warsaw, Poland.;Department of Pediatric Hematology, Oncology and Immunology, Olgahospital, Klinikum Stuttgart, Germany.;Deptartment of Surgery and Urology for Children and Adolescents, Medical University of Gdansk, Gdansk, Poland.;Department of Pediatric Surgery and Pediatric Urology, University Children's Hospital, Tuebingen, Germany.",
"authors": "Murawski|Maciej|M|0000-0003-1152-2659;Scheer|Monika|M|0000-0002-0665-6268;Leuschner|Ivo|I|;Stefanowicz|Joanna|J|0000-0001-8014-4263;Bonar|Jolanta|J|;Dembowska-Bagińska|Bożenna|B|;Kaliciński|Piotr|P|;Koscielniak|Ewa|E|;Czauderna|Piotr|P|;Fuchs|Jörg|J|",
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"title": "Undifferentiated sarcoma of the liver: Multicenter international experience of the Cooperative Soft-Tissue Sarcoma Group and Polish Paediatric Solid Tumor Group.",
"title_normalized": "undifferentiated sarcoma of the liver multicenter international experience of the cooperative soft tissue sarcoma group and polish paediatric solid tumor group"
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"abstract": "Sexsomnia is a parasomnia consisting of sexual behavior during non-rapid eye movement sleep. To date, there have been 116 clinical cases of sexsomnia reported and most were treated with clonazepam. We present a case of an adult male with sexsomnia that started during his college days. He presented to us because of problems in his current marriage arising from sexual behavior during sleep. Polysomnography revealed no significant sleep-disordered breathing, electroencephalography abnormality, or abnormal movement during non-rapid eye movement and rapid eye movement (REM) sleep. Alcohol consumption was reported to worsen his sexsomnia. To avoid the neuro-depressant effects of benzodiazepines, paroxetine was administered and resulted in complete resolution of sexsomnia.",
"affiliations": "Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, University of Southern California Keck School of Medicine, Los Angeles, California.;Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, University of Southern California Keck School of Medicine, Los Angeles, California.;Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, University of Southern California Keck School of Medicine, Los Angeles, California.",
"authors": "Kumar|Vineeth|V|;Grbach|Vincent X|VX|;Castriotta|Richard J|RJ|",
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"pages": "1213-1214",
"pmc": null,
"pmid": "32672534",
"pubdate": "2020-07-15",
"publication_types": "D002363:Case Reports",
"references": "17580590;30853039;19765888;19204265;11229449;3589730;27607155;25795266;9292833;9934946;28364495",
"title": "Resolution of sexsomnia with paroxetine.",
"title_normalized": "resolution of sexsomnia with paroxetine"
} | [
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"fulfillexpeditecriteria": "2",
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"activesubstancename": "PAROXETINE"
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{
"abstract": "Tourette syndrome (TS) is a condition wherein motor and vocal tics occur, provoked by an urge, but often not able to be completely voluntarily controlled. Tics are known to cause physical and emotional risks to quality of life, and in rare extreme cases, may have permanent consequences. We report the first cases, to our knowledge, of rhabdomyolysis due to extreme tic fits in two distinct patients with TS. Both patients presented with severe tics, leading to elevated creatine kinase and a diagnosis of rhabdomyolysis requiring hospitalisation and intravenous fluids. Neither had neuroleptic malignant syndrome. One patient was on concurrent neuroleptic therapy, but his laboratory parameters improved when tics subsided despite continued neuroleptic use. Our cases highlight the potential complication of rhabdomyolysis secondary to severe tic fits independent of neuroleptic use.",
"affiliations": "Department of Neurology, Fixel Institute for Neurological Diseases, University of Florida, Gainesville, Florida, USA.;Department of Neurology, Fixel Institute for Neurological Diseases, University of Florida, Gainesville, Florida, USA.;Department of Neurology, Fixel Institute for Neurological Diseases, University of Florida, Gainesville, Florida, USA Irene.Malaty@neurology.ufl.edu.",
"authors": "Au|Ka Loong Kelvin|KLK|http://orcid.org/0000-0001-6604-6384;Chiu|Shannon|S|;Malaty|Irene A|IA|",
"chemical_list": "D014150:Antipsychotic Agents",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2020-239874",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "14(3)",
"journal": "BMJ case reports",
"keywords": "medical management; movement disorders (other than parkinsons)",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D014150:Antipsychotic Agents; D006801:Humans; D011788:Quality of Life; D012206:Rhabdomyolysis; D020323:Tics; D005879:Tourette Syndrome",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "33653856",
"pubdate": "2021-03-02",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Rhabdomyolysis secondary to severe tic fits.",
"title_normalized": "rhabdomyolysis secondary to severe tic fits"
} | [
{
"companynumb": "US-ALEMBIC PHARMACUETICALS LIMITED-2021SCAL000405",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
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"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ARIPIPRAZOLE"
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"abstract": "Amniotic fluid embolism occurring following diagnostic amniocentesis is extremely rare. Only 2 cases have been reported in the English literature over the past 55 years, the most recent one approximately 3 decades ago. We present a case of amniocentesis at 24 weeks' gestation that was performed as part of an evaluation of abnormal fetal ultrasound findings. Immediately following amniotic fluid aspiration, maternal hemodynamic collapse occurred, initially diagnosed and treated as anaphylactic shock. Shortly after initial therapy, coagulopathy was noted and amniotic fluid syndrome suspected. Rapid response restored maternal hemodynamic stability; however, the fetus had suffered fatal damage.",
"affiliations": "Department of Obstetrics and Gynecology, Shaare Zedek Medical Center, affiliated with the Hebrew University Medical School, Jerusalem, Israel.",
"authors": "Drukker|Lior|L|;Sela|Hen Y|HY|;Ioscovich|Alexander|A|;Samueloff|Arnon|A|;Grisaru-Granovsky|Sorina|S|",
"chemical_list": "D011189:Potassium Chloride",
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000446983",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1015-3837",
"issue": "42(1)",
"journal": "Fetal diagnosis and therapy",
"keywords": "Amniocentesis; Amniotic fluid embolus; Amniotic fluid syndrome; Anaphylactic shock; Anaphylaxis; Disseminated intravascular coagulopathy",
"medline_ta": "Fetal Diagn Ther",
"mesh_terms": "D000328:Adult; D000649:Amniocentesis; D000707:Anaphylaxis; D003131:Combined Modality Therapy; D003937:Diagnosis, Differential; D004211:Disseminated Intravascular Coagulation; D004619:Embolism, Amniotic Fluid; D005260:Female; D005313:Fetal Death; D005311:Fetal Hypoxia; D006801:Humans; D015160:Hydrops Fetalis; D007557:Israel; D011189:Potassium Chloride; D011247:Pregnancy; D011262:Pregnancy Trimester, Second; D011296:Prenatal Diagnosis; D016896:Treatment Outcome; D016216:Ultrasonography, Prenatal",
"nlm_unique_id": "9107463",
"other_id": null,
"pages": "77-80",
"pmc": null,
"pmid": "27287307",
"pubdate": "2017",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Amniotic Fluid Embolism: A Rare Complication of Second-Trimester Amniocentesis.",
"title_normalized": "amniotic fluid embolism a rare complication of second trimester amniocentesis"
} | [
{
"companynumb": "IL-GENUS_LIFESCIENCES-USA-POI0580201800106",
"fulfillexpeditecriteria": "1",
"occurcountry": "IL",
"patient": {
"drug": [
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"actiondrug": null,
"activesubstance": {
"activesubstancename": "LEVOTHYROXINE"
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"abstract": "BACKGROUND\nMethicillin-resistant Staphylococcus aureus (MRSA) bacteremia confers considerable morbidity and mortality. Although vancomycin or daptomycin monotherapy is usually curative, prolonged bacteremia necessitating supplemental ceftaroline has occurred. The practice has led to the question of whether to continue with ceftaroline following bacteremia resolution.\n\n\nMETHODS\nAdult patients hospitalized with MRSA bacteremia at the University of Kentucky Medical Center between January 2015 and December 2017 were retrospectively reviewed. Study subjects required supplemental ceftaroline due to 4 or more days of bacteremia despite vancomycin or daptomycin. They additionally had accompanying native valve infective endocarditis, osteomyelitis, or brain abscess. Patients were divided into two cohorts. One group continued with ceftaroline plus vancomycin or daptomycin following bacteremia resolution (combination therapy group). The other group received vancomycin or daptomycin alone (monotherapy group). All involved received 6-8 weeks of therapy. Patients' Pitt bacteremia score (PBS) and Charlson comorbidity index (CCI) values were calculated. Treatment outcomes of inpatient mortality, recurrence of bacteremia, 30-day readmission, acute kidney injury, and leukopenia were recorded and compared.\n\n\nRESULTS\nA total of 30 patients comprised the study population. 15 patients were assigned to each cohort. The median PBS value of the combination therapy group was 2, compared with 1 among the monotherapy group. The median CCI score of both groups was 0. No statistically significant difference in the aforementioned treatment outcomes was seen between the two groups.\n\n\nCONCLUSIONS\nIn subjects with complicated and prolonged MRSA bacteremia requiring supplemental ceftaroline, clinical outcomes did not differ among patients prescribed vancomycin or daptomycin alone following bacteremia resolution versus patients who continued combination therapy.",
"affiliations": "Division of Infectious Diseases, University of Kentucky, Lexington, KY, USA. oahmad3@gmail.com.;Department of Population and Public Health Sciences, Wright State University, Dayton, OH, USA.;Division of Infectious Diseases, University of Kentucky, Lexington, KY, USA.",
"authors": "Ahmad|Omar|O|http://orcid.org/0000-0001-5726-3723;Crawford|Timothy N|TN|;Myint|Thein|T|",
"chemical_list": null,
"country": "New Zealand",
"delete": false,
"doi": "10.1007/s40121-019-00277-2",
"fulltext": "\n==== Front\nInfect Dis Ther\nInfect Dis Ther\nInfectious Diseases and Therapy\n2193-8229\n2193-6382\nSpringer Healthcare Cheshire\n\n31776844\n277\n10.1007/s40121-019-00277-2\nOriginal Research\nComparing the Outcomes of Ceftaroline Plus Vancomycin or Daptomycin Combination Therapy Versus Monotherapy in Adults with Complicated and Prolonged Methicillin-Resistant Staphylococcus Aureus Bacteremia Initially Treated with Supplemental Ceftaroline\nhttp://orcid.org/0000-0001-5726-3723\nAhmad Omar oahmad3@gmail.com\n\n1\nCrawford Timothy N. 2\nMyint Thein 1\n1 grid.266539.d 0000 0004 1936 8438 Division of Infectious Diseases, University of Kentucky, Lexington, KY USA\n2 grid.268333.f 0000 0004 1936 7937 Department of Population and Public Health Sciences, Wright State University, Dayton, OH USA\n28 11 2019\n28 11 2019\n3 2020\n9 1 7787\n11 10 2019\n© The Author(s) 2019\nhttps://creativecommons.org/licenses/by-nc/4.0/ This 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.\nIntroduction\n\nMethicillin-resistant Staphylococcus aureus (MRSA) bacteremia confers considerable morbidity and mortality. Although vancomycin or daptomycin monotherapy is usually curative, prolonged bacteremia necessitating supplemental ceftaroline has occurred. The practice has led to the question of whether to continue with ceftaroline following bacteremia resolution.\n\nMethods\n\nAdult patients hospitalized with MRSA bacteremia at the University of Kentucky Medical Center between January 2015 and December 2017 were retrospectively reviewed. Study subjects required supplemental ceftaroline due to 4 or more days of bacteremia despite vancomycin or daptomycin. They additionally had accompanying native valve infective endocarditis, osteomyelitis, or brain abscess. Patients were divided into two cohorts. One group continued with ceftaroline plus vancomycin or daptomycin following bacteremia resolution (combination therapy group). The other group received vancomycin or daptomycin alone (monotherapy group). All involved received 6–8 weeks of therapy. Patients’ Pitt bacteremia score (PBS) and Charlson comorbidity index (CCI) values were calculated. Treatment outcomes of inpatient mortality, recurrence of bacteremia, 30-day readmission, acute kidney injury, and leukopenia were recorded and compared.\n\nResults\n\nA total of 30 patients comprised the study population. 15 patients were assigned to each cohort. The median PBS value of the combination therapy group was 2, compared with 1 among the monotherapy group. The median CCI score of both groups was 0. No statistically significant difference in the aforementioned treatment outcomes was seen between the two groups.\n\nConclusion\n\nIn subjects with complicated and prolonged MRSA bacteremia requiring supplemental ceftaroline, clinical outcomes did not differ among patients prescribed vancomycin or daptomycin alone following bacteremia resolution versus patients who continued combination therapy.\n\nKeywords\n\nBacteremia\nCeftaroline\nDaptomycin\nMRSA\nVancomycin\nissue-copyright-statement© The Author(s) 2020\n==== Body\nKey Summary Points\n\nWhy carry out this study?\t\nSupplemental ceftaroline is an established option in the treatment of prolonged MRSA bacteremia refractory to vancomycin or daptomycin therapy.\t\nThe question of whether to continue with ceftaroline plus vancomycin or daptomycin following bacteremia resolution, however, remains unanswered.\t\nIn hopes of uncovering findings supporting a particular regimen, treatment outcomes were compared in patients prescribed vancomycin or daptomycin alone following bacteremia resolution versus patients who continued combination therapy.\t\nWhat was learned from the study?\t\nNo statistically significant difference in inpatient mortality, recurrence of bacteremia, 30-day readmission, acute kidney injury, or leukopenia was seen in patients prescribed vancomycin or daptomycin alone following bacteremia resolution versus patients who continued combination therapy.\t\nConsidering treatment outcomes did not differ in patients prescribed vancomycin or daptomycin alone following bacteremia resolution, our finding encourages confining ceftaroline use to active bacteremia.\t\n\nIntroduction\n\nMethicillin-resistant Staphylococcus aureus (MRSA) bacteremia is a formidable disease associated with considerable morbidity and mortality [1, 2]. Vancomycin or daptomycin has traditionally been the mainstay of therapy for invasive MRSA infection. However, treatment failures have happened in recent years, as defined by persistent bacteremia, bacteremia recurrence post-antimicrobial cessation, and/or death 30 days post-treatment [3]. Vancomycin’s slow bactericidal activity, as well as the development of increased glycopeptide tolerance in MRSA isolates administered vancomycin, have been blamed for these occurrences [4, 5]. The latter issue has also plagued daptomycin, with nonsusceptible isolates emerging during treatment being implicated in poor clinical outcomes [6].\n\nIn 2010, the Food and Drug Administration (FDA) approved the use of ceftaroline for the treatment of acute bacterial skin and skin-structure infections (ABSSSI) caused by MRSA. The antibiotic later received additional approval for the solitary treatment of ABSSSI-associated bacteremia [7]. Ceftaroline’s value in treating MRSA bacteremia secondary to non-ABSSSI causes such as infective endocarditis and osteomyelitis [8, 9] led to its investigational use as a salvage measure for vancomycin- or daptomycin-refractory MRSA bacteremia [9, 10]. Findings of bacteremia resolution plus in vitro evidence of antibiotic synergy [11, 12] motivated others to follow suit. Nowadays, it is common practice to add ceftaroline to patients with persistent bacteremia despite vancomycin or daptomycin.\n\nThe effectiveness of supplemental ceftaroline in treating refractory MRSA bacteremia is well established. However, the question of whether to continue with ceftaroline following bacteremia resolution remains unanswered. With this in mind, we studied adults with complicated and prolonged MRSA bacteremia prescribed ceftaroline plus vancomycin or daptomycin. We specifically compared treatment outcomes in those who continued with combination therapy following bacteremia resolution versus vancomycin or daptomycin alone in the hope of uncovering findings supporting a particular regimen.\n\nMethods\n\nStudy Design and Subject Selection\n\nAdult patients (aged 21–99 years) hospitalized between January 1, 2015 and December 31, 2017 at the University of Kentucky Medical Center with monomicrobial MRSA bacteremia were retrospectively identified. Subjects with bacteremia lasting 4 days or longer secondary to deep-seated infection i.e., native valve infective endocarditis (IE), osteomyelitis, and/or brain abscess underwent further analysis. Of these, only those who received supplemental ceftaroline following 4 or more days of bacteremia despite vancomycin or daptomycin were studied. Pregnant individuals, patients allergic to ceftaroline, and patients who were discharged against medical advice or had care withdrawn during their hospitalization, were excluded. Of note, none of the study subjects received antibiotics aside from vancomycin, daptomycin, or ceftaroline for more than 72 h following the detection of MRSA in blood culture specimens.\n\nIncluded patients were separated into two treatment groups. One cohort comprised subjects who continued on ceftaroline plus either vancomycin or daptomycin following bacteremia resolution (combination therapy group). The other cohort (monotherapy group) comprised subjects who received vancomycin or daptomycin alone following bacteremia resolution, with ceftaroline being discontinued no later than 24 h after the first finalized negative blood culture set. All patients received 6–8 weeks of antimicrobial(s) upon bacteremia resolution due to their underlying infections.\n\nAge, sex, comorbid conditions, length of MRSA bacteremia, and duration of antibiotics, as well as serum creatinine and white blood cell count results of subjects, were documented. Instances of death or bacteremia recurrence while hospitalized, along with instances of 30-day readmission, were recorded. Vital signs, need for intravenous vasopressor agents, need for mechanical ventilation, incidences of cardiac arrest, and patient mentation according to electronic medical record (EMR) documentation were noted the day of positive blood cultures.\n\nThe presented study received approval from the University of Kentucky Office of Research Integrity Institutional Review Board and conformed with the Helsinki Declaration of 1964 (as revised in 2013) concerning human and animal rights. On account of the investigation being carried out through retrospective review of medical records, ethics approval was not required due to no foreseeable impact on the rights and/or welfare of the subjects involved. Consent from study participants was additionally not obtained due to the study involving retrospective review of medical records.\n\nAntimicrobial Susceptibility Testing\n\nTwo discrete methods of antimicrobial susceptibility testing identified MRSA isolates in the study. This was due to a procedural change midway through the trial period. Antimicrobial gradient diffusion testing, i.e., bioMérieux Etest™, was employed between January 1, 2015 and March 31, 2016. During this time, S. aureus strains with a minimum inhibitory concentration (MIC) ≥ 4 μg/mL to oxacillin were classified as MRSA per Clinical and Laboratory Standards Institute (CLSI) criteria [13]. The BD Phoenix™ Automated Microbiology System was adopted thereafter. S. aureus strains identified as resistant to cefoxitin (defined by an MIC ≥ 8 μg/mL) underwent corroborative disk diffusion testing. Those exhibiting an inhibition zone diameter ≤ 21 mm to cefoxitin were thereafter classified as MRSA per CLSI criteria [13].\n\nVancomycin and daptomycin susceptibility testing were also performed using Etest™ and Phoenix™ methods, in line with the time intervals previously mentioned. MRSA isolates with a MIC ≤ 2 μg/mL to vancomycin were deemed vancomycin-susceptible, and those with an MIC ≤ 1 μg/mL to daptomycin were deemed daptomycin-susceptible. The designated breakpoints were shared by both Etest™ and Phoenix™. This aside, ceftaroline susceptibility testing was accomplished entirely by means of Etest™. MRSA isolates having an MIC ≤ 1 μg/mL to ceftaroline were labeled ceftaroline-susceptible.\n\nNo MRSA isolates in the study demonstrated daptomycin or ceftaroline resistance. Two isolates belonging to the combination therapy group developed borderline vancomycin susceptibility (MIC = 2 μg/mL) in the midst of vancomycin therapy, i.e., MIC creep. The instances occurred while Etest™ was employed. However, no MRSA isolates were vancomycin-intermediate or vancomycin-resistant according to CLSI definitions [13].\n\nClinical Data Collection and Definitions\n\nSubjects with MRSA bacteremia were identified via institutional blood culture data. Episodes of native valve IE, osteomyelitis, or brain abscess were identified via chart review. Cases of native valve IE were validated provided they met Infectious Diseases Society of America (IDSA)-endorsed modified Duke criteria [14]. Instances of osteomyelitis or brain abscess were validated if diagnosed intraoperatively, or had compatible computed tomography/magnetic resonance imaging findings. Acute kidney injury (AKI) was diagnosed per standardized risk, injury, failure, loss of kidney function, and end-stage kidney disease criteria in patients without pre-existing end-stage renal disease. However, logistical constraints led to only serum creatinine determinants being utilized. In keeping with standardized laboratory parameters, leukopenia was characterized by a serum white blood cell count below 3.7 k/μL. At least two consecutive eligible creatinine or white blood cell count values over a minimum span of 24 h were required for the respective diagnoses of AKI or leukopenia. This was to lessen the possibility of laboratory error.\n\nCharlson comorbidity index (CCI) and Pitt bacteremia score (PBS) values were calculated using conventional scoring methods. Relevant medical conditions detailed in EMR documentation determined individual CCI values [15]. PBS values incorporated patient clinical status, medical needs, and documented vital signs within 24 h of bacteremia detection. The highest computed amount was ultimately selected for analysis [16].\n\nAntimicrobial Dosing\n\nParenteral vancomycin was empirically dosed at 15–20 mg/kg every 8–12 h. The specific regimen was dependent upon individual renal function. Dosing was thereafter adjusted to attain IDSA-recommended trough levels of 15–20 μg/mL [17]. Daptomycin was dosed at 8–10 mg/kg once daily. This high-dose regimen was chosen over conventional 6 mg/kg daily dosing due to a reduced risk of antimicrobial resistance and the potential for accelerated bacterial clearance [18, 19]. Subjects with a creatinine clearance (CrCl) above 50 mL/min were prescribed 600 mg of intravenous ceftaroline every 8–12 h. Patients otherwise were dosed based on their calculated CrCl in accordance with FDA recommendations [20].\n\nStatistical Analysis\n\nData were analyzed using SAS v.9.4 (Cary, NC, USA). p values < 0.05 were regarded as statistically significant. Descriptive statistics were calculated with means, standard deviations, medians, and interquartile ranges for all continuous variables; frequencies and percentages for all categorical variables. To examine bivariate associations with drug type, χ2 tests and Fisher’s Exact tests were conducted for categorical variables, and t tests and Mann–Whitney U tests were conducted for continuous variables.\n\nInverse probability of treatment weighting (IPTW) was utilized to reduce potential bias and confounding by indication. Patient propensity scores were derived via logistic regression and incorporated age, CCI, and PBS values as covariates.\n\nResults\n\nPatient Selection\n\nDuring the study period, we identified 263 patients with MRSA bacteremia lasting 4 days or longer. All were prescribed either vancomycin or daptomycin. One hundred twenty-three of these patients were later prescribed supplemental ceftaroline. Seven patients, however, were removed from study consideration due to ceftaroline being started within 3 days of bacteremia onset.\n\nTwenty-eight of the remaining patients were excluded due to the absence of underlying native valve IE, osteomyelitis, or brain abscess. Three patients were additionally excluded due to care being withdrawn during their hospital stay. Finally, 5 patients were excluded due to leaving against medical advice. In the end, 80 subjects constituted our preliminary investigational population.\n\nFifty patients were later removed from the study. Specifically, 8 patients were excluded due to dying prior to bacteremia resolution. Twenty-five patients were additionally excluded due to being interhospital transfers with pre-existing MRSA bacteremia—thereby preventing requisite PBS value calculation. Finally, 17 patients were excluded due to being prescribed discordant antimicrobial regimens following bacteremia resolution. This resulted in a final study population of 30 subjects (Fig. 1).Fig. 1 Enrollment flow chart and inclusion/exclusion criteria\n\nMonotherapy Group Patient Characteristics and Outcomes\n\nFifteen patients (8 males, 7 females) comprised the monotherapy cohort. Ages ranged from 25 to 70 years old, with an average age of 41. Thirteen subjects had native valve IE (87%), 1 subject had osteomyelitis (7%), and 1 subject was diagnosed with both conditions (7%). Two of the 12 patients (17%) with native valve IE warranting early valve surgery [14] underwent valve replacement while bacteremic. Ceftaroline was begun within 4 to 11 days of refractory bacteremia, with a median value of 6 days. Bacteremia duration varied between 4 and 11 days, with a median value of 7 days. PBS values ranged from 0 to 6, corresponding to a median value of 1. CCI scores were between 0 and 5, with a median score of 0 (Table 1).Table 1 Patient characteristics and study outcomes\n\nVariable\tMonotherapy group (n = 15)\tCombination therapy group (n = 15)\tp value\t\nAge (years), mean (SD)\t41 (13.6)\t46 (15.9)\t0.42\t\nSex, n (%)\t\t\t0.71\t\n Female\t7 (47)\t5 (33)\t\t\n Male\t8 (53)\t10 (67)\t\t\nAccompanying infections, n (%)\t\n Osteomyelitis\t1 (7)\t7 (47)\t0.04\t\n Native valve IE\t13 (87)\t5 (33)\t0.01\t\n Osteomyelitis and native valve IE\t1 (7)\t2 (13)\t0.99\t\n Cerebral abscess\t0 (0)\t1 (7)\t0.99\t\nSurgical candidates who underwent valve replacement, n (%)\t2 (17)\t1 (14)\t0.99\t\nPBS score, median (IQR)\t1 (4.0)\t2 (4.0)\t0.61\t\nCCI score, median (IQR)\t0 (1.0)\t0 (2.0)\t0.85\t\nBacteremia duration preceding ceftaroline (days), median (IQR)\t6 (2.0)\t6 (3.0)\t0.85\t\nTotal bacteremia duration (days), median (IQR)\t7 (3.0)\t8 (4.0)\t0.22\t\nTreatment duration (weeks), median (IQR)\t6 (0)\t6 (1.5)\t0.39\t\nMRSA strains with MIC = 2 μg/mL\t2\t0\t0.48\t\nClinical outcomes, n (%)\t\n AKI\t6 (40)\t7 (47)\t0.36\t\n Leukopenia\t0 (0)\t1 (7)\t0.35\t\n Bacteremia recurrence\t1 (7)\t0 (0)\t0.27\t\n 30-Day readmission\t2 (13)\t0 (0)\t0.14\t\n Death\t1 (7)\t3 (20)\t0.24\t\nAKI acute kidney injury, CCI Charlson comorbidity index, IE infective endocarditis, IQR interquartile range, MIC minimum inhibitory concentration, MRSA methicillin-resistant Staphylococcus aureus, PBS Pitt bacteremia score, SD standard deviation\n\nVancomycin was initially prescribed to all subjects. Five patients, however, were later changed to daptomycin. This was due to AKI in 3 patients. The other 2 patients were changed to daptomycin on account of provider preference. In terms of treatment duration, 2 patients received 7 weeks of therapy and 12 subjects received 6 weeks of therapy. This amounted to a median value of 6 weeks.\n\nThere were no incidences of leukopenia in the monotherapy group. Six patients were diagnosed with AKI. None, however, required hemodialysis at the time of discharge. Two instances of 30-day readmission occurred, though they were unrelated to patients’ previous hospitalizations. One was a result of polymerase chain reaction-confirmed human metapneumovirus pneumonia. The other was to prevent an interruption in outpatient parenteral antimicrobial therapy. One subject encountered a brief 2-day period of bacteremia recurrence prior to ceftaroline discontinuation. It occurred as vancomycin was replaced with daptomycin due to vancomycin-induced AKI. This led to Ceftaroline being administered alone for approximately 12 h. Considering the circumstances, the bacteremia recurrence seemingly was provoked by treatment interruption as opposed to deficient therapy.\n\nOne patient in the monotherapy group expired. A 33-year-old female with native valve IE, she had an abrupt decline status-post bioprosthetic mitral valve replacement (5 days after bacteremia resolution). She was diagnosed with obstructive shock secondary to a post-operative pericardial thrombus. Despite undergoing emergent mediastinal exploration with successful evacuation of the clot, she ultimately arrested. No autopsy was performed following her death.\n\nCombination Therapy Group Patient Characteristics and Outcomes\n\nFifteen patients (10 males, 5 females) comprised the combination therapy cohort. Ages ranged from 24 to 73 years old, with an average age of 46. Seven subjects had osteomyelitis (47%), 5 subjects had native valve IE (33%), 2 subjects were diagnosed with both conditions (13%), and 1 person had a cerebral abscess (7%). One of the 7 patients (14%) with native valve IE warranting early valve surgery [14] underwent valve replacement while bacteremic. Ceftaroline was begun within 4 to 10 days of refractory bacteremia, with a median value of 6 days. Bacteremia duration varied between 5 and 14 days, with a median value of 8 days. PBS values ranged from 0 to 6, corresponding to a median value of 2. CCI scores were between from 0 and 3, with a median score of 0 (Table 1).\n\nVancomycin was initially prescribed to all subjects. Twelve patients, however, were later changed to daptomycin. This was due to the emergence of borderline vancomycin-susceptible MRSA strains in 2 patients, AKI in one person, an allergic reaction in one person, drug-induced neutropenia in one person, and an inability to attain a consistent vancomycin trough of 15–20 ug/mL in one person. The other 6 patients were changed to daptomycin on account of provider preference. In terms of treatment duration, 3 patients received 8 weeks of therapy and 9 patients received 6 weeks of therapy. This amounted to a median value of 6 weeks.\n\nThere was an instance of leukopenia in one person belonging to the combination therapy group. A mild aberration, it led to no particular intervention or detriment. Seven patients were diagnosed with AKI—2 of whom required continued hemodialysis upon hospital discharge. No instances of 30-day readmission or bacteremia recurrence occurred.\n\nThree patients in the combination therapy group expired. The first subject was a 40-year-old male with native valve IE who died 6 days following bacteremia resolution. Suffering from septic central nervous system emboli with hemorrhagic manifestations (first detected 3 days after admission), he expired due to subsequent uncal herniation. The second subject was a 36-year-old female with native valve IE who died 26 days following bacteremia resolution. She progressed well clinically up until sudden hypoxemia led to the diagnosis of acute pulmonary embolism with right heart strain. Despite anticoagulation and aggressive life support measures, she expired within 48 h. The third subject was a 69-year-old male with both native valve IE and osteomyelitis who died 23 days following bacteremia resolution. A few days after his unrivaled 14-day duration of bacteremia ended, acute hypoxemia led to the discovery of aortic valve perforation via echocardiography. He was deemed to not be a surgical candidate by cardiothoracic surgery on the account of clinical instability. He eventually expired due to progressive cardiac decompensation refractory to medical therapy. Of note, none of the above patients underwent autopsy.\n\nGroup Outcome Comparisons\n\nNo statistically significant difference in patient outcomes was seen after comparing the two treatment groups following IPTW standardization (Table 1). Bacteremia recurrence occurred in 1 person in the monotherapy group (7%) versus 0 in the combination therapy group (p = 0.27). Two cases of 30-day readmission occurred in the monotherapy group (13%) versus 0 in the combination therapy group (p = 0.14). While 3 patients died in the combination therapy group (20%) versus only 1 in the monotherapy group (7%), the difference was not statistically significant (p = 0.24). A total of 6 instances of AKI occurred in the monotherapy group (40%) versus 7 in the combination therapy group (47%) (p = 0.36). Finally, 1 episode of leukopenia occurred in the monotherapy group (7%) versus 0 in the combination therapy group (p = 0.35).\n\nDiscussion\n\nTo the best of our knowledge, this is the first published study investigating whether to continue with ceftaroline following bacteremia resolution in patients with prolonged MRSA bacteremia requiring combination therapy. As detailed previously, no statistically significant difference in treatment outcomes was seen between the combination therapy and monotherapy groups. The result complements an in vitro study reported by Barber [21] which compared MRSA isolates treated with daptomycin plus ceftaroline for 8 days to MRSA isolates treated with daptomycin plus ceftaroline for 4 days followed by a 4-day course of daptomycin alone. Pharmacokinetic/pharmacodynamic analysis found no significant difference in growth inhibition between the two regimens.\n\nConsidering treatment outcomes did not differ in patients prescribed vancomycin or daptomycin alone following bacteremia resolution, our finding encourages confining ceftaroline use to active bacteremia. It relatedly affords beneficial medical and financial repercussions. Adverse effects of ceftaroline ranging from mild intolerance, e.g., headache, nausea, diarrhea, etc. to worrisome Clostridioides difficile infection have been reported [22].Given this, requisite employment seems prudent from a patient safety standpoint. The perceived threat of future antimicrobial resistance further compels economical usage. Discontinuing ceftaroline following bacteremia resolution also potentially eliminates several weeks of ceftaroline therapy. In so doing, it allows for substantial cost savings individually as well as institutionally.\n\nNo universal length-related definition of prolonged MRSA bacteremia exists. We chose to investigate patients administered ceftaroline after at least 4 days of MRSA bacteremia given said duration has been associated with an increased risk of mortality [23]. This aside, there were concerns that patient degree of comorbidities and/or illness severity influenced medical providers’ decision to continue with ceftaroline following bacteremia resolution. Representative CCI and PBS values along with subject ages were consequently used in propensity score formulation. IPTW standardization of the trial population was thereafter implemented to diminish the likelihood of indication bias compromising our findings.\n\nRegarding study deaths, the occurrences seemingly were not due to substandard antibiotic therapy. The one monotherapy cohort patient likely instead expired from non-infectious complications of valve surgery. As for deaths in the combination therapy cohort, the 40-year-old male patient with native valve IE likely expired from medically unpreventable/untreatable disease sequelae given his pre-existing cerebral emboli. The 36-year-old female patient with native valve IE likely expired from a known consequence of critical illness—given her fatal acute pulmonary embolism. Finally, the 69-year-old male with both native valve IE and osteomyelitis likely expired from an unfortunate combination of disease severity plus inadequate source control given the protracted duration of his preceding bacteremia. However, evidence in support of these conclusions is unable to be provided due to absent autopsy results.\n\nOur study is not without a few limitations. Aside from the innate flaws associated with any retrospective investigation, the study population was admittedly modest. This was partly due to infrequent episodes of prolonged MRSA bacteremia necessitating ceftaroline at our institution. Two stipulations additionally pared the study census. A significant number of patients were excluded from study consideration due to absent accompanying osteomyelitis, native valve IE, or brain abscess. These requirements, though, were essential in ensuring subjects appropriately received several weeks of antimicrobial therapy. It was feared that shorter antibiotic courses could possibly obscure outcome differences between the treatment groups. Secondly, many patients were transferred from neighboring medical centers with known MRSA bacteremia. Limited accompanying medical records/patient data precluded PBS score calculation. The subsequent inability to eliminate severity of illness as a confounding factor warranted their removal.\n\nAnother study limitation pertained to patient deaths. As mentioned previously, three subjects were removed from the study population due to care being withdrawn during their hospital stay. This was necessary in maintaining study integrity. That being said, these patients all had a minimal chance for recovery. Study deaths may thus have been lessened by their removal.\n\nAlthough not a limitation per se, daptomycin replaced vancomycin in several patients once ceftaroline was begun. The change in therapy was largely due to AKI or provider preference. All involved MRSA isolates retained vancomycin susceptibility at the time. In this respect, the antibiotic change likely was inconsequential as both agents equally treat vancomycin-susceptible MRSA bacteremia [4]. As for the two combination therapy group patients prescribed daptomycin due to emergent borderline vancomycin-susceptible MRSA strains, fears of vancomycin ineffectiveness led to the substitution. Whether MIC creep absolutely demands vancomycin discontinuation in patients with MRSA bacteremia is unclear [26]. Regardless, the change in therapy likely did not affect assessed patient outcomes. The fact that it preceded bacteremia resolution and daptomycin was continued (along with ceftaroline) for 6–8 weeks as planned supports this conclusion.\n\nThe PBS model was chosen for risk stratification purposes as opposed to alternative scoring systems due to it being developed expressly for bacteremic subjects. The decision was further supported by the studies of Gasch [24] and Kim [25], which found PBS values greater than 3 to be associated with early mortality in patients with MRSA bacteremia. This gave context to our patients’ PBS values given that no universal score interpretation exists. The median PBS value of the combination therapy cohort was 2 and the median PBS value of the monotherapy cohort was 1. As such, both treatment groups lacked severely ill patients. This raises the question of whether our findings apply to sicker individuals. Also, the study population largely consisted of middle-aged subjects with no past medical history aside from intravenous drug abuse. The absence of subjects with multiple chronic medical problems led to a median CCI score of 0 for both cohorts. This raises the question of whether our findings apply to individuals with considerable comorbid conditions.\n\nConclusion\n\nIn summary, discontinuing ceftaroline following bacteremia resolution in patients with vancomycin- or daptomycin-refractory complicated and prolonged MRSA bacteremia resulted in no statistically significant difference in treatment outcomes versus patients who continued combination therapy. This finding suggests restricting supplemental ceftaroline to bacteremic patients. However, given the retrospective nature of our study and overall patient characteristics, future prospective trials involving more ill subjects with several chronic diseases would be worthwhile.\n\nAcknowledgements\n\nWe thank the patients who participated in the study.\n\nFunding\n\nNo funding or sponsorship was received either for the study or article publication. The Rapid Service Fee was funded by the authors.\n\nEditorial Assistance\n\nWe would like to thank Susan Shepherd, MS, for her assistance in drafting the antimicrobial susceptibility testing section of the manuscript.\n\nAuthorship\n\nAll named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship of this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.\n\nDisclosures\n\nOmar Ahmad, Timothy N. Crawford and Thein Myint declare that they have no conflict of interest.\n\nCompliance with Ethics Guidelines\n\nThe presented study received approval from The University of Kentucky Office of Research Integrity Institutional Review Board and conformed with the Helsinki Declaration of 1964 (as revised in 2013) concerning human and animal rights. On account of the investigation being carried out through retrospective review of medical records, ethics approval was not required due to no foreseeable impact on the rights and/or welfare of subjects involved. Consent from study participants was additionally not obtained due to the study solely involving retrospective review of medical records.\n\nOpen Access\n\nThis 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.\n\nEnhanced Digital Features\n\nTo view enhanced digital features for this article go to 10.6084/m9.figshare.10303835.\n==== Refs\nReferences\n\n1. Mylotte JM McDermott C Spooner JA Prospective study of 114 consecutive episodes of Staphylococcus aureus bacteremia Rev Infect Dis 1987 9 891 10.1093/clinids/9.5.891 3317734\n2. Shurland S Zhan M Bradham DD Roghmann MC Comparison of mortality risk associated with bacteremia due to methicillin-resistant and methicillin-susceptible Staphylococcus aureus Infect Control Hosp Epidemiol 2007 28 273 10.1086/512627 17326017\n3. Lodise TP Graves J Evans A Graffunder E Helmecke M Lomaestro BM Stellrecht K Relationship between vancomycin MIC and failure among patients with methicillin-resistant Staphylococcus aureus bacteremia treated with vancomycin Antimicrob Agents Chemother 2008 52 3315 10.1128/AAC.00113-08 18591266\n4. Kollef MH Limitations of vancomycin in the management of resistant staphylococcal infections Clin Infect Dis 2007 45 191 195 10.1086/519470\n5. Sakoulas G Moellering RC Increasing antibiotic resistance among methicillin-resistant Staphylococcus aureus strains Clin Infect Dis 2008 46 360 367 10.1086/533592\n6. Boucher HW Sakoulas G Perspectives on daptomycin resistance, with emphasis on resistance in Staphylococcus aureus Clin Infect Dis 2007 45 601 608 10.1086/520655 17682996\n7. Corey GR Wilcox M Talbot GH Friedland HD Baculik T Witherell GW Critchley I Das AF Thye D Integrated analysis of CANVAS 1 and 2: phase 3, multicenter, randomized, double-blind studies to evaluate the safety and efficacy of ceftaroline versus vancomycin plus aztreonam in complicated skin and skin-structure infection Clin Infect Dis 2010 51 641 650 10.1086/655827 20695801\n8. White BP Barber KE Stover KR Ceftaroline for the treatment of methicillin-resistant Staphylococcus aureus bacteremia Am J Health Syst Pharm 2017 74 201 208 10.2146/ajhp160006 28179245\n9. Cosimi RA Beik N Kubiak DW Johnson JA Ceftaroline for severe methicillin-resistant Staphylococcus aureus infections: a systematic review Open Forum Infect Dis 2017 4 ofx084 10.1093/ofid/ofx084 28702467\n10. Gritsenko D Fedorenko M Ruhe JJ Altshuler J Combination therapy with vancomycin and ceftaroline for refractory methicillin-resistant Staphylococcus aureus bacteremia: a case series Clin Ther 2017 39 212 218 10.1016/j.clinthera.2016.12.005 28038791\n11. Barber KE Rybak MJ Sakoulas GJ Vancomycin plus ceftaroline shows potent in vitro synergy and was successfully utilized to clear persistent daptomycin-non-susceptible MRSA bacteremia J Antimicrob Chemother 2015 70 311 313 10.1093/jac/dku322 25125677\n12. Shafiq I Bulman ZP Spitznogle SL Osorio JE Reilly IS Lesse AJ Parameswaran GI Mergenhagen KA Tsuji BT A combination of ceftaroline and daptomycin has synergistic and bactericidal activity in vitro against daptomycin nonsusceptible methicillin-resistant Staphylococcus aureus (MRSA) Infect Dis (Lond) 2017 49 410 416 10.1080/23744235.2016.1277587 28116950\n13. Clinical and Laboratory Standards Institute/NCCLS Performance Standards for Antimicrobial Susceptibility Testing. Sixteenth informational supplement M100-S16 2006 Wayne CLSI\n14. Baddour LM Wilson WR Bayer AS Fowler VG Tleyjeh IM Rybak MJ Barsic B Lockhart PB Gewitz MH Levison ME Bolger AF Steckelberg JM Baltimore RS Fink AM O’Gara P Taubert KA Infective endocarditis in adults: diagnosis, antimicrobial therapy, and management of complications: a scientific statement for healthcare professionals from the american heart association Circulation 2015 132 1435 10.1161/CIR.0000000000000296 26373316\n15. Charlson ME Pompei P Ales KL MacKenzie CR A new method of classifying prognostic comorbidity in longitudinal studies: development and validation J Chronic Dis 1987 40 373 383 10.1016/0021-9681(87)90171-8 3558716\n16. Chow JW Fine MJ Shlaes DM Quinn JP Hooper DC Johnson MP Ramphal R Wagener MM Miyashiro DK Yu VL Enterobacter bacteremia: clinical features and emergence of antibiotic resistance during therapy Ann Intern Med 1991 115 585 590 10.7326/0003-4819-115-8-585 1892329\n17. Liu C Bayer A Cosgrove SE Daum RS Fridkin SK Gorwitz RJ Kaplan SL Karchmer AW Levine DP Murray BE Rybak M Talan DA Chambers HF Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children Clin Infect Dis 2011 52 e18 e55 10.1093/cid/ciq146 21208910\n18. Wu G Abraham T Rapp J Vastey F Saad N Balmir E Daptomycin: evaluation of a high-dose treatment strategy Int J Antimicrob Agents 2011 38 192 196 10.1016/j.ijantimicag.2011.03.006 21549573\n19. Bassetti M Nicco E Ginocchio F Ansaldi F de Florentiis D Viscoli C High-dose daptomycin in documented Staphylococcus aureus infections Int J Antimicrob Agents 2010 36 459 461 10.1016/j.ijantimicag.2010.07.011 20846832\n20. Teflaro [package insert]. Saint Louis: Forest Pharmaceuticals; 2016.\n21. Barber KE Werth BJ Rybak MJ The combination of ceftaroline plus daptomycin allows for therapeutic de-escalation and daptomycin sparing against MRSA J Antimicrob Chemother 2015 70 505 509 10.1093/jac/dku378 25246437\n22. Duplessis C Crum-Cianflone NF Ceftaroline: a new cephalosporin with activity against methicillin-resistant Staphylococcus aureus (MRSA) Clin Med Rev Ther 2011 3 a2466 21785568\n23. van Hal SJ Jensen SO Vaska VL Espedido BA Paterson DL Gosbell IB Predictors of mortality in Staphylococcus aureus bacteremia Clin Microbiol Rev 2012 25 362 386 10.1128/CMR.05022-11 22491776\n24. Gasch O Camoez M Dominguez MA Padilla B Pintado V Almirante B Lepe JA Lagarde M Ruiz de Gopegui E Martínez JA Montejo M Torre-Cisneros J Arnáiz A Goenaga MA Benito N Rodríguez-Baño J Pujol M Predictive factors for early mortality among patients with methicillin-resistant Staphylococcus aureus bacteremia J Antimicrob Chemother 2013 68 1423 1430 10.1093/jac/dkt016 23404193\n25. Kim T Chong YP Park KH Bang KM Park SJ Kim SH Jeong JY Lee SO Choi SH Woo JH Kim YS Clinical and microbiological factors associated with early patient mortality from methicillin-resistant Staphylococcus aureus bacteremia Korean J Intern Med 2018 34 184 194 10.3904/kjim.2016.351\n26. Kalil AC Van Schooneveld TC Fey PD Rupp ME Association between vancomycin minimum inhibitory concentration and mortality among patients with Staphylococcus aureus bloodstream infections: a systematic review and meta-analysis JAMA 2014 312 1552 1564 10.1001/jama.2014.6364 25321910\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2193-6382",
"issue": "9(1)",
"journal": "Infectious diseases and therapy",
"keywords": "Bacteremia; Ceftaroline; Daptomycin; MRSA; Vancomycin",
"medline_ta": "Infect Dis Ther",
"mesh_terms": null,
"nlm_unique_id": "101634499",
"other_id": null,
"pages": "77-87",
"pmc": null,
"pmid": "31776844",
"pubdate": "2020-03",
"publication_types": "D016428:Journal Article",
"references": "25321910;17712746;20695801;22491776;28859468;17326017;28702467;26373316;23404193;21549573;21208910;1892329;28038791;21785568;25125677;20846832;28116950;28179245;3317734;3558716;17682996;18591266;25246437;18462091",
"title": "Comparing the Outcomes of Ceftaroline Plus Vancomycin or Daptomycin Combination Therapy Versus Monotherapy in Adults with Complicated and Prolonged Methicillin-Resistant Staphylococcus Aureus Bacteremia Initially Treated with Supplemental Ceftaroline.",
"title_normalized": "comparing the outcomes of ceftaroline plus vancomycin or daptomycin combination therapy versus monotherapy in adults with complicated and prolonged methicillin resistant staphylococcus aureus bacteremia initially treated with supplemental ceftaroline"
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"abstract": "BACKGROUND\nThe organ shortage is a global problem. A potential approach to expanding the deceased donor pool is to harvest organs from pediatric patients.\n\n\nMETHODS\nSeven cases of dual kidney transplantation from pediatric donors to adult recipients were performed between 2012 and 2014 in our center. The proximal end of the donor aorta (AO) was anastomosed to the right common iliac artery or external artery. The proximal end of the donor inferior vena cava (IVC) was anastomosed to the right external iliac vein. Recipients received basiliximab or antithymocyte globulin as induction therapy, followed by tacrolimus, mycophenolate mofetil, and prednisone. Prophylactic anticoagulation was not universal in our study.\n\n\nRESULTS\nDuring the 21-month study period, both patient and graft survivals were 100%. No patient showed thrombotic complications. Complications included an acute rejection episode in 1 patient, urine leakage in 2, and anticoagulation related hemorrhage in 1. All recipients had excellent graft function with normal serum creatinine ranging from 0.49 to 1.45 mg/dL and estimated glomerular filtration rate ranging from 56.89 to 145.27 mL/min/1.73 m(2).\n\n\nCONCLUSIONS\nDual kidney transplantation from pediatric donors to adult recipients is a promising way to expand the donor pool. Using the proximal end of the AO/IVC for anastomosis brings satisfactory results.",
"affiliations": "Urologic Organ Transplantation Department, the Second Xiang-Ya Hospital, Central South University, Changsha, China.;Operation Department, the Second Xiang-Ya Hospital, Central South University, Changsha, China.;Urologic Organ Transplantation Department, the Second Xiang-Ya Hospital, Central South University, Changsha, China.;Urologic Organ Transplantation Department, the Second Xiang-Ya Hospital, Central South University, Changsha, China.;Urologic Organ Transplantation Department, the Second Xiang-Ya Hospital, Central South University, Changsha, China.;Urologic Organ Transplantation Department, the Second Xiang-Ya Hospital, Central South University, Changsha, China. Electronic address: plk3000@163.com.",
"authors": "Yu|S-J|SJ|;Liu|H-C|HC|;Song|L|L|;Dai|H-L|HL|;Peng|F-H|FH|;Peng|L-K|LK|",
"chemical_list": null,
"country": "United States",
"delete": false,
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"issn_linking": "0041-1345",
"issue": "47(6)",
"journal": "Transplantation proceedings",
"keywords": null,
"medline_ta": "Transplant Proc",
"mesh_terms": "D000328:Adult; D002675:Child, Preschool; D005260:Female; D005500:Follow-Up Studies; D006085:Graft Survival; D006801:Humans; D007223:Infant; D016030:Kidney Transplantation; D008297:Male; D014019:Tissue Donors; D066027:Transplant Recipients",
"nlm_unique_id": "0243532",
"other_id": null,
"pages": "1727-31",
"pmc": null,
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"pubdate": "2015",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Dual Kidney Transplantation From Pediatric Donors to Adult Recipients.",
"title_normalized": "dual kidney transplantation from pediatric donors to adult recipients"
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"activesubstancename": "BASILIXIMAB"
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"abstract": "While bisphosphonates have been shown to be effective in reducing the incidence of typical osteoporotic fractures, long-term bisphosphonate may be associated with atypical femoral fractures. We report a case of a bisphosphonate-related impending atypical femoral fracture which progressed despite prophylactic cephalomedullary nailing. The fracture healed without further surgical intervention after correcting the patient's bone metabolic profile and stopping the possible offending factors. Although prophylactic fixation of these fractures is recommended, our case and relevant literature review demonstrate that a simple fixation without optimizing other possible predisposing factors may not prevent progression of these fractures.",
"affiliations": "SUNY Downstate Medical Center, Department of Orthopaedic Surgery and Rehabilitation, Brooklyn, NY, United States.;SUNY Downstate Medical Center, Department of Orthopaedic Surgery and Rehabilitation, Brooklyn, NY, United States.;SUNY Downstate Medical Center, Department of Orthopaedic Surgery and Rehabilitation, Brooklyn, NY, United States.;SUNY Downstate Medical Center, Department of Orthopaedic Surgery and Rehabilitation, Brooklyn, NY, United States.",
"authors": "Maheshwari|Aditya V|AV|;Yarmis|Samantha J|SJ|;Tsai|Justin|J|;Jauregui|Julio J|JJ|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.1016/j.jcot.2016.06.003",
"fulltext": null,
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"issn_linking": "0976-5662",
"issue": "7(Suppl 1)",
"journal": "Journal of clinical orthopaedics and trauma",
"keywords": "Atypical femur fractures; Bisphosphonate associated fractures; Bisphosphonates; Pathologic fractures; Stress fractures",
"medline_ta": "J Clin Orthop Trauma",
"mesh_terms": null,
"nlm_unique_id": "101559469",
"other_id": null,
"pages": "92-98",
"pmc": null,
"pmid": "28018083",
"pubdate": "2016",
"publication_types": "D002363:Case Reports",
"references": "15687150;16295817;19198962;20493982;20675513;20809164;21350886;21542743;21561306;21940585;22125247;22146214;22733959;22870488;23324969;23365544;23712442;24660094;25574419;25817305;25943378;29252244;29252422;29252698;29252845",
"title": "Progression of bisphosphonate-associated impending atypical femoral fracture despite prophylactic cephalomedullary nailing: A case report and review of literature.",
"title_normalized": "progression of bisphosphonate associated impending atypical femoral fracture despite prophylactic cephalomedullary nailing a case report and review of literature"
} | [
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"companynumb": "US-APOTEX-2017AP006433",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
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"actiondrug": "1",
"activesubstance": {
"activesubstancename": "LENALIDOMIDE"
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... |
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"abstract": "BACKGROUND\nStercoral perforation of the colon is a rare pathology, which is believed to be caused by an increased intraluminal pressure created by a fecaloma. Opioid induced constipation is a rare and often unsuspected cause of colonic perforation.\n\n\nMETHODS\nWe report the case of a 58-year-old woman, who presented to the emergency department (ED) with severe hypotension, abdominal pain and gastrointestinal bleeding. She was found to have a diffusely tender and distended abdomen. Her history was positive for long-term suboxone use and chronic constipation. Abdominopelvic computed tomography (CT) scan revealed a bowel perforation, ascites and fecal impaction. Emergency laparotomy revealed extensive stool in the peritoneal cavity as well as hemoperitoneum. There was a fecal bolus with perforation located in the sigmoid colon. On postoperative day (POD) six, a second abdominopelvic CT scan was performed and results revealed the necessity of a second exploratory laparotomy. She had multiple loculated abscesses within the small bowel and other areas, which were opened and washed out.\n\n\nCONCLUSIONS\nDue to the inflating use of drugs in the opioid class, the recognition of this pathology has become increasingly important. The action of the drug on the mu-opioid receptors, any patients taking opioid medications are at risk for constipation progressing to stercoral perforation and should be monitored closely.\n\n\nCONCLUSIONS\nPatients presenting with chronic constipation, fecal impaction on imaging and clinical signs of peritonitis or sepsis, should consider stercoral perforation in their differential diagnosis since early detection is key to reduce mortality rates in these cases.",
"affiliations": "Avalon University School of Medicine, Youngstown, OH, United States. Electronic address: reneelexiepoitras@gmail.com.;Avalon University School of Medicine, Youngstown, OH, United States.;Department of General Surgery, Raleigh General Hospital, Beckley, WV, United States.",
"authors": "Poitras|Renée|R|;Warren|Daun'Lee|D|;Oyogoa|Sylvanus|S|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.ijscr.2017.11.060",
"fulltext": "\n==== Front\nInt J Surg Case RepInt J Surg Case RepInternational Journal of Surgery Case Reports2210-2612Elsevier S2210-2612(17)30640-510.1016/j.ijscr.2017.11.060ArticleOpioid drugs and stercoral perforation of the colon: Case report and review of literature Poitras Renée reneelexiepoitras@gmail.coma⁎Warren Daun’Lee aOyogoa Sylvanus ba Avalon University School of Medicine, Youngstown, OH, United Statesb Department of General Surgery, Raleigh General Hospital, Beckley, WV, United States⁎ Corresponding author at: Avalon University School of Medicine, P.O. BOX 480, Girard, OH 44420, United States.Avalon University School of MedicineYoungstownOHUnited States reneelexiepoitras@gmail.com07 12 2017 2018 07 12 2017 42 94 97 26 6 2017 28 11 2017 28 11 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/).Highlights\n• Patient’s condition was further compounded by splenic rupture.\n\n• Recovery was complicated by post-op sepsis and intraabdominal abscesses.\n\n• Constipation may be missed due to encopresis and the analgesic effects of opioids.\n\n\n\nIntroduction\nStercoral perforation of the colon is a rare pathology, which is believed to be caused by an increased intraluminal pressure created by a fecaloma. Opioid induced constipation is a rare and often unsuspected cause of colonic perforation.\n\nPresentation of case\nWe report the case of a 58-year-old woman, who presented to the emergency department (ED) with severe hypotension, abdominal pain and gastrointestinal bleeding. She was found to have a diffusely tender and distended abdomen. Her history was positive for long-term suboxone use and chronic constipation. Abdominopelvic computed tomography (CT) scan revealed a bowel perforation, ascites and fecal impaction. Emergency laparotomy revealed extensive stool in the peritoneal cavity as well as hemoperitoneum. There was a fecal bolus with perforation located in the sigmoid colon. On postoperative day (POD) six, a second abdominopelvic CT scan was performed and results revealed the necessity of a second exploratory laparotomy. She had multiple loculated abscesses within the small bowel and other areas, which were opened and washed out.\n\nDiscussion\nDue to the inflating use of drugs in the opioid class, the recognition of this pathology has become increasingly important. The action of the drug on the mu-opioid receptors, any patients taking opioid medications are at risk for constipation progressing to stercoral perforation and should be monitored closely.\n\nConclusion\nPatients presenting with chronic constipation, fecal impaction on imaging and clinical signs of peritonitis or sepsis, should consider stercoral perforation in their differential diagnosis since early detection is key to reduce mortality rates in these cases.\n\nAbbreviations\nCT, computed tomographyED, emergency departmentPOD, postoperative dayKeywords\nStercoral perforationConstipationSuboxoneOpioidsBuprenorphine\n==== Body\n1 Introduction\nStercoral perforation was first described by Berry to the Pathological Society of London in 1894 [1]. Colon perforation caused by stercoral ulcer is extremely rare, with fewer than 150 cases reported in the English language to date [2]. The pathogenesis is thought to be caused by an increased intraluminal pressure by the stercoraceous mass, causing localized ischemic pressure necrosis of the bowel. Ulceration, bowel wall thinning and subsequent bacterial invasion progresses to perforation [3]. There are many causes of stercoral perforation, such as chronic constipation, Chagas disease, Hirschsprung’s disease, toxic colitis and megacolon. We will focus on stercoral perforation caused by opioid induced chronic constipation, as was the case with our patient.\n\nThis case report has been reported in line with the SCARE criteria [4].\n\n2 Presentation of case\nA 58-year-old female was admitted to the department of surgery through the ED with a chief complaint of severe abdominal pain and discomfort as well as a syncopal episode thought to be related to patient's hypotensive state. She had a history of chronic pain syndrome treated with long-term sublingual 8 mg–2 mg Suboxone film therapy, current infection of hepatitis C, chronic untreated constipation, reported history of irregular heartbeat and possible history of coronary artery disease treated as outpatient with Plavix. The patient was unable to provide any family history. She currently lives with her husband and is unemployed. She stated that her only positive drug history was the suboxone. Her past surgical history revealed a partial hysterectomy, a cholecystectomy as well as an appendectomy.\n\nOn initial physical exam, the patient was found to have a diffusely tender and distended abdomen and hematochezia. She was afebrile and hypotensive with a systolic blood pressure in the 80s–90s. Her white blood count on admission was 6.5 × 109/L. Abdominopelvic CT scan revealed a bowel perforation most likely in the distal colon, ascites and fecal impaction of the large bowel (Fig. 1, Fig. 2). The initial diagnosis was perforated ischemic bowel. Emergency surgery was performed by Dr. Sylvanus Oyogoa. Intraoperatively, she was found to have extensive stool in the peritoneal cavity as well as hemoperitoneum. There was a large fecal mass located in the sigmoid colon causing pressure necrosis on surrounding tissues that had progressed to bowel perforation. Fecal material was protruding through the perforation site into the peritoneal cavity. Hartmann’s procedure was used to resect the affected bowel. A splenic rupture was also noted and a splenectomy was performed (Fig. 3). The colostomy was created in the full quadrant bisecting with simple fashion and a wound VAC was placed following closure. The patient was given antibodies initially and was given Zosyn, Flagyl and Vancomycin. Post-op diagnosis was perforated bowel, fecal peritonitis, hemoperitoneum and splenic rupture. Postoperatively, she continued to show signs of sepsis as well as continual complaints of worsening abdominal pain. On POD six, a second abdominopelvic CT scan was performed and revealed increased free fluid within the abdominal cavity, increased attenuation more dependently, extraluminal oral contrast is seen in the fluid within the abdominal cavity consistent with bile leak. High-density fluid present in the left upper quadrant was suggestive of a contrast leak at the location of splenectomy (Fig. 4). This raised concern for possible venous leak and a second exploratory laparotomy with washout was performed on POD seven. Preoperative diagnosis was perforated gut with fecal peritonitis, intraabdominal abscess, and sepsis. Upon exploration of the cavity, the patient had lots of murky dusky looking fluid in the abdomen. There was no evidence of compromised bowel, she had multiple loculated abscesses within the small bowel and other areas, which were opened and washed out very gently with antibiotic solution and sterile solution. The patient tolerated the procedure well and was brought to the recovery room in stable condition. Post-op diagnosis was intraabdominal abscesses and sepsis. After re-operation, she showed steady recovery with conservative treatment.Fig. 1 Preoperative CT Abdomen/Pelvis showing significant amount of fecal matter within the pelvis.\n\nFig. 1Fig. 2 Preoperative axial CT Abdomen showing small pockets of free gas at the anterior abdominal wall, colonic perforation and fecal impaction of the large bowel.\n\nFig. 2Fig. 3 Preoperative axial CT Abdomen showing spleen that was found to be ruptured during laparotomy.\n\nFig. 3Fig. 4 POD6 axial CT Abdomen with hyperdense area in LUQ.\n\nFig. 4\n\n3 Discussion\nStercoral perforation or “perforation of the large bowel due to pressure necrosis from a fecal mass” [5] is a rare, yet dangerous condition that carries a mortality rate ranging from 32 to 57% [6]. It is thought to be the cause of 3.2% of all colonic perforations and 2.2% of randomly selected autopsy examinations [7]. The mean patient age in cases of stercoral perforation is 59 years and the age range is 22–85 years of age [8]. Mauer et al., proposed four diagnostic criteria for classification as stercoral perforation: 1) A round and ovoid antimesenteric colonic perforation larger than 1 cm in diameter 2). The colon full of stool that protrudes through the perforation site 3) Microscopic evidence of multiple pressure ulcer and acute inflammatory reaction surrounding the perforation 4) Absence of external injury, diverticulitis or obstruction due to neoplasm or adhesions [9]. The four diagnostic criteria were met in our case.\n\nThis patient suffered from chronic drug-induced constipation, which is one of the well-documented risk factors of stercoral perforation. Many drugs currently prescribed carry a high incidence of constipation as a side effect including, amongst others, opioids, anti-cholinergics, antispasmodics, tricyclic antidepressants and calcium channel blockers. Our patient was treated with sublingual 8 mg–2 mg Suboxone film therapy for chronic pain syndrome, causing her decreased gastrointestinal (GI) motility. Constipation is a common side effect of Suboxone use, experienced in 5–12.1% of all Suboxone users [10]. Buprenorphine, the major constituent of Suboxone, is a partial agonist of the mu and delta opioid receptor as well as an antagonist of the kappa-opioid receptor. Mu-opioid receptor agonists inhibit gastric emptying, increase pyloric muscle tone, induce pyloric and duodenojejunal phasic pressure activity, disturb the migrating myoelectric complex, delay transit through the small and large intestine, and elevate the resting anal sphincter pressure [11]. The decreased velocity of stool through the GI systems increases fecal contact time with the GI mucosa and promotes excessive absorption of water and electrolytes causing bulkier, firm stools. Due to their action on mu-opioid receptors, any patient taking opioid medications are at risk for this condition and should be monitored closely. Treating the constipation before a fecaloma can develop would eliminate the development of pressure necrosis caused by increased intraluminal pressure thus halting the incidence of stercoral perforation.\n\n4 Conclusion\nThis case report has identified and presented a 58-year-old female patient with stercoral perforation. In our case, the patient had chronic pain treated with long-term sublingual 8 mg–2 mg Suboxone film therapy causing her chronic constipation. Due to its high mortality rate, early identification of patients at risk for stercoral perforation is important. Only 10% of patients with this condition are correctly diagnosed before surgery [12]. Some patients with a fecaloma may experience episodes of bowel incontinence as a result of encopresis and get wrongfully treated with antidiarrheal medication thus causing further progression of the pathology. Stercoral perforation of the colon is an often-overlooked complication of opioid use. Due to the widespread use of this class of drugs, early identification of this complication is crucial. Any patient presenting with chronic constipation, fecal impaction on x-ray or CT scan and clinical signs of peritonitis or sepsis, should have stercoral perforation included in their differential diagnosis.\n\nConflicts of interest\nThere are no conflicts of interest.\n\nFunding\nThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\n\nEthical approval\nEthical approval has been exempted by Raleigh General Hospital’s Ethical and Compliance committee, no reference number was given for their judgement.\n\nConsent\nWritten informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.\n\nAuthor contribution\nRenee Poitras: Responsible for research, organization, and composition of this case report.\n\nDaun'Lee Warren: Responsible for critical review and corrections of this case report.\n\nSylvanus Oyogoa, MD: Responsible for the interview, exam, and surgical management of the patient.\n\nRegistration of research studies\nThis is inapplicable to our case report.\n\nGuarantor\nRenée Poitras.\n==== Refs\nReferences\n1 Huang Wen-Shih Wang Chia-Siu Hsieh Ching-Chuan Lin Paul Y. Chin Chih-Chien Wang Jeng-Yi Management of patients with stercoral perforation of the sigmoid colon: report of five cases World J. Gastroenterol. 12 3 2006 500 16489660 \n2 Kang Jeonghyun Min Chung A stercoral perforation of the descending colon J. Korean Surg. Soc. 82 2 2012 125 22347716 \n3 Alexander-Williams J. Hollingworth J. Stercoral perforation of the colon Br. J. Surg. 68 6 1991 763 \n4 Agha R.A. Fowler A.J. Saetta A. Barai I. Rajmohan S. Orgill D.P. for the SCARE Group The SCARE statement: consensus-based surgical case report guidelines Int. J. Surg. 34 2016 180 186 27613565 \n5 Kang Jeonghyun Min Chung A stercoral perforation of the descending colon J. Korean Surg. Soc. 82 2012 125 127 22347716 \n6 Shiv Kumar Bunkar Stercoral perforation of the sigmoid colon in a schizophrenic patient JCDR 9 1 2015 PD07 PD08 \n7 Bhatt Vijaya R. Perforation in a patient with stercoral colitis and diverticulosis: who did it? J. Commun. Hosp. Intern. Med. Perspect. 4 1 2014 \n8 Maurer C.A. Renzulli P. Mazzucchelli L. Egger B. Seiler C.A. Büchler M.W. Use of accurate diagnostic criteria may increase incidence of stercoral perforation of the colon Dis. Colon Rectum 43 2000 991 998 10910249 \n9 Davies Andrew Stercoral perforation of the colon a potentially fatal complication of opioid-induced constipation J. Pain Symptom Manage. 50 2 2015 260 262 25847850 \n10 Buprenorphine/naloxone (Rx).Suboxone, Zubsolv (buprenorphine/naloxone) Dosing, Indications, Interactions, Adverse Effects, and More 2017 Medscape Web. 20 May 2017. 02 May \n11 Holzer Peter Opioid receptors in the gastrointestinal tract Regul. Pept. 155 1-3 2009 11 17 19345246 \n12 Yang Bo Ni Huai-Kun Diagnosis and treatment of spontaneous colonic perforation: analysis of 10 cases World J. Gastroenterol. 14 28 2008 4569 4572 PMC. Web. 2 2017 18680241\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2210-2612",
"issue": "42()",
"journal": "International journal of surgery case reports",
"keywords": "Buprenorphine; Constipation; Opioids; Stercoral perforation; Suboxone",
"medline_ta": "Int J Surg Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101529872",
"other_id": null,
"pages": "94-97",
"pmc": null,
"pmid": "29232630",
"pubdate": "2018",
"publication_types": "D016428:Journal Article",
"references": "19345246;24596650;25738027;25847850;18680241;22347716;2070253;16489660;27613565;10910249",
"title": "Opioid drugs and stercoral perforation of the colon: Case report and review of literature.",
"title_normalized": "opioid drugs and stercoral perforation of the colon case report and review of literature"
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"companynumb": "US-PURDUE-GBR-2017-0051826",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BUPRENORPHINE"
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"drugadditional": "3",
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{
"abstract": "Bloom syndrome is an autosomal recessive condition characterized by severe pre- and postnatal growth deficiency, immunodeficiency, an increased risk for malignancies, craniofacial dysmorphisms, and \"typical\" erythematous sun-sensitive skin lesions of the face. This facial rash has a butterfly-shaped distribution around the nose and is usually observed for the first time during the early years of life. Though reported as being a main feature of Bloom syndrome, there seems to be phenotypic variability regarding this facial skin rash among patients. It has been previously reported that in some individuals with Bloom syndrome these sun-sensitive lesions are less prominent or even absent. In this report we describe a 36 year old woman with short stature, microcephaly, several dysmorphisms, congenital hypothyroidism and premature ovarian failure. She was diagnosed with nasopharyngeal carcinoma at 36 years of age, only a few months after her consultation at the department of Clinical Genetics. Whole Exome Sequencing demonstrated that she had Bloom syndrome caused by a compound heterozygous mutation in BLM (c.2207_2212delinsTAGATTC; p.(Tyr736Leufs*5) and c.3681del; p.(Lys1227Asnfs*52)). She did not have facial sun-sensitive erythematous rash during childhood nor adulthood. We conclude that Bloom syndrome does not always present with erythematous sun-sensitive skin lesions of the face. We would like to underline that phenotypic variation regarding this \"hallmark\" feature of Bloom syndrome exists. Being aware of this might prevent a delay in diagnosing this rare short-stature syndrome and, subsequently, its potential clinical implications.",
"affiliations": "Department of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands; Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands.;Department of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands.;Department of Head and Neck Oncology and Surgery, The Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.;Department of Head and Neck Oncology and Surgery, The Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.;Department of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands. Electronic address: p.lakeman@amc.uva.nl.",
"authors": "Bouman|Arjan|A|;van Koningsbruggen|Silvana|S|;Karakullukcu|M Bariş|MB|;Schreuder|Willem Hans|WH|;Lakeman|Phillis|P|",
"chemical_list": "C097151:Bloom syndrome protein; D053484:RecQ Helicases",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.ejmg.2017.10.010",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1769-7212",
"issue": "61(2)",
"journal": "European journal of medical genetics",
"keywords": "BLM; Bloom syndrome; Facial erythema; Facial rash; Short stature",
"medline_ta": "Eur J Med Genet",
"mesh_terms": "D000328:Adult; D001816:Bloom Syndrome; D003937:Diagnosis, Differential; D004890:Erythema; D005260:Female; D006801:Humans; D010641:Phenotype; D053484:RecQ Helicases; D013472:Sunlight",
"nlm_unique_id": "101247089",
"other_id": null,
"pages": "94-97",
"pmc": null,
"pmid": "29056561",
"pubdate": "2018-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Bloom syndrome does not always present with sun-sensitive facial erythema.",
"title_normalized": "bloom syndrome does not always present with sun sensitive facial erythema"
} | [
{
"companynumb": "NL-ACCORD-064504",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
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"actiondrug": null,
"activesubstance": {
"activesubstancename": "LEVOTHYROXINE"
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"drugadditional": null,
"... |
{
"abstract": "OBJECTIVE\nTo evaluate the maternal-neonatal outcome in magnesium (Mg)-intoxicated women with preeclampsia with severe features (PESF) treated with magnesium sulfate (MgSO4).\n\n\nMETHODS\nA total of 19 Mg intoxicated PESF women (cases) were compared with 166 PESF women without signs of intoxication (controls).\n\n\nRESULTS\nMg serum levels of cases was higher compared to control group (12.36 ± 3.54 mg/dl versus 2.69 ± 0.83 mg/dl). 3 women died and 3 had major maternal morbidity in cases group compared with zero in the control group (P = 0.009). Mg intoxication was also significantly associated with perinatal deaths and low Apgar scores at 1 and 5 minutes.\n\n\nCONCLUSIONS\nMg intoxication is associated with a increased risk of maternal and perinatal mortality and morbidity.",
"affiliations": "Department Obstetrics and Gynecology, Faculty of Medicine, Universitas Airlangga , Surabaya, Indonesia.;Department Obstetrics and Gynecology, DR. Soetomo General Academic Hospital , Surabaya, Indonesia.;Department Obstetrics and Gynecology, Faculty of Medicine, Universitas Airlangga , Surabaya, Indonesia.;Department Obstetrics and Gynecology, Dr. Moewardi General Hospital, Faculty of Medicine Universitas Sebelas Maret , Solo, Indonesia.;Department Obstetrics and Gynecology, Faculty of Medicine, Universitas Airlangga , Surabaya, Indonesia.;Department Obstetrics and Gynecology, Faculty of Medicine, Universitas Airlangga , Surabaya, Indonesia.;Department Obstetrics and Gynecology, Faculty of Medicine, Universitas Airlangga , Surabaya, Indonesia.",
"authors": "Akbar|Muhammad Ilham Aldika|MIA|https://orcid.org/0000-0002-2003-9282;Yoseph|Daniel|D|;-|Aditiawarman|A|;Bachnas|Muhammad Adrianes|MA|https://orcid.org/0000-0002-1710-3909;Dachlan|Erry Gumilar|EG|;Dekker|Gustaaf Albert|GA|;Ernawati|||https://orcid.org/0000-0002-9344-3606",
"chemical_list": "D008278:Magnesium Sulfate; D008274:Magnesium",
"country": "England",
"delete": false,
"doi": "10.1080/10641955.2020.1754851",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1064-1955",
"issue": "39(3)",
"journal": "Hypertension in pregnancy",
"keywords": "Magnesium intoxication; hypermagnesemia; magnesium sulfate; preeclampsia with severe features",
"medline_ta": "Hypertens Pregnancy",
"mesh_terms": "D000328:Adult; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D008274:Magnesium; D008278:Magnesium Sulfate; D063130:Maternal Death; D066087:Perinatal Death; D011225:Pre-Eclampsia; D011247:Pregnancy; D011256:Pregnancy Outcome; D055815:Young Adult",
"nlm_unique_id": "9421297",
"other_id": null,
"pages": "221-227",
"pmc": null,
"pmid": "32336169",
"pubdate": "2020-08",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Magnesium intoxication in women with preeclampsia with severe features treated with magnesium sulfate.",
"title_normalized": "magnesium intoxication in women with preeclampsia with severe features treated with magnesium sulfate"
} | [
{
"companynumb": "ID-FRESENIUS KABI-FK202008194",
"fulfillexpeditecriteria": "1",
"occurcountry": "ID",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "MAGNESIUM SULFATE"
},
"drugadditional": n... |
{
"abstract": "Enzyme replacement therapy (ERT) is one of the available therapies for mucopolysaccharidosis (MPS). This study presents a follow-up of two siblings with MPS IVA (Morquio A disease) that received ERT. Both siblings received weekly intravenous infusions of elosulfase alfa for 4.5 years. One sibling (patient 1, P1; male) started therapy at 54 months of age, and the other sibling (patient 2, P2; female) started at 11 months of age. ERT was well-tolerated. In comparison to P1, P2's growth curves deviated less from the norm. The orthopedic deformities of P1 were more severe than those of P2 and required several surgical corrections. P1's sleep test at 48 months revealed obstructive sleep apnea, while by the age of 102 months, parameters were normal. P2 never had sleep apnea. Only P1 demonstrated ear, nose, and throat clinical illnesses. In comparison to P1, P2's physical function was better maintained. In conclusion, ERT was safe in both patients during a 4.5-year follow-up. Although the typical characteristics of this disease were similar in both patients, P1 had a complex clinical course in comparison to P2, which influenced function and quality of life. Therefore, in order to make the most of ERT, it may be more beneficial when initiated at a relatively young age.",
"affiliations": "Department of Pediatric Rehabilitation, Edmond and Lily Safra Children's Hospital, Chaim Sheba Medical Center, Ramat-Gan 5265601, Israel.;The Sackler School of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel.;The National AT Center, Chaim Sheba Medical Center, Ramat Gan 5265601, Israel.;Pediatric Endocrine and Diabetes Unit, Chaim Sheba Medical Center, Edmond and Lily Safra Children's Hospital, Ramat-Gan 5265601, Israel.;Department of Pediatric Rehabilitation, Edmond and Lily Safra Children's Hospital, Chaim Sheba Medical Center, Ramat-Gan 5265601, Israel.;Department of Pediatric Rehabilitation, Edmond and Lily Safra Children's Hospital, Chaim Sheba Medical Center, Ramat-Gan 5265601, Israel.;Pediatric Orthopedic Unit, Edmond and Lilly Safra Children Hospital, Chaim Sheba Medical Center, Ramat Gan 5265601, Israel.;Institute of Rare Diseases, Edmond and Lily Safra Children's hospital, Chaim Sheba Medical Center, Ramat Gan 5265601, Israel.;Department of Pediatric Rehabilitation, Edmond and Lily Safra Children's Hospital, Chaim Sheba Medical Center, Ramat-Gan 5265601, Israel.",
"authors": "Barak|Sharon|S|;Anikster|Yair|Y|;Sarouk|Ifat|I|;Stern|Eve|E|;Eisenstein|Etzyona|E|;Yissar|Tamar|T|;Sherr-Lurie|Nir|N|;Raas-Rothschild|Annick|A|;Guttman|Dafna|D|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3390/diagnostics10020108",
"fulltext": "\n==== Front\nDiagnostics (Basel)\nDiagnostics (Basel)\ndiagnostics\nDiagnostics\n2075-4418 MDPI \n\n10.3390/diagnostics10020108\ndiagnostics-10-00108\nCase Report\nLong-Term Outcomes of Early Enzyme Replacement Therapy for Mucopolysaccharidosis IV: Clinical Case Studies of Two Siblings\nBarak Sharon 12* Anikster Yair 345 Sarouk Ifat 67 Stern Eve 8 Eisenstein Etzyona 1 Yissar Tamar 1 Sherr-Lurie Nir 9 Raas-Rothschild Annick 1011 Guttman Dafna 1 1 Department of Pediatric Rehabilitation, Edmond and Lily Safra Children’s Hospital, Chaim Sheba Medical Center, Ramat-Gan 5265601, Israel; Etzyona.Eisenstein@sheba.health.gov.il (E.E.); Tamar.Yissar@sheba.health.gov (T.Y.); Dafna.Gutman@sheba.health.gov.il (D.G.)\n2 Kaye Academic College of Education, M.Ed. programs, Beer-Sheva 8414201, Israel\n3 The Sackler School of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel; Yair.Anikster@sheba.gov.il\n4 Edmond and Lily Safra Children’s Hospital, Chaim Sheba Medical Center, Ramat Gan 5265601, Israel\n5 Wohl Institute for Translational Medicine, Chaim Sheba Medical Center, Ramat Gan 5265601, Israel\n6 The National AT Center, Chaim Sheba Medical Center, Ramat Gan 5265601, Israel; Ifat.Sarouk@sheba.gov.il\n7 The Pediatric Pulmonology Unit, Chaim Sheba Medical Center, Edmond and Lilly Safra Children Hospital, Tel HaShomer, Ramat Gan 5265601, Israel\n8 Pediatric Endocrine and Diabetes Unit, Chaim Sheba Medical Center, Edmond and Lily Safra Children’s Hospital, Ramat-Gan 5265601, Israel; zipporaheve.stern@sheba.health.gov.il\n9 Pediatric Orthopedic Unit, Edmond and Lilly Safra Children Hospital, Chaim Sheba Medical Center, Ramat Gan 5265601, Israel; Nir.Sherr@sheba.health.gov.il\n10 Institute of Rare Diseases, Edmond and Lily Safra Children’s hospital, Chaim Sheba Medical Center, Ramat Gan 5265601, Israel; Annick.Rothschild@sheba.health.gov.il\n11 The Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel\n* Correspondence: sharoni.baraki@gmail.com; Tel.: +972-3-5305038\n17 2 2020 \n2 2020 \n10 2 10820 11 2019 05 2 2020 © 2020 by the authors.2020Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).Enzyme replacement therapy (ERT) is one of the available therapies for mucopolysaccharidosis (MPS). This study presents a follow-up of two siblings with MPS IVA (Morquio A disease) that received ERT. Both siblings received weekly intravenous infusions of elosulfase alfa for 4.5 years. One sibling (patient 1, P1; male) started therapy at 54 months of age, and the other sibling (patient 2, P2; female) started at 11 months of age. ERT was well-tolerated. In comparison to P1, P2’s growth curves deviated less from the norm. The orthopedic deformities of P1 were more severe than those of P2 and required several surgical corrections. P1’s sleep test at 48 months revealed obstructive sleep apnea, while by the age of 102 months, parameters were normal. P2 never had sleep apnea. Only P1 demonstrated ear, nose, and throat clinical illnesses. In comparison to P1, P2’s physical function was better maintained. In conclusion, ERT was safe in both patients during a 4.5-year follow-up. Although the typical characteristics of this disease were similar in both patients, P1 had a complex clinical course in comparison to P2, which influenced function and quality of life. Therefore, in order to make the most of ERT, it may be more beneficial when initiated at a relatively young age.\n\ncase reportenzyme replacement therapyglycosaminoglycandeficient N-acetylgalactosamine 6-sulfatasemucopolysaccharidosisMorquio syndrome\n==== Body\n1. Introduction\nMucopolysaccharidosis (MPS) IVA (Morquio A disease) is one of a family of progressive genetic disorders that are caused by defects in glycosaminoglycan (GAG) catabolism, resulting in accumulation within lysosomes of partially degraded GAG [1]. The disease is caused by mutations in the gene encoding the lysosomal enzyme N-acetylgalactosamine 6-sulfatase (GALNS) [2,3,4]. The reduced GALNS activity causes an impairment in the catabolism of two GAGs, namely, keratan sulfate [5] and chondroitin-6-sulfate [6]. The distribution of GAGs in tissues is evident in the disease’s clinical presentation and mainly located in cartilaginous, bony, and muscular tissues [2,3,7].\n\nChildren with MPS IVA appear normal at birth [8] and by the end of the second year of life commonly present multiorgan disease involvement (e.g., skeletal and pulmonary), requiring complex multi-disciplinary medical attention [9,10]. The search for the optimal definitive treatment is still under investigation and currently consists of hematopoietic stem cell transplantation, gene therapy, and enzyme replacement therapy (ERT) [11].\n\nHematopoietic stem cell transplantation has proven to be a viable treatment option for patients with MPS types I, II, IVA, VI, and VII [12]. However, there is a need for more research to better understand this treatment in patients with MPS IVA [12]. Another treatment modality is gene therapy. The goal of gene therapy is to correct the genetic defect by direct insertion of normal deoxyribonucleic acid into the affected cells in order to institute endogenous production of the deficient enzyme by these cells. Findings on the effectiveness of gene therapy are encouraging, but additional work pertaining to immune reaction, choice of vector, and optimal route of administration is needed [13]. Finally, in 2014, ERT for MPS IVA using recombinant human GALNS, referred to as elosulfase alfa, was approved [14]. ERT is a lifelong appropriate therapy for some types of MPS with the purpose of reducing GAG accumulation [15,16,17,18,19]. Clinical trials show that ERT can improve quality of life and clinical and physical function, although eventually in the longterm, improvement reaches a plateau [20,21]. Overall, the current literature supports the safety and efficacy of ERT [22], especially when started at a young age [23,24,25,26].\n\nThere is a lack of long-term clinical studies that evaluate safety and efficacy of the use of ERT for MPS IVA. Moreover, there are studies showing that ERT for patients with MPS IVA might not always be useful. For example, according to Do Cao et al. [27] and Doherty et al. [28], early ERT did not improve skeletal outcomes in a patient with severe MPS IVA. Until now, there has been no proof that ERT has an impact on bone lesions. Still, according to Akyol et al. [29], the data are mainly limited to ERT among patients who initiated ERT relatively late into their disease progression. The limited data may cause reimbursement companies and physicians to not support ERT in relatively young children [30]. As the early initiation of ERT will likely have an effect on the course of the disease, there is a need for additional longitudinal observational studies of patients with this condition [11]. The purpose of this study is to present an approximately 4.5-year follow-up of two siblings with MPS IVA after initiation of ERT. One sibling (patient 1, P1; male) started therapy before the age of 5 years old, and the other sibling (patient 2, P2; female) started therapy at a younger age, before the age of 1 year old.\n\n2. Materials and Methods\n2.1. Selection of Subjects\nTwo siblings, a boy (P1) and a girl (P2) with MPS IVA that had started ERT at a young age, were identified from a Pediatric Rehabilitation Department. P1 was diagnosed when he was 49 months of age. P2, the younger sister of P1, was diagnosed after her brother at six months of age. Informed consent was obtained from the children’s parents. The study was approved (study code - 6625-19-SMC ; approval date – January 29, 2020) by the ethics committee of the Chaim Sheba Medical Center, Tel Hashomer, Israel.\n\n2.2. Outcome Measures\nOnce diagnosed, the patients underwent regular assessments to evaluate the severity and progression of the disease. All data were retrospectively retrieved from the patients’ medical records and the treating physicians. The following is a description of the assessed outcome measures.\n\nSafety and compliance—safety evaluations included continuous monitoring of adverse events. Absences from treatment sessions were recorded.\n\nHospitalization and surgeries history—data regarding the surgical and hospitalization (inpatient and outpatient) history of P1 and P2 were retrieved from medical records.\n\nGrowth—height and weight were measured in routine visitations to the clinic.\n\nOrthopedic and radiographic assessments and procedures—orthopedic and radiographic assessments were routinely conducted in order to assess structural changes. As recommended, the radiographic assessments mainly focused on the lower extremities (e.g., presence of progressive hip dysplasia, genu valgus, and ankle valgus), upper extremities, cervical spine, and thoracolumbar spine [31]. All orthopedic procedures were documented.\n\nRespiratory function and sleep test—the respiratory function evaluation consisted of a pediatric pulmonologist physical examination, spirometry test (forced vital capacity, forced expiratory volume in one second), and oxygen saturation and overnight sleep study.\n\nEar, nose, and throat (ENT) manifestations—patients underwent a routine evaluation by an otorhinolaryngologist.\n\nPhysical function—evaluation of physical function was routinely conducted by physical and occupational therapists. The evaluation focused on the patient’s impairment levels (e.g., muscle strength, range of motion), mobility ability (e.g., walking and stair climbing ability), activities of daily living (e.g., offing and doffing), and equilibrium and protective reactions.\n\n3. Results\nP1 was diagnosed with MPS IVA at age 49 months and P2 at six months of age, after her brother’s diagnosis. Both were found to be compound heterozygote for G139S and R386C. Upon diagnosis, GALNS activity for both patients was 1.1 nmol/h/mg. Current GALNS activity is 0.1 micromol/L/h (cut-off value > 0.2). P1 and P2 started ERT with elosulfase alfa (VIMIZIM® by BioMarin©) 5 months post-diagnosis at age 4.5 years and 11 months, respectively, with an intravenous dose of 1.0 mg/kg/week. The follow-up period of ERT is 4.5 years, whereas overall data include an additional 19 months prior to diagnosis for P1.\n\n3.1. Safety and Compliance\nNeither sibling has experienced any drug-related adverse events or infusion-associated reactions. Compliance with treatment was very good for both, with less than 10% of the programmed infusions missed per year.\n\n3.2. Growth\nP1 had been under pediatric endocrinology follow-up from age 18 months due to short stature and started growth hormone (GH) therapy at the age of 43 months for idiopathic short stature. Initially, he had a good response to the therapy with a height velocity of 4.2 cm in the first year following treatment initiation, compared with 0 cm in the prior year. GH therapy continued for 5 years and then discontinued because of growth failure and even height loss. P1 did grow somewhat once ERT was started; however, his height remained below the 10th percentile and his weight increased from the 10th to the 25th percentile of patients with MPS IVA. P2’s height and weight were at the 50th percentile of the normal population up to the age of 24 months, then significantly decreased, requiring the use of MPS IVA population curves [32]. On those curves, her height stabilized on the 50th percentile and weight on the 75th percentile until the end of the follow-up period (see Figure 1). Figure 2 shows the height differences between P1, P2, and their sibling.\n\n3.3. Clinical Course\nP1 was first admitted to the Pediatric Intensive Care Unit at the age of 30 months because of high cervical spine subluxation with cord contusion. Odontoid hypoplasia was noted on consecutive radiological studies. Treatment was conservative, using a neck and chest brace 24 h/d and an extended rehabilitation process. The brace was used for 4 years and then removed one year after he had C1-C2 posterior spinal fusion. By that time, he remained with mild left upper extremity monoparesis and overall muscular wasting and weakness. P1 underwent his second extended orthopedic surgery, which consisted of a shelf procedure for both hips, proximal femoral osteotomies, and insertion of eight plates for bilateral genu-valgus repair at 84 months of age, 30 months after ERT initiation. Subsequently, P1 received 6 months of daycare therapy in a rehabilitation center. Surgical procedures were conducted in a specialized center abroad. P1 received 18 months of ERT at the Pediatric Intensive Care Unit because of his fragile clinical status. Subsequent treatments were given at home. P1 has had regular weekly multiple therapies in a community setting since the age of 3 years (36 months) including physical therapy, occupational therapy, hydrotherapy, and psychological therapy.\n\nIn all follow-up years, P2 did not require surgeries and received ERT at the pediatric daycare department for 18 months. Following this, ERT was continued at home. P2 started community-based physical and occupational therapy sessions at the age of 4.5 years old.\n\n3.4. Orthopedic and Radiographic Assessments and Procedures\nBoth patients presented timely and typical skeletal changes of MPS IVA involving the spine (odontoid hypoplasia and kyphoscoliosis), chest cage deformities, upper extremities abnormalities (ulnar deviation and elbow valgus), and lower extremities abnormalities (hips dysplasia, genu valgus, calcaneal valgus, and pronated feet). The main differences between the siblings are the severity of the deformities and the stability of the cervical spine (see Figure 3 and Figure 4).\n\n3.5. Pulmonology and Ear, Nose, and Throat (ENT) Manifestations\nP1 presented effortful, noisy breathing and snoring since birth and through all follow-up years, which alternated with morning fatigue and daytime sleepiness. He has been under regular follow-up since the age of 42 months. Physical examinations revealed thoracic cage deformities with restrictive movement and enlarged adenoid tissue. P1 also suffered from recurrent bilateral severe otitis media, which required the insertion of ventilation tubes at the age of 66 months under anesthesia, resulting in partial improvement. P1 underwent multiple sequential respiratory and sleep tests for obstructive sleep apnea, which showed upper respiratory tract involvement with fair pulmonary functions (see Table 1). P1 had a single audiometry test at 5 years old, which showed mild hearing loss.\n\nDuring the follow-up period, P2 had no respiratory symptoms or sleeping complaints, except for occasional snoring. A single pulmonary examination at the age of 48 months was normal. Baseline sleep and hearing evaluations were within a normal range.\n\n3.6. Physical Function\nThe first evaluation of P1 was at 30 months of age, two years before ERT. The first evaluation of P2 was at 48 months of age, three years after ERT. Table 2 provides details of the patients’ physical function.\n\n3.6.1. Impairment Level\nBoth patients presented various limitations in their range of motion, endurance, balance, and protective reactions. However, P1’s impairments were considerably more severe in comparison to P2 (see Table 2).\n\n3.6.2. Mobility\nBoth patients presented mobility difficulties, with significant differences between siblings in severity level (i.e., performance level, use of assistive devices, and environmental adaptations) (see Table 2).\n\n3.6.3. Activities of Daily Living\nAt 48 months, P1 still needed support with offing and doffing, whereas P2 was independent and age-appropriate. For additional information, see Table 2.\n\nIn summary, during follow-up, both patients presented progression of limitations. However, in comparison to P1, P2’s functional level was better maintained and more closely resembled age-appropriate developmental milestones.\n\n4. Discussion\nThis case study provides clinical evidence regarding the 4.5-year efficacy and safety of elosulfase alfa treatment for MPS IVA in two siblings. Moreover, this is a unique opportunity to describe the effect of ERT started at a relatively young age (<1 year) [26] as we compare two patients with identical genetic data and shared environmental conditions.\n\n4.1. Safety and Compliance\nOur study is consistent with the results of other clinical studies, showing acceptable compliance and an acceptable safety profile [23,26,33,34].\n\n4.2. Growth\nThe study showed that ERT has a limited effect on growth. These results are consistent with studies comparing ERT effects on the growth of MPS IVA patients [28,35,36]. Moreover, P2’s growth curve demonstrates a major change in growth velocity around the age of two years, which is typical for MPS IVA patients. In addition, until that age (before one year of age), the growth of children with MPS IVA does not differ from the normal population [28]. Finally, it is important to note that the initiation of GH even before diagnosis did not change the course of growth development.\n\n4.3. Clinical Course, and Orthopedic and Radiographic Assessments\nPatients with MPS IVA typically need numerous orthopedic procedures throughout their lifetime [9,10,11]. Moreover, these patients are at high risk for anesthesia morbidity and mortality [37]. Both patients presented typical MPS IVA skeletal deformities. However, the remarkable difference between the two was the stability of the cervical spine, which is a common problem in MPS IVA. When present and untreated, it may have serious consequences [8,38,39,40]. Even though P1’s surgical intervention operation for C1–C2 fixation was successful, it influenced his overall developmental course. Unlike P1, P2 did not require any surgical intervention by the end of the follow-up at the age of 66 months, although she did present typical changes in the lower extremities. These findings are encouraging as children with MPS IVA do commonly require surgical intervention as young as 48 months of age [39].\n\nFurthermore, in a 5-year period, P1 had two prolonged rehabilitation periods in a rehabilitation hospital followed by unceasing physiotherapy, occupational therapy, and later, psychotherapy. P2, except for a limited period of weekly hospital visits for ERT, had only outpatient clinic visits, and physical and occupational therapies at the kindergarten. Given the clinical course, it appears that relatively early ERT did not prevent orthopedic deformities; however, it decreased the rate of progression and possibly postponed the need for surgical interventions. Any lessening of the need for surgery is beneficial to the child’s and family’s quality of life, as surgery is a stressful event for both the child and their family.\n\n4.4. Respiratory Function and Sleep Test\nP1 presented moderate-to-severe obstructive sleep apnea prior to ERT initiation, which was normalized 4.5 years post-treatment. Considering the increased tendency of MPS IVA patients to have upper airway obstruction [8,38], it appears that ERT might be beneficial in reducing the severity of respiratory complications. As for P2, one can carefully assume that starting ERT at a relatively young age was beneficial in preventing typical respiratory problems. These results are consistent with a multicenter study including 20 patients with MPS IVA, which reported sustained improvements in respiratory function using elosulfase alfa [41]. In a more recent study, Kenth and colleagues [42] also showed that ERT in MPS type IVA might attenuate the natural progression of respiratory dysfunction, especially in oximetry tests. Another possible physiological mechanism for the attenuated respiratory problems observed in both P1 and P2 is the functional ability of the children, especially in P2. More specifically, at the end of the follow-up period, P2 was still not using a powered wheelchair and walked 400 m in the six-minute walk test. As active individuals show higher spirometric results [43], staying physically active may have a beneficial effect on respiratory function.\n\n4.5. ENT Manifestations\nOver 90% of patients with MPS IVA present ENT complications at an early age, even while being treated with ERT [44,45,46]. In the current study, considering both siblings’ findings, it appears that P1’s clinical course is consistent with the literature. In contrast, starting ERT at a younger age (before 1 year of age) might be helpful in preventing or lessening ENT involvement.\n\n4.6. Physical and Functional Status\nBoth patients presented progression of limitations in physical and functional status. However, in comparison to P1, P2’s functional level was better maintained and more closely resembled age-appropriate developmental milestones. Overall, these findings do not suggest that ERT was useful in achieving significant skeletal changes, whereas it did have an effect on functional capacity, including endurance, balance, and activities of daily living. These findings are not surprising as ERT with elosulfase alfa has been shown to improve endurance and exercise capacity [20,35,47], partially due to improved respiratory function and oxygen utilization [13].\n\n4.7. Study Limitations and Conclusions\nThe present study is subject to limitations. This is not a pre-designed clinical trial, and P1 presented a complicating spinal cord injury. Therefore, there was variability regarding the medical evaluations schedule. Next, this study did not have a single endpoint other than safety aspects of ERT. Finally, it is difficult to make definite conclusions based on a 4.5-year follow-up and on the two case studies without conducting a longer follow-up and a comparison to a control group. However, it is important to note that in comparison to P2, P1 did start ERT at a much older age and the experience presented in this study reflects what clinicians probably encounter in daily practice.\n\nIn conclusion, ERT with elosulfase alfa in two siblings with MPS IVA was well-tolerated. Despite the treatment starting at a young age, the disease still progressed but at a different rate. Therefore, our findings highlight the importance of starting ERT as early as possible. Moreover, although an early initiation of ERT did not prevent orthopedic and growth problems, relatively early ERT initiation might delay the need for early-on complex surgeries and can be beneficial in maintaining health, functional ability, and quality of life. Nonetheless, despite the benefits of early ERT initiation observed in the study, considering the study limitations and ERT’s limited efficacy in preventing or resolving the disease’s progression (e.g., development of typical skeletal changes of MPS IVA), the study results should be interpreted with caution and further studies on ERT and other novel potential treatments are necessary.\n\nAuthor Contributions\nConceptualization, D.G.; methodology, D.G. and S.B.; formal analysis, D.G. and S.B.; data curation, D.G., T.Y., E.E., and S.B.; writing—original draft preparation, S.B.; writing—review and editing, I.S., E.S., E.E., Y.A., N.S.-L., A.R.-R., and D.G.; supervision, D.G. All authors have read and agreed to the published version of the manuscript.\n\nFunding\nThis research received no external funding.\n\nConflicts of Interest\nThe authors declare no conflict of interest.\n\nAbbreviations\nMPS\tMucopolysaccharidosis\t\nGAG\tGlycosaminoglycan\t\nGALNS\tN-acetylgalactosamine 6-sulfatase\t\nERT\tEnzyme replacement therapy\t\nGH\tGrowth hormone\t\nP1\tPatient 1\t\nP2\tPatient 2\t\nENT\tEar, nose, and throat\t\nFigure 1 Growth charts of males and females with mucopolysaccharidosis IVA (MPS IVA) and study participants: (a) patient 1 height; (b) patient 2 height; (c) patient 1 weight; (d) patient 2 weight. Note: ERT, enzyme replacement therapy; GH, growth hormone; the dotted and blue lines show the 50th percentile values for normal males and females; the Xs show study participants; revised from Montaño et al. [32].\n\nFigure 2 Height of patients 1 and 2, and their sibling.\n\nFigure 3 Lower limbs deformities: (a) patient 1 (72 months); (b) patient 2 (48 months).\n\nFigure 4 Radiographic pictures of the lower extremities of patients 1 and 2: (a) patient 1 (84 months); (b) patient 2 (48 months).\n\ndiagnostics-10-00108-t001_Table 1Table 1 Patient 1’s respiratory function and sleep test.\n\nAge\tOxygen Drop\tMinimal Oxygen Saturation (%) \tApnea-Hypopnea Index\tObstructive Sleep Apnea\tForced Vital Capacity (%)\tForced Expiratory Volume in 1 Second (%)\t\n48\t74\t66\t8.4\tModerate to severe\t75\t80\t\n54\t45\t78\t5.5\tModerate\t80\t85\t\n102\t16\t90\t2.3\tNormal\t82\t89\t\ndiagnostics-10-00108-t002_Table 2Table 2 Summary of patients 1 and 2—age of initiation of limitations in physical function.\n\nFunction\tAge (Months)\tPatient 1\tPatient 2\t\nRange of motion\t30–78\tNeck and chest brace\t\n\t\n\n\t48\tElbow extension\tElbow extension\t\nStrength\t36\tProgressive weakness in four limbs and trunk\tPelvic girdle weakness; moderate trunk weakness\t\nProtective reactions and balance\t36\tPartial protection reactions; impaired static and dynamic balance\tMild impairment in balance\t\nSitting\t84\tDifficulty in sitting upright\tIndependent\t\nWalking\t36\tIndependent for short distances on even surfaces/indoors; supervision for walking outdoors; poor endurance.\t\n\t\n\n\t48\tWalking only indoors; outdoors—using toddler ride-on toy on even surfaces and for short distances\tIndependent with no assistance devices on even surfaces for short and long distances with postural compensations\t\n\n\t66\tSee aforementioned\tSix-minute walk test—400 m (age-expected—573 m)\t\n\n\t102\tPowered wheelchair\t\n\t\nStanding up\t36\tGower’s sign/external support\tIndependent, partial Gower’s sign; postural compensations\t\nStairs\t36–66\tAssistance, non-reciprocating\tHandrail support\t\nOffing and doffing\t48\tPartially independent\tIndependent\t\nDrinking and eating\t66\tPartially independent\tPartially independent\n==== Refs\nReferences\n1. 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Safety and clinical activity of elosulfase alfa in pediatric patients with Morquio A syndrome (mucopolysaccharidosis IVA) less than 5 y Pediatr Res. 2015 78 717 722 10.1038/pr.2015.169 26331768 \n37. Dullenkopf A. Holzmann D. Feurer R. Gerber A. Weiss M. Tracheal intubation in children with Morquio syndrome using the angulated video-intubation laryngoscope Can. J. Anaesth. 2002 49 198 202 10.1007/BF03020496 11823401 \n38. Montaño A.M. Tomatsu S. Gottesman G.S. Smith M. Orii T. International Morquio A Registry: clinical manifestation and natural course of Morquio A disease J. Inherit. Metab. Dis. 2007 30 165 174 10.1007/s10545-007-0529-7 17347914 \n39. Tomatsu S. Mackenzie W.G. Theroux M.C. Mason R.W. Thacker M.M. Shaffer T.H. Montano A.M. Rowan D. Sly W. Almeciga-Diaz C.J. Current and emerging treatments and surgical interventions for Morquio A syndrome: A review RRED 2012 65 77 10.2147/RRED.S37278 \n40. Hughes D.G. Chadderton R.D. Cowie R.A. Wraith J.E. Jenkins J.P.R. MRI of the brain and craniocervical junction in Morquio’s disease Neuroradiology 1997 39 381 385 10.1007/s002340050429 9189888 \n41. Hendriksz C. Vellodi A. Jones S. Takkele H. Lee S. Chesler S. Decker C. Long Term Outcomes of a Phase 1/2, Multicenter, Open-Label, Dose-Escalation Study to Evaluate the Safety, Tolerability, and Efficacy of BMN 110 in Patients with Mucopolysaccharidosis IVA (Morquio A Syndrome) Mol. Genet. Metab. 2012 105 S35 10.1016/j.ymgme.2011.11.076 \n42. Kenth J.J. Thompson G. Fullwood C. Wilkinson S. Jones S. Bruce I.A. The characterisation of pulmonary function in patients with mucopolysaccharidoses IVA: A longitudinal analysis Mol. Genet. Metab. Rep. 2019 20 100487 10.1016/j.ymgmr.2019.100487 31341787 \n43. Luzak A. Karrasch S. Thorand B. Nowak D. Holle R. Peters A. Schulz H. Association of physical activity with lung function in lung-healthy German adults: Results from the KORA FF4 study BMC Pulm. Med. 2017 17 215 10.1186/s12890-017-0562-8 29282101 \n44. Parini R. Rigoldi M. Tedesco L. Boffi L. Brambilla A. Bertoletti S. Boncimino A. Del Longo A. De Lorenzo P. Gaini R. Enzymatic replacement therapy for Hunter disease: Up to 9years experience with 17 patients Mol. Genet. Metab. Rep. 2015 3 65 74 10.1016/j.ymgmr.2015.03.011 26937399 \n45. Brands M.M.M.G. Oussoren E. Ruijter G.J.G. Vollebregt A.A.M. van den Hout H.M.P. Joosten K.F.M. Hop W.C.J. Plug I. van der Ploeg A.T. Up to five years experience with 11 mucopolysaccharidosis type VI patients Mol. Genet. Metab. 2013 109 70 76 10.1016/j.ymgme.2013.02.013 23523338 \n46. Horovitz D.D.G. Magalhães T.S.P.C. Acosta A. Ribeiro E.M. Giuliani L.R. Palhares D.B. Kim C.A. de Paula A.C. Kerstenestzy M. Pianovski M.A.D. Enzyme replacement therapy with galsulfase in 34 children younger than five years of age with MPS VI Mol. Genet. Metab. 2013 109 62 69 10.1016/j.ymgme.2013.02.014 23535281 \n47. Hughes D. Giugliani R. Guffon N. Jones S.A. Mengel K.E. Parini R. Matousek R. Hawley S.M. Quartel A. Clinical outcomes in a subpopulation of adults with Morquio A syndrome: results from a long-term extension study of elosulfase alfa Orphanet J. Rare Dis. 2017 12 10.1186/s13023-017-0634-0 28100251\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2075-4418",
"issue": "10(2)",
"journal": "Diagnostics (Basel, Switzerland)",
"keywords": "Morquio syndrome; case report; deficient N-acetylgalactosamine 6-sulfatase; enzyme replacement therapy; glycosaminoglycan; mucopolysaccharidosis",
"medline_ta": "Diagnostics (Basel)",
"mesh_terms": null,
"nlm_unique_id": "101658402",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "32079294",
"pubdate": "2020-02-17",
"publication_types": "D002363:Case Reports",
"references": "6808304;25346323;31019230;15126989;28983456;29282101;18412124;30772512;24388732;7741581;23523338;19117887;12572847;21506915;27761411;11823401;1755850;820169;20332769;26331768;24011228;31341787;28649537;21291356;31196221;9189888;25284089;21930407;17879143;26937399;10617747;22210671;24810369;19968667;18056156;31455839;28535791;9918480;26910003;18502162;24839594;23535281;23413237;17347914",
"title": "Long-Term Outcomes of Early Enzyme Replacement Therapy for Mucopolysaccharidosis IV: Clinical Case Studies of Two Siblings.",
"title_normalized": "long term outcomes of early enzyme replacement therapy for mucopolysaccharidosis iv clinical case studies of two siblings"
} | [
{
"companynumb": "IL-BIOMARINAP-IL-2020-129320",
"fulfillexpeditecriteria": "1",
"occurcountry": "IL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ELOSULFASE ALFA"
},
"drugadditional": "3",... |
{
"abstract": "Direct acting antiviral (DAA) regimens containing ritonavir have been developed to treat hepatitis C, with fewer side effects than that by interferon-based regimens. However prescribers must be aware of drug-drug interactions. There are multiple reports of iatrogenic Cushing syndrome (CS) caused by ritonavir, when used to treat human immunodeficiency virus, increasing the bioavailability of exogenous steroids by inhibiting cytochrome p450 enzymes in the liver and gut wall and thus reducing steroid metabolism. We herein report a novel scenario of CS due to interaction between ritonavir for hepatitis C treatment and oral budesonide for autoimmune hepatitis.",
"affiliations": "Department of Gastroenterology and Hepatology, Eastern Health, Level 2, 5 Arnold Street, Box Hill, Victoria 3128, Australia.",
"authors": "Yeoh|Sern Wei|SW|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.1016/j.jceh.2016.05.006",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0973-6883",
"issue": "6(3)",
"journal": "Journal of clinical and experimental hepatology",
"keywords": "ACTH, adrenocorticotropic hormone; ALP, alkaline phosphatase; ALT, alanine aminotransferase; CS, Cushing syndrome; Cushing syndrome; DAA, direct acting antiviral; HIV, human immunodeficiency virus; HMG CoA, 3-hydroxy-3-methylglutaryl-coenzyme A; SVR, sustained virological response; budesonide; drug interactions; hepatitis C; ritonavir",
"medline_ta": "J Clin Exp Hepatol",
"mesh_terms": null,
"nlm_unique_id": "101574137",
"other_id": null,
"pages": "246-249",
"pmc": null,
"pmid": "27746623",
"pubdate": "2016-09",
"publication_types": "D016428:Journal Article",
"references": "24720679;20460021;26869556;22844010;12949438;15355126;22712167;20653496;26976799;11737390;23807527;24725237;16698415;25770114;21558486",
"title": "Iatrogenic Cushing Syndrome from Interaction Between Ritonavir and Oral Budesonide During Direct Acting Antiviral Hepatitis C Therapy.",
"title_normalized": "iatrogenic cushing syndrome from interaction between ritonavir and oral budesonide during direct acting antiviral hepatitis c therapy"
} | [
{
"companynumb": "AU-MYLANLABS-2016M1051097",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DASABUVIR"
},
"drugadditional": null,
... |
{
"abstract": "An emphysema in a lower limb is usually a clinical sign of a severe and life-threatening infection. We report a rare case of subcutaneous emphysema of the left lower limb associated with a massive retro-pneumoperitoneum and pneumatosis intestinalis after cardiac transplantation in a 4-year-old girl. The child was nearly asymptomatic beside an abdominal distension. A benign pneumoperitoneum associated with an extensive pneumatosis intestinalis is a rare complication after organ transplantation and should be treated conservatively. The association with an emphysema in a lower limb in a child has not been previously reported to our knowledge in the literature.",
"affiliations": "Clinic of General Pediatric Surgery, Children's Hospital \"Regina Margher ita,\" \"Città della Salute e della Scienza,\" Turin, Italy. Electronic address: drsalvatoregarofalo@yahoo.it.;Clinic of Pediatric Cardiac Surgery, Children's Hospital \"Regina Margherita,\" \"Città della Salute e della Scienza,\" Turin, Italy.;Clinic of General Pediatric Surgery, Children's Hospital \"Regina Margher ita,\" \"Città della Salute e della Scienza,\" Turin, Italy.;Clinic of Pediatric Cardiac Surgery, Children's Hospital \"Regina Margherita,\" \"Città della Salute e della Scienza,\" Turin, Italy.;Clinic of General Pediatric Surgery, Children's Hospital \"Regina Margher ita,\" \"Città della Salute e della Scienza,\" Turin, Italy.;Clinic of General Pediatric Surgery, Children's Hospital \"Regina Margher ita,\" \"Città della Salute e della Scienza,\" Turin, Italy.;Imaging and Diagnostics, Children's Hospital \"Meyer,\" Florence, Italy.;Clinic of General Pediatric Surgery, Children's Hospital \"Regina Margher ita,\" \"Città della Salute e della Scienza,\" Turin, Italy.",
"authors": "Garofalo|S|S|;Aidala|E|E|;Teruzzi|E|E|;Pace Napoleone|C|C|;Carbonaro|G|G|;Cerrina|A|A|;De Filippi|C|C|;Schleef|J|J|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1345",
"issue": "47(7)",
"journal": "Transplantation proceedings",
"keywords": null,
"medline_ta": "Transplant Proc",
"mesh_terms": "D002675:Child, Preschool; D005260:Female; D016027:Heart Transplantation; D006801:Humans; D035002:Lower Extremity; D011006:Pneumatosis Cystoides Intestinalis; D011027:Pneumoperitoneum; D013352:Subcutaneous Emphysema",
"nlm_unique_id": "0243532",
"other_id": null,
"pages": "2176-8",
"pmc": null,
"pmid": "26361672",
"pubdate": "2015-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Massive Retro-Pneumoperitoneum and Lower Limb Subcutaneous Emphysema After Pediatric Heart Transplantation: A Case Report.",
"title_normalized": "massive retro pneumoperitoneum and lower limb subcutaneous emphysema after pediatric heart transplantation a case report"
} | [
{
"companynumb": "IT-ACCORD-034405",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "THYMOCYTE IMMUNE GLOBULIN NOS"
},
"drugadditional": nu... |
{
"abstract": "We describe here a clinical daptomycin treatment failure in a patient with recurrent methicillin-resistant Staphylococcus aureus (MRSA) bacteremia in whom daptomycin was administered after a failed empirical treatment course with vancomycin and piperacillin-tazobactam. We had the opportunity to compare the genome sequences of an isogenic pair of daptomycin-susceptible and -resistant MRSA isolates obtained before and after initiation of daptomycin therapy, respectively. The genotype of both isolates was USA800, ST5, SCCmec type IV, agr type II. There was no increase in cell wall thickness in the daptomycin-resistant strain despite having decreased susceptibility to both vancomycin and daptomycin. By comparing the genome sequences by pyrosequencing, we identified a polymorphism (S337L) in the tenth transmembrane segment of the multiple peptide resistance factor, MprF, encoding lysyl phosphatidylglycerol transferase. This enzyme has been shown previously to promote repulsion of daptomycin at the cell surface by addition of positively charged lysine to phosphatidylglycerol. Also, the hlb open reading frame (ORF) encoding the β-toxin was interrupted by a prophage in the daptomycin-susceptible strain; this phage was missing in the daptomycin-resistant isolate and the hlb ORF was restored. Loss of the phage in the resistant isolate also resulted in loss of the virulence factor genes clpP, scn, and sak. This is the first study to use pyrosequencing to compare the genomes of a daptomycin-susceptible/resistant MRSA isolate pair obtained during failed daptomycin therapy in humans.",
"affiliations": "Department of Pediatrics, University of Chicago, KCBD 4152, 900 E 57th Street, Chicago, IL 60657, USA. sboyleva@uchicago.edu",
"authors": "Boyle-Vavra|Susan|S|;Jones|Marcus|M|;Gourley|Brett L|BL|;Holmes|Michael|M|;Ruf|Rebecca|R|;Balsam|Ashley R|AR|;Boulware|David R|DR|;Kline|Susan|S|;Jawahir|Selina|S|;Devries|Aaron|A|;Peterson|Scott N|SN|;Daum|Robert S|RS|",
"chemical_list": "D000900:Anti-Bacterial Agents; D014640:Vancomycin; D017576:Daptomycin",
"country": "United States",
"delete": false,
"doi": "10.1128/AAC.01593-10",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0066-4804",
"issue": "55(5)",
"journal": "Antimicrobial agents and chemotherapy",
"keywords": null,
"medline_ta": "Antimicrob Agents Chemother",
"mesh_terms": "D000900:Anti-Bacterial Agents; D017576:Daptomycin; D024881:Drug Resistance, Bacterial; D005838:Genotype; D006801:Humans; D008297:Male; D055624:Methicillin-Resistant Staphylococcus aureus; D046529:Microscopy, Electron, Transmission; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D017211:Treatment Failure; D014640:Vancomycin",
"nlm_unique_id": "0315061",
"other_id": null,
"pages": "2018-25",
"pmc": null,
"pmid": "21343446",
"pubdate": "2011-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "17991040;10524952;1402017;19295462;16495273;17682996;16452413;19273776;17954690;17302811;18378708;10085071;18472990;15561842;10698988;16145133;11734738;18824611;19721075;17620372;16299304;15814879;19915718;17888634;10952568;19208891;11897611;14605147;18628509;20498310;11342591;16715807;18068843;16914702;2533245;17550889;17629567;16569891;17652653;10488222;10325427;19171803;19332678;7691599;16207998;19843483;3334158;19329640;17404001;16914701;15306996;17940231;12878516;20713669;9738837;16963232;17078814;19919306;15980344;16377683;16455939;17994102;16652325;15972563;16723576",
"title": "Comparative genome sequencing of an isogenic pair of USA800 clinical methicillin-resistant Staphylococcus aureus isolates obtained before and after daptomycin treatment failure.",
"title_normalized": "comparative genome sequencing of an isogenic pair of usa800 clinical methicillin resistant staphylococcus aureus isolates obtained before and after daptomycin treatment failure"
} | [
{
"companynumb": "US-009507513-1504USA016149",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "VANCOMYCIN"
},
"drugadditional": null,
... |
{
"abstract": "Background: Long term data on the real-life use of secukinumab are scant. The aim of this study was to investigate the real-life effectiveness, safety and treatment persistence of secukinumab in patients with moderate-to-severe psoriasis. Research design and methods: This 84-week, multicenter (n = 7) retrospective study analyzed data from patients who initiated and received at least 6 months of secukinumab treatment between June 2016 and June 2018 in the Campania region of Italy. Patient demographic and treatment characteristics, duration of treatment and reasons for discontinuation as well as Psoriasis Area and Severity Index (PASI), Body Surface Area (BSA), and Dermatology Life Quality Index (DLQI) scores were assessed. Results: 324 patients (63% male, mean age 50.2 years) were enrolled and received a mean 11.7 months of secukinumab treatment. Overall, 9.5% discontinued secukinumab, including 5.2% who discontinued due to secondary inefficacy and 1.8% due to adverse events. PASI, BSA and DLQI scores were significantly improved from baseline at every follow-up visit (p < 0.001) and mean PASI decreased from 15.3 ± 6.3 at baseline to 0.5 ± 1.0 at week 84. Secukinumab had comparable effectiveness in biologic naïve and non-naïve patients. Conclusions: This study confirmed the effectiveness and safety of secukinumab in real-world patients with psoriasis.",
"affiliations": "a Department of Dermatology , University of Naples Federico II , Naples , Italy.;b Dermatology Unit , G. Rummo Hospital , Benevento , Italy.;c Dermatology Unit , University of Campania Luigi Vanvitelli , Naples , Italy.;d Department of Advanced Biomedical Sciences , University of Naples Federico II , Naples , Italy.;e Dermatology Unit , \"Ospedale del Mare\" , Naples , Italy.;b Dermatology Unit , G. Rummo Hospital , Benevento , Italy.;f Dermatology and Venereology Unit , Sacro Cuore di Gesù Fatebenefratelli Hospital , Benevento , Italy.;c Dermatology Unit , University of Campania Luigi Vanvitelli , Naples , Italy.;g Department of Medicine, Surgery and Dentistry , \"Scuola Medica Salernitana\" University of Salerno , Salerno , Italy.;e Dermatology Unit , \"Ospedale del Mare\" , Naples , Italy.;h Sant'Anna and San Sebastiano Hospital , Caserta , Italy.;a Department of Dermatology , University of Naples Federico II , Naples , Italy.;a Department of Dermatology , University of Naples Federico II , Naples , Italy.",
"authors": "Megna|Matteo|M|0000-0003-1803-2046;Di Costanzo|Luisa|L|;Argenziano|Giuseppe|G|;Balato|Anna|A|;Colasanti|Paola|P|;Cusano|Francesco|F|;Galluccio|Antonia G|AG|;Gambardella|Alessio|A|;Lembo|Serena|S|;Mozzillo|Raffaele|R|;Scotto Di Luzio|Genoveffa|G|;Fabbrocini|Gabriella|G|;Balato|Nicola|N|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; C555450:secukinumab",
"country": "England",
"delete": false,
"doi": "10.1080/14712598.2019.1622678",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1471-2598",
"issue": "19(8)",
"journal": "Expert opinion on biological therapy",
"keywords": "Anti-IL-17; PASI; biologic drugs; psoriasis; real life; secukinumab",
"medline_ta": "Expert Opin Biol Ther",
"mesh_terms": "D000328:Adult; D061067:Antibodies, Monoclonal, Humanized; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007558:Italy; D008297:Male; D008875:Middle Aged; D011565:Psoriasis; D012189:Retrospective Studies; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "101125414",
"other_id": null,
"pages": "855-861",
"pmc": null,
"pmid": "31140882",
"pubdate": "2019-08",
"publication_types": "D000068397:Clinical Study; D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Effectiveness and safety of secukinumab in Italian patients with psoriasis: an 84 week, multicenter, retrospective real-world study.",
"title_normalized": "effectiveness and safety of secukinumab in italian patients with psoriasis an 84 week multicenter retrospective real world study"
} | [
{
"companynumb": "PHHY2019IT127993",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "SECUKINUMAB"
},
"drugadditional": null,
"dru... |
{
"abstract": "Splenic artery pseudoaneurysms are infrequently encountered but critical to recognize. Limited literature to date describes associations with pancreatitis, trauma, and rarely peptic ulcer disease. Hemorrhage and abdominal pain are the most common manifestations. There is typically overt gastrointestinal blood loss but bleeding can also extend into the peritoneum, retroperitoneum, adjacent organs, or even a pseudocyst. Most patients with ruptured splenic artery pseudoaneurysms present with hemodynamic instability. Here, we describe a patient recovering from acute illness in the intensive care unit but with otherwise no obvious risk factors or precipitants for visceral pseudoaneurysm. He presented with acute onset altered mental status, nausea, and worsening back and abdominal pain and was found to be in hypovolemic shock. The patient was urgently stabilized until more detailed imaging could be performed, which ultimately revealed the source of blood loss and explained his rapid decompensation. He was successfully treated with arterial coiling and embolization. Thus, we herein emphasize the importance of prompt recognition of hemorrhagic shock and of aggressive hemodynamic stabilization, as well as a focused diagnostic approach to this problem with specific treatment for splenic artery pseudoaneurysm. Finally, we recommend that multidisciplinary management should be the standard approach in all patients with splenic artery pseudoaneurysm.",
"affiliations": "Department of Medicine, Medical University of South Carolina, Charleston, SC, USA.;Department of Radiology, Medical University of South Carolina, Charleston, SC, USA.;Department of Medicine, Medical University of South Carolina, Charleston, SC, USA.",
"authors": "Schatz|Richard A|RA|;Schabel|Stephen|S|;Rockey|Don C|DC|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1177/2324709615577816",
"fulltext": "\n==== Front\nJ Investig Med High Impact Case RepJ Investig Med High Impact Case RepHICsphicJournal of Investigative Medicine High Impact Case Reports2324-7096SAGE Publications Sage CA: Los Angeles, CA 10.1177/232470961557781610.1177_2324709615577816ArticleIdiopathic Splenic Artery Pseudoaneurysm Rupture as an Uncommon Cause of Hemorrhagic Shock Schatz Richard A. MD1Schabel Stephen MD2Rockey Don C. MD11 Department of Medicine, Medical University of South Carolina, Charleston, SC, USA2 Department of Radiology, Medical University of South Carolina, Charleston, SC, USADon C. Rockey, Department of Internal Medicine, Medical University of South Carolina, 96 Jonathan Lucas Street, Suite 803, Charleston, SC 29425, USA. Email: rockey@musc.edu13 4 2015 Apr-Jun 2015 3 2 2324709615577816© 2015 American Federation for Medical Research2015American Federation for Medical ResearchThis article is distributed under the terms of the Creative Commons Attribution 3.0 License (http://www.creativecommons.org/licenses/by/3.0/) which permits any 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 (http://www.uk.sagepub.com/aboutus/openaccess.htm).Splenic artery pseudoaneurysms are infrequently encountered but critical to recognize. Limited literature to date describes associations with pancreatitis, trauma, and rarely peptic ulcer disease. Hemorrhage and abdominal pain are the most common manifestations. There is typically overt gastrointestinal blood loss but bleeding can also extend into the peritoneum, retroperitoneum, adjacent organs, or even a pseudocyst. Most patients with ruptured splenic artery pseudoaneurysms present with hemodynamic instability. Here, we describe a patient recovering from acute illness in the intensive care unit but with otherwise no obvious risk factors or precipitants for visceral pseudoaneurysm. He presented with acute onset altered mental status, nausea, and worsening back and abdominal pain and was found to be in hypovolemic shock. The patient was urgently stabilized until more detailed imaging could be performed, which ultimately revealed the source of blood loss and explained his rapid decompensation. He was successfully treated with arterial coiling and embolization. Thus, we herein emphasize the importance of prompt recognition of hemorrhagic shock and of aggressive hemodynamic stabilization, as well as a focused diagnostic approach to this problem with specific treatment for splenic artery pseudoaneurysm. Finally, we recommend that multidisciplinary management should be the standard approach in all patients with splenic artery pseudoaneurysm.\n\nhemorrhageimagingretroperitoneumangiographycover-dateApril-June 2015\n==== Body\nIntroduction\nThe sudden development of shock represents a true medical emergency and can be caused by a multitude of different disorders. Major causes of shock include hypovolemic, cardiogenic, and distributive (the latter typically due to an acute and dramatic reduction in systemic vascular resistance). When hypovolemic shock is due to acute blood loss, the source of blood loss is usually obvious. However, the source of blood loss is not always clinically apparent. Here, we present a patient in whom the cause of blood loss was unknown initially but became clear after his symptoms directed specific investigation.\n\nCase Presentation\nA 79-year-old man developed acute-onset altered mental status, nausea, and worsening back and abdominal pain. He had been admitted to the intensive care unit 7 days prior with sepsis from community-acquired pneumonia and was finishing antibiotic treatment with ceftriaxone and azithromycin. His hospital course had been complicated by hypercarbic respiratory failure requiring intubation in the setting of volume overload, but his respiratory status had returned to baseline and he had been extubated 2 days prior.\n\nThe past history was remarkable for a chronic obstructive pulmonary disease, gastroesophageal reflux disease, hypertension, hyperlipidemia, coronary artery disease, and abdominal aortic aneurysm. He had an inferior wall myocardial infarction at age 63 years followed by angioplasty with the placement of a single metal stent in the right coronary artery and underwent endovascular repair of the abdominal aortic aneurysm at age 70 years. He smoked 2 packs of cigarettes daily for 50 years but had stopped smoking 10 years ago. He did not use alcohol or illicit drugs. Aside from the antibiotics listed above, his medications included aspirin, simvastatin, furosemide, lisinopril, omeprazole, a budesonide/formoterol inhaler, and albuterol/ipratropium nebulizers.\n\nOn physical examination, he was uncomfortable appearing in moderate respiratory distress, pale, and disoriented. His temperature was 36.3°C, blood pressure 86/46 mm Hg, heart rate 110 bpm, respiratory rate 24, and oxygen saturation 93% supplemented on 4 L oxygen via nasal cannula. He had cool, clammy extremities and equal pulses bilaterally. His abdomen was firm, moderately distended, and diffusely tender to palpation with hypoactive bowel sounds. The patient exhibited voluntary guarding but no obvious peritoneal signs. Rectal exam revealed no melena or red blood.\n\nLaboratory data were notable for a hemoglobin of 6.7 g/dL (from 8.8 g/dL 10 hours earlier), hematocrit 22%, white blood count 8700/mm3, platelets 270 600/mm3, blood urea nitrogen 21 mg/dL, creatinine 0.7 mg/dL, bicarbonate 33 mm/L, international normalized ratio 1.2, and lactate 2.6 mm/L. Serum lipase, aminotransaminases, troponin, and bilirubin levels were normal.\n\nThe portable chest radiograph revealed bibasilar atelectasis but a normal cardiac silhouette and mediastinum; an abdominal film showed mildly dilated loops of small bowel but no evidence of obstruction or free air. Electrocardiography showed q waves and nonspecific ST-T wave abnormalities in the inferior leads but this was unchanged from prior tracings. Bedside echocardiography showed hyperdynamic left ventricular function without focal wall motion abnormality. The inferior vena cava measured 1.2 cm in diameter with marked respiratory variation.\n\nThe patient was emergently stabilized by placement of a high-flow non-rebreather oxygen mask and volume resuscitated with 2 L of normal saline and 2 units of packed red blood cells. His vital signs rapidly normalized. Once hemodynamically stable, a computed tomography (CT) scan with contrast of the abdomen and pelvis was obtained and revealed a large left-sided retroperitoneal hematoma with a 4.5 × 2.6 cm contrast-filled structure emanating from the splenic artery consistent with a pseudoaneurysm (Figure 1A and B). Low-density perisplenic and perihepatic free fluid with further fluid extension to the right paracolic gutter and into the pelvis was also noted.\n\nFigure 1. Computed tomography scan of the abdomen and pelvis.\n\n(A) An axial view of a contrast-enhanced portal venous phase CT scan demonstrates a 4.5 × 2.6 cm splenic artery pseudoaneurysm (short arrow) with associated retroperitoneal and perinephric fat stranding (long arrow). A dense abdominal free-fluid collection (arrowhead), likely from hemorrhage, is present. (B) A sagittal view of a contrast-enhanced portal venous phase CT scan demonstrates the splenic artery pseudoaneurysm (short arrow), associated retroperitoneal and perinephric fat stranding (long arrow), and the free-fluid collection (arrowhead).\n\nThe patient promptly underwent direct catheter angiography, which demonstrated the splenic artery aneurysm and the previously known aortobiiliac stent graft in place (Figure 2A). Subsequently, 14 detachable coils were used to embolize the main splenic artery and occlude the aneurysm (Figure 2B). He required 3 more units of blood throughout the rest of his hospitalization but was discharged home 1 week later without further complication.\n\nFigure 2. Splenic artery angiography.\n\n(A) The digital subtraction image of the splenic artery arteriogram demonstrates extravasation of contrast into a large mid splenic artery pseudoaneurysm (arrow). The angiocatheter is seen in the proximal portion of the splenic artery. Also, an aortic stent graft is also seen (diamond arrow). (B) This digital subtraction image depicts the successfully embolized splenic artery with detachable coils (arrows) throughout the course of the artery. The arteriogram confirms complete stasis of flow within the artery without residual filling of the pseudoaneurysm.\n\nDiscussion\nSplenic artery pseudoaneurysms are infrequently encountered (<250 cases reported in the literature) but critical to recognize. They are most commonly associated with pancreatitis (acute and chronic), trauma (including iatrogenic causes), and even rarely intra-abdominal processes such as complicated peptic ulcer disease. There are no reported cases of unprovoked, spontaneous splenic artery pseudoaneurysm to date. The clinical presentation varies from incidental finding to acute hemodynamic collapse.1,2 Hemorrhage, typically overt with melena and hematochezia from bleeding into the pancreatic duct (known as hemosuccus pancreaticus), and abdominal pain are the most common manifestations.1 Ruptured pseudoaneurysms can result in gastrointestinal hemorrhage not only through the pancreatic duct but also into the peritoneum, retroperitoneum, adjacent organs, or even a developing pseudocyst. As in our patient, the majority of patients with active bleeding are hemodynamically unstable at the time of presentation. Splenic artery pseudoaneurysms carry a much higher risk of rupture than true splenic artery aneurysms since they lack at least one component of the traditional arterial wall (adventitia, media, intima). Prompt detection and intervention is critical as these carry up to a 90% mortality rate if untreated.3\n\nAt presentation, the patient’s sudden development of tachycardia, hypotension, and altered mental status is consistent with shock. Shock, broadly characterized into 3 major categories (Table 1), is a physiologic state characterized by systemic reduction in tissue perfusion resulting in poor tissue oxygen delivery, which can progress to end-organ dysfunction. Whereas distributive (septic, neurogenic, or anaphylactic) shock manifests as a consequence of decreased systemic vascular resistance, cardiogenic shock is due to reduced cardiac output due to pump failure or decreased stroke volume, and hypovolemic shock from a global reduction in cardiac preload. Recognizing the presentation and specific type of shock is essential to clarifying the etiology of his acute picture. Most notable is the substantial drop in hemoglobin and hematocrit, which suggests hypovolemic shock secondary to acute blood loss. Stabilizing the patient with suspected hypovolemic shock from active blood loss is the most important initial priority. Ensuring a patent and protected airway and establishing large bore intravenous access are paramount.\n\nTable 1. Categories of Shock.\n\nCategory\tPhysiology\tCommon Causes\tBasic Treatment\t\nHypovolemic\t↓ Cardiac preload and cardiac output\t• Hemorrhage\tFirst line: Volume resuscitation\t\n\t\t• Fluid losses (GI, burns)\tSecond line: Vasopressors\t\n\t\tDehydration\t\t\nCardiogenic\t↓ Stroke volume and cardiac output\tIntracardiac\t• Treat underlying cause\t\n\t\t• Myocardial infarction\t• Aggressive volume management (ie, bolus vs dieresis depending on etiology)\t\n\t\t• Arrhythmia (ie, atrial fibrillation with rapid ventricular response, unstable ventricular tachycardia, ventricular fibrillation)\t• Vasopressors ± inotropes\t\n\t\t• Aortic stenosis\t\t\n\t\t• Mitral regurgitation\t\t\n\t\tExtracardiac\t\t\n\t\t• Volume overload\t\t\n\t\t• Tension pneumothorax\t\t\n\t\t• Massive pulmonary embolus\t\t\n\t\t• Cardiac tamponade\t\t\nDistributive (septic, anaphylactic, neurogenic)\t↓ Systemic vascular resistance from ↑ vasodilatation\tSevere inflammatory response with massive cytokine release (ie, infection, pancreatitis, burns), allergic reaction, spinal injury/anesthesia\tFirst line: Volume resuscitation\t\n\t\t\tSecond line: Vasopressors\t\n\t\t\t±: Antibiotics, steroids/epinephrine\t\nThe degree of intravascular volume depletion, classified in stages I to IV of hypovolemic shock, is important to understand as this directs resuscitative measures. The body can initially compensate up to ~15% reduction in blood volume (stage I) via peripheral arterial vasoconstriction. However, compensatory mechanisms become overwhelmed with the loss of 15% to 30% of circulating blood volume (stage II). Acute loss of 30% to 45% blood volume (stage III) best characterizes this patient’s presentation with his low systolic blood pressure (<100 mm Hg), marked tachycardia, tachypnea, altered mental status, and cool extremities. Prompt recognition can prevent progression to profound hypotension and end-organ collapse (stage IV).\n\nThis patient’s situation was remarkable due to his rapid decompensation without overt blood loss. While the differential diagnosis for hypovolemic shock without external blood loss is wide, it can be quickly focused. His abnormal abdominal physical examination and history of known vascular disease initially raised the possibility intra-abdominal sepsis due to many different causes (ie, abscess, hepatobiliary disease, perforation of a viscous), acute mesenteric ischemia, an acute vascular disorder (involving the spleen, pancreas, or kidneys), hemorrhagic pancreatitis, or colitis. Although the absence of melena, hematochezia, or hematemesis argued against hemorrhage within the gastrointestinal lumen, intra-abdominal blood loss required a thorough evaluation.\n\nThe patient’s prior history of repaired abdominal aortic aneurysm was concerning for aneurysmal hemorrhage. The triad of abdominal pain, shock, and a pulsatile abdominal mass essentially confirms a ruptured abdominal aortic aneurysm, a surgical emergency. Indeed, the patient complained of worsening abdominal and back pain and met shock criteria but a thorough abdominal examination did not reveal an underlying pulsatile mass. Still, rapidly increasing abdominal distention in the setting of hemodynamic instability was concerning for developing abdominal compartment syndrome, also a surgical emergency. Type 1 aortic dissection can also present similarly in an elderly man with hypertension and atherosclerotic disease. Likewise, the prior history of significant coronary artery disease warranted evaluation for acute myocardial infarction causing cardiogenic shock. Although unlikely in this particular case, patients with large declines in hematocrit that cannot be readily explained may have more chronically occult or obscure gastrointestinal bleeding as the gastrointestinal tract is large and blood can be hidden within it or unable to be visualized with standard endoscopic procedures.4 In the absence of clear gastrointestinal tract bleeding, several other disorders including large volume fluid shifts, occult sepsis, severe hemolytic anemia, and large hematomas should also be considered.5\n\nIf visceral aneurysm and pseudoaneurysm are suspected, the distinction between these 2 entities is important since this guides further clinical decision making. Splenic artery aneurysms differ from pseudoaneurysms in etiology, natural history, outcome, and management. The distinction can often be made radiographically as true aneurysms typically show evidence of atherosclerosis and calcification and pseudoaneurysms often hold a multilobular appearance. The splenic artery is the third most common location for true intra-abdominal aneurysm and the vast majority are discovered incidentally. Their incidence has increased with more widespread use of advanced imaging.6 Similar to abdominal aortic aneurysm, splenic artery aneurysm has hypothesized associations with atherosclerosis and hypertension, but can also be encountered with portal hypertension and cirrhosis, previous liver transplant, and pregnancy.7,8 While the risk of rupture is fairly low (2% to 3%), ruptured aneurysms have potentially catastrophic consequences.9 Current practice favors treating asymptomatic aneurysms greater than 2 cm.7,8\n\nThis case also highlights the utility of CT absorption density in determining the nature of abdominal fluid collections. The density of the blood within the abdominal aorta measures 250 Hounsfield units, typical of arterial blood in the portal venous phase of enhancement. The pseudoaneurysm contents measured 140 Hounsfield units, typical of portal venous phase enhanced blood mixed with arterial blood. The absence of gas suggests that the lesion is not a gastrointestinal fistula, and the lack of very high-density oral contrast suggests that the lesion does not communicate with the gastrointestinal tract. Of note, the perisplenic ascites measured 14 Hounsfield units, most compatible with extracellular fluid that contains a mix of cellular and/or blood proteins.\n\nStandard evaluation and treatment for splenic pseudoaneurysm is angiographic-directed embolization (with either coils, inert particles, or gel-foam),10,11 which the patient underwent after the initial CT scan. While CT angiography and magnetic resonance angiography may offer better resolution, these methods do not allow concurrent therapeutic intervention. However, these advanced imaging methods can only be performed in patients with adequate renal function since they require the administration of intravenous contrast. In the past, splenic artery ligation and splenectomy with or without partial pancreatectomy were most commonly performed but novel, less invasive methods are now favored with better outcomes and less morbidity.12 CT-guided thrombin injection can be used if patients are not candidates for endovascular treatment.13 There is little correlation between size and risk of rupture; hence, once diagnosed, prompt intervention should be sought.1\n\nIn summary, hemorrhagic shock caused by splenic artery pseudoaneurysm without sentinel gastrointestinal bleeding is relatively uncommon but critical to accurately diagnose and manage. Although the initial diagnosis in this patient was unclear, this patient’s presentation highlights the necessity of prompt recognition of hemorrhagic shock, the importance of aggressive stabilization, and, subsequently, a focused diagnostic approach with specific treatment. In this particular disorder, multidisciplinary involvement (with interventional radiology and surgical consultation) should be sought early.\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\nFunding: The author(s) received no financial support for the research, authorship, and/or publication of this article.\n==== Refs\nReferences\n1. \nTessier DJ Stone WM Fowl RJ \nClinical features and management of splenic artery pseudoaneurysm: case series and cumulative review of literature . J Vasc Surg . 2003 ;38 :969 -974 .14603202 \n2. \nNicaise N Golzarian J van Gansbeke D Cremer M Struyven J Deviere J \nRupture of pseudoaneurysm: a cause of delayed hemorrhage after endoscopic cystoenterostomy; angiographic diagnosis and treatment . Gastrointest Endosc . 1998 ;47 :186 -189 .9512288 \n3. \nHuang IH Zuckerman DA Matthews JB \nOcclusion of a giant splenic artery pseudoaneurysm with percutaneous thrombin-collagen injection . J Vasc Surg . 2004 ;40 :574 -577 .15337894 \n4. \nRockey DC \nOccult gastrointestinal bleeding . N Engl J Med . 1999 ;341 :38 -46 .10387941 \n5. \nOng B Rockey DC \nThe syndrome of a large drop in hematocrit in hospitalized patients: clinical features and gastrointestinal bleeding outcomes . J Investig Med . 2014 ;62 :963 -967 .\n6. \nRøkke O Søndenaa K Amundsen S Bjerke-Larssen T Jensen D \nThe diagnosis and management of splanchnic artery aneurysms . Scand J Gastroenterol . 1996 ;31 :737 -743 .8858739 \n7. \nAgrawal GA Johnson PT Fishman EK \nSplenic artery aneurysms and pseudoaneurysms: clinical distinctions and CT appearances . AJR Am J Roentgenol . 2007 ;188 :992 -999 .17377035 \n8. \nAbbas MA Stone WM Fowl RJ \nSplenic artery aneurysms: two decades experience at Mayo Clinic . Ann Vasc Surg . 2002 ;16 :442 -449 .12089631 \n9. \nMattar SG Lumsden AB \nThe management of splenic artery aneurysms: experience with 23 cases . Am J Surg . 1995 ;169 :580 -584 .7771620 \n10. \nArepally A Dagli M Hofmann LV Kim HS Cooper M Klein A \nTreatment of splenic artery aneurysm with use of a stent-graft . J Vasc Interv Radiol . 2002 ;13 :631 -633 .12050305 \n11. \nGuillon R Garcier JM Abergel A \nManagement of splenic artery aneurysms and false aneurysms with endovascular treatment in 12 patients . Cardiovasc Intervent Radiol . 2003 ;26 :256 -260 .14562974 \n12. \nDave SP Reis ED Hossain A Taub PJ Kerstein MD Hollier LH \nSplenic artery aneurysm in the 1990s . Ann Vasc Surg . 2000 ;14 :223 -229 .10796953 \n13. \nKrueger K Zaehringer M Lackner K \nPercutaneous treatment of a splenic artery pseudoaneurysm by thrombin injection . J Vasc Interv Radiol . 2005 ;16 :1023 -1025 .16002512\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2324-7096",
"issue": "3(2)",
"journal": "Journal of investigative medicine high impact case reports",
"keywords": "angiography; hemorrhage; imaging; retroperitoneum",
"medline_ta": "J Investig Med High Impact Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101624758",
"other_id": null,
"pages": "2324709615577816",
"pmc": null,
"pmid": "26425639",
"pubdate": "2015",
"publication_types": "D016428:Journal Article",
"references": "14603202;12089631;12050305;14562974;10796953;25203151;17377035;8858739;15337894;16002512;10387941;9512288;7771620",
"title": "Idiopathic Splenic Artery Pseudoaneurysm Rupture as an Uncommon Cause of Hemorrhagic Shock.",
"title_normalized": "idiopathic splenic artery pseudoaneurysm rupture as an uncommon cause of hemorrhagic shock"
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"companynumb": "US-BAYER-2017-161426",
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"activesubstancename": "FUROSEMIDE"
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"abstract": "OBJECTIVE\nNeurotoxicity is a side effect of acyclovir. We report the first case, to our knowledge, whereby Bayesian-informed clearance estimates supported a therapeutic intervention for acyclovir-associated neurotoxicity.\n\n\nMETHODS\nA 62-year-old male with the diagnosis of disseminated zoster was being treated with intravenous (IV) acyclovir when he developed symptoms of acute neurotoxicity. Acyclovir had been dose-adjusted for renal dysfunction according to traditional creatinine clearance estimates; however, as the patient was also on vancomycin, Bayesian estimates of vancomycin clearances were performed, which revealed a 2-fold lower creatinine clearance. In response to the Bayesian estimates, acyclovir was discontinued, and improvements in mentation were noted within 24 hours.\n\n\nCONCLUSIONS\nAlternate approaches to estimate renal function beyond Cockcroft-Gault, such as a Bayesian approach used in our patient, should be considered when population estimates are likely to be inaccurate and potentially dangerous to the patient.",
"affiliations": "Department of Pharmacy, Northwestern Memorial Hospital, Chicago, IL, USA.;Department of Pharmacy, Northwestern Memorial Hospital, Chicago, IL, USA.;Department of Infectious Disease, Cleveland Clinic Florida, Weston, FL, USA.;Division of Infectious Diseases, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.;Department of Pharmacy, Northwestern Memorial Hospital, Chicago, IL, USA.",
"authors": "Watson|W A|WA|;Rhodes|N J|NJ|;Echenique|I A|IA|http://orcid.org/0000-0002-6301-0121;Angarone|M P|MP|;Scheetz|M H|MH|http://orcid.org/0000-0002-1091-6130",
"chemical_list": "D000998:Antiviral Agents; D014640:Vancomycin; D003404:Creatinine; D000212:Acyclovir",
"country": "England",
"delete": false,
"doi": "10.1111/jcpt.12520",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0269-4727",
"issue": "42(3)",
"journal": "Journal of clinical pharmacy and therapeutics",
"keywords": "acyclovir; adverse effects; pharmacodynamics; pharmacokinetics; statistical model",
"medline_ta": "J Clin Pharm Ther",
"mesh_terms": "D000212:Acyclovir; D000998:Antiviral Agents; D001499:Bayes Theorem; D003404:Creatinine; D004305:Dose-Response Relationship, Drug; D006562:Herpes Zoster; D006801:Humans; D008297:Male; D008875:Middle Aged; D020258:Neurotoxicity Syndromes; D014640:Vancomycin",
"nlm_unique_id": "8704308",
"other_id": null,
"pages": "350-355",
"pmc": null,
"pmid": "28370067",
"pubdate": "2017-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "14605302;3341668;12748346;17651180;7103443;8559507;7973922;6305245;20038622;16540518;8430717;15244498;7249508;19187258;3706943;8562758;7103460;23851913;9169653;16107379",
"title": "Resolution of acyclovir-associated neurotoxicity with the aid of improved clearance estimates using a Bayesian approach: A case report and review of the literature.",
"title_normalized": "resolution of acyclovir associated neurotoxicity with the aid of improved clearance estimates using a bayesian approach a case report and review of the literature"
} | [
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"companynumb": "US-HERITAGE PHARMACEUTICALS-2017HTG00107",
"fulfillexpeditecriteria": "1",
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"activesubstancename": "ACYCLOVIR"
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"abstract": "A 47-year-old woman with aspirin-exacerbated respiratory disease visited our hospital complaining of persistent chest pain that manifested in the evenings and early mornings. Holter monitoring revealed ST elevation during chest pain and coronary angiography showed coronary vasospasm, which led to the diagnosis of variant angina. Chest pain persisted despite administration of a coronary vasodilator. The patient experienced an increase in peripheral blood eosinophils during the clinical course and received prednisolone for the same, which resulted in the resolution of her chest pain. Prednisolone was therefore seen to be effective for treating variant angina that manifested as a non-respiratory tract symptom of aspirin-exacerbated respiratory disease.",
"affiliations": "Naito Clinic.",
"authors": "Naito|Tatsuo|T|",
"chemical_list": "D011239:Prednisolone; D001241:Aspirin",
"country": "Japan",
"delete": false,
"doi": "10.15036/arerugi.65.123",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0021-4884",
"issue": "65(2)",
"journal": "Arerugi = [Allergy]",
"keywords": null,
"medline_ta": "Arerugi",
"mesh_terms": "D000788:Angina Pectoris, Variant; D001241:Aspirin; D004342:Drug Hypersensitivity; D005260:Female; D006801:Humans; D008875:Middle Aged; D011239:Prednisolone; D012140:Respiratory Tract Diseases",
"nlm_unique_id": "0241212",
"other_id": null,
"pages": "123-7",
"pmc": null,
"pmid": "27086958",
"pubdate": "2016-03",
"publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "A CASE OF ASPIRIN-EXACERBATED RESPIRATORY DISEASE COMPLICATED BY REFRACTORY VARIANT ANGINA, WHICH SHOWED EXCELLENT RESPONSE TO STEROID TREATMENT.",
"title_normalized": "a case of aspirin exacerbated respiratory disease complicated by refractory variant angina which showed excellent response to steroid treatment"
} | [
{
"companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2016RR-119250",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
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"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
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"dr... |
{
"abstract": "BACKGROUND\nAlzheimer disease (AD) is a neurodegenerative disease characterized by progressive cognitive dysfunction, which is mainly manifested as memory impairment and a reduced ability to self-care, often accompanied by neuropsychiatric and behavioral disorders. Donepezil is the second drug to be approved by the US FDA for the treatment of AD. Of the five FDA-approved drugs for AD treatment, donepezil is currently the most widely used. Here, we report an extrapyramidal adverse reaction to donepezil in an elderly patient with AD.\nAn 87-year-old woman presented with a 1-year history of forgetfulness that was aggravated since the past 2 months. She had a long-term history of multiple major conditions, including hypertension, diabetes, osteoporosis, and arterial plaques. Brain imaging showed age-related changes, and her Mini Mental State Examination score was 20. Other tests revealed no abnormalities apart from multiple thyroid nodules on ultrasonography.\n\n\nMETHODS\nShe was diagnosed with AD, hypertension, type 2 diabetes mellitus, diabetic neuropathy, osteoporosis, carotid and lower-extremity arterial plaques, thyroid nodules.\n\n\nMETHODS\nShe was treated with donepezil (5 mg/day), amlodipine besylate (5 mg/day), glimepiride (4 mg/day), methylcobalamin (1.5 mg/day), calcium carbonate D3 (600 mg/day), simvastatin (20 mg/day) and enteric-coated aspirin (100 mg/day).\n\n\nRESULTS\nFour days later, she experienced fatigue, panic, sweating, and one episode of vomiting. On the 5th day, she developed increased muscle tension, speech difficulty, and involuntary tremors. Imaging and blood tests revealed no obvious abnormality, and the patient was not receiving psychotropic drugs. An extrapyramidal adverse reaction to donepezil was considered, and the drug was discontinued, after which the symptoms gradually disappeared.\n\n\nCONCLUSIONS\nSerious adverse reactions to donepezil can occur in elderly patients, who typically require multiple medications for a variety of comorbidities. In particular, extrapyramidal reactions have occurred when donepezil is administered in combination with psychotropic drugs. However, in our patient, an extrapyramidal adverse reaction occurred in the absence of psychotropic drugs. Thus, clinicians must be aware of inter-individual differences in drug actions and possible serious adverse reactions, and carefully monitor these patients to ensure the timely detection of adverse events and their safe treatment.",
"affiliations": "Department of Geriatrics, Tongde Hospital of Zhejiang Province, Hangzhou, China.",
"authors": "Li|Hong-Chun|HC|;Luo|Ke-Xue|KX|;Wang|Jie-Sheng|JS|;Wang|Qin-Xian|QX|",
"chemical_list": "D002800:Cholinesterase Inhibitors; D000077265:Donepezil",
"country": "United States",
"delete": false,
"doi": "10.1097/MD.0000000000019443",
"fulltext": "\n==== Front\nMedicine (Baltimore)\nMedicine (Baltimore)\nMEDI\nMedicine\n0025-7974 1536-5964 Wolters Kluwer Health \n\n32176074\nMD-D-19-04077\n10.1097/MD.0000000000019443\n19443\n4600\nResearch Article\nClinical Case Report\nExtrapyramidal side effect of donepezil hydrochloride in an elderly patient\nA case reportLi Hong-Chun MM Luo Ke-Xue MM Wang Jie-Sheng MM Wang Qin-Xian MM∗ NA. Department of Geriatrics, Tongde Hospital of Zhejiang Province, Hangzhou, China.\n∗ Correspondence: Qin-Xian Wang, Department of Geriatrics, Tongde hospital of Zhejiang Province, No. 234 Gucui Road, Hangzhou 310012, China (e-mail: Li_8406@163.com).\n13 3 2020 \n3 2020 \n99 11 e1944328 5 2019 22 12 2019 6 2 2020 Copyright © 2020 the Author(s). Published by Wolters Kluwer Health, Inc.2020This 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/4.0Abstract\nIntroduction:\nAlzheimer disease (AD) is a neurodegenerative disease characterized by progressive cognitive dysfunction, which is mainly manifested as memory impairment and a reduced ability to self-care, often accompanied by neuropsychiatric and behavioral disorders. Donepezil is the second drug to be approved by the US FDA for the treatment of AD. Of the five FDA-approved drugs for AD treatment, donepezil is currently the most widely used. Here, we report an extrapyramidal adverse reaction to donepezil in an elderly patient with AD.\n\nPatient concerns:\nAn 87-year-old woman presented with a 1-year history of forgetfulness that was aggravated since the past 2 months. She had a long-term history of multiple major conditions, including hypertension, diabetes, osteoporosis, and arterial plaques. Brain imaging showed age-related changes, and her Mini Mental State Examination score was 20. Other tests revealed no abnormalities apart from multiple thyroid nodules on ultrasonography.\n\nDiagnosis:\nShe was diagnosed with AD, hypertension, type 2 diabetes mellitus, diabetic neuropathy, osteoporosis, carotid and lower-extremity arterial plaques, thyroid nodules.\n\nInterventions:\nShe was treated with donepezil (5 mg/day), amlodipine besylate (5 mg/day), glimepiride (4 mg/day), methylcobalamin (1.5 mg/day), calcium carbonate D3 (600 mg/day), simvastatin (20 mg/day) and enteric-coated aspirin (100 mg/day).\n\nOutcomes:\nFour days later, she experienced fatigue, panic, sweating, and one episode of vomiting. On the 5th day, she developed increased muscle tension, speech difficulty, and involuntary tremors. Imaging and blood tests revealed no obvious abnormality, and the patient was not receiving psychotropic drugs. An extrapyramidal adverse reaction to donepezil was considered, and the drug was discontinued, after which the symptoms gradually disappeared.\n\nConclusion:\nSerious adverse reactions to donepezil can occur in elderly patients, who typically require multiple medications for a variety of comorbidities. In particular, extrapyramidal reactions have occurred when donepezil is administered in combination with psychotropic drugs. However, in our patient, an extrapyramidal adverse reaction occurred in the absence of psychotropic drugs. Thus, clinicians must be aware of inter-individual differences in drug actions and possible serious adverse reactions, and carefully monitor these patients to ensure the timely detection of adverse events and their safe treatment.\n\nKeywords\nadvanced agedonepezil hydrochloridedrug interactionextrapyramidal reactionOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nAlzheimer disease (AD) is a devastating, progressive, and irreversible neurodegenerative disorder,[1] which is primarily affects the elderly.[2] It is the most common type of dementia and represents 70% of all dementia cases.[3] Donepezil is the second drug to be approved by the US FDA for the treatment of AD. Clinical studies in many countries have shown that this drug can improve the cognitive ability and daily life of patients with mild-to-moderate AD.[4] Donepezil also ameliorates neurological and psychiatric symptoms.[5] Furthermore, it effective in treating AD patients with or without cerebrovascular diseases.[6] Of the five FDA-approved drugs for AD treatment, donepezil is currently the most widely used. However, some adverse reactions to donepezil use have been reported in the literature[7,8] Here, we report an extrapyramidal adverse reaction to donepezil in an elderly patient with AD.\n\n2 Case presentation\nAn 87-year-old woman was admitted to our department on March 15, 2018 due to a 1-year history of forgetfulness (described as “forgetting recent events”) that had been aggravated since the past 2 months. She had a medical history of multiple major illnesses: a 30-year history of hypertension treated with amlodipine besylate (5 mg/day), a 17-year history of type 2 diabetes mellitus treated with glimepiride (4 mg/day), a 10-year history of diabetic neuropathy treated with methylcobalamin (1.5 mg/day), a 10-year history of osteoporosis treated with calcium carbonate D3 (600 mg/day), and a history of carotid and lower-extremity arterial plaques treated with simvastatin (20 mg/day) and enteric-coated aspirin (100 mg/day). She had no history of drug or food allergies or of smoking or drinking. She had been educated up to the junior high school level.\n\nA physical examination showed that her vitals were as follows: body temperature, 36.7°C; pulse, 65/min; respiratory rate, 19/min; and blood pressure, 127/67 mm Hg. A neurological examination revealed no nystagmus at eye level. Ultrasonography showed multiple nodules in the left and right lobes of the thyroid gland. A plain computed tomography (CT) scan of the brain showed ventricule, cistern and sulcus enlargement, but no abnormal density. Laboratory examinations revealed a fasting plasma glucose level of 6.96 mmol/L. Her Mini Mental State Examination score was 20 points. The results of other tests, such as urinalysis, and liver- and kidney-function tests, showed no obvious abnormalities. Based on the above findings, we made a diagnosis of AD associated with hypertension, type 2 diabetes with neurological diabetic complications, osteoporosis, atherosclerosis, and multiple thyroid nodules.\n\nTo her preexisting treatment plan, we added donepezil hydrochloride tablets (5 mg/day). On the fourth day after the initiation of this treatment, the patient experienced fatigue, panic, sweating, and one episode of vomiting. A random blood sugar level at this time was 7.8 mmol/L. On the fifth day, she developed general fatigue, was unable to get up, and exhibited left-sided torticollis. Her expression was indifferent; she had difficulty in speech and showed slight involuntary tremors of the upper limbs. A CT scan of the head performed at this time revealed no obvious abnormality, and blood tests showed no difference in blood electrolyte levels, and liver and kidney function. She had not experienced similar symptoms in the past, and had not taken any other medications on her own. We, therefore, considered a diagnosis of an adverse reaction to donepezil. We advised the patient to stop taking the drug, and closely monitored her for further changes. Her symptoms disappeared after donepezil treatment was stopped and have not recurred since.\n\n3 Discussion\nOur patient developed tremor of the upper limbs, indifferent expression, and increased muscle tension after receiving donepezil treatment for AD. Her symptoms disappeared after the drug was discontinued. Both prior to and during the symptomatic period, the patient had not taken any other drugs that could have explained these symptoms. Furthermore, no acute cerebrovascular disease or electrolyte abnormalities were found on auxiliary examinations, and the patient had not experienced similar symptoms in the past. These findings indicated that donepezil use had a temporal relationship with the adverse reaction in our patient. Therefore, according to the principle of the correlative evaluation of adverse drug reactions, we concluded that the extrapyramidal side effects in our patient were possibly caused by donepezil.\n\nAD is a common age-related disease. With the aging of the population, the number of AD cases is increasing. According to the statistics released by the International Association for Alzheimer Disease, there were about 46.8 × 106 dementia patients in the world in 2015; moreover, the number of patients with dementia has doubled every 20 years, indicating that dementia has become a serious threat to the health and quality of life of the elderly.[9] The pathological features of AD include senile plaques formed by the extracellular deposition of β-amyloid, neurofibrillary tangles formed by the intracellular superphosphorylation of Tau protein, and neuron loss.[10] At present, the etiology and pathogenesis of AD are not completely clear. Studies have shown that a decrease in the central neurotransmitter acetylcholine is related to the pathogenesis of AD.\n\nDonepezil hydrochloride is a second-generation cholinesterase inhibitor that reversibly inhibits acetyl choline degradation in the brain and thereby indirectly increases the level of choline in the cerebral cortex, delaying the development of AD and vascular dementia.[11,12] The drug is safe in terms of the cardiovascular health of elderly patients.[13] According to the current researches, the safe dosage scale of donepezil is no more than 23 mg/day.[14,15] However, excessive cholinergic action can cause gastrointestinal and neurological adverse reactions. Adverse reactions to donepezil most commonly involve the digestive system (42.86%), followed by the nervous system (22.86%).[5] Extrapyramidal symptoms are rare.\n\nDonepezil is metabolized by cytochrome P450 (CYP450) in the liver, and is mainly eliminated by the kidneys.[16,17] In addition to donepezil, our patient was taking amlodipine besylate, simvastatin, and glimepiride, all of which are metabolized by CYP450. This may have led to the competitive inhibition of donepezil metabolism and increased the level of acetylcholine. Furthermore, elderly patients often have a decline in liver and kidney function. On average, the creatinine clearance rate is 40% lower in elderly people (>80 years) than in other adults.[18] With the prolongation of clearance half-life, the same drug dose may lead to an increased blood drug concentration.[18,19] The above reasons may have led to an adverse drug reaction caused by excessive cholinergic action.\n\nElderly patients often suffer from a variety of diseases and require treatment with multiple drugs at the same time. Patients with AD, in particular, often have accompanying mental problems. When AD medication is combined with psychotropic drugs, rare adverse reactions such as extrapyramidal side effects are more likely to occur due to the imbalance of acetylcholine/dopamine content. Magnuson and Liu both reported a case of an extrapyramidal adverse reaction caused by donepezil combined with risperidone.[20,21] In Magnuson's reported case, the patient used donepezil 10 mg/night, the adverse event occurred within 2 weeks. In Liu reported case, the patient used donepezil 5 mg/day, the adverse event occurred after 3 days. In our patient, however, an extrapyramidal adverse reaction occurred despite the use of a conventional dosage of donepezil and without the combined use of psychotropic drugs.\n\nAlthough there are some limitations in this case report, such as the absence of blood concentration of drug, it has positive significance in reminding clinicians to pay attention to the inter-individual differences and safety of drug actions in elderly patients.[20,22] The present case report illustrates that rare adverse reactions, such as extrapyramidal reactions, can occur in patients receiving a conventional dosage of donepezil alone without combination with psychotropic drugs. Thus, clinicians must be aware of inter-individual differences in drug actions, carefully monitor drug use in elderly patients, and be highly alert to promptly detect adverse reactions and improve the safety of clinical medications.\n\nAuthor contributions\nConceptualization: Hong-Chun Li, Ke-Xue Luo, Jie-Sheng Wang, Qin-Xian Wang.\n\nData curation: Hong-Chun Li, Ke-Xue Luo, Jie-Sheng Wang, Qin-Xian Wang.\n\nFormal analysis: Ke-Xue Luo, Jie-Sheng Wang.\n\nFunding acquisition: Hong-Chun Li.\n\nInvestigation: Hong-Chun Li.\n\nMethodology: Hong-Chun Li.\n\nValidation: Hong-Chun Li.\n\nVisualization: Jie-Sheng Wang, Qin-Xian Wang.\n\nWriting – original draft: Jie-Sheng Wang, Qin-Xian Wang.\n\nWriting – review & editing: Hong-Chun Li, Ke-Xue Luo.\n\nAbbreviations: AD = Alzheimer disease, CT = computer tomography, CYP450 = Cytochrome P450, FDA = Food and Drug Administration, US = United States.\n\nHow to cite this article: Li HC, Luo KX, Wang JS, Wang QX. Extrapyramidal side effect of donepezil hydrochloride in an elderly patient: A case report. Medicine. 2020;99:11(e19443).\n\nThis study was approved by the ethics committee of Tongde hospital of Zhejiang province. All procedures performed in 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.\n\nWritten informed consent was obtained from individual participants. Patient has provided informed consent for publication of the case\n\nThe authors declare that they have no conflict of interest.\n==== Refs\nReferences\n[1] Jadoopat R \nReview of Alzheimer's disease treatment and potential future therapies\n. Annu Rev Chang Healthc \n2018 ;2 :1 –0\n.\n[2] Singh M Murthy V Ramassamy C \nModulation of hydrogen peroxide and acrolein-induced oxidative stress, mitochondrial dysfunctions and redox regulated pathways by the Bacopa monniera extract: potential implication in Alzheimer's disease\n. J Alzheimers Dis \n2010 ;21 :229 –47\n.20421692 \n[3] Gonzalo Flores G Flores-Gómez GD de Jesús Gomez-Villalobos M \nNeuronal changes after chronic high blood pressure in animal models and its implication for vascular dementia\n. Synapse \n2016 ;70 :198 –205\n.26789133 \n[4] Molinuevo JL Berthier ML Rami L \nDonepezil provides greater benefits in mild compared to moderate Alzheimer's disease: implications for early diagnosis and treatment\n. Arch Gerontol Geriatr \n2011 ;52 :18 –22\n.19948364 \n[5] Carrasco MM Aguera L Gil P \nSafety and effectiveness of donepezil on behavioral symptoms in patients with Alzheimer disease\n. Alzheimer Dis Assoc Disord \n2011 ;25 :333 –40\n.21399485 \n[6] Na HR Kim S Choi SH \nDonepezil treatment in Alzheimer's disease patients with and without cerebrovascular lesions: a preliminary report\n. Geriatr Gerontol Int \n2011 ;11 :90 –7\n.20825496 \n[7] Vanacore N Suzzareddu G Maggini M \nPisa syndrome in a cohort of Alzheimer's disease patients\n. Acta Neurol Scand \n2005 ;111 :199 –201\n.15691290 \n[8] Chew AP Lim WS Tan KT \nDonepezil-induced hepatotoxicity in an elderly adult taking fluoxetine\n. J Am Geriatr Soc \n2014 ;62 :2009 –11\n.25333550 \n[9] Khan MT Ikram A Saeed O \nDeep vein thrombosis in acute stroke - a systemic review of the literature\n. Cureus \n2017 ;9 :e1982 .29503776 \n[10] Li LWX Peng Y \nNatural products against Alzheimer's disease and the pharmacology research progress\n. Chin Pharmacol Bullet \n2016 ;32 :149 –55\n.\n[11] Waldemar G Gauthier S Jones R \nEffect of donepezil on emergence of apathy in mild to moderate Alzheimer's disease\n. Int J Geriatr Psychiatry \n2011 ;26 :150 –7\n.20597141 \n[12] Droogsma E van Asselt D Diekhuis M \nInitial cognitive response to cholinesterase inhibitors and subsequent long-term course in patients with mild Alzheimer's disease\n. Int Psychogeriatr \n2015 ;27 :1323 –33\n.25779465 \n[13] Isik AT Yildiz GB Bozoglu E \nCardiac safety of donepezil in elderly patients with Alzheimer disease\n. Intern Med \n2012 ;51 :575 –8\n.22449664 \n[14] Cummings JL Geldmacher D Farlow M \nHigh-dose donepezil (23 mg/day) for the treatment of moderate and severe Alzheimer's disease: drug profile and clinical guidelines\n. CNS Neurosci Thera \n2013 ;19 :294 –301\n.\n[15] Han SH1 Lee JH Kim SY \nDonepezil23 mg in Asian patients with moderate-to-severe Alzheimer's disease\n. Acta Neurol Scand \n2017 ;135 :252 –6\n.26923256 \n[16] Li H \nThe clinical research progress of drugs for curing Alzhei mer's disease\n. Chinese journal of new drugs \n2017 ;26 :648 –55\n.\n[17] Ginestet L Ferrario JE Raisman-Vozari R \nDonepezil induces a cholinergic sprouting in basocortical degeneration\n. J Neurochem \n2007 ;102 :434 –40\n.17394553 \n[18] Stahlmann R Lode H \nSafety considerations of fluoroquinolones in the elderly: an update\n. Drugs Aging \n2010 ;27 :193 –209\n.20210367 \n[19] Graber H Ludwing E Arr M \nDifference in multiple-dose pharmacokinetics of ofloxacin in young and aged patients [abstract no. 94]\n. Geneva : International Symposium on New Quinolones ; 1986 .\n[20] Magnuson TM Keller BK Burke WJ \nExtrapyramidal side effects in a patient treated with risperidone plus donepezil\n. Am J Psychiatry \n1998 ;155 :1458 –9\n.\n[21] Liu H.C Lin S.K Sung SM \nExtrapyramidal side-effect due to drug combination of risperidone and donepezil\n. Psychiatry Clin Neurosci \n2002 ;56 :479 .12109969 \n[22] Marshall K Fritz K Thom W Xiong GL \nToxic interaction between fluoxetine and donepezil: a case of cholinergic toxidrome\n. J Neuropsychiatry Clin Neurosci \n2012 ;24 :E50 .\n\n",
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"title": "Extrapyramidal side effect of donepezil hydrochloride in an elderly patient: A case report.",
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"abstract": "OBJECTIVE\nRecently, phase III trials assessed a new combination of lenalidomide, bortezomib, and dexamethasone (RVD) in induction therapy in transplantation-eligible multiple myeloma (MM) patients, before consolidation with RVD and lenalidomide maintenance. We present a retrospective study evaluating this approach with patients from the real life.\n\n\nMETHODS\nWe conducted a retrospective single-arm study to assess efficacy and safety of RVD combination in induction therapy before high-dose chemotherapy with melphalan followed by autologous stem cell transplantation, and RVD consolidation followed by lenalidomide maintenance, from February 2011 to May 2016.\n\n\nRESULTS\nForty patients were enrolled. The mean age at diagnosis was 56 years. Median progression-free survival was 45 months, and median overall survival was 76 months. The only factor found associated with better PFS was a negative minimal residual disease (P < .01). Twenty-six (65%) patients experimented adverse events: 8 patients (20%) underwent 12 serious AE (≥grade 3). Treatment discontinuation occurred in 2 patients (5%) because of severe AE.\n\n\nCONCLUSIONS\nTo our knowledge, this work provides the first evidence of the efficacy and the safety of RVD combination in patients treated in common practice.",
"affiliations": "Hematology and Cellular Therapy Department, La Conception University Hospital of Marseille, Marseille, France.;Hematology and Cellular Therapy Department, La Conception University Hospital of Marseille, Marseille, France.;Hematology and Cellular Therapy Department, La Conception University Hospital of Marseille, Marseille, France.;Hematology Laboratory, La Timone University Hospital of Marseille, Marseille, France.;Hematology and Cellular Therapy Department, La Conception University Hospital of Marseille, Marseille, France.;Hematology and Cellular Therapy Department, La Conception University Hospital of Marseille, Marseille, France.;Hematology and Cellular Therapy Department, La Conception University Hospital of Marseille, Marseille, France.;Hematology and Cellular Therapy Department, La Conception University Hospital of Marseille, Marseille, France.;Genetic Department, La Timone, University Hospital of Marseille, Marseille, France.;Hematology Laboratory, La Conception University Hospital of Marseille, Marseille, France.;Pharmacy Unit, La Conception University Hospital of Marseille, Marseille, France.;Pharmacy Unit, La Conception University Hospital of Marseille, Marseille, France.;Pharmacy Unit, La Conception University Hospital of Marseille, Marseille, France.;Hematology and Cellular Therapy Department, La Conception University Hospital of Marseille, Marseille, France.",
"authors": "Arcani|Robin|R|https://orcid.org/0000-0002-5567-354X;Venton|Geoffroy|G|;Colle|Julien|J|;Suchon|Pierre|P|;Ivanov|Vadim|V|;Mercier|Cédric|C|;Farnault|Laure|L|;Roche|Pauline|P|;Lafage|Marina|M|;Brunet|Corinne|C|;Azouza|Wakil|W|;Pourroy|Bertrand|B|;Fanciullino|Raphaëlle|R|;Costello|Regis|R|",
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"title": "Efficacy and safety of autologous stem cell transplantation after induction therapy with lenalidomide, bortezomib, and dexamethasone.",
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"abstract": "Intra-abdominal fibromatosis (IAF) commonly develops in patients who had abdominal surgery. In rare instances, it occurs subsequent to gastrointestinal stromal tumor (GIST). This special situation has clinical significance in imatinib era. About 1000 patients with GIST in our institution from 1993 to 2010 were re-evaluated based on their clinical and pathological data, the treatment strategies and the follow-up information. We identified 2 patients who developed IAF after GIST resection. Patient 1 was a 54 year-old male and had 5 cm × 4.5 cm × 3.5 cm jejunal GIST excised on February 22, 1994. Three years later, an abdominal mass with 7 cm × 6 cm × 3 cm was identified. He was diagnosed as recurrent GIST from clinical point of view. After excision, the second tumor was confirmed to be IAF. Patient 2 was a 45-year-old male and had 6 cm × 4 cm × 3 cm duodenal GIST excised on August 19, 2008. One year later, a 4 cm mass was found at the original surgical site. The patient refused to take imatinib until the tumor increased to 8 cm six months later. The tumor continued to increase after 6 months' imatinib therapy, decision of surgical resection was made by multidisciplinary team. The second tumor was confirmed to be IAF with size of 17 cm × 13 cm × 11 cm. Although IAF subsequent to GIST is very rare, it is of clinical significance in imatinib era as an influencing factor for making clinical decision.\nThe virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1076715989961803.",
"affiliations": "Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai 200032, PR China.",
"authors": "Jiang|Dongxian|D|;He|Deming|D|;Hou|Yingyong|Y|;Lu|Weiqi|W|;Shi|Yuan|Y|;Hu|Qin|Q|;Lu|Shaohua|S|;Xu|Chen|C|;Liu|Yalan|Y|;Liu|Ju|J|;Tan|Yunshan|Y|;Zhu|Xiongzeng|X|",
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"fulltext": "\n==== Front\nDiagn PatholDiagn PatholDiagnostic Pathology1746-1596BioMed Central 1746-1596-8-1252390267510.1186/1746-1596-8-125Case ReportSubsequent intra-abdominal fibromatosis mimicking recurrent gastrointestinal stromal tumor Jiang Dongxian 112211210001@fudan.edu.cnHe Deming 110211210001@fudan.edu.cnHou Yingyong 1houyingyong@hotmail.comLu Weiqi 2lu.weiqi@zs-hospital.sh.cnShi Yuan 1shi.yuan@zs-hospital.sh.cnHu Qin 1hu.qin@zs-hospital.sh.cnLu Shaohua 1lu.shaohua@zs-hospital.sh.cnXu Chen 1xu.chen@zs-hospital.sh.cnLiu Yalan 1liu.yalan@zs-hospital.sh.cnLiu Ju 1liu.ju@zs-hospital.sh.cnTan Yunshan 1tan.yunshan@zs-hospital.sh.cnZhu Xiongzeng 3xiongzengzhu@126.com1 Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China2 Department of Oncology Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China3 Department of Pathology, Cancer hospital, Fudan University, Shanghai 200032, P.R. China2013 31 7 2013 8 125 125 6 4 2013 4 7 2013 Copyright © 2013 Jiang et al.; licensee BioMed Central Ltd.2013Jiang et al.; licensee BioMed Central Ltd.This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Abstract\nIntra-abdominal fibromatosis (IAF) commonly develops in patients who had abdominal surgery. In rare instances, it occurs subsequent to gastrointestinal stromal tumor (GIST). This special situation has clinical significance in imatinib era. About 1000 patients with GIST in our institution from 1993 to 2010 were re-evaluated based on their clinical and pathological data, the treatment strategies and the follow-up information. We identified 2 patients who developed IAF after GIST resection. Patient 1 was a 54 year-old male and had 5 cm × 4.5 cm × 3.5 cm jejunal GIST excised on February 22, 1994. Three years later, an abdominal mass with 7 cm × 6 cm × 3 cm was identified. He was diagnosed as recurrent GIST from clinical point of view. After excision, the second tumor was confirmed to be IAF. Patient 2 was a 45-year-old male and had 6 cm × 4 cm × 3 cm duodenal GIST excised on August 19, 2008. One year later, a 4 cm mass was found at the original surgical site. The patient refused to take imatinib until the tumor increased to 8 cm six months later. The tumor continued to increase after 6 months’ imatinib therapy, decision of surgical resection was made by multidisciplinary team. The second tumor was confirmed to be IAF with size of 17 cm × 13 cm × 11 cm. Although IAF subsequent to GIST is very rare, it is of clinical significance in imatinib era as an influencing factor for making clinical decision.\n\nVirtual slides\nThe virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1076715989961803\n\nGISTIntra-abdominal fibromatosis (IAF)Imatinib\n==== Body\nIntroduction\nGastrointestinal stromal tumor (GIST) is the most common gastrointestinal mesenchymal tumor and mainly treated with surgical resection in the past era without effective drugs. The identification of KIT mutations in recent years has led to the development of specific, targeted therapies with tyrosine kinase inhibitors such as imatinib mesylate (STI571, Gleevec; Novartis Pharmaceuticals, Basel, Switzerland) and sunitinib malate (SU11248, Sutent; Pfizer, Inc, New York, USA), which are more effective for unresectable, metastatic and recurrent diseases [1].\n\nWith the accumulation of knowledges on GIST and long-time follow-up information, GIST patients are found to simultaneously or metachronously have other types of tumors [2-7], some of which are easier to be differentiated from GIST [4,6], while others might be confused with recurrent GIST from the clinical point of view [2,3].\n\nIntra-abdominal fibromatosis (IAF) is a rare mesenchymal tumor which does not metastasize but tends to exhibit a high degree of local infiltration and invasion, thus becoming lethal in some cases [8-11]. IAF developed after abdominal surgery and individual with both GIST and IAF were reported recently [2,3] and non-random association between GIST and IAF was established very recently based on data from 10 medical centers [12].\n\nIn this report, we describe 2 additional GIST patients who admitted to our institution before and after imatinib era, respectively, and developed IAF at the site of GIST resection beds. Both of the two cases created the first impression of GIST recurrence. Surgical excision of the lesion was done without any hesitation in the first patient, however, difficult decision owing to the suspicion of metastatic disease when imatinib therapy was available in the second patient. These 2 cases highlight the importance of recognizing the coexistence of other diseases in patients with chronic GIST since the metachronous tumor subsequent to GIST is easy to be mis-regarded as recurrent tumor and treated with imatinib in molecular-targeted therapeutic era.\n\nMaterials and methods\nTumor specimens\nMedical records and tissue specimens of about 1375 primary mesenchymal tumors of GI tract with the years ranging from 1993 to 2010 were retrieved from Zhongshan Hospital, Fudan University. Among them, 1055 cases were primary mesenchymal tumors previously characterized as leiomyoma, leiomyosarcoma, leiomyoblastoma, schwannoma, stromal or smooth muscle tumors originated from GI tract. Out of these 1055 cases, 997 cases underwent surgery and immunohistochemically or histologically identified as GISTs based on KIT positive immunohistochemical detection or histopathological spectrum with KIT-positive tissues. All tumor slides were reviewed by two experienced pathologists. Another 195 GIST patients were collected from our own consultant files from January 2003 to March 2010. Tumor tissue collection and the following analyses were approved by the review boards of Zhongshan Hospital, Fudan University.\n\nClinical records\nPatient demographics and clinical data were retrieved from the medical records. Data on gender, age at diagnosis, KIT, PDGFRA mutation status and follow-up information were collected.\n\nHistological evaluation\nHematoxylin and eosin (H&E)-stained slides for each patient were reviewed and the following features were recorded: predominant cell type, pleomorphism, nuclear atypia, necrosis, mitotic count, invasion, and risk levels [13].\n\nImmunohistochemical evaluation\nImmunohistochemical staining was performed based on the method previously reported [14]. Formalin-fixed paraffin sections were prepared from one representative block and subjected to immunohistochemical staining with a panel of antibodies against CD117 (rabbit polyclonal anti-human KIT, diluted 1:150; Dako, Denmark), CD34 (mouse monoclonal antibody, clone QBEnd 10, diluted 1:200; Dako), α-smooth muscle actin (mouse monoclonal antibody, clone 1A4, diluted 1:200; Dako), desmin (mouse monoclonal antibody, clone D33, diluted 1:200; Dako), S-100 protein (polyclonal, diluted 1:300; Dako) and vimentin (mouse monoclone antibody, V9, diluted 1:1000; Dako). The slides were first treated with 0.01M citrate buffer (pH 6.0) by microwave method for antigen retrieval, and incubated overnight at 4°C. Immunohistochemical detection was performed with EnVision-based system using a commercial kit (Dako). Diaminobenzidine was used as the chromogen, and all sides were counterstained with hematoxylin.\n\nResults\nReport of two cases\nPatient 1: A 54-year-old male admitted to Zhongshan Hospital (Fudan University, Shanghai, China) on Feb 8th, 1994 due to tarry black stools for four months. Gastroscopy found no abdominal changes. Mesenteric artery angiography showed a jejunal tumor. Emission computerized tomography (ECT) examination found active bleeding near the junction of the jejunum and ileum. Primary impression was small intestinal leiomyoma. The patient was treated with radical resection of part of the jejunum. Pathological examination found a non-mitotic submucosae tumor with a small ulcer. The tumor was 5 cm × 4.5 cm × 3.5 cm in size and showed outward growth pattern. The primary diagnosis was cellular leiomyoma and now reviewed as GIST based on morphology (Figure 1) and immunohistochemical staining results, which showed that the tumor cells were positive for CD117, but negative for CD34, a-SMA, desmin and S-100. The patient was classified into low risk level according to the current risk level classification [15]. He recovered smoothly after surgery and was disease free without any further therapy. However, in Feb 1997, he admitted to our hospital again due to back ache. Computed tomography (CT) scanning showed a mass in the retroperitoneum of the right lower quadrant. Since clinical impression was a recurrent tumor, he was treated with laparotomy without any hesitation. A lower right retroperitoneal tumor with partial small intestine and partial ureter were successfully excised. Gross examination found a 7 cm × 6 cm × 3 cm mass attached to small intestine, and the ureter was entrapped in it. The tumor sections were gray-white. Microscopical examination found spindle cells with abundant collagen, no demarcated boundary between the tumor cells and the muscularis propria of jejunum (Figure 2), and no more than 3 mitotic ureter cells per 50 high power fields. The tumor was different from the primary tumor morphologically. The tumor cells were negative for α-SMA, S-100, desmin, CD34 and CD117. He was diagnosed to have IAF after discussion with senior pathologists in Department of Pathology, Cancer Hospital, Fudan university since the situation was very rare in clinical practice. The patient survived another 18.5 years after two operations.\n\nFigure 1 Characteristics of GIST showed spindle cells with intersecting growth pattern Hemotoxylin eosin staining 5 ×.\n\nFigure 2 Histological images (1 ×) of the tumor. Hematoxylin-eosin staining showing 1) proliferating non-dysplastic fibroblasts, 2) prominent dilated thin-walled veins, 3) interwoven spindle cells and varying amounts of collagen, 4) tumor cells invading the muscle layer of the jejunum with intact mucosal layer.\n\nPatient 2: A 45-year-old male was found to have duodenal tumor by physical examination in Aug 2008. He was treated with partial duodenal resection together with tumor on Aug 19th, 2008 in a local hospital (Haining County People’s Hospital, Zhejiang Province). The tumor was 6 cm × 4 cm × 3 cm in size. Microscopical examination found non-mitotic, spindle cells with intersecting growth pattern. The tumor cells were positive for CD117 and CD34, but negative for α-SMA, desmin and S-100 by immunohistochemistry. He was diagnosed as GIST and classified into moderate risk level. The patient was not treated with any adjuvant therapy after the operation. Twelve months later, a solitary and localized abdominal tumor with 4 cm in diameter was detected in the left upper abdominal cavity in routine CT scanning. The patient was reluctant to treatment. Six months later, the tumor was increased to 8 cm. He was initially treated with imatinib (400 mg daily) on Mar 28th, 2010 since the first clinical impression was recurrence of GIST. But CT scan performed 3 months after initiation of imatinib therapy found the tumor size was increased and CT scan performed 6 months after initiation of imatinib therapy revealed significant progression of the left abdominal tumor: its size enlarged to 15 cm. At this point, the patient was referred to our hospital for further management. A multidisciplinary team (MDT) meeting was convened. Physical examination identified a huge palpable mass in the left middle abdominal cavity. Abdominal ultrasonography revealed a homogeneous low-echoic tumor of 15 cm in diameter. CT scan revealed a low-dense, homogeneous tumor, mainly involving mesentery and mesenteric veins and adjacent to jejunum and colon, the ureter was also entrapped in it (Figures 3 and 4). Angiography showed a hypovascular tumor encroaching on superior mesenteric artery and vein, and their branches. Urography found the tumor obstructing the upper part of the left ureter, causing left side hydronephrosis. Furthermore, the primary duodenal GIST (Figure 5) was reevaluated as borderline nature and no KIT and PDGFRA mutation was found in the tumor. Therefore, a MDT decision was made to resect the lesion surgically. Prior to surgery, detailed examinations were performed. On Nov. 11th, 2010, the patient underwent exploratory laparotomy. The mesenteric tumor was successfully excised completely with adherent tissues and organs. Laparotomy revealed a hard tumor of 15 cm which appeared to originate from jejunal mesentery, involving proximal jejunum and the descending colon. The tumor also invaded and entrapped a segment of the upper part of ureter. The involved parts of jejunum and the tumor-bearing jejunal mesentery were resected en bloc along with the affected part of the mesocolon and the left kidney and the ureter. Grossly, the mass was resected with adequate margins and measured as 17 cm × 13 cm × 11cm. On section, the tumor was white and firm mass without necrosis, cystic change and hemorrhage (Figure 6). Microscopic examination of the tumor showed that non-dysplastic fibroblasts proliferating in the jejunal mesentery had infiltrated into the adjacent small intestine and ureter (Figure 7). The tumor cells were negative for CD117, S100, CD34, a-SMA and desmin. Therefore, the lesion was diagnosed as a mesenteric IAF. The postoperative course was uneventful without adjuvant therapy and no local recurrence has been noted as of October 2012.\n\nFigure 3 Preoperative CT scan images of the tumor. A contrast-enhanced CT image showing a homogeneous low-dense tumor with slight enhancement involving the proximal jejunum and descending colon.\n\nFigure 4 The upper ureter entrapped in the inside of the tumor.\n\nFigure 5 Histological images of the tumor with spindle cells and intersecting growth pattern Hemotoxylin eosin staining 5 ×.\n\nFigure 6 Images of resected specimen, showing an intra-abdominal tumor with sacrifice of partial resection of the jejunum, colon, and left kidney in the small bowel mesentery and its surface section appearance, which is white and compact,and has no necrosis, hemorrhage or cystic changes. The size of the tumor was 17 cm × 13 cm × 11 cm.\n\nFigure 7 Microscopic images of the tumor (5×), showing loosely arranged spindle cells with bland, oval nuclei and minimal cytoplasm, plump spindle cells with tapering ends, oval, vesicular nuclei, moderate amounts of eosinophilic cytoplasm, and several thin-walled vessels of varying calibers.\n\nDiscussion\nFibromatosis is a group of fibroblastic or myofibroblastic tissues that can be locally aggressive but do not metastasize [16]. The incidence of desmoids tumor has been reported as 2–4 cases per 1 million population, and deep fibromatosis, such as those arising in the abdominal cavity, are often referred to as IAF [17], which accounts for 8% of fibromatosis [18]. Although rare, IAF is the most common primary mesenteric tumor with spindle cell morphology [19]. Its causes and underlying mechanisms are unknown. Although most cases are sporadic, about 20% cases are associated with familial adenomatous polyposis (FAP) in a syndrome known as Gardner syndrome [20], about 10% cases with abdominal surgery or trauma experiences for various reasons [17,21-24], and rare cases with prior radiation therapy [25,26]. The two cases reported here were associated with previous abdominal surgery for GIST.\n\nOf the above-mentioned situations, IAF developed after surgical resection for other tumors has special clinical significance. IAF has been observed in the sites of previous abdominal surgery for tumors [23,24]. Its diagnosis often is difficult to establish preoperatively, and it is usually misdiagnosed as recurrence at first clinical impression [2,22,23,27]. Surgical excision of the lesion is a difficult decision owing to the suspicion of metastasis mainly due to the following reasons. 1) The appearance of IAF on contrast enhanced imaging is not specific, therefore, the imaging diagnosis of IAF developed after abdominal surgery for other tumors is very difficult except in patients with familial adenomatous polyposis [20,28]. 2) The time interval between surgery and development of fibromatosis ranges from 2 months to several years (2.6 years on average) [17], which overlaps with recurrent disease.\n\nRecently, there have been prior several case reports describing IAF arising on the site of a previously excised GIST. In these cases, IAF was first misdiagnosed as GIST recurrence [2,3]. Very recently, a non-random association between GIST and IAF was described. However, it’s different from a non-random association between GIST and myeloid leukemia [4], since an accurate diagnosis could only be established after surgical removal and pathological examination, as there are no typical imaging findings to suggest a IAF. Although it is a very rare event, IAF developed synchronously or metachronously with GIST could occur in most medical centers, for example, 28 IAF patients were collected from 10 medical centers [19].\n\nIntroduction of imatinib has greatly changed the clinical approach to intra-abdominal stromal spindle cell tumors. GIST is the most common mesenchymal tumor in gastrointestinal tract. Oncogenic mutations in KIT or PDGFRA have been identified as central tumor-initiating events in many GISTs [29]. Treatments with imatinib and sunitinib, two small-molecule inhibitors of the mutant KIT and PDGFRA receptor tyrosine kinases, significantly prolong survival of patients with GIST [1]. The median time for disease progression is 18–24 months in imatinib-treated patients with unresectable GIST. The clinical decision has been changed in patients with recurrent GIST.\n\nIn this study, the first patient had the disease in the era before imatinib. Since GIST is resistant to conventional cytotoxic chemotherapy [30], surgical resection was the first option for the patients. The second patient had the disease in the imatinib era, therefore, imatinib therapy was the first recommendation. However, the patient was not benefited from imatinib treatment: the tumor continued to grow rapidly after six months of imatinib therapy. After referred to our hospital, pathological re-evaluation suggested that the primary GIST was of borderline nature and the opportunity for recurrence was very low based on our previous experiences [31,32]. Furthermore, mutations in KIT and PDGFRA were not found in GIST. Since imatinib is less effective against GIST without KIT or PDGFRA mutation [33], and initial studies suggest that sunitinib treatment rarely results in objective responses in GIST [34,35], debulking surgery remains a recognized standard practice in the case of local progression because such procedure could prolong survival of patients who are resistant or insensitive to imatinib treatment [36]. Therefore, the decision of surgical resection was made for cure and definite diagnosis after MDT discussion.\n\nSurgical intervention for IAF is generally considered to be the treatment of choice and is curative in many cases. Some studies have reported better prognosis for IAF patients with non-Gardner’s-associated IAF than for those complicated by Gardner’s syndrome [8,10,17,37]. In the study, both patients had no family history of FAP and uneventful prognosis. Complete surgical resection remains the cornerstone of management of IAF, while unresectable or residual disease can be treated with multiple choices. Nonsurgical treatment protocols mainly rely on sulindac [28], toremifene [38], cytotoxic chemotherapy [39], or in some circumstances, radiotherapy [40]. Each of them has variable and unpredictable efficacy [28]. Therefore. new treatment protocols for IAF are gradually being recommended, such as imatinib [41], sunitinib [42], bevacizumab [43], or sorafenib [44]. However, the two cases reported had been treated with imatinib at a dose of 400 mg for liver metastatic GIST. One achieved four years of long-term stable control [3] and the other achieved 11 months of disease control [2], but both developed IAF in primary GIST bed. The second patient was not benefit from imatinib therapy at this dosage.\n\nMace et al. recommended imatinib treatment at dose of 400 mg giving twice per day as a new therapeutic approach for desmoids tumor [45]. In Dumont’s cases, a patient who received imatinib at 400 mg/day for gastric GIST developed IAF on the posterior wall of the gastric antrum 35 months after initial diagnosis. After increasing imatinib dose to 800 mg/day, patient partially responded to both tumors [12], suggesting that patients with IAF might benefit from high dosage of imatinib.\n\nNevertheless, surgical trauma at the GIST excision site may predispose to the development of the IAF. This situation broads differential diagnosis and elicits a range of potential treatment options ranging from imatinib therapy to aggressive surgical re-excision for IAF. An accurate diagnosis is possible only after surgical removal and pathological examination, as there are no typical imaging findings to suggest IAF. Excluding diagnosis of recurrence of GIST is crucial for further management of our patients due to the increasing use of imatinib in the treatment of advanced GIST. In rare instances as illustrated in our cases, co-existence of another disease should be considered. The current two cases highlight the need for careful consideration of IAF when a rapidly growing spindle cell tumor is encountered in a post-GIST patient.\n\nConsent\nWritten informed consents were obtained from patients and their family members for publication of this report.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nAuthors’ contributions\nAll authors read and approved the final manuscript.\n\nAcknowledgements\nThis study was funded by ①The National Natural Science foundation of Youth Science foundation, grant number 81101809 and ②Shanghai Science and Technology Foundation, grant number 13411950802.\n==== Refs\nDemetri GD Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors N Engl J Med 2002 347 7 472 80 10.1056/NEJMoa020461 12181401 \nKhan M Mesenteric desmoid tumor developing on the site of an excised gastrointestinal stromal tumor Rare Tumors 2010 2 2 e33 21139835 \nLee CK When is a GIST not a GIST? A case report of synchronous metastatic gastrointestinal stromal tumor and fibromatosis World J Surg Oncol 2009 7 8 10.1186/1477-7819-7-8 19159438 \nMiettinen M A nonrandom association between gastrointestinal stromal tumors and myeloid leukemia Cancer 2008 112 3 645 9 10.1002/cncr.23216 18041070 \nRuka W Other malignant neoplasms in patients with gastrointestinal stromal tumors (GIST) Med Sci Monit 2004 10 8 LE13 4 15278004 \nWronski M Synchronous occurrence of gastrointestinal stromal tumors and other primary gastrointestinal neoplasms World J Gastroenterol 2006 12 33 5360 2 16981268 \nMacias-Garcia L Collision tumour involving a rectal gastrointestinal stromal tumour with invasion of the prostate and a prostatic adenocarcinoma Diagn Pathol 2012 7 150 10.1186/1746-1596-7-150 23111239 \nColombo C FAP-related desmoid tumors: a series of 44 patients evaluated in a cancer referral center Histol Histopathol 2012 27 5 641 9 22419028 \nPajares B Multimodal treatment of desmoid tumours: the significance of local control Clin Transl Oncol 2011 13 3 189 93 10.1007/s12094-011-0639-4 21421464 \nQuintini C Mortality of intra-abdominal desmoid tumors in patients with familial adenomatous polyposis: a single center review of 154 patients Ann Surg 2012 255 3 511 6 10.1097/SLA.0b013e31824682d4 22323009 \nSchlemmer M Desmoid tumors and deep fibromatoses Hematol Oncol Clin North Am 2005 19 3 565 71 vii-viii 10.1016/j.hoc.2005.03.008 15939197 \nDumont AG A nonrandom association of gastrointestinal stromal tumor (GIST) and desmoid tumor (deep fibromatosis): case series of 28 patients Ann Oncol 2012 23 5 1335 40 10.1093/annonc/mdr442 21994214 \nRutkowski P Risk criteria and prognostic factors for predicting recurrences after resection of primary gastrointestinal stromal tumor Ann Surg Oncol 2007 14 7 2018 27 10.1245/s10434-007-9377-9 17473953 \nHou YY Schwannoma of the gastrointestinal tract: a clinicopathological, immunohistochemical and ultrastructural study of 33 cases Histopathology 2006 48 5 536 45 10.1111/j.1365-2559.2006.02370.x 16623779 \nFletcher CD Diagnosis of gastrointestinal stromal tumors: a consensus approach Hum Pathol 2002 33 5 459 65 10.1053/hupa.2002.123545 12094370 \nAllen PW The fibromatoses: a clinicopathologic classification based on 140 cases Am J Surg Pathol 1977 1 3 255 70 10.1097/00000478-197709000-00007 920873 \nBurke AP Intra-abdominal fibromatosis. A pathologic analysis of 130 tumors with comparison of clinical subgroups Am J Surg Pathol 1990 14 4 335 41 10.1097/00000478-199004000-00004 2321698 \nReitamo JJ The desmoid tumor. I. Incidence, sex-, age- and anatomical distribution in the Finnish population Am J Clin Pathol 1982 77 6 665 73 7091046 \nAl-Nafussi A Wong NA Intra-abdominal spindle cell lesions: a review and practical aids to diagnosis Histopathology 2001 38 5 387 402 10.1046/j.1365-2559.2001.01119.x 11422475 \nSoravia C Desmoid disease in patients with familial adenomatous polyposis Dis Colon Rectum 2000 43 3 363 9 10.1007/BF02258303 10733118 \nDe Cian F Desmoid tumor arising in a cesarean section scar during pregnancy: monitoring and management Gynecol Oncol 1999 75 1 145 8 10.1006/gyno.1999.5539 10502442 \nKomatsu S Intra-abdominal desmoid tumor mimicking lymph node recurrence after gastrectomy for gastric cancer J Gastroenterol Hepatol 2006 21 7 1224 6 10.1111/j.1440-1746.2006.04210.x 16824087 \nLawatsch EJ Intra-abdominal desmoid tumor following retroperitoneal lymph node dissection for testicular germ cell tumor Int J Urol 2006 13 1 84 6 10.1111/j.1442-2042.2006.01231.x 16448440 \nWeiss ES Burkart AL Yeo CJ Fibromatosis of the remnant pancreas after pylorus-preserving pancreaticoduodenectomy J Gastrointest Surg 2006 10 5 679 88 10.1016/j.gassur.2005.09.029 16773761 \nSchlager A Mesenteric fibromatosis masquerading as an ovarian neoplasm twenty years after Chernobyl radiation exposure Gynecol Oncol 2006 102 3 587 9 10.1016/j.ygyno.2006.03.037 16678243 \nWegner HE Fleige B Dieckmann KP Mesenteric desmoid tumor 19 years after radiation therapy for testicular seminoma Urol Int 1994 53 1 48 9 10.1159/000282632 7974887 \nMizuno R Intra-abdominal desmoid tumor mimicking locoregional recurrence after colectomy in a patient with sporadic colon cancer: report of a case Surg Today 2011 41 5 730 2 10.1007/s00595-010-4340-y 21533952 \nMiddleton SB Phillips RK Surgery for large intra-abdominal desmoid tumors: report of four cases Dis Colon Rectum 2000 43 12 1759 62 discussion 1762–3 10.1007/BF02236864 11156464 \nHirota S Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors Science 1998 279 5350 577 80 10.1126/science.279.5350.577 9438854 \nGold JS Outcome of metastatic GIST in the era before tyrosine kinase inhibitors Ann Surg Oncol 2007 14 1 134 42 17080234 \nHou YY Predictive values of clinical and pathological parameters for malignancy of gastrointestinal stromal tumors Histol Histopathol 2009 24 6 737 47 19337972 \nShi Y Clinical and pathological studies of borderline gastrointestinal stromal tumors Chin Med J (Engl) 2010 123 18 2514 20 21034620 \nHeinrich MC Correlation of kinase genotype and clinical outcome in the North American intergroup phase III trial of imatinib mesylate for treatment of advanced gastrointestinal stromal tumor: CALGB 150105 study by cancer and leukemia group B and southwest oncology group J Clin Oncol 2008 26 33 5360 7 10.1200/JCO.2008.17.4284 18955451 \nHeinrich MC Primary and secondary kinase genotypes correlate with the biological and clinical activity of sunitinib in imatinib-resistant gastrointestinal stromal tumor J Clin Oncol 2008 26 33 5352 9 10.1200/JCO.2007.15.7461 18955458 \nJaneway KA Sunitinib treatment in pediatric patients with advanced GIST following failure of imatinib Pediatr Blood Cancer 2009 52 7 767 71 10.1002/pbc.21909 19326424 \nDesai J Clonal evolution of resistance to imatinib in patients with metastatic gastrointestinal stromal tumors Clin Cancer Res 2007 13 18 Pt 1 5398 405 17875769 \nWilkinson MJ Surgical resection for non-familial adenomatous polyposis-related intra-abdominal fibromatosis Br J Surg 2012 99 5 706 13 10.1002/bjs.8703 22359346 \nBrooks MD Desmoid tumours treated with triphenylethylenes Eur J Cancer 1992 28A 6–7 1014 8 1385717 \nOkuno SH Edmonson JH Combination chemotherapy for desmoid tumors Cancer 2003 97 4 1134 5 10.1002/cncr.11189 12569616 \nBallo MT Desmoid tumor: prognostic factors and outcome after surgery, radiation therapy, or combined surgery and radiation therapy J Clin Oncol 1999 17 1 158 67 10458229 \nMace J Response of extraabdominal desmoid tumors to therapy with imatinib mesylate Cancer 2002 95 11 2373 9 10.1002/cncr.11029 12436445 \nSkubitz KM Response of imatinib-resistant extra-abdominal aggressive fibromatosis to sunitinib: case report and review of the literature on response to tyrosine kinase inhibitors Cancer Chemother Pharmacol 2009 64 3 635 40 10.1007/s00280-009-1010-0 19404642 \nCosta LA Successful treatment of an intra-abdominal desmoid tumor with irinotecan, fluorouracil, and leucovorin plus bevacizumab in a patient with familial adenomatous polyposis Int J Colorectal Dis 2012 27 2 257 9 10.1007/s00384-011-1201-0 21533592 \nGounder MM Activity of Sorafenib against desmoid tumor/deep fibromatosis Clin Cancer Res 2011 17 12 4082 90 10.1158/1078-0432.CCR-10-3322 21447727 \nGroden J Identification and characterization of the familial adenomatous polyposis coli gene Cell 1991 66 3 589 600 10.1016/0092-8674(81)90021-0 1651174\n\n",
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"issue": "8()",
"journal": "Diagnostic pathology",
"keywords": null,
"medline_ta": "Diagn Pathol",
"mesh_terms": "D000970:Antineoplastic Agents; D001549:Benzamides; D003951:Diagnostic Errors; D013505:Digestive System Surgical Procedures; D004379:Duodenal Neoplasms; D018221:Fibromatosis, Abdominal; D046152:Gastrointestinal Stromal Tumors; D006801:Humans; D000068877:Imatinib Mesylate; D007580:Jejunal Neoplasms; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D010879:Piperazines; D011237:Predictive Value of Tests; D011743:Pyrimidines; D012086:Reoperation; D012307:Risk Factors; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome; D047368:Tumor Burden; D019564:Unnecessary Procedures",
"nlm_unique_id": "101251558",
"other_id": null,
"pages": "125",
"pmc": null,
"pmid": "23902675",
"pubdate": "2013-07-31",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "21533592;16773761;11156464;1651174;19337972;18955451;10733118;12436445;7974887;16981268;9438854;21139835;22419028;12569616;22359346;15278004;17875769;11422475;21994214;10502442;18955458;22323009;15939197;16448440;16678243;19159438;21034620;7091046;23111239;19326424;17080234;12094370;21447727;18041070;1385717;19404642;21533952;10458229;21421464;16623779;12181401;17473953;16824087;2321698;920873",
"title": "Subsequent intra-abdominal fibromatosis mimicking recurrent gastrointestinal stromal tumor.",
"title_normalized": "subsequent intra abdominal fibromatosis mimicking recurrent gastrointestinal stromal tumor"
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"abstract": "Osteonecrosis of the jaw (ONJ) associated with the use of bisphosphonates has been rarely reported in metastatic renal cell cancer (RCC) patients. Since the introduction of combined therapies consisting of nitrogen-containing bisphosphonates (NBPs) and targeted agents, an increasing number of RCC patients were reported to develop ONJ, suggesting that therapeutic angiogenesis suppression might increase the risk of ONJ in NBPs users. We performed a multicenter retrospective study and reviewed literature data to assess the occurrence and to investigate the nature of ONJ in RCC patients taking NBPs and targeted agents. Nine Italian Centers contributed to the data collection. Patients with exposed and nonexposed ONJ were eligible for the study if they had been taking NBPs and were receiving targeted agents at the time of ONJ diagnosis. Forty-four RCC patients were studied. Patients were mostly male (82%), with a median age of 63 years (range, 45-85 years). Zoledronic acid (93%) and sunitinib (80%) were the most frequently used NBP and antiangiogenic agent, respectively. Other agents included Pamidronate, ibandronate, sorafenib, bevacizumab, mammalian target of rapamycin inhibitors. Forty-nine sites of ONJ were encountered, with the mandible being the preferred site of ONJ (52%); both jaws were affected in 5 cases (12%). The most common precipitating event was dental/periodontal infection (34%), followed by tooth extraction (30%). Oral triggers of ONJ were missing in 10 cases (23%). This unexpectedly high number of ONJ cases, in comparison with literature data, suggests that frequency of ONJ in RCC patients might be largely underestimated and suggests a potential role for targeted agents in the incremental risk of ONJ.",
"affiliations": "Medical Oncology Unit, Department of Oncology and Hematology, Ospedale SS Antonio e Biagio e C Arrigo Alessandria, Alessandria, Italy. Electronic address: vfusco@ospedale.al.it.;Medical Oncology, I.R.C.C.S. San Matteo University Hospital Foundation, Pavia, Italy; Italian Nephro-Oncology Group (Gruppo Italiano di Oncologia Nefrologica, G.I.O.N.), Italy.;Unit of Maxillofacial Surgery, Department of Neurosciences, University of Padova, Padova, Italy.;Medical Oncology, I.R.C.C.S. San Matteo University Hospital Foundation, Pavia, Italy; Italian Nephro-Oncology Group (Gruppo Italiano di Oncologia Nefrologica, G.I.O.N.), Italy.;Unit of Maxillofacial Surgery, Department of Neurosciences, University of Padova, Padova, Italy.;CTO, Azienda Ospedaliera Universitaria \"Città della salute\", Torino, Italy.;Department of Dentistry, Ospedale Papa Giovanni XXIII, Bergamo, Italy.;Department of Otolaryngological/Dental/Ophthalmological and Cervico-Facial Sciences, University of Parma, Parma, Italy.;Department of Otolaryngological/Dental/Ophthalmological and Cervico-Facial Sciences, University of Parma, Parma, Italy.;Medical Oncology, Santa Maria degli Angeli Hospital, Pordenone.;Medical Oncology Unit, Department of Oncology and Hematology, Ospedale SS Antonio e Biagio e C Arrigo Alessandria, Alessandria, Italy.;Department of Surgical, Oncological and Oral Sciences, Sector of Oral Medicine \"V. Margiotta\", University of Palermo, Palermo, Italy.;Department of Surgical, Oncological and Oral Sciences, Sector of Oral Medicine \"V. Margiotta\", University of Palermo, Palermo, Italy.;Unit of Maxillofacial Surgery, Department of Neurosciences, University of Padova, Padova, Italy.",
"authors": "Fusco|Vittorio|V|;Porta|Camillo|C|;Saia|Giorgia|G|;Paglino|Chiara|C|;Bettini|Giordana|G|;Scoletta|Matteo|M|;Bonacina|Riccardo|R|;Vescovi|Paolo|P|;Merigo|Elisabetta|E|;Lo Re|Giovanni|G|;Guglielmini|Pamela|P|;Di Fede|Olga|O|;Campisi|Giuseppina|G|;Bedogni|Alberto|A|",
"chemical_list": "D020533:Angiogenesis Inhibitors; D004164:Diphosphonates; D007093:Imidazoles; D007211:Indoles; D011758:Pyrroles; D000077211:Zoledronic Acid; D000077210:Sunitinib",
"country": "United States",
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"doi": "10.1016/j.clgc.2014.12.002",
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"issn_linking": "1558-7673",
"issue": "13(4)",
"journal": "Clinical genitourinary cancer",
"keywords": "Bevacizumab; Sorafenib; Sunitinib; Zoledronic acid; m-TOR inhibitor",
"medline_ta": "Clin Genitourin Cancer",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors; D000971:Antineoplastic Combined Chemotherapy Protocols; D002292:Carcinoma, Renal Cell; D004164:Diphosphonates; D005260:Female; D006801:Humans; D007093:Imidazoles; D007211:Indoles; D007558:Italy; D007568:Jaw; D007680:Kidney Neoplasms; D008297:Male; D008875:Middle Aged; D010020:Osteonecrosis; D011758:Pyrroles; D012189:Retrospective Studies; D000077210:Sunitinib; D000077211:Zoledronic Acid",
"nlm_unique_id": "101260955",
"other_id": null,
"pages": "287-294",
"pmc": null,
"pmid": "25586958",
"pubdate": "2015-08",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D016454:Review",
"references": null,
"title": "Osteonecrosis of the Jaw in Patients With Metastatic Renal Cell Cancer Treated With Bisphosphonates and Targeted Agents: Results of an Italian Multicenter Study and Review of the Literature.",
"title_normalized": "osteonecrosis of the jaw in patients with metastatic renal cell cancer treated with bisphosphonates and targeted agents results of an italian multicenter study and review of the literature"
} | [
{
"companynumb": "IT-ACTAVIS-2016-09567",
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"activesubstancename": "SUNITINIB"
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"... |
{
"abstract": "Idarucizumab is approved for patients treated with dabigatran when reversal of the anticoagulant effects is needed. Like dabigatran, idarucizumab is excreted in the urine. The effect of renal dysfunction on drug elimination is uncertain, as patients in the RE-VERSE AD trial had a median creatinine clearance of 58 mL/min. Also, dabigatran accumulation can occur if the international normalized ratio (INR) is greater than two. A 73-year-old female was admitted for lower extremity edema and increased abdominal girth. On admission, the patient was in acute kidney injury (AKI) with an estimated creatinine clearance of 34.5 mL/min. Her prothrombin time (PT) on admission was 17 seconds, her INR was 1.4, and her hemoglobin was 8.7 gm/dL (12-16 gm/dL). Throughout her admission, she was continued on her home regimen of dabigatran 150 mg twice daily for atrial fibrillation. On day 4, she had rectal bleeding and altered mental status. At this time, her PT was elevated to 25.6 seconds, her INR had increased to 2.3, and her hemoglobin had dropped to 6.8 gm/dL. Two doses of idarucizumab 2.5 gm were administered, and dabigatran was successfully reversed with cessation of bleeding and normalization of the INR to 1.5. An additional dose of idarucizumab was not required. The patient was discharged home two days later. Idarucizumab successfully reversed the bleeding and coagulopathy associated with dabigatran in a patient with AKI.",
"affiliations": null,
"authors": "Vidal|Jennifer|J|;DePalma|Richard|R|;Forouzan|Leila|L|",
"chemical_list": null,
"country": "United States",
"delete": false,
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"issn_linking": "1052-1372",
"issue": "43(12)",
"journal": "P & T : a peer-reviewed journal for formulary management",
"keywords": "anticoagulant; anticoagulant reversal; creatinine clearance; direct thrombin inhibitor; gastrointestinal bleed; idarucizumab; international normalized ratio",
"medline_ta": "P T",
"mesh_terms": null,
"nlm_unique_id": "9015516",
"other_id": null,
"pages": "748-749",
"pmc": null,
"pmid": "30559587",
"pubdate": "2018-12",
"publication_types": "D002363:Case Reports",
"references": "21103660;24151507;26095746;27547476;27581709;29343478",
"title": "Reversal of Dabigatran Bleeding and Coagulopathy Using Idarucizumab in a Patient With Acute Kidney Injury.",
"title_normalized": "reversal of dabigatran bleeding and coagulopathy using idarucizumab in a patient with acute kidney injury"
} | [
{
"companynumb": "US-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2018-BI-061514",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
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{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "DABIGATRAN ETEXILATE MESYLATE"
... |
{
"abstract": "Sleep-related eating disorder (SRED) is classified within parasomnia and is characterised by recurrent episodes of abnormal, dysfunctional eating during sleep. This report describes a case of SRED in a 19-year-old woman admitted to the psychiatric ward with worsening anxiety, low mood and suicidal ideation. She was started on low-dose mirtazapine for mood stabilisation and, following an incremental increase to 30 mg, she developed nocturnal binge eating of which she retained only partial memory on waking. She developed adverse health consequences as a result of these recurrent episodes. The subject's symptoms were relieved rapidly following reduction of the dose of mirtazapine back to 15 mg.",
"affiliations": "General Adult Psychiatry, Surrey and Borders Partnership NHS Foundation Trust, Leatherhead, Surrey, UK.;General Adult Psychiatry, Surrey and Borders Partnership NHS Foundation Trust, Leatherhead, Surrey, UK.;Ashford and St Peters Hospitals NHS Foundation Trust, Chertsey, UK.;Ashford and St Peters Hospitals NHS Foundation Trust, Chertsey, UK.",
"authors": "Shinith|Dhanya|D|http://orcid.org/0000-0001-7441-8248;Mathilakath|Anand|A|;Kim|Da-In|DI|;Patel|Biren|B|",
"chemical_list": "D000928:Antidepressive Agents; D000078785:Mirtazapine",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2018-224676",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2018()",
"journal": "BMJ case reports",
"keywords": "drugs: psychiatry; psychiatry; psychiatry (drugs and medicines); sleep disorders",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000928:Antidepressive Agents; D003866:Depressive Disorder; D003937:Diagnosis, Differential; D001068:Feeding and Eating Disorders; D005260:Female; D006801:Humans; D000078785:Mirtazapine; D020447:Parasomnias; D055815:Young Adult",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "30344142",
"pubdate": "2018-10-21",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "22652058;22976557;20701825;15003084;9017762;25203463;23130910;12143918;23436890;19107832;20877520;14592194",
"title": "Sleep-related eating disorder with mirtazapine.",
"title_normalized": "sleep related eating disorder with mirtazapine"
} | [
{
"companynumb": "GB-IMPAX LABORATORIES, LLC-2018-IPXL-03629",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LAMOTRIGINE"
},
"drugadditio... |
{
"abstract": "A 62-year-old woman underwent a right mastectomy with axillary node dissection for a poorly differentiated ductal carcinoma. One month later, she underwent a left nephrectomy for a renal cell carcinoma. Two weeks after, she received her first cycle of cyclophosphamide, methotrexate, and 5FU (CMF) as a part of her breast cancer treatment. We describe an unusual case of non-occlusive saddle pulmonary embolus with extensive bilateral deep vein thrombosis and severe bronchiolitis obliterans with organizing pneumonia developing simultaneously after the first CMF chemotherapy for breast cancer.",
"affiliations": "Department of Intensive Care, College of Medicine, King Saud bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City, National Guard Health Affairs, Jeddah, Kingdom of Saudi Arabia. E-mail. fahadalhameed@hotmail.com.",
"authors": "Al-Hameed|Fahad M|FM|",
"chemical_list": "D003520:Cyclophosphamide; D005472:Fluorouracil; D008727:Methotrexate",
"country": "Saudi Arabia",
"delete": false,
"doi": "10.15537/smj.2015.6.11305",
"fulltext": "\n==== Front\nSaudi Med JSaudi Med JSaudiMedJSaudi Medical Journal0379-52841658-3175Saudi Medical Journal Saudi Arabia 25987120SaudiMedJ-36-74710.15537/smj.2015.6.11305Case ReportSaddle pulmonary embolus and bronchiolitis obliterans with organizing pneumonia develop simultaneously after first cyclophosphamide, methotrexate, 5FU chemotherapy for breast cancer Al-Hameed Fahad M. MD, FRCPCFrom the Department of Intensive Care, College of Medicine, King Saud bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City, National Guard Health Affairs, Jeddah, Kingdom of Saudi ArabiaAddress correspondence and reprint request to: Dr. Fahad M. Al-Hameed, Department of Intensive Care, College of Medicine, King Saud bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City, National Guard Health Affairs, Jeddah, Kingdom of Saudi Arabia. E-mail: fahadalhameed@hotmail.com6 2015 36 6 747 750 22 1 2015 27 4 2015 Copyright: © Saudi Medical Journal2015This 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.A 62-year-old woman underwent a right mastectomy with axillary node dissection for a poorly differentiated ductal carcinoma. One month later, she underwent a left nephrectomy for a renal cell carcinoma. Two weeks after, she received her first cycle of cyclophosphamide, methotrexate, and 5FU (CMF) as a part of her breast cancer treatment. We describe an unusual case of non-occlusive saddle pulmonary embolus with extensive bilateral deep vein thrombosis and severe bronchiolitis obliterans with organizing pneumonia developing simultaneously after the first CMF chemotherapy for breast cancer.\n==== Body\nPulmonary embolism (PE) is a serious condition that commonly develops in hypercoagulable states such as malignancy and post chemotherapy treatment.1 When associated with hemodynamic instability, immediate recognition, and treatment are essential for a favorable outcome.2 Elevated pulmonary artery pressures (PAP) and pulmonary vascular resistance (PVR) may be the clue to diagnosis and subsequently the treatment of PE.3 Bronchiolitis obliterans with organizing pneumonia (BOOP) is another serious disease that is frequently misdiagnosed and is associated with significant morbidity and mortality. Early recognition and treatment usually leads to better outcomes.4 The objective in presenting this particular case is to describe a rare case of significant pulmonary embolism and severe BOOP developing simultaneously after the first cyclophosphamide, methotrexate, 5FU (CMF) chemotherapy for breast cancer.\n\nCase Report\nA 62-year-old woman underwent a right mastectomy with axillary node dissection for a poorly differentiated ductal carcinoma. One month later she underwent left nephrectomy for renal cell carcinoma. After 14 days, she received her first cycle of CMF as a part of her breast cancer treatment. Two weeks later, she developed progressive shortness-of-breath, dry cough, and mild fever, for which she was started on antibiotics for possible pneumonia. Two days later, her respiratory status deteriorated and she required intubation and mechanical ventilation. Because of hemodynamic instability and hypotension, she was started on inotropes and transferred to the intensive care unit. On examination, her blood pressure was 110/70 mm Hg, pulse of 104 beats per minute, normal temperature, and her jugular venous pressure was 8 cm above the sternal angle. Chest examinations revealed bilateral bronchial breathing and diffuse crackles. Cardiovascular and abdominal examinations were unremarkable. Her initial chest x-ray showed bilateral mixed alveolar and interstitial infiltrates with volume loss (Figure 1). Her arterial blood gases on room air prior to intubation, were partial pressure of oxygen 47torr, partial pressure of carbon dioxide 32torr, pH 7.49, bicarbonate 21, O2 saturation was 85%. The PAP was 36/21 mm Hg, pulmonary capillary wedge pressure 12 mm Hg, central venous pressure 20 cm H2O, cardiac index of 2.0 L/min/m2, and calculated PVR was 560 dynes sec/cm-5 (Figure 2). A spiral CT of the chest showed a non-occlusive saddle pulmonary embolism with multiple bilateral pulmonary emboli (Figures 3 & 4). She was treated with thrombolytics (100 mg rt-PA) followed by heparin without complications. She improved hemodynamically, and the inotropes were discontinued. Doppler ultrasound of the legs confirmed bilateral deep vein thrombosis. Because of persistent pulmonary infiltrates (Figures 1 & 2), she underwent a fiberoptic bronchoscopy with bronchoalveolar lavage, which was negative. This was followed by open lung biopsy that showed loose organizing granulation tissue in the small airways consistent with BOOP (Figure 5). She was treated with a pulse of steroids (1 g of methylprednisolone intravenously daily for 3 days followed by 1 mg/kg of prednisone daily). She was extubated 8 days later. She was transferred to the medical ward and was discharged home on long-term anticoagulation and steroids 2 weeks later. She had a chest x-ray before discharge, which showed near resolution of the infiltrate and restoration of lung volumes (Figure 6).\n\nFigure 1 Initial chest x-ray showed bilateral mixed alveolar and interstitial infiltrates.\n\nFigure 2 Chest x-ray after intubation and pulmonary artery catheter insertion, showed endotracheal tube and pulmonary artery catheter in good place with bilateral air space.\n\nFigure 3 Spiral CT scan of the chest showed a non occlusive saddle pulmonary embolism.\n\nFigure 4 Spiral CT scan of the chest showed multiple bilateral pulmonary emboli and bilateral air space.\n\nFigure 5 Arrows show loose organizing granulation tissue in small airways consistent with an organizing pneumonia pattern of cryptogenic organizing pneumonia or bronchiolitis obliterans with organizing pneumonia.\n\nFigure 6 Chest x-ray before discharge, which showed near resolution of the infiltrate and restoration of lung volumes.\n\nDiscussion\nMassive PE is a catastrophic entity that often results in acute right ventricular failure, hemodynamic instability, and death.1 The diagnosis of massive PE relies mainly upon clinical suspicion followed by the appropriate investigation.2 Spiral CT of the chest is the diagnostic modality that is most often used in ventilated patients, although pulmonary angiogram remains the gold standard.3 Clinical instability may interfere with the institution of an effective diagnostic strategy, and could therefore delay early therapy. In our case, pulmonary artery catheter data led to the suspicion of PE and subsequent appropriate investigation and early therapeutic intervention. Thrombolysis is currently the standard treatment of massive PE with hemodynamic instability.2\n\nBronchiolitis obliterans with organizing pneumonia is another distinct clinical entity of unknown etiology. It is also called cryptogenic organizing pneumonia, and is defined pathologically by the presence in the distal air spaces of buds of granulation tissue progressing from fibrin exudates to loose collagen containing fibroblasts.4,5 It is commonly presented with pneumonia-like symptoms that do not respond to antibiotics. Organizing pneumonia (BOOP) may be classified into 3 categories according to its cause: organizing pneumonia of determined cause, organizing pneumonia of undetermined cause but occurring in a specific and relevant context, and cryptogenic (idiopathic) organizing pneumonia. Several possible causes and/or associated disorders may co-exist in the same patient. There are no clear distinguishing clinical and radiological features between cryptogenic and secondary organizing pneumonia.5,6\n\nWith drug-induced organizing pneumonia, it is sometimes difficult to determine causality since organizing pneumonia may also be associated with the underlying disease. In many cases however, it is not possible to determine whether the drug is responsible or not, for example, in patients with cancer or hematological malignancies who may be treated with several drugs that are able to induce organizing pneumonia.6 Bleomycin and busulphan are the most common chemotherapy drugs associated with BOOP. However, on MEDLINE review, we were unable to source CMF described in the literature as a cause of BOOP after the first cycle of chemotherapy. Chemotherapy, particularly cyclophosphamide, has been used as a second line treatment after steroids for BOOP. Though cyclophosphamide and methotrexate treatment have been rarely reported in the literature to cause BOOP, 5-FU has not been reported to cause BOOP.7,8 Systemic corticosteroid therapy is the mainstay of treatment with initial doses of 0.75 to 1 mg/kg per day, and gradual weaning over 6 to 12 months.9 Because of her respiratory failure requiring mechanical ventilation, our patient received a pulse of steroids over 3 days followed by 1 mg/kg of prednisone daily.10\n\nThis case highlights the importance of using the new chemotherapy regimen for breast cancer with fewer side effects including lung toxicities. In our case, BOOP was suspected after ruling out active infection and following an adequate course of antibiotic coverage. Open lung biopsy provided the definite diagnosis. Corticosteroids remain the mainstay of therapy.\n\nIn conclusion, multiple primary causes for respiratory failure in a single patient are not uncommon. In a patient at risk for PE, the diagnosis should be pursued further in the presence of unexplained high PAP and PVR. Bronchiolitis obliterans with organizing pneumonia is being increasingly diagnosed as a cause of respiratory failure and should, in the classical setting be commonly included in the differential diagnosis. The presence of an evident cause for respiratory failure should not deter further investigation.\n\n\nDisclosure. The author has no conflict of interests, and the work was not supported or funded by any drug company.\n\n\n\n\n\nRelated Articles\nThabet FC, Alhejaili AS, Alodayani AN, Chehab MS. Septic pulmonary embolism secondary to Staphylococcus aureus septic thrombophlebitis in a pediatric patient. Saudi Med J 2013; 34: 1080-1082.\n\nDarwish HS, Qamar SR. Paddlewheel multi-slice helical computed tomography reformation in the detection of pulmonary embolism. An initial experience. Saudi Med J 2013; 34: 896-900.\n\nEl-Essawy MT, Al-Harbi SR. Multiple pulmonary and systemic ectopic emboli following endoscopic injection sclerotherapy for gastric fundal varices. Saudi Med J 2012; 33: 321-323.\n==== Refs\n1 Konstantinides S Goldhaber SZ Pulmonary embolism: risk assessment and management Eur Heart J 2012 33 3014 3022 22961946 \n2 Cohen AT Dobromirski M Gurwith MM Managing pulmonary embolism from presentation to extended treatment Thromb Res 2014 133 139 148 24182642 \n3 Stein PD Kayali F Hull RD Spiral computed tomography for the diagnosis of acute pulmonary embolism Thromb Haemost 2007 98 713 720 17938792 \n4 Ward E Rog J Bronchiolitis obliterans organizing pneumonia mimicking community-acquired pneumonia J Am Board Fam Pract 1998 11 41 45 9456446 \n5 Lohr RH Boland BJ Douglas WW Dockrell DH Colby TV Swensen SJ et al Organizing pneumonia. Features and prognosis of cryptogenic, secondary, and focal variants Arch Intern Med 1997 157 1323 1329 9201006 \n6 Schlesinger C Koss MN The organizing pneumonias: an update and review Curr Opin Pulm Med 2005 11 422 430 16093817 \n7 Garrido M O’Brien A González S Clavero JM Orellana E Cryptogenic organizing pneumonitis during oxaliplatin chemotherapy for colorectal cancer: case report Chest 2007 132 1997 1999 18079234 \n8 Lee EJ Lee SY In KH Kim CH Park S Organizing pneumonia associated with oxaliplatin-combined chemotherapy: a case report Med Princ Pract 2012 21 89 92 22025010 \n9 Bradley B Branley HM Egan JJ Greaves MS Hansell DM Harrison NK Interstitial lung disease guideline: the British Thoracic Society in collaboration with the Thoracic Society of Australia and New Zealand and the Irish Thoracic Society Thorax 2008 63 Suppl 5 v1 v58 18757459 \n10 Schlesinger C Koss MN The organizing pneumonias : a critical review of current concepts and treatment Treat Respir Med 2006 5 193 206 16696589\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0379-5284",
"issue": "36(6)",
"journal": "Saudi medical journal",
"keywords": null,
"medline_ta": "Saudi Med J",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D001365:Axilla; D001943:Breast Neoplasms; D018270:Carcinoma, Ductal, Breast; D002292:Carcinoma, Renal Cell; D018549:Cryptogenic Organizing Pneumonia; D003520:Cyclophosphamide; D005260:Female; D005472:Fluorouracil; D006801:Humans; D007680:Kidney Neoplasms; D008197:Lymph Node Excision; D008408:Mastectomy; D008727:Methotrexate; D008875:Middle Aged; D009378:Neoplasms, Multiple Primary; D009392:Nephrectomy; D011655:Pulmonary Embolism; D036542:Tomography, Spiral Computed; D020246:Venous Thrombosis",
"nlm_unique_id": "7909441",
"other_id": null,
"pages": "747-50",
"pmc": null,
"pmid": "25987120",
"pubdate": "2015-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "9201006;9456446;16093817;16696589;24182642;18079234;18757459;22025010;22961946;17938792",
"title": "Saddle pulmonary embolus and bronchiolitis obliterans with organizing pneumonia develop simultaneously after first cyclophosphamide, methotrexate, 5FU chemotherapy for breast cancer.",
"title_normalized": "saddle pulmonary embolus and bronchiolitis obliterans with organizing pneumonia develop simultaneously after first cyclophosphamide methotrexate 5fu chemotherapy for breast cancer"
} | [
{
"companynumb": "SA-BAUSCH-BL-2015-017082",
"fulfillexpeditecriteria": "1",
"occurcountry": "SA",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHOTREXATE"
},
"drugadditional": null,
... |
{
"abstract": "A 60-year-old man underwent total gastrectomy with Japanese D2 lymph node dissection for advanced gastric cancer. The resected specimen was diagnosed as well-differentiated tubular carcinoma, pT3, pN1, cM0, and the final stage was considered as ⅡB. During adjuvant chemotherapy with S-1 (120 mg/day, administered for 4 weeks and then stopped for 2 weeks), multiple liver metastases were detected by contrast-enhanced CT images 6 months after the operation. Eight courses of XP therapy (capecitabine 1,600 mg/m2/day: day 1-14, cisplatin 70 mg/m2/day: day 1, then stopped until days 15-21) were administered in consideration of the recurrence during adjuvant chemotherapy with S-1, resulting in a partial response. Adverse events such as grade 1-2 abdominal pain, general fatigue, and the resultant deterioration of ADL led to discontinuation of chemotherapy. The residual liver metastasis was treated with RFA therapy, causing it to disappear completely. Serum CEA level was 5.5 ng/mL postoperatively, elevated to 13.9 ng/mL at the time of recurrence and 2.4 ng/mL after XP and RFA therapy. He is doing well without any recurrence 2 years and 6 months later.",
"affiliations": "Dept. of Surgery, Itami City Hospital.",
"authors": "Katsuyama|Shinsuke|S|;Murata|Masaru|M|;Tanaka|Nobuo|N|;Asai|Kensuke|K|;Saso|Kazuhiro|K|;Yamada|Moyuru|M|;Yagi|Tomoko|T|;Sawami|Hirokazu|H|;Takahashi|Hidekazu|H|;Takayama|Osamu|O|;Baba|Masashi|M|;Yamamoto|Masayuki|M|;Hiratsuka|Masahiro|M|",
"chemical_list": "D000069287:Capecitabine; D002945:Cisplatin",
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-0684",
"issue": "42(12)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
"keywords": null,
"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D000069287:Capecitabine; D017115:Catheter Ablation; D002945:Cisplatin; D005743:Gastrectomy; D006801:Humans; D008113:Liver Neoplasms; D008297:Male; D008875:Middle Aged; D012074:Remission Induction; D013274:Stomach Neoplasms; D013997:Time Factors",
"nlm_unique_id": "7810034",
"other_id": null,
"pages": "1614-6",
"pmc": null,
"pmid": "26805114",
"pubdate": "2015-11",
"publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "A Case of Gastric Cancer with Multiple Liver Metastases Treated with XP Chemotherapy and RFA Resulting in a Complete Response for a Long Time.",
"title_normalized": "a case of gastric cancer with multiple liver metastases treated with xp chemotherapy and rfa resulting in a complete response for a long time"
} | [
{
"companynumb": "JP-HQ SPECIALTY-JP-2016INT000441",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CAPECITABINE"
},
"drugadditional": nul... |
{
"abstract": "BACKGROUND\nStrokelike migraine attack after radiation therapy is a recently described clinical entity characterized by transient hemispheric dysfunction manifesting as, but not limited to, visuospatial deficits, confusion, hemisensory deficits, hemiparesis, aphasia, seizures, and, most prominently, headache in patients with a history of remote external beam radiation therapy to the brain. The radiographic hallmark on magnetic resonance imaging is the presence of transient, diffuse, unilateral gadolinium enhancement of the cortex with white matter sparing, usually corresponding to the previous radiation field.\n\n\nMETHODS\nWe present a case of strokelike migraine attacks after radiation therapy syndrome diagnosed immediately following a craniotomy and temporal lobectomy for recurrent metastatic tumor resection after prior gamma knife radiosurgery and whole-brain radiation therapy.\n\n\nCONCLUSIONS\nSMART syndrome should be considered in the differential diagnosis of postsurgical patients with remote history of cranial irradiation and significant, new transient neurologic deficits not explainable by any other mechanism. It is possible that manipulation of the trigeminal ganglion, or the dura of the Meckel cave, contributed to triggering the manifestations of this syndrome in our patient during the immediate postoperative period.",
"affiliations": "Department of Neurosurgery, Mayo Clinic, College of Medicine, Rochester, Minnesota, USA.;Department of Neurology, Mayo Clinic, College of Medicine, Rochester, Minnesota, USA.;Department of Neurosurgery, Mayo Clinic, College of Medicine, Rochester, Minnesota, USA.;Department of Neurosurgery, Mayo Clinic, College of Medicine, Rochester, Minnesota, USA. Electronic address: link.michael@mayo.edu.",
"authors": "Maloney|Patrick R|PR|;Rabinstein|Alejandro A|AA|;Daniels|David J|DJ|;Link|Michael J|MJ|",
"chemical_list": "D000893:Anti-Inflammatory Agents; D003907:Dexamethasone",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1878-8750",
"issue": "82(1-2)",
"journal": "World neurosurgery",
"keywords": "Radiation; SMART syndrome; Trigeminovascular system",
"medline_ta": "World Neurosurg",
"mesh_terms": "D000230:Adenocarcinoma; D038481:Anterior Temporal Lobectomy; D000893:Anti-Inflammatory Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D001943:Breast Neoplasms; D003399:Craniotomy; D003907:Dexamethasone; D005260:Female; D006261:Headache; D006801:Humans; D008175:Lung Neoplasms; D008279:Magnetic Resonance Imaging; D015412:Mastectomy, Segmental; D008875:Middle Aged; D008881:Migraine Disorders; D009422:Nervous System Diseases; D011183:Postoperative Complications; D011832:Radiation Injuries; D016634:Radiosurgery; D013577:Syndrome",
"nlm_unique_id": "101528275",
"other_id": null,
"pages": "240.e7-12",
"pmc": null,
"pmid": "23314030",
"pubdate": "2014",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Surgically induced SMART syndrome: case report and review of the literature.",
"title_normalized": "surgically induced smart syndrome case report and review of the literature"
} | [
{
"companynumb": "PHHY2014US184302",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LETROZOLE"
},
"drugadditional": null,
"druga... |
{
"abstract": "OBJECTIVE\nTo report a case series of three patients with hepatitis C virus infection who all presented with severe type B lactic acidosis shortly after starting treatment with ombitasvir-paritaprevir-ritonavir-dasabuvir.\n\n\nMETHODS\nCase series.\n\n\nMETHODS\nICU.\n\n\nMETHODS\nThree patients, all who had HCV cirrhosis with mild hepatic impairment (Child-Pugh A) and had started taking ombitasvir-paritaprevir-ritonavir-dasabuvir within the preceding 2 weeks, presented with similar nonspecific symptoms of lethargy, fatigue, and nausea. All had elevated lactate levels at admission without evidence of hypovolemia, cardiogenic failure, or vasodilatory shock.\n\n\nMETHODS\nAll patients were given appropriate supportive intensive care for what was initially suspected to be sepsis, including a minimum of 30 mL/kg of IV fluids, infectious workup including blood cultures, broad-spectrum antibiotics, and mechanical ventilatory support. The first patient received continuous veno-venous hemofiltration. The second patient received hemodialysis. The third patient was initially started on hemodialysis despite high norepinephrine requirements and ultimately transitioned to continuous veno-venous hemofiltration.\n\n\nRESULTS\nThe first patient died despite maximal intensive care. The second patient improved immediately upon starting hemodialysis and was extubated within 48 hours and discharged home. The third patient eventually became hypotensive and was treated with repeated sessions of renal replacement therapy. He ultimately was extubated and discharged home. The infectious workup was negative for all three patients, and antibiotics were discontinued after 2 days in the second and third patients.\n\n\nCONCLUSIONS\nOmbitasvir-paritaprevir-ritonavir-dasabuvir may cause type B lactic acidosis. Further study is warranted to identify risk factors and elucidate the mechanisms of excessive lactate production.",
"affiliations": "Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY.",
"authors": "Oberg|Catherine L|CL|;Hiensch|Robert J|RJ|;Poor|Hooman D|HD|",
"chemical_list": "D000813:Anilides; D000998:Antiviral Agents; D002219:Carbamates; D003521:Cyclopropanes; D004338:Drug Combinations; D047029:Lactams, Macrocyclic; D047028:Macrocyclic Compounds; D013449:Sulfonamides; C000607373:Viekira Pak; C586094:ombitasvir; D014498:Uracil; D011392:Proline; D015081:2-Naphthylamine; C588260:dasabuvir; D014633:Valine; D019438:Ritonavir; C585405:paritaprevir",
"country": "United States",
"delete": false,
"doi": "10.1097/CCM.0000000000002086",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0090-3493",
"issue": "45(3)",
"journal": "Critical care medicine",
"keywords": null,
"medline_ta": "Crit Care Med",
"mesh_terms": "D015081:2-Naphthylamine; D000140:Acidosis, Lactic; D000813:Anilides; D000998:Antiviral Agents; D002219:Carbamates; D003521:Cyclopropanes; D004338:Drug Combinations; D005260:Female; D005440:Fluid Therapy; D006440:Hemofiltration; D019698:Hepatitis C, Chronic; D006801:Humans; D047029:Lactams, Macrocyclic; D008103:Liver Cirrhosis; D047028:Macrocyclic Compounds; D008297:Male; D008875:Middle Aged; D011392:Proline; D006435:Renal Dialysis; D012121:Respiration, Artificial; D019438:Ritonavir; D013449:Sulfonamides; D014498:Uracil; D014633:Valine",
"nlm_unique_id": "0355501",
"other_id": null,
"pages": "e321-e325",
"pmc": null,
"pmid": "27661862",
"pubdate": "2017-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Ombitasvir-Paritaprevir-Ritonavir-Dasabuvir (Viekira Pak)-Induced Lactic Acidosis.",
"title_normalized": "ombitasvir paritaprevir ritonavir dasabuvir viekira pak induced lactic acidosis"
} | [
{
"companynumb": "US-ABBVIE-15P-163-1474700-00",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "DASABUVIR\\OMBITASVIR\\PARITAPREVIR\\RITONAVIR"
},
... |
{
"abstract": "To evaluate the prevalence of past infection with hepatitis B virus (HBV) in patients with rheumatoid arthritis (RA) and the incidence of its reactivation under treatment with biological and/or nonbiological disease-modifying antirheumatic drugs (DMARDs), 239 patients receiving DMARD therapy were consecutively enrolled and tested for HBV-DNA, using a real-time polymerase chain reaction assay, HBV serology including hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (anti-HBc), and serum levels of aminotransferase. Data prior to DMARD therapy and during follow-up were examined by reviewing medical records. Two patients (0.8%) were positive for HBsAg at the start of therapy. Sixty patients (25.1%) showed HBsAg-negative and anti-HBc-positive serology indicative of past HBV infection. Among these 60 patients, 2 patients (3.3%) experienced reactivation of viral replication (<2.1 log copies/ml) during DMARD therapy. One had been receiving tacrolimus, prednisolone, and methotrexate (MTX); the other had been treated with adalimumab, prednisolone, and MTX. Their serum aminotransferase levels remained normal, and HBsAg was negative. Ten weeks after reactivation of viral replication had been noted, the HBV-DNA titer in the former patient had increased to 2.9 log copies/ml, and HBsAg and hepatitis B e antigen had become weakly positive. In contrast, the latter patient had become negative for viral DNA without any antiviral prophylaxis. In conclusion, the use of biological and nonbiological DMARDs is relatively safe in most RA patients with past HBV infection, even when no anti-HBV prophylaxis is administered. Considering the high prevalence of past infection in RA patients and the high cost of prophylaxis against HBV reactivation, universal prophylaxis is impractical. Regular monitoring of serum viral DNA seems to be the most rational approach to preventing the development of clinically apparent hepatitis.",
"affiliations": "Clinical Research Center for Rheumatic Disease, Department of Rheumatology, NHO Kumamoto Saishunsou National Hospital, 2659 Suya, Kohshi, Kumamoto 861-1196, Japan. moris@saisyunsou1.hosp.go.jp",
"authors": "Mori|Shunsuke|S|",
"chemical_list": "D018501:Antirheumatic Agents; D004279:DNA, Viral",
"country": "England",
"delete": false,
"doi": "10.1007/s10165-011-0458-z",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1439-7595",
"issue": "21(6)",
"journal": "Modern rheumatology",
"keywords": null,
"medline_ta": "Mod Rheumatol",
"mesh_terms": "D000368:Aged; D018501:Antirheumatic Agents; D001172:Arthritis, Rheumatoid; D004279:DNA, Viral; D005260:Female; D006509:Hepatitis B; D006515:Hepatitis B virus; D006801:Humans; D008297:Male; D008875:Middle Aged; D055502:Secondary Prevention",
"nlm_unique_id": "100959226",
"other_id": null,
"pages": "621-7",
"pmc": null,
"pmid": "21528424",
"pubdate": "2011-12",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "19412102;20472596;20668905;17567635;20595296;17917544;16627542;19399803;17382608;17206687;18173926;19883325;18643758;17112622;21246383;12150847;20948875;20535784;20049753;18512708;18433400;17894766;20461789;20191573;19447932;20927592;19941642;19280622;16911678;20556450;20008922;20444750;17118297;19346146",
"title": "Past hepatitis B virus infection in rheumatoid arthritis patients receiving biological and/or nonbiological disease-modifying antirheumatic drugs.",
"title_normalized": "past hepatitis b virus infection in rheumatoid arthritis patients receiving biological and or nonbiological disease modifying antirheumatic drugs"
} | [
{
"companynumb": "JP-TEVA-725764ISR",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ADALIMUMAB"
},
"drugadditional": "3",
"drug... |
{
"abstract": "This case series was designed to educate and inform health care professionals on the importance of providing adequate education on injectable antidiabetic agents and highlighting common medication errors related to diabetes care seen in ambulatory practice. The discussion following case descriptions will attempt to characterize patients who may be at high risk for these errors and identify ways to reduce the potential for error.\n\n\n\nIn a diabetes care clinic, 4 cases were identified in which the patient experienced an escalation of insulin or other injectable antidiabetic medication doses with no improvement in glycemic control. Two of the cases involved failure to remove an inner needle cap because of a poor understanding of pen use. One case was attributed to switching formulations without providing proper education for an adult patient with a learning impairment, and the other was attributed to suboptimal absorption of insulin doses from lipohypertrophy. Three of the 4 cases resulted in multiple instances of hypoglycemia, and all 4 patients exhibited markedly improved glycemic control once the injection error was corrected. The clinic pharmacist played an essential role in identifying and correcting administration errors within an interdisciplinary team.\n\n\n\nBased on the observations from the 4 cases, clinicians should be prompted to review antidiabetic medication injection techniques before initiation and periodically thereafter with their patients. Factors that should prompt further education include low health literacy, language barrier, initiation of medication by another provider, switch of medication product or formulation, obvious discrepancies between refill history and patient's self-reported adherence, observed lipohypertrophy, and escalation of doses without any improvement in glycemic control. A referral to the clinic pharmacist should be considered to provide more detailed education for these patients.",
"affiliations": null,
"authors": "Wei|Erin T|ET|;Koh|Eileen|E|;Kelly|Mary S|MS|;Wright|Lorena A|LA|;Tylee|Tracy S|TS|",
"chemical_list": "D007004:Hypoglycemic Agents; D007328:Insulin",
"country": "United States",
"delete": false,
"doi": "10.1016/j.japh.2020.02.030",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1086-5802",
"issue": "60(5)",
"journal": "Journal of the American Pharmacists Association : JAPhA",
"keywords": null,
"medline_ta": "J Am Pharm Assoc (2003)",
"mesh_terms": "D000328:Adult; D003920:Diabetes Mellitus; D006801:Humans; D007003:Hypoglycemia; D007004:Hypoglycemic Agents; D007328:Insulin; D008508:Medication Errors",
"nlm_unique_id": "101176252",
"other_id": null,
"pages": "e76-e80",
"pmc": null,
"pmid": "32229089",
"pubdate": "2020",
"publication_types": "D016428:Journal Article",
"references": "22488512;23821088;29100941;29941537",
"title": "Patient errors in use of injectable antidiabetic medications: A need for improved clinic-based education.",
"title_normalized": "patient errors in use of injectable antidiabetic medications a need for improved clinic based education"
} | [
{
"companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2020R1-267311",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "INSULIN GLARGINE"
},
... |
{
"abstract": "Posterior reversible encephalopathy syndrome (PRES) is characterized by headache, altered sensorium, visual disturbances, and diagnosed by magnetic resonance imaging (MRI). Here we report a case of cisplatin-induced PRES which was mimicking stroke and diagnosed by serial MRI and recovered completely on treatment, emphasizing fact that early diagnosis, removal of cause, and treatment can prevent the complication. How to cite this article: Admane SS, Yelne TS, Giri PJ. A Case of Posterior Reversible Encephalopathy Syndrome Mimicking Stroke. Indian J Crit Care Med 2020;24(9):877-878.",
"affiliations": "Department of Critical Care, Neuron Brain, Spine and Critical Care Center, Nagpur, Maharashtra, India.;Department of Critical Care, Neuron Brain, Spine and Critical Care Center, Nagpur, Maharashtra, India.;Department of Neuro Surgery, Neuron Brain, Spine and Critical Care Center, Nagpur, Maharashtra, India.",
"authors": "Admane|Sushant S|SS|;Yelne|Tushar S|TS|;Giri|Pramod J|PJ|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.5005/jp-journals-10071-23588",
"fulltext": "\n==== Front\nIndian J Crit Care Med\nIndian J Crit Care Med\nIJCCM\nIndian Journal of Critical Care Medicine : Peer-reviewed, Official Publication of Indian Society of Critical Care Medicine\n0972-5229 1998-359X Jaypee Brothers Medical Publishers \n\n10.5005/jp-journals-10071-23588\nCase Report\nA Case of Posterior Reversible Encephalopathy Syndrome Mimicking Stroke\nAdmane Sushant S 1 Yelne Tushar S 2 Giri Pramod J 3 1,2 Department of Critical Care, Neuron Brain, Spine and Critical Care Center, Nagpur, Maharashtra, India\n3 Department of Neuro Surgery, Neuron Brain, Spine and Critical Care Center, Nagpur, Maharashtra, India\nSushant S Admane, Department of Critical Care, Neuron Brain, Spine and Critical Care Center, Nagpur, Maharashtra, India, Phone: +91 9320596396, e-mail: sushmum12@yahoo.com\n9 2020 \n24 9 877 878\nCopyright © 2020; Jaypee Brothers Medical Publishers (P) Ltd.2020© The Author(s). 2020 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by-nc/4.0/), which permits unrestricted use, distribution, and non-commercial 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.Abstract\nPosterior reversible encephalopathy syndrome (PRES) is characterized by headache, altered sensorium, visual disturbances, and diagnosed by magnetic resonance imaging (MRI). Here we report a case of cisplatin-induced PRES which was mimicking stroke and diagnosed by serial MRI and recovered completely on treatment, emphasizing fact that early diagnosis, removal of cause, and treatment can prevent the complication.\n\nHow to cite this article: Admane SS, Yelne TS, Giri PJ. A Case of Posterior Reversible Encephalopathy Syndrome Mimicking Stroke. Indian J Crit Care Med 2020;24(9):877–878.\n\nKeywords\nCisplatinMagnetic resonance imagingPosterior reversible encephalopathy syndrome\n==== Body\nIntroduction\nPosterior reversible encephalopathy syndrome (PRES) is a clinicoradiological entity characterized by headache, altered mental status, seizures, and visual disturbances and is associated with characteristic reversible lesions on neuroimaging in a severe arterial hypertension setting.1 This condition is usually seen in patients who had received immunosuppressive therapy, eclampsia, hypertension, and autoimmune diseases.2 Typically, PRES involves parieto-occipital lobes and can also involve other cerebral areas, such as brain stem and cerebellum.3 Early recognition and treatment are important to prevent neurologic sequelae. PRES is reversible once the underlying precipitating cause is treated. Here, we present a case of cisplatin induced PRES mimicking stroke with atypical magnetic resonance imaging (MRI) features.\n\nCase Description\nA 46-year-old female patient admitted with complaints of repeated vomiting, aphasia, and right upper limb weakness since 12 hours. Patient was operated case of Ca colon 5 months back. She was on chemotherapy and received eighth cycle of cisplatin 8 days back.\n\nOn Examination\nVitals stable. Central nervous system (CNS) examination conscious, following verbal commands, aphasia present, no neck stiffness, pupils – B/L 2 mm reacting to light, moving all 4 limbs, right upper limb grip weak, and plantars-flexor. Rest examination was normal. GCS E3 M6 V2 = 11/15.\n\nOn investigation: Complete blood count, liver function test, and kidney function test was normal. Computed tomography (CT) of thr brain was normal. Magnetic resonance imaging brain suggestive of restricted diffusion involving bilateral cerebral white matter, including centrum semiovale, corpus callosum, and posterior limb of internal capsule suggestive of chemotherapy induced neurotoxicity (Fig. 1). MRI venography was normal.\n\nPatient was treated with mannitol, dexamethasone, and levetiracetam. The patient responded to the treatment and aphasia recovered. But on next day evening, the patient again had an episode of aphasia and focal convulsions. The patient was treated with fosphenytoin and continued with antiepileptics, mannitol, and steroids. Patient responded well, aphasia recovered. MRI brain done after 2 days showed complete resolution of white matter abnormalities (Fig. 2). Patient's right upper limb grip and aphasia improved completely, and no further episode of convulsion was observed.\n\nFig. 1 Magnetic resonance imaging brain DWI image showing restricted diffusion in cerebral white matter in centrum semiovale, corona radiata, corpus callosum and posterior limb of internal capsule\n\nFig. 2 Magnetic resonance imaging brain done after 2 days showing complete resolution of white matter changes\n\nDiscussion\nThe mechanism by which immunosuppressive and cytotoxic agents cause PRES is the alteration in blood–brain barrier due to direct impairment of endothelium results in extravasation of fluid leading to vasogenic edema.4–6 Many conditions may resemble PRES including ictal or post-ictal state (with or without status epilepticus), infectious encephalitis, vasculitis, cerebral venous sinus thrombosis, and ischemic stroke.7\n\nChemotherapy agents that can cause PRES are cisplatin, gemcitabine, oxaliplatin, carboplatin, cytarabine, methotrexate, vincristine, bevacizumab, sunitinib, rituximab, and infliximab.7–10 Condition that can cause PRES eclampsia, preeclampsia, autoimmune diseases, and hypertensive crisis.\n\nMRI brain is the first investigation of choice for the diagnosis of PRES. Nonconvulsive status epilepticus should be ruled out by electroencephalogram.\n\nTreatment includes correction of underlying cause of PRES, control of blood pressure, antiedema measure, and antiepileptic drugs. Patient may require withdrawal of chemotherapy or immunosuppressive drugs, cesarean section in case of eclampsia, and other interventions. Risk of ischemia and bleeding can be reduced by treating the underlying precipitating cause.\n\nConclusion\nAlthough the clinical presentation of PRES is nonspecific, most patients have variable symptoms. High index of suspicion should be kept for patients of PRES having new onset of seizures, altered sensorium, and new onset of neuro deficit with normal CT brain on presentation and presence of strong predisposing factors such as recent chemotherapy, PIH, and uncontrolled hypertension.\n\nMRI is crucial for diagnosing PRES, monitoring the course, and assessing the treatment effectiveness. Repeated cerebral imaging helps to support the diagnosis. Risk of ischemia, bleeding, and death can be prevented by early diagnosis and treatment of underlying cause of PRES.\n\nOur case is important as patient presented with symptoms mimicking of left-sided stroke with initial CT brain normal on presentation and MRI suggestive of atypical findings. MRI should be the first investigation of choice for diagnosing PRES. Early recognition and resolution of the underlying cause lead to complete recovery.\n\nConsent of Patient\nThe authors certify that they have done all appropriate patient consent formalities. Patient has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names, and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.\n\nSource of support: Nil\n\nConflict of interest: None\n==== Refs\nReferences\n1. Hinchey J Chaves C Appignani B Breen J Pao L Wang A et al. A reversible posterior leukoencephalopathy syndrome. N Engl J Med 1996 334 8 494 500 DOI: 10.1056/NEJM199602223340803 8559202 \n2. Lee VH Wijdicks EF Manno EM Rabinstein AA. Clinical spectrum of reversible posterior leuko encephalopathy syndrome. Arch Neurol 2008 65 205 210 18268188 \n3. Ahn KJ You WJ Jeong SL Lee JW Kim BS Lee JH et al. Atypical manifestations of reversible posterior leuko encephalopathy syndrome: findings on diffusion imaging and ADC mapping. Neuroradiology 2004 46 12 978 983 DOI: 10.1007/s00234-004-1276-1 15536557 \n4. Pande AR Ando K Ishikura R Nagami Y Takada Y Wada A et al. Clinicoradiological factors influencing the reversibility of posterior reversible encephalopathy syndrome: a multicenter study. Radiat Med 2006 24 10 659 668 DOI: 10.1007/s11604-006-0086-2 17186320 \n5. De Seze J Mastain B Stojkovic T Ferriby D Pruvo JP Destee A et al. Unusual MR findings of the brain in arterial hypertension. Am J Neuroradiol 2000 21 2 391 394 10696029 \n6. Kitaguchi H Tomimoto H Miki Y Yamamoto A Terada K Satoi H et al. A brainstem variant of reversible posterior leukoencephalopathy syndrome. Neuroradiology 2005 47 9 652 656 DOI: 10.1007/s00234-005-1399-z 15947925 \n7. Trikha A Sharma A Kumar R. Posterior reversible encephalopathy syndrome. J Obstet Anaesth Crit Care 2014 4 Issue 2 59 63 DOI: 10.4103/2249-4472.143873 \n8. Zahir MN Masood N Shabbir-Moosajee M. Cisplatin-induced posterior reversible encephalopathy syndrome and successful re-treatment in a patient with non-seminomatous germ cell tumor: a case report. J Med Case Rep 2012 6 1 409 DOI: 10.1186/1752-1947-6-409 23194133 \n9. Mirzamoradi M Hosseini M-S Saleh M Esmaeili S. Posterior reversible encephalopathy syndrome (PRES) associated with eclampsia: a case study. Int J Med Res Health Sci 2017 6 3 41 47 \n10. Abraham J Truong QV Nagaiah G Newton M Veltri L. Gemcitabine associated with Posterior reversible encephalopathy syndrome (PRES): a case report and review of the literature. Clin Adv Hematol Oncol 2012 10 9\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "0972-5229",
"issue": "24(9)",
"journal": "Indian journal of critical care medicine : peer-reviewed, official publication of Indian Society of Critical Care Medicine",
"keywords": "Cisplatin; Magnetic resonance imaging; Posterior reversible encephalopathy syndrome",
"medline_ta": "Indian J Crit Care Med",
"mesh_terms": null,
"nlm_unique_id": "101208863",
"other_id": null,
"pages": "877-878",
"pmc": null,
"pmid": "33132577",
"pubdate": "2020-09",
"publication_types": "D002363:Case Reports",
"references": "15947925;15536557;18268188;8559202;17186320;23073128;23194133;10696029",
"title": "A Case of Posterior Reversible Encephalopathy Syndrome Mimicking Stroke.",
"title_normalized": "a case of posterior reversible encephalopathy syndrome mimicking stroke"
} | [
{
"companynumb": "IN-ACCORD-207609",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CISPLATIN"
},
"drugadditional": "3",
"drugad... |
{
"abstract": "BACKGROUND\nHeparin is commonly recommended for warfarin-induced skin necrosis; however, there is currently no established therapy for this disease. We present a serious case of warfarin-induced skin necrosis that was successfully treated with oral rivaroxaban, a factor Xa inhibitor.\n\n\nMETHODS\nA 48-year-old woman was admitted to the hospital for cellulitis of the right lower extremity. After antibiotic treatment, she developed pain and swelling of the left lower extremity, and deep vein thrombosis of both lower extremities was diagnosed. She was treated with a continuous heparin injection; subsequently, oral warfarin was concomitantly administered. Heparin was terminated after the therapeutic range was reached. On the following day, the patient had swelling and pain in the left lower extremity. In addition to decrease in protein S activity due to systemic lupus erythematosus, warfarin also reduced protein C activity, resulting in further hypercoagulation and skin necrosis. Warfarin was discontinued, and continuous heparin injection was resumed. Although the patient had to undergo amputation of the distal end of her left foot, continuous heparin injection was switched to oral rivaroxaban, and she was eventually discharged from the hospital in remission.\n\n\nCONCLUSIONS\nAdministration of direct oral anticoagulants instead of warfarin is important in patients with decreased protein S and C activity.",
"affiliations": "Department of Internal Medicine, Hyogo Prefectural Tamba Medical Center, Tamba 669-3395, Japan.;Division of Community Medicine and Career Development, Kobe University Graduate School of Medicine, Kobe 652-0032, Japan. smile.kenzaka@jichi.ac.jp.",
"authors": "Kamada|Momoka|M|;Kenzaka|Tsuneaki|T|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.12998/wjcc.v7.i24.4285",
"fulltext": "\n==== Front\nWorld J Clin CasesWJCCWorld Journal of Clinical Cases2307-8960Baishideng Publishing Group Inc jWJCC.v7.i24.pg428510.12998/wjcc.v7.i24.4285Case ReportSuccessful treatment of warfarin-induced skin necrosis using oral rivaroxaban: A case report Kamada Momoka Department of Internal Medicine, Hyogo Prefectural Tamba Medical Center, Tamba 669-3395, JapanKenzaka Tsuneaki Division of Community Medicine and Career Development, Kobe University Graduate School of Medicine, Kobe 652-0032, Japan. smile.kenzaka@jichi.ac.jpAuthor contributions: Kamada M managed the case and redaction and correction of the manuscript; Kenzaka T assisted with redaction, correction, and reconstruction of the manuscript; all authors read and approved the final manuscript.\n\nCorresponding author: Tsuneaki Kenzaka, MD, PhD, Professor, Division of Community Medicine and Career Development, Kobe University Graduate School of Medicine, 2-1-5, Arata-cho, Hyogo-ku, Kobe 652-0032, Japan. smile.kenzaka@jichi.ac.jp\n\nTelephone: +81-78-3826732 Fax: +81-78-3826283\n\n26 12 2019 26 12 2019 7 24 4285 4291 2 9 2019 17 11 2019 30 11 2019 ©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.2019This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is 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.BACKGROUND\nHeparin is commonly recommended for warfarin-induced skin necrosis; however, there is currently no established therapy for this disease. We present a serious case of warfarin-induced skin necrosis that was successfully treated with oral rivaroxaban, a factor Xa inhibitor.\n\nCASE SUMMARY\nA 48-year-old woman was admitted to the hospital for cellulitis of the right lower extremity. After antibiotic treatment, she developed pain and swelling of the left lower extremity, and deep vein thrombosis of both lower extremities was diagnosed. She was treated with a continuous heparin injection; subsequently, oral warfarin was concomitantly administered. Heparin was terminated after the therapeutic range was reached. On the following day, the patient had swelling and pain in the left lower extremity. In addition to decrease in protein S activity due to systemic lupus erythematosus, warfarin also reduced protein C activity, resulting in further hypercoagulation and skin necrosis. Warfarin was discontinued, and continuous heparin injection was resumed. Although the patient had to undergo amputation of the distal end of her left foot, continuous heparin injection was switched to oral rivaroxaban, and she was eventually discharged from the hospital in remission.\n\nCONCLUSION\nAdministration of direct oral anticoagulants instead of warfarin is important in patients with decreased protein S and C activity.\n\nSkin necrosisWarfarinHeparinRivaroxabanSystemic lupus erythematosusCase report\n==== Body\nCore tip: We present a serious case of warfarin-induced skin necrosis that was successfully treated with oral rivaroxaban, a factor Xa inhibitor. Administration of direct oral anticoagulants instead of warfarin is important in patients with decreased protein S and C activity.\n\nINTRODUCTION\nIn warfarin-induced skin necrosis, the production of protein C and S is inhibited in an early stage after warfarin administration, which increases coagulability and thrombosis formation in the capillaries and venules of the dermis or subcutaneous tissue, leading to skin ischemia or necrosis[1]. Although there is currently no established treatment for warfarin-induced skin necrosis, heparin is commonly recommended[1]. However, the use of non-vitamin K antagonist anticoagulants is recommended in some case reports[2-6].\n\nWe report the case of a patient who developed serious warfarin-induced skin necrosis as well as protein S deficiency caused by systemic lupus erythematosus (SLE), who was then successfully treated with oral rivaroxaban.\n\nCASE PRESENTATION\nChief complaints\nA 48-year-old woman presented to the emergency room with chief complaints of swelling of the right lower extremity and pyrexia.\n\nHistory of present illness\nRegarding her present illness, pyrexia and redness, and swelling of the right lower extremity developed 10 and 5 d before hospitalization, respectively. She visited our hospital because the pyrexia was unresolved, and the symptoms of the lower extremity worsened.\n\nHistory of past illness\nHer medical history included paronychia of the right big toe. She was gravida 3 and para 3, with no history of abortion.\n\nPersonal and family history\nHer father had a history of cerebral infarction.\n\nPhysical examination upon admission\nThe patient’s physical examination findings during examination were as follows: Body temperature, 39.4 °C; blood pressure, 107/65 mmHg; pulse rate, 81 beats/min and regular; respiratory rate, 13 breaths/min; and oxygen saturation, 97% (room air). Physical findings included swelling, warmth, redness, and pain in the right lower extremity as well as tinea unguium in the right foot.\n\nLaboratory examinations\nBlood test findings on admission were as follows: White blood cell count, 4800 cells/μL; C-reactive protein, 9.51 mg/dL; prothrombin time (PT), 13.5 seconds; activated partial thromboplastin time, 34.5 s; and D-dimer, 6.9 μg/mL (Table 1).\n\nTable 1 Laboratory data upon admission\n\nParameter\tRecorded value\tStandard value\t\nWhite blood cell count\t4800/µL\t4500-7500/µL\t\nLymphocyte count\t1300/µL\t\t\nRed blood cell count\t327 × 103/µL\t380-480 × 103/µL\t\nHemoglobin\t9.4 g/dL\t11.3-15.2 g/dL\t\nHematocrit\t31.3%\t36%-45%\t\nPlatelet count\t10.6 × 103/µL\t13-35 × 103/µL\t\nInternational normalized ratio\t1.05\t0.80-1.20\t\nActivated partial thromboplastin time\t34.5 s\t26.9-38.1 s\t\nFibrinogen\t374 mg/L\t150-400 mg/dL\t\nD-dimer\t6.9 µg/mL\t≤ 1.0 µg/mL\t\nC-reactive protein\t9.51 mg/L\t≤ 1.0 mg/L\t\nTotal protein\t7.5 g/dL\t6.9-8.4 g/dL\t\nAlbumin\t3.6 g/dL\t3.9-5.1 g/dL\t\nTotal bilirubin\t0.6 mg/dL\t0.2-1.2 mg/dL\t\nAspartate aminotransferase\t22 U/L\t11-30 U/L\t\nAlanine aminotransferase\t24 U/L\t4-30 U/L\t\nLactate dehydrogenase\t262 U/L\t109-216 U/L\t\nCreatine phosphokinase\t75 U/L\t40-150 U/L\t\nBlood urea nitrogen\t7.6 mg/dL\t8-20 mg/dL\t\nCreatinine\t0.43 mg/dL\t0.63-1.03 mg/dL\t\nSodium\t137 mEq/L\t136-148 mEq/L\t\nPotassium\t3.6 mEq/L\t3.6-5.0 mEq/L\t\nChloride\t103 mEq/L\t98-108 mEq/L\t\nGlucose\t146 mg/dL\t70-109 mg/dL\t\nHemoglobin A1c\t5.7%\t≤ 5.8%\t\nThe patient was admitted to the hospital for cellulitis of the right lower extremity. Cefazolin (1 g) was administered every 8 h; subsequently, pyrexia declined. However, she redeveloped pyrexia (temperature, 39 °C). Considering the possibility of drug fever, we switched the antibiotic to clindamycin (600 mg) and administered it every 8 h from day 4 of hospitalization. As skin findings improved, the treatment of cellulitis was completed after 8 d.\n\nImaging examinations\nOn day 8 of hospitalization, the patient developed swelling of the left lower extremity. Deep vein thrombosis was suspected because she was on bed rest for the treatment of cellulitis. Contrast-enhanced computed tomography revealed deep vein thrombi in both femoral veins (Figure 1); she was diagnosed with bilateral deep vein thrombosis of the lower extremities. Blood tests for the evaluation of thrombophilia as a risk factor for the development of deep vein thrombosis revealed decreased protein S activity (Table 2); therefore, the patient was diagnosed with deep vein thrombosis caused by protein S deficiency.\n\nFigure 1 Contrast-enhanced computed tomography on hospitalization day 8. Deep vein thrombi in both femoral veins were observed.\n\nTable 2 Tests of thrombophilia\n\nParameter\tRecorded value\tStandard value\t\nAnti-cardiolipin β2-glycoprotein I complex antibody\t2.0 U/mL\t< 3.5 U/mL\t\nLupus anticoagulant\t1.3\t< 1.3\t\nProtein S activity\t< 10%\t56%-126%\t\nProtein C activity\t83%\t64%-146%\t\nAntithrombin III\t79%\t79%-121%\t\nContinuous intravenous infusion of heparin was initiated for deep vein thrombosis on day 8 of hospitalization, and oral warfarin was concomitantly administered from day 14 of hospitalization. Continuous heparin injection was completed on day 19 of hospitalization when the PT-international normalized ratio (INR) reached the therapeutic target range (1.6-2.5). Immediately after heparin cessation, the patient developed pain, swelling, redness, and blisters in her left lower extremity, as well as cold peripheries and skin necrosis (Figure 2). The activities of protein S and C at this time were both < 10%. Warfarin administration during the period of low protein S activity subsequently led to decreased protein C activity, and discontinuation of the heparin injection caused hypercoagulation, leading to the onset of skin necrosis. The patient had a score of 7 points on the Naranjo adverse drug reaction probability scale[7]. Accordingly, we diagnosed her with warfarin-induced skin necrosis.\n\nFigure 2 Skin necrosis observed in the left lower extremity on hospitalization day 19. A: Left calf; B: Left foot.\n\nWhen evaluating the cause of decrease in protein S activity in this patient, we observed that she developed pleurisy approximately at the same time as the onset of bilateral deep vein thrombosis of the lower extremities. Along with lymphopenia, the patient fulfilled 2 clinical and 3 immunologic criteria of the Systemic Lupus International Collaborating Clinics classification[7]: Antinuclear antibody-positive (640-fold, homogeneous); low complement C4 (10 mg/dL; reference value, 17-45 mg/dL), C3 (56 mg/dL; reference value, 86-160 mg/dL) and CH50 (25 U/mL; reference value, 30-45 U/mL) levels; and direct Coombs test-positive. Therefore, the patient was diagnosed with SLE.\n\nThe activities of protein S and C over time are shown in Figure 3. Protein S activity was normalized with 30 mg of prednisolone (PSL). Based on these results, the decrease in protein S activity in this patient was attributed to SLE. Warfarin was discontinued on the day 22 of hospitalization, and continuous heparin injection was resumed for warfarin-induced skin necrosis, and protein C activity was normalized. Necrotic tissue debridement was performed on day 35 of hospitalization (Figure 4), and left side toe amputation and free flap surgery were performed on day 67 of hospitalization (Figure 5). Subsequently, heparin was discontinued, and the patient was switched to oral rivaroxaban (15 mg/d) on day 68 of hospitalization. She was admitted to another hospital for rehabilitation on day 86 of hospitalization. At the 2-year follow-up, no aggravations of skin necrosis were observed, and the activities of both proteins S and C remained normal.\n\nFigure 3 Clinical course of the patient. The course of treatment with prednisolone and anticoagulants as well as the activities of proteins C and S are shown. PSL: Prednisolone.\n\nFigure 4 Debridement of necrotic tissue in the left lower extremity (hospitalization day 35). A: Left calf; B: Left foot.\n\nFigure 5 Left toe amputation and free flap surgery were performed on hospitalization day 67. A: Pre-surgery of left foot; B: Post-surgery of left foot.\n\nFINAL DIAGNOSIS\nDecreased protein S activity caused by systemic lupus erythematosus, and warfarin-induced skin necrosis decreased with protein C activity.\n\nTREATMENT\nPrednisolone and rivaroxaban.\n\nOUTCOME AND FOLLOW-UP\nAt the 2-year follow-up, no aggravations of skin necrosis were observed, and the activities of both proteins S and C remained normal. Activity of systemic lupus erythematosus was stable.\n\nDISCUSSION\nIn this report, the patient developed warfarin-induced skin necrosis as well as decreased protein S activity secondary to SLE. Warfarin-induced skin necrosis occurred after discontinuation of heparin; however, the skin necrosis was not aggravated by the SLE treatment or oral administration of rivaroxaban, a direct factor Xa inhibitor. Only three other cases showing response to rivaroxaban for warfarin-induced skin necrosis have been previously reported[4-6].\n\nOur patient developed bilateral deep vein thrombosis of the lower extremities during the treatment for cellulitis. A detailed examination for thrombophilia revealed markedly decreased protein S activity. Protein S deficiency can occur due to the following: Congenital factors, pregnancy, oral hormonal contraceptive use, disseminated intravascular coagulation, acute thromboembolism, human immunodeficiency virus infection, nephrotic syndrome, liver disease, L-asparaginase chemotherapy, varicella recovery, antiphospholipid antibody syndrome, oral steroid use, and vitamin K deficiency (i.e., decreased food intake, biliary obstruction, and oral warfarin administration)[8]. Protein S deficiency has been rarely reported in patients with SLE[9,10]. Our patient developed pleurisy during the clinical course. She was diagnosed with SLE after she fulfilled the Systemic Lupus International Collaborating Clinics classification criteria (i.e., clinical criteria of pleurisy and lymphopenia as well as the immunologic criteria of positive antinuclear antibody, low complement, and positive direct Coombs-test)[7]. She had no family history, history of abortion, hepatic dysfunction, or renal dysfunction suggestive of congenital diseases. After initiating PSL treatment, protein S activity returned to normal as SLE improved, indicating that decreased protein S activity was caused by SLE.\n\nWarfarin induced skin necrosis develops when proteins C and S production is inhibited in the early stage after the administration of warfarin, a vitamin K antagonist, resulting in increased coagulability and hypercoagulation[11]. Our case demonstrated that serious skin necrosis can occur in the early stage of treatment despite achieving a PT-INR within the therapeutic range. Onset of skin necrosis can occur within a few hours or several weeks after warfarin administration[11]. There are no currently established anticoagulant therapies for patients with decreased proteins S and C activities. Heparin, which is not a vitamin K antagonist, is commonly used for the treatment of warfarin-induced necrosis[11]. However, direct oral anticoagulants, such as dabigatran and rivaroxaban, have been found to be more effective for our patient based on previous findings[2-6]. We could find only three studies reporting that oral rivaroxaban was effective[7-9]. Heparin requires continuous intravenous injection, and its administration is not suitable for patients with deep vein thrombosis who require long-term anticoagulant therapy, such as our patient, because of the route of administration and necessity of hospitalization.\n\nCONCLUSION\nWe report the case of a patient with warfarin-induced skin necrosis who was successfully treated with oral rivaroxaban, a factor Xa inhibitor. It is important to administer DOACs instead of warfarin in patients with decreased activities of protein S and C, which are vitamin K-dependent coagulation inhibitors. During treatment of bilateral deep vein thrombosis of the lower extremities, it is necessary to closely examine the patient for the presence of thrombophilia and avoid warfarin administration until confirmation of the examination results. Furthermore, continuous heparin injections should be carefully discontinued when warfarin is administered.\n\nInformed consent statement: Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor of this journal.\n\nConflict-of-interest statement: The authors declare that they have no competing interests.\n\nCARE Checklist (2016) statement: The authors have read the CARE Checklist statement, and the manuscript was prepared and revised according to the CARE Checklist statement.\n\nManuscript source: Unsolicited manuscript\n\nPeer-review started: September 2, 2019\n\nFirst decision: November 13, 2019\n\nArticle in press: November 30, 2019\n\nSpecialty type: Medicine, research and experimental\n\nCountry of origin: Japan\n\nPeer-review report classification\n\nGrade A (Excellent): 0\n\nGrade B (Very good): B, B\n\nGrade C (Good): 0\n\nGrade D (Fair): 0\n\nGrade E (Poor): 0\n\nP-Reviewer: Ciccone MM, De Ponti F S-Editor: Ma YJ L-Editor: A E-Editor: Liu JH\n==== Refs\n1 Kakagia DD Papanas N Karadimas E Polychronidis A Warfarin-induced skin necrosis Ann Dermatol 2014 26 96 98 24648693 \n2 Tripodi A Martinelli I Chantarangkul V Clerici M Artoni A Passamonti S Peyvandi F Thrombin generation and other coagulation parameters in a patient with homozygous congenital protein S deficiency on treatment with rivaroxaban Int J Hematol 2016 103 165 172 26586461 \n3 Bakoyiannis C Karaolanis G Patelis N Maskanakis A Tsaples G Klonaris C Georgopoulos S Liakakos T Dabigatran in the Treatment of Warfarin-Induced Skin Necrosis: A New Hope Case Rep Dermatol Med 2016 2016 3121469 27110410 \n4 Martinelli I Bucciarelli P Artoni A Fossali EF Passamonti SM Tripodi A Peyvandi F Anticoagulant treatment with rivaroxaban in severe protein S deficiency Pediatrics 2013 132 e1435 e1439 24144709 \n5 Lai J Ramai D Alchi R Bloomfield D Anticoagulation therapy for thromboembolism prevention: a case of warfarin-induced skin necrosis in the setting of protein C deficiency BMJ Case Rep 2017 2017 \n6 Menon N Sarode R Zia A Rivaroxaban dose adjustment using thrombin generation in severe congenital protein C deficiency and warfarin-induced skin necrosis Blood Adv 2018 2 142 145 29365322 \n7 Petri M Orbai AM Alarcón GS Gordon C Merrill JT Fortin PR Bruce IN Isenberg D Wallace DJ Nived O Sturfelt G Ramsey-Goldman R Bae SC Hanly JG Sánchez-Guerrero J Clarke A Aranow C Manzi S Urowitz M Gladman D Kalunian K Costner M Werth VP Zoma A Bernatsky S Ruiz-Irastorza G Khamashta MA Jacobsen S Buyon JP Maddison P Dooley MA van Vollenhoven RF Ginzler E Stoll T Peschken C Jorizzo JL Callen JP Lim SS Fessler BJ Inanc M Kamen DL Rahman A Steinsson K Franks AG Jr Sigler L Hameed S Fang H Pham N Brey R Weisman MH McGwin G Jr Magder LS Derivation and validation of the Systemic Lupus International Collaborating Clinics classification criteria for systemic lupus erythematosus Arthritis Rheum 2012 64 2677 2686 22553077 \n8 Bauer KA Protein S deficiency. 2017 Available from: https://www.uptodate.com/contents/protein-s-deficiency?search=Protein%20S%20deficiencysource=search_resultselectedTitle=1~76usage_type=defaultdisplay_rank=1 \n9 Lertnawapan R Sakonlaya D Lupus protein-losing enteropathy patient with protein C and protein S deficiency-induced thrombosis: A case report with review of the literature Acta Reumatol Port 2017 42 265 268 28375198 \n10 Ginsberg JS Demers C Brill-Edwards P Bona R Johnston M Wong A Denburg JA Acquired free protein S deficiency is associated with antiphospholipid antibodies and increased thrombin generation in patients with systemic lupus erythematosus Am J Med 1995 98 379 383 7709951 \n11 Naranjo CA Busto U Sellers EM Sandor P Ruiz I Roberts EA Janecek E Domecq C Greenblatt DJ A method for estimating the probability of adverse drug reactions Clin Pharmacol Ther 1981 30 239 245 7249508\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2307-8960",
"issue": "7(24)",
"journal": "World journal of clinical cases",
"keywords": "Case report; Heparin; Rivaroxaban; Skin necrosis; Systemic lupus erythematosus; Warfarin",
"medline_ta": "World J Clin Cases",
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"nlm_unique_id": "101618806",
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"pubdate": "2019-12-26",
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"title": "Successful treatment of warfarin-induced skin necrosis using oral rivaroxaban: A case report.",
"title_normalized": "successful treatment of warfarin induced skin necrosis using oral rivaroxaban a case report"
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"abstract": "Hereditary myoclonus dystonia is often due to changes in the SGCE gene. Dystonia (DYT)-SGCE has a variable phenotype that can involve focal or generalized myoclonus and various forms of task-specific, segmental, or generalized dystonia. Psychiatric comorbidities are common.\n\n\n\nWe report a case of a young woman with generalized myoclonus, dystonia, and intellectual disability. She was found to have a novel SGCE splice site variant.\n\n\n\nThis novel variant is very likely pathogenic by in silico analysis and has not been previously reported. Additionally, her intellectual disability may constitute a novel phenotype for patients with SGCE variants.",
"affiliations": "Department of Neurology, Pennsylvania Hospital, Philadelphia, PA, USA.;Department of Neurology, Pennsylvania Hospital, Philadelphia, PA, USA.;Department of Neurology, Pennsylvania Hospital, Philadelphia, PA, USA.;Department of Neurology, Pennsylvania Hospital, Philadelphia, PA, USA.",
"authors": "Coughlin|David G|DG|;Bardakjian|Tanya M|TM|;Spindler|Meredith|M|;Deik|Andres|A|",
"chemical_list": "C526572:SGCE protein, human; D049031:Sarcoglycans",
"country": "England",
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"doi": "10.7916/D8J11FRZ",
"fulltext": "\n==== Front\nTremor Other Hyperkinet Mov (N Y)Tremor Other Hyperkinet Mov (N Y)TOHMTremor and Other Hyperkinetic Movements2160-8288Columbia University Libraries/Information Services 10.7916/D8J11FRZCase ReportsHereditary Myoclonus Dystonia: A Novel SGCE Variant and Phenotype Including Intellectual Disability Novel SGCE Variant and PhenotypeCoughlin David G. 1*Bardakjian Tanya M. 1Spindler Meredith 1Deik Andres 11 Department of Neurology, Pennsylvania Hospital, Philadelphia, PA, USALouis Elan D. Yale University, USA*To whom correspondence should be addressed. E-mail: David.Coughlin@uphs.upenn.edu2018 28 3 2018 8 54714 2 2018 9 3 2018 © 2018 Coughlin et al.2018Coughlin et al.This is an open-access article distributed under the terms of the Creative Commons Attribution–Noncommerical–No Derivatives License, which permits the user to copy, distribute, and transmit the work provided that the original author and source are credited; that no commercial use is made of the work; and that the work is not altered or transformed.Background\nHereditary myoclonus dystonia is often due to changes in the SGCE gene. Dystonia (DYT)-SGCE has a variable phenotype that can involve focal or generalized myoclonus and various forms of task-specific, segmental, or generalized dystonia. Psychiatric comorbidities are common.\n\nCase Report\nWe report a case of a young woman with generalized myoclonus, dystonia, and intellectual disability. She was found to have a novel SGCE splice site variant.\n\nDiscussion\nThis novel variant is very likely pathogenic by in silico analysis and has not been previously reported. Additionally, her intellectual disability may constitute a novel phenotype for patients with SGCE variants.\n\nDYT11intellectual disabilitymyoclonus dystoniaSGCEsarcoglycan\n==== Body\nIntroduction\nHereditary myoclonus dystonia associated with SGCE variants was first reported in 2001.1 The phenotypic spectrum of this condition is broad, but most commonly features myoclonus of the upper trunk and arms, along with cervical or brachial dystonia.2 Isolated lower limb dystonia with myoclonus emerging years later has also been described.3 Classically, handwriting will exacerbate arm dystonia, and arm and cervical myoclonus.4 In many cases the myoclonus is alcohol responsive. Variants in the SGCE gene are estimated to be responsible for 30–50% of myoclonus dystonia syndromes,1 but variants in RELN,5\nANO3,6\nTOR1A,7 and the locus for DYT158 have been reported to have similar phenotypes. DYT-SGCE has been reported with psychiatric comorbidities such as anxiety and obsessive compulsive disorder.9–11 The condition can be managed medically with a variety of agents including valproate, leviteracetam,12 clonazepam, tetrabenazine,13 and sodium oxybate.14 Pallidal deep brain stimulation has been shown to provide benefit for some patients as well.15–19 Cognitive profiles of patients with DYT-SGCE are varied among reports. Some describe no abnormalities in cognition.9,10,20 Others have indicated above-average verbal intellectual functioning with impairments in free recall and executive functioning.21,22 Frank intellectual disability has not been previously described in these patients. Here we report a patient with a novel SGCE variant and a history of intellectual disability.\n\nCase report\nA 21-year-old female presented to our clinic with a history of generalized myoclonus since childhood with developmental delay and intellectual disability. She was the product of an uneventful pregnancy and was delivered by C-section due to fetal distress. She had Apgar scores of 8 and 9 at 5 and 10 minutes of life, respectively, an unremarkable postnatal course, and was able to be discharged home on her third day of life. Whole-body occasional jerking with preservation of consciousness was noted at about 1 year. Her jerking seemed to worsen with activity. She had delayed gross and fine motor milestones (sitting at 9 months, walking at 19 months, difficulty running). She was originally assessed by two local child neurologists; a definitive diagnosis was not reached after a work-up that included a normal magnetic resonance imaging (MRI) brain scan and normal electroencephalogram although a provisional diagnosis of cerebral palsy was entertained. At age 10, she was administered the Wechsler Intelligence Scale for children, fourth edition.23 Performance on that assessment showed a full-scale intelligence quotient of 74 with deficiencies in perceptual reasoning, working memory, and processing speed (see Supplementary Figure 1). She graduated from a high school special education program and enrolled in a few community college courses with special accommodations. Over the intervening years, her myoclonus worsened in severity and began to interfere with handwriting and other daily activities, and she would occasionally fall. It was not known if the jerking lessened with alcohol consumption. There were reports of abnormal arm posturing during writing but no other complaints of neck or leg cramping, stiffness, or posturing. She also had a history of Restless Leg Syndrome (RLS) and generalized anxiety. Previous treatment with topiramate and clonazepam had been ineffective at controlling movement. Family history was significant for jerky movements in her father and paternal grandfather, who were both intellectually normal. The proband’s brother had been previously diagnosed with Sydenham’s chorea (see Figure 1). Clinical examination was notable for global hypotonia, moderate generalized spontaneous myoclonus that worsened with activity, mild cervical dystonia, and writer’s cramp (see Video 1). The Unified Myoclonus Rating Scale24 was administered with a total score of 99 (see Supplementary Figure 2). Her father was also noted to have milder generalized myoclonus during her initial office visit.\n\nFigure 1 Pedigree. The proband has 2 male siblings, one of which was diagnosed with Syndenham chorea but has declined genetic testing. The proband’s father has mild generalized myoclonus and was found to have the same mutation. His father was reportedly ‘jerky’ but is now deceased.\nVideo 1 Video of Neurological Exam. Mild cervical dystonia with left turn. Myoclonus affecting the neck and trunk. Myoclonus is elicited by auditory and tactile stimuli and worsened in the trunk and arms with posture and intention. The gait is slightly wide based and appears hypotonic. Handwriting induces worsening of cervical dystonia and neck and truncal myoclonus. Myoclonus affects handwriting and water pouring.\nMRI of the brain with a 1.5-T Siemens scanner was normal. A dystonia comprehensive sequencing panel was carried out by Invitae Laboratories and showed a novel, likely pathogenic variant in SGCE, c.825+1_825+2delGT (NM_003919.2). This test was performed using next-generation sequencing, and deletion/duplication analysis was performed on the same assay utilizing an in-house algorithm that determines the copy number at each target. The variants identified through next-generation sequencing were subsequently confirmed via appropriate methods, including, in this case, Sanger sequencing. This 2-base pair deletion at the consensus donor splice site is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product with an 'Human Splicing Finder (HSF) score of 3.0 and Combined Annotation Dependent Depletion (CADD) prediction score of 27.6.25,26 This variant is absent from population databases (gnomAD27) and has not been previously reported in individuals with SGCE-related disease. Testing of her father revealed the same variant. The family does not have contact with the father’s extended family. Her mother and siblings have not consented to genetic testing as yet. Owing to the presence of intellectual disability, a whole-genome array comparative genomic hybridization with single-nucleotide polymorphism (SNP) analysis from GeneDx™ was performed and failed to show any abnormalities. This test is performed on a custom-designed oligonucleotide microarray (GenomeDx v5) and the design is based on human genome build GRCh37/UCSChg19 and contains approximately 118,000 probes that provide copy number data and 66,000 probes that generate genotype information through analysis of SNPs. A repeat neuropsychological evaluation was performed and showed deficits, including abstract reasoning, working memory, receptive and expressive language, and executive functioning in the setting of anxiety with intact short-term memory, and delayed visual recall (see Supplementary Figure 3). She was initially treated with higher doses of clonazepam but was limited by somnolence. Leviteracetam was also trialed but failed to control her myoclonus adequately. She has undergone bilateral pallidal deep brain stimulation and, at her last follow up two months postoperatively, has demonstrated reduction in myoclonus.\n\nDiscussion\nHereditary myoclonus dystonia associated with SGCE variants was first reported in 2001.1 There are a wide variety of clinical presentations and genetic changes that have been reported in association with the phenotype.1,5,6,8,28 Most variants have no reported abnormalities in cognition.9,10 Others have indicated above-average verbal intellectual functioning with impairments in free recall and executive functioning.20,22 This family illustrates the well-documented variability in penetrance and phenotypic expression that is thought to be due to maternal imprinting.1,29 The proband illustrates a novel phenotype that includes intellectual disability. We do not think it likely that her birth history contributed to her intellectual disability given her Apgar scores, reported lack of encephalopathy after birth, and normal brain MRI. With these items she would not meet criteria for hypoxic ischemic encephalopathy or cerebral palsy. We attempted to rule out other genetic causes of intellectual disability with a SNP array panel but acknowledge the limitation of this approach. The significance of this variant is predicted to by highly pathogenic given its location by in silico programs; however, we did not attempt to determine the effect of this variant on the RNA level.\n\nIn conclusion, we describe a case of DYT-SGCE due to a novel SGCE variant. In light of the novel phenotype herein decribed, clinicians should not discount the possibility of an SGCE variant in a patient who otherwise exhibits compatible signs. Such patients may benefit from similar medical management or pallidal deep brain stimulation,15–18 and continued attention to psychiatric comorbidities that have been described in patients with other SGCE variant.\n\nFunding: None.\n\nFinancial Disclosures: T.B. is a consultant for Genome Medical Inc. A.D. has attended advisory boards for Teva pharmaceuticals and Adamas pharmaceuticals in the past year.\n\nConflict of Interests: The authors report no conflict of interest.\n\nEthics Statement: All patients that appear on video have provided written informed consent; authorization for the videotaping and for publication of the videotape was provided.\n==== Refs\nReferences\n1 Zimprich A Grabowski M Asmus F Naumann M Berg D Bertram M et al Mutations in the gene encoding [varepsilon]-sarcoglycan cause myoclonus-dystonia syndrome Nat Genet 2001 29 66 doi: 10.1038/ng709 11528394 \n2 Koukouni V Valente EM Cordivari C Bhatia KP Quinn NP Unusual familial presentation of epsilon‐sarcoglycan gene mutation with falls and writer's cramp Mov Disord 2008 23 1913 1915 doi: 10.1002/mds.21935 18702114 \n3 Peall KJ Kurian MA Wardle M Waite AJ Hedderly T Lin JP et al SGCE and myoclonus dystonia: motor characteristics, diagnostic criteria and clinical predictors of genotype J Neurolo 2014 261 2296 2304 doi: 10.1007/s00415-014-7488-3 \n4 Kinugawa K Vidailhet M Clot F Apartis E Grabli D Roze E Myoclonus‐dystonia: an update Mov Disord 2009 24 479 489 doi: 10.1002/mds.22425 19117361 \n5 Groen JL Ritz K Jalalzadeh H van der Salm SMA Jongejan A Mook OR et al RELN rare variants in myoclonus‐dystonia Mov Disord 2015 30 415 419 doi: 10.1002/mds.26070 25648840 \n6 Stamelou M Charlesworth G Cordivari C Schneider SA Kägi G Sheerin UM et al The phenotypic spectrum of DYT24 due to ANO3 mutations Mov Disord 2014 29 928 934 doi: 10.1002/mds.25802 24442708 \n7 Kabakci K Hedrich K Leung JC Mitterer M Vieregge P Lencer R et al Mutations in DYT1 . Extension of the phenotypic and mutational spectrum Neurology 2004 62 395 400 doi: 10.1212/01.WNL.0000113024.84178.F7 14872019 \n8 Han F Racacho L Lang AE Bulman DE Grimes DA Refinement of the DYT15 locus in myoclonus dystonia Mov Disord 2007 22 888 892 doi: 10.1002/mds.21400 17274032 \n9 van Tricht MJ Dreissen YE Cath D Cognition and psychopathology in myoclonus-dystonia J Neurol Neurosurg Psychiatry 2012 83 814 820 doi: 10.1136/jnnp-2011-301386 22626943 \n10 Foncke EM Cath D Zwinderman K Smit J Schmand B Tijssen M Is psychopathology part of the phenotypic spectrum of myoclonus-dystonia? a study of a large Dutch MD family Cogn Behav Neurol 2009 22 127 133 doi: 10.1097/WNN.0b013e3181a7228f 19506430 \n11 Saunders–Pullman R Shriberg J Heiman G Raymond D Wendt K Kramer P et al Myoclonus dystonia: possible association with obsessive–compulsive disorder and alcohol dependence Neurology 2002 58 242 245 doi: 10.1212/WNL.58.2.242 11805251 \n12 Striano P Manganelli F Boccella P Perretti A Striano S Levetiracetam in patients with cortical myoclonus: a clinical and electrophysiological study Mov Disord 2005 20 1610 1614 doi: 10.1002/mds.20530 16078205 \n13 Luciano AY Jinnah H Pfeiffer RF Truong DD Nance MA LeDoux MS Treatment of myoclonus-dystonia syndrome with tetrabenazine Parkinsonism Relat Disord 2014 20 1423 1426 doi: 10.1016/j.parkreldis.2014.09.029 25406829 \n14 Frucht SJ Bordelon Y Houghton WH Reardan D A pilot tolerability and efficacy trial of sodium oxybate in ethanol‐responsive movement disorders Mov Disord 2005 20 1330 1337 doi: 10.1002/mds.20605 15986420 \n15 Kimura Y Mihara M Kawarai T Kishima H Sakai N Takahashi MP et al Efficacy of deep brain stimulation in an adolescent patient with DYT11 myoclonus‐dystonia Neurol Clin Neurosci 2014 2 57 59 doi: 10.1111/ncn3.75 \n16 FitzGerald J Rosendal F De Pennington N Joint C Forrow B Fletcher C et al Long-term outcome of deep brain stimulation in generalised dystonia: a series of 60 cases J Neurol Neurosurg Psychiatry 2014 85 1371 1376 doi: 10.1136/jnnp-2013-306833 24691580 \n17 Azoulay-Zyss J Roze E Welter M-L Navarro S Yelnik J Clot F et al Bilateral deep brain stimulation of the pallidum for myoclonus-dystonia due to ε-sarcoglycan mutations: a pilot study Arch Neurol 2011 68 94 98 doi: 10.1001/archneurol.2010.338 21220679 \n18 Gruber D Kühn AA Schoenecker T Kivi A Trottenberg T Hoffmann KT et al Pallidal and thalamic deep brain stimulation in myoclonus‐dystonia Mov Disord 2010 25 1733 1743 doi: 10.1002/mds.23312 20623686 \n19 Rughani AI Lozano AM Surgical treatment of myoclonus dystonia syndrome Mov Disord 2013 28 282 287 doi: 10.1002/mds.25326 23401150 \n20 Doheny D Brin M Morrison C Smith CJ Walker RH Abbasi S et al Phenotypic features of myoclonus-dystonia in three kindreds Neurology 2002 59 1187 1196 doi: 10.1212/WNL.59.8.1187 12391346 \n21 Doheny D Danisi F Smith C Morrison C Velickovic M de Leon D et al Clinical findings of a myoclonus-dystonia family with two distinct mutations Neurology 2002 59 1244 1246 doi: 10.1212/WNL.59.8.1244 12391355 \n22 Ben‐Pazi H Jaworowski S Shalev RS Cognitive and psychiatric phenotypes of movement disorders in children: a systematic review Dev Med Child Neurol 2011 53 1077 1084 doi: 10.1111/j.1469-8749.2011.04134.x 21950517 \n23 Wechsler D Wechsler intelligence scale for children—WISC-IV San Antonio, TX Psychological Corporation 2003 \n24 Frucht SJ Leurgans SE Hallett M Fahn S The unified myoclonus rating scale Adv Neurol 2002 89 361 376 11968461 \n25 Desmet F-O Hamroun D Lalande M Collod-Béroud G Claustres M Béroud C Human Splicing Finder: an online bioinformatics tool to predict splicing signals Nucleic Acids Res 2009 37 e67 doi: 10.1093/nar/gkp215 19339519 \n26 Kircher M Witten DM Jain P O'roak BJ Cooper GM Shendure J A general framework for estimating the relative pathogenicity of human genetic variants Nat Genet 2014 46 310 doi: 10.1038/ng.2892 24487276 \n27 Lek M Karczewski KJ Minikel EV Samocha KE Banks E Fennell T et al Analysis of protein-coding genetic variation in 60,706 humans Nature 2016 536 285 doi: 10.1038/nature19057 27535533 \n28 Gatto EM Pardal MM Micheli FE Unusual phenotypic expression of the DYT1 mutation Parkinsonism Relat Disord 2003 9 277 279 doi: 10.1016/S1353-8020(02)00128-1 12781594 \n29 Müller B Hedrich K Kock N Dragasevic N Svetel M Garrels J et al Evidence that paternal expression of the ε-sarcoglycan gene accounts for reduced penetrance in myoclonus-dystonia Am J Hum Genet 2002 71 1303 1311 doi: 10.1086/344531 12444570\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2160-8288",
"issue": "8()",
"journal": "Tremor and other hyperkinetic movements (New York, N.Y.)",
"keywords": "DYT11; SGCE; intellectual disability; myoclonus dystonia; sarcoglycan",
"medline_ta": "Tremor Other Hyperkinet Mov (N Y)",
"mesh_terms": "D020821:Dystonic Disorders; D005260:Female; D014644:Genetic Variation; D006801:Humans; D008607:Intellectual Disability; D010641:Phenotype; D049031:Sarcoglycans; D055815:Young Adult",
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"pmid": "29607243",
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"publication_types": "D002363:Case Reports; D016428:Journal Article; D059040:Video-Audio Media",
"references": "22626943;11968461;25209853;19506430;24691580;21220679;12444570;12391346;16078205;15986420;23401150;11805251;27535533;14872019;17274032;24442708;19339519;25406829;24487276;18702114;20623686;12391355;25648840;19117361;11528394;21950517;12781594",
"title": "Hereditary Myoclonus Dystonia: A Novel SGCE Variant and Phenotype Including Intellectual Disability.",
"title_normalized": "hereditary myoclonus dystonia a novel sgce variant and phenotype including intellectual disability"
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"abstract": "After an accepted technique of abdominoplasty, a 66-year-old woman developed Clostridium difficile-associated diarrhea, leading to toxic megacolon and subsequent subtotal colectomy. The presumed etiology is chronic use of a proton pump inhibitor. This was addressed in a 2012 \"white paper\" warning issued by the Food and Drug Administration. This article presents the course of this case as well as a review of the pertinent literature.",
"affiliations": "From the Plastic Surgery in the Department of Surgery, LSU Health Sciences Center, New Orleans, LA.",
"authors": "Wade|James W|JW|",
"chemical_list": "D054328:Proton Pump Inhibitors; D064098:Esomeprazole",
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"issue": "72(6)",
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"mesh_terms": "D061645:Abdominoplasty; D000368:Aged; D003082:Colectomy; D004761:Enterocolitis, Pseudomembranous; D064098:Esomeprazole; D005260:Female; D006801:Humans; D007413:Intestinal Mucosa; D008532:Megacolon, Toxic; D009336:Necrosis; D054328:Proton Pump Inhibitors",
"nlm_unique_id": "7805336",
"other_id": null,
"pages": "S170-1",
"pmc": null,
"pmid": "24667886",
"pubdate": "2014",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Toxic megacolon after abdominoplasty: a case report.",
"title_normalized": "toxic megacolon after abdominoplasty a case report"
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"abstract": "BACKGROUND\nGastric cancer is the 2nd leading cause of cancer death worldwide. Malignant bowel obstruction (mbo) is a common complication in advanced gastric cancer because of peritoneal dissemination. A multicentre prospective study reported that patients with peritoneal dissemination of gastric origin survive for a median of 3.1 months. The aim of the present study was therefore to evaluate the efficacy and safety of metronomic combination chemotherapy with 5-fluorouracil and cisplatin in inoperable mbo from peritoneal dissemination in gastric cancer.\n\n\nMETHODS\nGastric cancer patients diagnosed with inoperable mbo because of peritoneal dissemination were treated with infusional 5-fluorouracil 300 mg/m(2) daily on days 1-5 and 8-12, and cisplatin 5 mg/m(2) daily on days 1-4 and 8-11 every 3 weeks. The primary endpoint was symptom control (remission of obstruction); the secondary endpoint was symptom control time and survival; the tertiary endpoint was adverse effects.\n\n\nRESULTS\nBetween January 2013 and December 2014, 26 patients received the study treatment. Before treatment, 18 patients (69.2%) were nil per os, and 8 (30.8%) could consume liquids. After a mean of 3.3 cycles of the study treatment, just 4 patients (15.4%) was still nil per os. Of the remaining 22 patients, 3 (11.5%) could consume liquids, 7 (26.9%) could consume soft solids, and 12 (46.2%) ate a full diet. The improved ability to eat was statistically significant (p < 0.0001). Median duration of remission from mbo was 105 days. Median survival was 182 days. The 3-month survival rate was 69.2%, and the 6-month survival rate was 53.8%. Treatment was well tolerated, with grade iii toxicities consisting of thrombocytopenia in 1 patient (3.84%) and mucositis in 2 patients (7.7%). No abnormalities in serum creatinine were observed.\n\n\nCONCLUSIONS\nMetronomic combination chemotherapy with 5-fluorouracil and cisplatin is well tolerated and shows activity in inoperable mbo because of peritoneal dissemination in gastric cancer. Metronomic combination chemotherapy with 5-fluorouracil and cisplatin provides a rationale for exploring this medical problem in the future.",
"affiliations": "Department of Medical Oncology, Anhui Provincial Cancer Hospital, Anhui Medical University, P.R.C.;Department of Medical Oncology, Anhui Provincial Cancer Hospital, Anhui Medical University, P.R.C.;Department of Medical Oncology, Anhui Provincial Cancer Hospital, Anhui Medical University, P.R.C.;Department of Medical Oncology, Anhui Provincial Cancer Hospital, Anhui Medical University, P.R.C.;Department of Medical Oncology, Anhui Provincial Cancer Hospital, Anhui Medical University, P.R.C.;Department of Medical Oncology, Anhui Provincial Cancer Hospital, Anhui Medical University, P.R.C.;Department of Medical Oncology, Anhui Provincial Cancer Hospital, Anhui Medical University, P.R.C.",
"authors": "Yang|S|S|;Li|S|S|;Yu|H|H|;Li|S|S|;Liu|W|W|;Liu|X|X|;Ma|H|H|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3747/co.23.3010",
"fulltext": null,
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"issn_linking": "1198-0052",
"issue": "23(3)",
"journal": "Current oncology (Toronto, Ont.)",
"keywords": "5-fluorouracil; Gastric cancer; chemotherapy; malignant bowel obstruction",
"medline_ta": "Curr Oncol",
"mesh_terms": null,
"nlm_unique_id": "9502503",
"other_id": null,
"pages": "e248-52",
"pmc": null,
"pmid": "27330361",
"pubdate": "2016-06",
"publication_types": "D016428:Journal Article",
"references": "21714777;10796761;12772880;23733778;23109694;20531380;17160651;22773238;23649709;22868084;11808972;23880474;10640968;20809660;20410174;11034757;22927096;16877730;21296855;15170445;23932009;18359221",
"title": "Metronomic chemotherapy with 5-fluorouracil and cisplatin for inoperable malignant bowel obstruction because of peritoneal dissemination from gastric cancer.",
"title_normalized": "metronomic chemotherapy with 5 fluorouracil and cisplatin for inoperable malignant bowel obstruction because of peritoneal dissemination from gastric cancer"
} | [
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"companynumb": "CN-HQ SPECIALTY-CN-2016INT000866",
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"abstract": "We present the case of a 52-year-old woman who presented to the emergency department with chest and neck pain. Initial cervical spine magnetic resonance imaging shows an abnormal flow void in the left vertebral artery, which prompted a computed tomographic angiogram. This demonstrated a hyperdense thickened ascending aortic wall, which extended into the great vessel origins. Clinically and radiographically interpreted as an acute aortic syndrome and/or intramural hematoma, the patient underwent ascending aortic repair with graft. An unusual aortic and/or periaortic mass was encountered in surgery and final pathology demonstrated IgG4 periaortitis. A rare clinical disease, IgG4-mediated processes are often mimickers of other pathologic entities and frequently lead to misdiagnosis. All pathologically similar, IgG4-mediated disease processes can involve the pancreas, salivary glands, orbits, retroperitoneum, and the vasculature.",
"affiliations": "Department of Radiology, University of Nebraska Medical Center, 981045 Nebraska Medical Center, Omaha, NE 68198-1045, USA.;Department of Radiology, University of Nebraska Medical Center, 981045 Nebraska Medical Center, Omaha, NE 68198-1045, USA.;Department of Pathology, University of Nebraska Medical Center, Omaha, NE, USA.;Department of Radiology, University of Nebraska Medical Center, 981045 Nebraska Medical Center, Omaha, NE 68198-1045, USA.",
"authors": "Moore|Drew W|DW|;Hansen|Neil J|NJ|;DiMaio|Dominick J|DJ|;Harrison|William L|WL|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.radcr.2016.08.006",
"fulltext": "\n==== Front\nRadiol Case RepRadiol Case RepRadiology Case Reports1930-0433Elsevier S1930-0433(16)30120-010.1016/j.radcr.2016.08.006Case ReportThe great imitator: IgG4 periaortitis masquerading as an acute aortic syndrome on computed tomographic angiography Moore Drew W. DOaHansen Neil J. MDnjhansen@unmc.edua∗DiMaio Dominick J. MDbHarrison William L. MDaa Department of Radiology, University of Nebraska Medical Center, 981045 Nebraska Medical Center, Omaha, NE 68198-1045, USAb Department of Pathology, University of Nebraska Medical Center, Omaha, NE, USA∗ Corresponding author. njhansen@unmc.edu20 9 2016 12 2016 20 9 2016 11 4 287 291 17 5 2016 12 7 2016 12 8 2016 © 2016 The Authors2016This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).We present the case of a 52-year-old woman who presented to the emergency department with chest and neck pain. Initial cervical spine magnetic resonance imaging shows an abnormal flow void in the left vertebral artery, which prompted a computed tomographic angiogram. This demonstrated a hyperdense thickened ascending aortic wall, which extended into the great vessel origins. Clinically and radiographically interpreted as an acute aortic syndrome and/or intramural hematoma, the patient underwent ascending aortic repair with graft. An unusual aortic and/or periaortic mass was encountered in surgery and final pathology demonstrated IgG4 periaortitis. A rare clinical disease, IgG4-mediated processes are often mimickers of other pathologic entities and frequently lead to misdiagnosis. All pathologically similar, IgG4-mediated disease processes can involve the pancreas, salivary glands, orbits, retroperitoneum, and the vasculature.\n\nKeywords\nAcute aortic syndromeIgG4AortitisIntramural hematomaCT angiographyPeriaortitis\n==== Body\nCase report\nA 52-year-old woman with a medical history of gastroesophageal reflux, hiatal hernia, and hypertension presented to the emergency department with ongoing intermittent chest and neck pain. She stated that 10 days before admission, she experienced severe chest and left shoulder pain with associated temporary loss of left arm function. In addition, her entire arm temporarily turned gray and dusky. While these arm symptoms resolved, the neck and chest pain continued and prompted her to seek medical care. On initial presentation to the emergency room, her physical examination was entirely normal.\n\nDue to concern that her clinical symptoms were related to a compressive neuropathy, cervical spine magnetic resonance imaging was obtained (Fig. 1). This magnetic resonance imaging demonstrated an abnormal lack of flow void in the left vertebral artery. Subsequently, computed tomographic (CT) angiography of the head, neck, and chest (Fig. 2) revealed hyperdensity and thickening of the ascending aorta and proximal arch aortic wall. Extension into the origin of the great vessels resulted in near complete occlusion of the left vertebral artery (Fig. 3). The remainder of the arterial vasculature, including the descending thoracic aorta, the abdominal aorta, and all major branch vessels were widely patent and normal with no wall thickening. All abdominal parenchymal organs were normal. Specifically, the pancreas demonstrated normal morphology with no enlargement or other features of autoimmune pancreatitis.\n\nOn imaging, the differential diagnosis for aortic wall thickening is limited. Given the mild hyperdense appearance on the noncontrast portion of the CT obtained, and the clinical suspicion for an acute aortic pathology, the leading differential diagnosis was an acute intramural hematoma. Occasionally, an aortic dissection with a thrombosed false lumen can have a similar imaging appearance (but it is managed similarly so imaging distinction is unimportant). Infectious and inflammatory vasculitides can cause aortic wall thickening and appear similar on imaging. Clinically, these entities usually have a more insidious onset of symptoms without an acute component as was seen in this case. Aortic wall neoplasms (typically sarcomas) are exceedingly rare and usually have more of an irregular intraluminal or exophytic mass-like morphology.\n\nGiven the clinical presentation and imaging findings, the patient went to the operating room for repair of a presumed acute aortic syndrome involving the ascending aorta. Transesophageal echocardiography done during the median sternotomy identified a possible intraluminal flap in the ascending aorta. During the operation, concentric blue mass-like hard thickening was observed to involve the distal ascending aorta and proximal arch. Surgical repair of the ascending aorta was done with placement of a 26-mm tube graft. The patient tolerated the procedure well, and postoperative CT angiography demonstrated no postoperative complications (Fig. 4). Pathologic evaluation demonstrated a lymphoplasmacytic inflammatory infiltrate involving the entire thickness of the ascending aortic wall (Fig. 5). Fibrosis was present in the adjacent periaortic soft tissues. A predominance of B-cells was found on immunophenotyping with an increased ratio of IgG4 in relation to other immunoglobulins. The final diagnosis was IgG4-related periaortitis. Her serum IgG4 level was normal at 50 mg/dL (normal serum levels are seen in up to 15% of patients with IgG4-related diseases). The patient was treated with systemic immunosuppressive drugs including prednisone, rituximab, and methotrexate, but during the course of her therapy discontinued immunosuppression for perceived drug side effects and is currently not on therapy and asymptomatic. Three postoperative CT scans (1, 12, and 18 months postoperative) have remained stable while off therapy with no new changes.\n\nDiscussion\nIgG4-related diseases (IgG4-RD) were first recognized in autoimmune pancreatitis and have been identified in numerous other organ systems [1], [2], [3]. Organs that can be involved include the salivary glands, thyroid, mediastinum, heart, kidneys, retroperitoneum, and the large vessels such as the aorta. IgG4-related periaortitis is a pathologic diagnosis that has only been described in the last decade, predominately in case reports and small series of cases. The pathology is typically described as being similar to other IgG4-RD, with lymphoplasmacytic infiltrate enriched fibrosis being the dominant feature. This has been termed storiform fibrosis due to its morphology. Periaortitis has been the preferred term over aortitis, and the following criteria are used: histologic appearance consistent with aortitis or periaortitis and not explained by other disease processes (eg, atherosclerosis), at least 50% plasma cells stain for IgG4, and at least 50% of cells are IgG4 plasma cells per high-powered field [3]. Given IgG4 plasma cells are elevated, serum IgG4 levels are typically but not always increased. This is not a specific finding; however, as serum IgG4 levels can be increased in a variety of infections and neoplastic processes.\n\nThere are only a few other reports similar to this, where IgG4 periaortitis was mistaken for an acute aortic syndrome, and a patient went to the operating room [4], [5], [6]. In these cases, similar operative findings were encountered in terms of the aorta and adjacent tissues having a blue or whitish tinge and being firm to palpation. Conventionally, autoimmune-mediated vasculitides are treated with immune modulation and suppression rather than operative intervention. However, diagnostic and clinical management dilemmas occur when acute presentations involve anatomic locations that are usually treated with surgery (eg, ascending aorta). To complicate matters further, the inflamed vascular wall may have a propensity toward concomitant acute aortic pathology, as an acute dissection related to IgG4 periaortitis has been reported [7].\n\nThere is no standard treatment for IgG4 periaortitis as of yet. In some reports, when operative findings were not typical for an intramural hematoma, surgical repair was aborted, and the patient was successfully treated with steroids [6]. Current case reports and/or series and clinical trials are evaluating the efficacy of traditional immunomodulatory drugs such as steroids and methotrexate, although newer agents such as the anti-CD20 antibody rituximab are also being studied to treat these autoimmune vasculitides [5], [8], [9].\n\nPrecise imaging signs that may differentiate an acute intramural hematoma from an inflammatory periaortitis have yet to be fully elucidated—and in cases this differentiation may be impossible with imaging. Given the risks of not treating an intramural hematoma involving the ascending aorta, surgical intervention in cases such as this may occur when clinical symptoms are acute. It is up to the radiologist to raise the possibility of vasculitis and periaortitis in these scenarios. Further investigation into this area is needed to investigate whether imaging may be able to differentiate these entities and avoid unnecessary surgery.\n\nCompeting Interests: The authors have declared that no competing interests exist.\n\nConsent: The consent was obtained directly from the patient involved before submission of this manuscript.\n\nHuman and animal rights: Not applicable to this case report.\n\nFig. 1 Axial T2-weighted image through the cervical spine demonstrates an abnormal lack of flow void in the left vertebral artery, which is high signal (arrow). The right vertebral artery (arrowhead) demonstrates a normal flow void.\n\nFig. 1Fig. 2 Axial (A) and coronal oblique (B) noncontrast CT images demonstrate thickening and subtle hyperdensity of the aortic wall involving the ascending aorta and proximal arch (white arrow and arrowhead). Postcontrast CT angiogram confirms the presence of aortic wall thickening (up to 7 mm—black arrowhead in C), which extended up along the walls of the brachiocephalic (black arrow—D) and left subclavian arteries.\n\nFig. 2Fig. 3 Axial contrast-enhanced CT angiogram image at the level just above the great vessel origins demonstrates near occlusion of the left vertebral artery (arrow) just after its takeoff related to aortic wall thickening.\n\nFig. 3Fig. 4 Postoperative axial contrast-enhanced CT angiography images (A and B) demonstrate an uncomplicated appearance of the ascending thoracic aorta status after repair. Arrows demonstrate surgical material at the origin and touchdown sites of the surgical graft. Coronal oblique precontrast (C) and postcontrast (D) images show the length of the graft (arrowheads), which extended for the entire length of the ascending aorta to the proximal arch.\n\nFig. 4Fig. 5 (A) Within the aorta and adjacent soft tissue, there is a lymphoplasmacytic inflammatory infiltrate. A prominent number of plasma cells and Mott cells (black arrows) are present (H&E, 200×). Mott cells are plasma cells that have multiple cytoplasmic inclusions (called Russell bodies) that represent immunoglobulins. (B) Immunohistochemistry staining for IgG4 demonstrated increased expression within the plasma cell population (IgG4, 100×).\n\nFig. 5\n==== Refs\nReferences\n1 Hirano K. Komatsu Y. Yamamoto N. Nakai Y. Sasahira N. Toda N. Pancreatic mass lesions associated with raised concentration of IgG4 Am J Gastroenterol 99 10 2004 2038 2040 15447769 \n2 Islam A.D. Selmi C. Datta-Mitra A. Sonu R. Chen M. Gershwin M.E. The changing faces of IgG4-related disease: clinical manifestations and pathogenesis Autoimmun Rev 14 10 2015 914 922 26112170 \n3 Stone J.R. Aortitis, periaortitis, and retroperitoneal fibrosis, as manifestations of IgG4-related systemic disease Curr Opin Rheumatol 23 1 2011 88 94 21037477 \n4 Colombier S. Ruchat P. Gronchi F. Pretre R. Niclauss L. Surgical procedure in immunoglobulin G4-related ascending aortitis? Ann Thorac Surg 97 4 2014 e111 e113 24694451 \n5 Tay D.Z. Goh P.Y. Teo T.K. Boey M.L. Chachlani N. Wong P.S. Immunoglobulin G4-related aortitis mimicking an intramural hematoma Asian Cardiovasc Thorac Ann 23 2015 1083 1086 24782568 \n6 Byeon K. Han J. Kim J.S. Kim W.S. Choe Y.H. Lee E.J. Immunoglobulin G4-related periaortitis mimicking an intramural hematoma Ann Thorac Surg 92 4 2011 1506 1508 21958804 \n7 Stone J.H. Khosroshahi A. Hilgenberg A. Spooner A. Isselbacher E.M. Stone J.R. IgG4-related systemic disease and lymphoplasmacytic aortitis Arthritis Rheum 60 10 2009 3139 3145 19790067 \n8 Maritati F. Corradi D. Versari A. Casali M. Urban M.L. Buzio C. Rituximab therapy for chronic periaortitis Ann Rheum Dis 71 7 2012 1262 1264 22586161 \n9 Mizushima I. Inoue D. Yamamoto M. Yamada K. Saeki T. Ubara Y. Clinical course after corticosteroid therapy in IgG4-related aortitis/periaortitis and periarteritis: a retrospective multicenter study Arthritis Res Ther 16 4 2014 R156 25056443\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "1930-0433",
"issue": "11(4)",
"journal": "Radiology case reports",
"keywords": "Acute aortic syndrome; Aortitis; CT angiography; IgG4; Intramural hematoma; Periaortitis",
"medline_ta": "Radiol Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101467888",
"other_id": null,
"pages": "287-291",
"pmc": null,
"pmid": "27920845",
"pubdate": "2016-12",
"publication_types": "D002363:Case Reports",
"references": "26112170;24782568;21958804;21037477;24694451;25056443;19790067;22586161;15447769",
"title": "The great imitator: IgG4 periaortitis masquerading as an acute aortic syndrome on computed tomographic angiography.",
"title_normalized": "the great imitator igg4 periaortitis masquerading as an acute aortic syndrome on computed tomographic angiography"
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"abstract": "BACKGROUND\nIsolated basilar artery dissection (IBAD) is a rare but important cause of ischemic stroke. Anti-thrombotic therapy is often used to treat IBAD-related ischemic stroke, but selected cases might need more aggressive treatment. There is no previous report of emergent stenting for IBAD-related ischemic stroke after intravenous thrombolysis.\n\n\nMETHODS\nA 53-year-old Japanese woman was admitted to our hospital with disturbance of consciousness, right hemiplegia, severe dysarthria, and total gaze paralysis. Brain magnetic resonance imaging revealed no ischemic lesion, but magnetic resonance angiography showed stenosis in the basilar artery. After initiation of intravenous thrombolysis, her neurological symptoms dramatically improved. Five hours later, however, her symptoms deteriorated again. Cerebral angiography showed IBAD. Emergent stenting was successfully performed. At 90 days after stroke onset, she had no significant disability, with a modified Rankin scale score of 1.\n\n\nCONCLUSIONS\nEmergent stenting can be an effective treatment for patients with IBAD-related ischemic stroke who are resistant to IV-rtPA.",
"affiliations": "Department of Stroke Medicine, Kawasaki Medical School, Matsushima, Kurashiki, Okayama, 577701-0192, Japan. to4aki.5da.takaraduka@gmail.com.;Department of Stroke Medicine, Kawasaki Medical School, Matsushima, Kurashiki, Okayama, 577701-0192, Japan.;Department of Stroke Medicine, Kawasaki Medical School, Matsushima, Kurashiki, Okayama, 577701-0192, Japan.;Department of Neurosurgery, Kawasaki Medical School, Okayama, Japan.;Department of Neurosurgery, Kawasaki Medical School, Okayama, Japan.;Department of Neurosurgery, Kawasaki Medical School, Okayama, Japan.;Department of Stroke Medicine, Kawasaki Medical School, Matsushima, Kurashiki, Okayama, 577701-0192, Japan.",
"authors": "Goda|Toshiaki|T|http://orcid.org/0000-0003-4648-3485;Oyama|Naoki|N|;Iwamoto|Takanori|T|;Takai|Hiroki|H|;Matsubara|Shunji|S|;Uno|Masaaki|M|;Yagita|Yoshiki|Y|",
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"doi": "10.1186/s13256-021-02675-y",
"fulltext": "\n==== Front\nJ Med Case Rep\nJ Med Case Rep\nJournal of Medical Case Reports\n1752-1947\nBioMed Central London\n\n2675\n10.1186/s13256-021-02675-y\nCase Report\nEmergent stenting after intravenous thrombolysis for isolated basilar artery dissection in a patient with acute ischemic stroke: a case report\nhttp://orcid.org/0000-0003-4648-3485\nGoda Toshiaki to4aki.5da.takaraduka@gmail.com\n\n1\nOyama Naoki oyama@med.kawasaki-m.ac.jp\n\n1\nIwamoto Takanori ganmo1117@khh.biglobe.ne.jp\n\n1\nTakai Hiroki greenhousesouvaioasus@yahoo.co.jp\n\n2\nMatsubara Shunji matsubara@med.kawasaki-m.ac.jp\n\n2\nUno Masaaki muno@med.kawasaki-m.ac.jp\n\n2\nYagita Yoshiki yyagita@med.kawasaki-m.ac.jp\n\n1\n1 grid.415086.e 0000 0001 1014 2000 Department of Stroke Medicine, Kawasaki Medical School, Matsushima, Kurashiki, Okayama 577701−0192 Japan\n2 grid.415086.e 0000 0001 1014 2000 Department of Neurosurgery, Kawasaki Medical School, Okayama, Japan\n9 3 2021\n9 3 2021\n2021\n15 1198 8 2019\n11 1 2021\n© The Author(s) 2021\nOpen 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\nIsolated basilar artery dissection (IBAD) is a rare but important cause of ischemic stroke. Anti-thrombotic therapy is often used to treat IBAD-related ischemic stroke, but selected cases might need more aggressive treatment. There is no previous report of emergent stenting for IBAD-related ischemic stroke after intravenous thrombolysis.\n\nCase presentation\n\nA 53-year-old Japanese woman was admitted to our hospital with disturbance of consciousness, right hemiplegia, severe dysarthria, and total gaze paralysis. Brain magnetic resonance imaging revealed no ischemic lesion, but magnetic resonance angiography showed stenosis in the basilar artery. After initiation of intravenous thrombolysis, her neurological symptoms dramatically improved. Five hours later, however, her symptoms deteriorated again. Cerebral angiography showed IBAD. Emergent stenting was successfully performed. At 90 days after stroke onset, she had no significant disability, with a modified Rankin scale score of 1.\n\nConclusions\n\nEmergent stenting can be an effective treatment for patients with IBAD-related ischemic stroke who are resistant to IV-rtPA.\n\nKeywords\n\nBasilar artery dissection\nIschemic stroke\nIntravenous thrombolysis\nEmergent stenting\nissue-copyright-statement© The Author(s) 2021\n==== Body\nBackground\n\nIsolated basilar artery (BA) dissection (IBAD) is a rare but important cause of ischemic stroke (incidence, 1/400,000/year) [1]. It is known to have a poor prognosis, with a mortality rate ranging from 10 to 78.9% [2]. Anti-thrombotic therapy is often used to treat IBAD-related ischemic stroke, but selected cases might need more aggressive treatment [3]. Although some cases of endovascular stenting for IBAD have been reported, the procedures were performed electively for progressive ischemic symptoms despite adequate anti-thrombotic therapy [2–5]. To the best of our knowledge, there is no previous report of emergent stenting for IBAD-related ischemic stroke after intravenous thrombolysis. We report a case of IBAD in a patient with acute ischemic stroke who underwent emergent stenting for neurological deterioration after intravenous thrombolysis.\n\nCase presentation\n\nA 53-year-old Japanese woman with a medical history of diabetes mellitus and no other risk factors for arteriosclerosis was admitted to our hospital. Physical examination showed a Glasgow Coma Scale score of E3V3M4, right hemiplegia, severe dysarthria, and total gaze paralysis. The National Institute of Health Stroke Scale (NIHSS) score was 22. Brain magnetic resonance imaging (MRI) at 90 minutes from the onset of symptoms revealed no high-intensity area on diffusion-weighted imaging (Fig. 1a). Brain magnetic resonance angiography showed stenosis in the BA (Fig. 1b). After initiation of intravenous administration of recombinant tissue plasminogen activator (IV-rtPA), neurological symptoms improved with an NIHSS of 4; however, 5 hours after IV-rtPA, the symptoms deteriorated again with an NIHSS of 22. Cerebral angiography showed severe stenosis and double lumen in the BA (Fig. 1c–f). We deployed Enterprise Vascular Reconstruction Device (VRD) 4.5 × 22 mm2 and 4.5 × 28 mm2 (Johnson & Johnson Codman, Miami, FL, USA) from the right posterior cerebral artery to the left vertebral artery (Fig. 1g) after administration of 200 mg of aspirin and 300 mg of clopidogrel. On day 2, 100 mg/day aspirin and 75 mg/day clopidogrel were initiated. Although MRI revealed small pontine infarction (Fig. 1h), the patient’s neurological deficit gradually improved. She was transferred to the rehabilitation center on day 23 with an NIHSS of 3. At 90 days from stroke onset, she had no significant disability with an NIHSS of 0 and a modified Rankin scale score of 1.Fig. 1 a Brain magnetic resonance imaging (MRI) at 90 minutes from symptom onset showing no high-intensity area on diffusion-weighted imaging (DWI). b Brain magnetic resonance angiography showing stenosis in the middle portion of the basilar artery (BA). c Cerebral angiography (45° right-anterior oblique view) showing intimal flap and double lumen in the middle and distal portions of the BA. Maximum intensity projection images of 3D rotational angiography showing double lumen of the BA in the coronal view (d), sagittal view (e), and axial view (f). g Cerebral angiography (45° right-anterior oblique view) after stenting. Enterprise VRD 4.5 × 22 mm2 (arrow: distal and proximal marker) and 4.5 × 28 mm2 (arrowhead: distal and proximal marker) was deployed from the P1 portion of the right posterior cerebral artery to the V4 portion of the left vertebral artery. h Brain MRI on day 6 showing left-sided pontine infarction on DWI\n\nDiscussion and conclusions\n\nThis is the first case report of a patient with acute ischemic stroke due to IBAD who underwent emergent stenting for neurological deterioration after IV-rtPA. Although some cases of stenting for IBAD have been reported, most of the procedures in these cases were performed after at least 3 days of dual antiplatelet therapy [2–5], and there is only one report of stenting in the hyper-acute phase of ischemic stroke [3]. There is no previous report of emergent stenting after IV-rtPA for IBAD-related ischemic stroke. Our case suggests that even for patients with IBAD-related ischemic stroke who are resistant to IV-rtPA, stenting can be a safe and effective treatment option.\n\nOptimal treatment for ischemic stroke with IBAD has not been established. In clinical practice, anticoagulant or antiplatelet therapies are usually used. However, conservative management occasionally results in a poor prognosis [3, 6]. Efficacy and safety of IV-rtPA for ischemic stroke due to intracranial artery dissection have not been established, and in some cases, neurological deterioration after IV-rtPA is noted [7]. For patients presenting with progressive ischemia despite adequate medical treatments including IV-rtPA, stenting can be an alternative treatment option with a relatively good prognosis.\n\nThe benefits of stenting for IBAD are not completely understood. Occlusion of perforating branches of the BA is reported to be the main mechanism underlying IBAD-related ischemic stroke [8]. We speculate that thrombus formation in the false lumen might obstruct the blood flow in perforating branches by compressing the origin of these branches, resulting in brainstem infarction. IV-rtPA can prevent thrombus formation, but its efficacy is transient. In contrast, stenting can repair the intimal flap, which is the inflow route of the false lumen. Reduced blood flow into the false lumen will lead to less thrombus formation in this structure.\n\nIn conclusion, emergent stenting can be an effective treatment for patients with IBAD-related ischemic stroke who are resistant to IV-rtPA.\n\nAbbreviations\n\nBA Basilar artery\n\nIBAD Isolated basilar artery dissection\n\nNIHSS National Institute of Health Stroke Scale\n\nMRI Magnetic resonance imaging\n\nIV-rtPA Intravenous recombinant tissue plasminogen activator\n\nDWI Diffusion-weighted imaging\n\nAcknowledgements\n\nNone.\n\nAuthors’ contributions\n\nTG was responsible for the conception and design of the work as well as data analysis and interpretation. NO, TI, HT, SM, MU, and YY were responsible for data collection. TG drafted the article, which was critically revised by NO, TI, HT, SM, MU, and YY. TG, NO, TI, HT, SM, MU, and YY were responsible for the final approval of the version to be published.\n\nFunding\n\nThe authors have no funding to declare.\n\nAvailability of data and materials\n\nNot applicable.\n\nEthics approval and consent to participate\n\nNot applicable.\n\nConsent for publication\n\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\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. Ruecker M Furtner M Knoflach M Werner P Gotwald T Chemelli A Basilar artery dissection: Series of 12 consecutive cases and review of the literature Cerebrovas Dis. 2010 30 267 276 10.1159/000319069\n2. Li L Li T Xue J Wang Z Bai W Zhu L Stent treatment for basilar artery dissection: A single-center experience of 21 patients Interv Neuroradiol. 2016 22 260 265 10.1177/1591019915622162 26842610\n3. Kim BM Suh SH Park SI Shin YS Chung EC Lee MH Management of clinical outcome of acute basilar artery dissection Am J Neuroradiol. 2008 29 1937 1941 10.3174/ajnr.A1243 18687744\n4. Jiang C Li Q Liu JM Huang QH Endovascular treatment for the basilar artery dissection Cardiovasc Intervent Radiol. 2014 37 646 656 10.1007/s00270-013-0737-5 24042961\n5. Li C Li Y Jiang C Wu Z Wang Y Yang X Stent alone treatment for dissections and dissecting aneurysms involving the basilar artery J Neurointerv Surg. 2015 7 50 55 10.1136/neurintsurg-2013-010967 24385558\n6. Pozzati E Andreoli A Padovani R Nuzzo G Dissecting aneurysms of the basilar artery Neurosurgery. 1995 36 254 258 10.1227/00006123-199502000-00003 7731504\n7. Bernardo F Nannoni S Strambo D Bartolini B Michel P Sirimarco G Intravenous thrombolysis in acute ischemic stroke due to intracranial artery dissection: a single-center case series and a review of literature J Thromb Thrombolysis. 2019 13 1 6\n8. Kwon JY Kim N-Y Suh DC Kang DW Kwon SU Kim JS Intracranial and extracranial arterial dissection presenting with ischemic stroke: lesion location and stroke mechanism J Neurol Sci. 2015 358 371 376 10.1016/j.jns.2015.09.368 26434614\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1752-1947",
"issue": "15(1)",
"journal": "Journal of medical case reports",
"keywords": "Basilar artery dissection; Emergent stenting; Intravenous thrombolysis; Ischemic stroke",
"medline_ta": "J Med Case Rep",
"mesh_terms": "D001488:Basilar Artery; D002545:Brain Ischemia; D004210:Dissection; D005260:Female; D006801:Humans; D000083242:Ischemic Stroke; D008875:Middle Aged; D020521:Stroke; D015912:Thrombolytic Therapy; D016896:Treatment Outcome",
"nlm_unique_id": "101293382",
"other_id": null,
"pages": "119",
"pmc": null,
"pmid": "33685504",
"pubdate": "2021-03-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "31302824;7731504;24042961;24385558;26434614;18687744;26842610;20664260",
"title": "Emergent stenting after intravenous thrombolysis for isolated basilar artery dissection in a patient with acute ischemic stroke: a case report.",
"title_normalized": "emergent stenting after intravenous thrombolysis for isolated basilar artery dissection in a patient with acute ischemic stroke a case report"
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"abstract": "Nonanaphylactic noncardiogenic pulmonary edema leading to cardiorespiratory arrest related to the magnetic resonance imaging contrast agent gadobutrol has rarely been reported in the literature. Rarer is the association of hypokalemia with acidosis. We report 2 patients who had severe pulmonary edema associated with the use of gadobutrol contrast in the absence of other inciting agents or events. These cases were unique not only for their rare and severe presentations but also because they exemplified the increasing role of extracorporeal membrane oxygenation in resuscitation. Emergency extracorporeal membrane oxygenation resuscitation can be rapidly initiated and successful in the setting of a well-organized workflow, and it is a viable alternative and helps improve patient outcome in cases refractory to conventional resuscitative measures.",
"affiliations": "Department of Anesthesiology and Critical Care, Mayo Clinic, Rochester, MN.;Department of Anesthesiology and Critical Care, Mayo Clinic, Rochester, MN.;Department of Radiology, Mayo Clinic, Rochester, MN.;Department of Anesthesiology and Critical Care, Mayo Clinic, Rochester, MN.;Department of Anesthesiology and Critical Care, Mayo Clinic, Rochester, MN.;Department of Anesthesiology and Critical Care, Mayo Clinic, Rochester, MN.;Department of Radiology, Mayo Clinic, Rochester, MN; Division of Cardiovascular Disease, Mayo Clinic, Rochester, MN.;Department of Anesthesiology and Critical Care, Mayo Clinic, Rochester, MN.;Department of Radiology, Mayo Clinic, Rochester, MN.;Department of Anesthesiology and Critical Care, Mayo Clinic, Rochester, MN; Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN.;Department of Anesthesiology and Critical Care, Mayo Clinic, Rochester, MN; Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN.;Department of Anesthesiology and Critical Care, Mayo Clinic, Rochester, MN; Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN. Electronic address: Schears.Gregory@mayo.edu.",
"authors": "Guru|Pramod K|PK|;Bohman|J Kyle|JK|;Fleming|Chad J|CJ|;Tan|Hon L|HL|;Sanghavi|Devang K|DK|;De Moraes|Alice Gallo|AG|;Barsness|Gregory W|GW|;Wittwer|Erica D|ED|;King|Bernard F|BF|;Arteaga|Grace M|GM|;Flick|Randall|R|;Schears|Gregory J|GJ|",
"chemical_list": "D003287:Contrast Media; D009942:Organometallic Compounds; C090600:gadobutrol",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
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"issn_linking": "0025-6196",
"issue": "91(3)",
"journal": "Mayo Clinic proceedings",
"keywords": null,
"medline_ta": "Mayo Clin Proc",
"mesh_terms": "D016887:Cardiopulmonary Resuscitation; D003287:Contrast Media; D004632:Emergency Medical Services; D015199:Extracorporeal Membrane Oxygenation; D006323:Heart Arrest; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D008910:Minnesota; D009942:Organometallic Compounds; D011654:Pulmonary Edema; D016896:Treatment Outcome",
"nlm_unique_id": "0405543",
"other_id": null,
"pages": "362-6",
"pmc": null,
"pmid": "26856779",
"pubdate": "2016-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Severe Acute Cardiopulmonary Failure Related to Gadobutrol Magnetic Resonance Imaging Contrast Reaction: Successful Resuscitation With Extracorporeal Membrane Oxygenation.",
"title_normalized": "severe acute cardiopulmonary failure related to gadobutrol magnetic resonance imaging contrast reaction successful resuscitation with extracorporeal membrane oxygenation"
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"companynumb": "US-BAYER-2016-034328",
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"abstract": "The emergence of resistance-associated substitutions (RASs) can compromise the high efficacy of direct-acting antivirals (DAAs). Little is known about RASs selection at very early time points during DAA treatment. Therefore, we analyzed the potential emergence of RASs immediately after therapy initiation. Samples of 71 patients treated with different DAAs were collected at baseline, during therapy (hours 4 and 8; days 1-7; weeks 2-4) or until target not detected. HCV-RNA levels were determined by qPCR, and RASs were detected by deep sequencing. Sixty-three (89%) patients achieved a sustained virological response (SVR), 7 (10%) relapsed, and 1 (1%) experienced a breakthrough. Almost all non-SVR (7/8, 88%) showed RASs either at baseline or relapse. High-frequency RASs detected at baseline (Y93H and L159F+C316N) remained detectable at early time points during therapy and reappeared as most prevalent substitutions at relapse. Conversely, emergent RASs at relapse (Q80R, D168E/V, R155K and L31V) were not observed during the first hours-days, before HCV-RNA became undetectable. HCV-RNA decay and genetic evolution of the quasispecies followed a similar pattern during the first hours of therapy in SVR and non-SVR patients. In conclusion, the absence of early RASs selection and the similar dynamics of HCV kinetics and quasispecies in SVR and non-SVR patients after therapy initiation suggest that RASs selection may occur at later stages in the remaining reservoir, where viral populations persist hidden at very low replication levels. Nevertheless, we cannot completely exclude very early selection, when RASs are present below the sensitivity limit of deep sequencing.",
"affiliations": "Liver Unit, Hospital Clínic, IDIBAPS, CIBEREHD, Universitat de Barcelona, Barcelona, Spain.;Liver Unit, Hospital Clínic, IDIBAPS, CIBEREHD, Universitat de Barcelona, Barcelona, Spain.;Joint Research Unit Infección y Salud Pública, FISABIO-Universitat de València, I2SysBio, CIBERESP, Valencia, Spain.;Liver Unit, Liver Disease Laboratory-Viral Hepatitis, Internal Medicine Department, Vall d'Hebron Institut Recerca (VHIR)-Hospital Universitari Vall d'Hebron (HUVH), CIBEREHD, Barcelona, Spain.;Liver Unit, Hospital Clínic, IDIBAPS, CIBEREHD, Universitat de Barcelona, Barcelona, Spain.;Liver Unit, Hospital Clínic, IDIBAPS, CIBEREHD, Universitat de Barcelona, Barcelona, Spain.;Liver Unit, Liver Disease Laboratory-Viral Hepatitis, Internal Medicine Department, Vall d'Hebron Institut Recerca (VHIR)-Hospital Universitari Vall d'Hebron (HUVH), CIBEREHD, Barcelona, Spain.;Liver Unit, Liver Disease Laboratory-Viral Hepatitis, Internal Medicine Department, Vall d'Hebron Institut Recerca (VHIR)-Hospital Universitari Vall d'Hebron (HUVH), CIBEREHD, Barcelona, Spain.;Liver Unit, Hospital Clínic, IDIBAPS, CIBEREHD, Universitat de Barcelona, Barcelona, Spain.;Liver Unit, Hospital Clínic, IDIBAPS, CIBEREHD, Universitat de Barcelona, Barcelona, Spain.;Liver Unit, Hospital Clínic, IDIBAPS, CIBEREHD, Universitat de Barcelona, Barcelona, Spain.;Liver Unit, Hospital Clínic, IDIBAPS, CIBEREHD, Universitat de Barcelona, Barcelona, Spain.;Liver Unit, Hospital Clínic, IDIBAPS, CIBEREHD, Universitat de Barcelona, Barcelona, Spain.;Liver Unit, Liver Disease Laboratory-Viral Hepatitis, Internal Medicine Department, Vall d'Hebron Institut Recerca (VHIR)-Hospital Universitari Vall d'Hebron (HUVH), CIBEREHD, Barcelona, Spain.;Joint Research Unit Infección y Salud Pública, FISABIO-Universitat de València, I2SysBio, CIBERESP, Valencia, Spain.;Liver Unit, Hospital Clínic, IDIBAPS, CIBEREHD, Universitat de Barcelona, Barcelona, Spain.;Liver Unit, Hospital Clínic, IDIBAPS, CIBEREHD, Universitat de Barcelona, Barcelona, Spain.",
"authors": "Perpiñán|Elena|E|0000-0002-7055-7328;Caro-Pérez|Noelia|N|0000-0002-2776-5842;García-González|Neris|N|0000-0001-9089-4033;Gregori|Josep|J|0000-0002-4253-8015;González|Patricia|P|0000-0002-1429-528X;Bartres|Concepción|C|;Soria|Maria Eugenia|ME|0000-0002-4719-3351;Perales|Celia|C|0000-0003-1618-1937;Lens|Sabela|S|0000-0003-4900-411X;Mariño|Zoe|Z|0000-0001-6321-9534;Londoño|María Carlota|MC|0000-0002-6533-1586;Ariza|Xavier|X|0000-0002-3110-5716;Koutsoudakis|George|G|0000-0003-1168-3364;Quer|Josep|J|0000-0003-0014-084X;González-Candelas|Fernando|F|0000-0002-0879-5798;Forns|Xavier|X|0000-0002-8188-1764;Pérez-Del-Pulgar|Sofía|S|0000-0002-9890-300X",
"chemical_list": "D000998:Antiviral Agents; D012367:RNA, Viral",
"country": "England",
"delete": false,
"doi": "10.1111/jvh.12986",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1352-0504",
"issue": "25(12)",
"journal": "Journal of viral hepatitis",
"keywords": "direct-acting antivirals; hepatitis C virus; quasispecies; resistance-associated substitutions",
"medline_ta": "J Viral Hepat",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019943:Amino Acid Substitution; D000998:Antiviral Agents; D024882:Drug Resistance, Viral; D005260:Female; D016174:Hepacivirus; D019698:Hepatitis C, Chronic; D006801:Humans; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D012367:RNA, Viral; D060888:Real-Time Polymerase Chain Reaction; D012008:Recurrence; D012641:Selection, Genetic; D000072230:Sustained Virologic Response; D019562:Viral Load",
"nlm_unique_id": "9435672",
"other_id": null,
"pages": "1515-1525",
"pmc": null,
"pmid": "30141252",
"pubdate": "2018-12",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Hepatitis C virus early kinetics and resistance-associated substitution dynamics during antiviral therapy with direct-acting antivirals.",
"title_normalized": "hepatitis c virus early kinetics and resistance associated substitution dynamics during antiviral therapy with direct acting antivirals"
} | [
{
"companynumb": "ES-JNJFOC-20170805836",
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"occurcountry": "ES",
"patient": {
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"actiondrug": "6",
"activesubstance": {
"activesubstancename": "SIMEPREVIR"
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"drugadditional": null,
... |
{
"abstract": "After colectomy for ulcerative colitis (UC), very severe and sometimes lethal enteritis can develop. However, the clinical features remain uncertain because of the low incidence, diversity of symptoms, and undefined diagnostic criteria. The aim of this study was to define postoperative ulcerative colitis-related severe enteritis (UCRSE) and to investigate its clinical features.\n\n\n\nA retrospective multicenter study was performed as a survey of major medical facilities utilizing surgical supplies for inflammatory bowel disease in Japan from 2001 to 2014. UCRSE was defined as a case with massive intestinal bleeding, intestinal perforation, high-output stoma, and/or a requirement for medications, such as steroids and biologics. Patients with gastroduodenal lesions or pouchitis alone were excluded. The incidence, symptoms, involvement of bacteria, cytomegalovirus reactivation, treatment, and prognosis were examined for patients with UCRSE after colectomy.\n\n\n\nForty-two (0.8%) out of 5284 cases met the criteria for UCRSE. Major symptoms were massive intestinal bleeding (76.2%), which required a median of 3850 (560-18900) mL blood transfusion; high-output stoma (38.1%) with excretion of fluid of 5000 (2000-7800) mL/day; and intestinal perforation (7.1%). Hypovolemic shock (35.7%) and/or disseminated intravascular coagulation (31.0%) developed as serious complications. Tests for cytomegalovirus reactivation were positive in 26.2% of cases. The presence of pathogenic bacteria was confirmed in only 5 cases. Corticosteroids or infliximabs were effective in half of the patients. Thirteen cases (31.0%) were treated surgically and 22 cases (56.4%) required maintenance therapy. The mortality rate was 11.9%.\n\n\n\nUCRSE is a rare but serious complication after colectomy and is sometimes life-threatening.",
"affiliations": "Department of Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, 980-8574, Japan. atsushikoh@surg.med.tohoku.ac.jp.;Department of Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, 980-8574, Japan.;Department of Inflammatory Bowel Disease, Yokohama Municipal Citizen's Hospital, Yokohama, Japan.;Department of Surgery, Fukuoka University, Chikushi Hospital, Fukuoka, Japan.;Department of Inflammatory Bowel Disease, Hyogo College of Medicine, Nishinomiya, Japan.;Department of Colorectal Surgery, Tohoku Rosai Hospital, Sendai, Japan.;Inflammatory Bowel Disease Center, Toho University Sakura Medical Center, Sakura, Japan.;Division of Surgical and Molecular Pathophysiology, Tohoku University Graduate School of Medicine, Sendai, Japan.",
"authors": "Kohyama|Atsushi|A|0000-0001-5807-668X;Watanabe|Kazuhiro|K|;Sugita|Akira|A|;Futami|Kitaro|K|;Ikeuchi|Hiroki|H|;Takahashi|Ken-Ichi|KI|;Suzuki|Yasuo|Y|;Fukushima|Kouhei|K|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": "10.1007/s00535-020-01742-3",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0944-1174",
"issue": "56(3)",
"journal": "Journal of gastroenterology",
"keywords": "Bacteria; Colectomy; Cytomegalovirus; Enteritis; Ulcerative colitis",
"medline_ta": "J Gastroenterol",
"mesh_terms": null,
"nlm_unique_id": "9430794",
"other_id": null,
"pages": "240-249",
"pmc": null,
"pmid": "33155079",
"pubdate": "2021-03",
"publication_types": "D016428:Journal Article",
"references": "16837533;30863646",
"title": "Ulcerative colitis-related severe enteritis: an infrequent but serious complication after colectomy.",
"title_normalized": "ulcerative colitis related severe enteritis an infrequent but serious complication after colectomy"
} | [
{
"companynumb": "JP-PFIZER INC-2021670873",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METRONIDAZOLE"
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{
"abstract": "In current clinical guidelines, such as those provided by the National Comprehensive Cancer Network (NCCN), evidence for treatment is based on a small clinical trial that included patients with HLRCC. They support the use of the combination of erlotinib and bevacizumab as the first therapeutic option in this rare condition. In the present study, we report a rare case of this condition in an 18-year-old male with a family history of kidney cancer whom we successfully treated with surgery and a novel drug treatment modality based on the combination of an immune check-point inhibitor (ICPI) and a tyrosine-kinase inhibitor (TKI) with excellent and promising results.",
"affiliations": "Medical Oncology Department, Miguel Servet University Hospital, 50009 Zaragoza, Spain.;Medical Oncology Department, Obispo Polanco Hospital, 440002 Teruel, Spain.;Pathology Department, Miguel Servet University Hospital, 50009 Zaragoza, Spain.;Medical Oncology Department, Miguel Servet University Hospital, 50009 Zaragoza, Spain.",
"authors": "Gurruchaga Sotés|Ibon|I|0000-0003-2519-8079;Alves|Ana Nuño|AN|;Arregui|Sandra Vicente|SV|;Santander Lobera|Carmen|C|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D000077784:Axitinib; C582435:pembrolizumab",
"country": "Switzerland",
"delete": false,
"doi": "10.3390/curroncol28040216",
"fulltext": "\n==== Front\nCurr Oncol\nCurr Oncol\ncurroncol\nCurrent Oncology\n1198-0052\n1718-7729\nMDPI\n\n34202275\n10.3390/curroncol28040216\ncurroncol-28-00216\nCase Report\nResponse to Combination of Pembrolizumab and Axitinib in Hereditary Leyomiomatosis and Renal Cell Cancer (HLRCC)\nhttps://orcid.org/0000-0003-2519-8079\nGurruchaga Sotés Ibon 1*\nAlves Ana Nuño 2\nArregui Sandra Vicente 3\nSantander Lobera Carmen 1\n1 Medical Oncology Department, Miguel Servet University Hospital, 50009 Zaragoza, Spain; csantanderl@salud.aragon.es\n2 Medical Oncology Department, Obispo Polanco Hospital, 440002 Teruel, Spain; anunno@salud.aragon.es\n3 Pathology Department, Miguel Servet University Hospital, 50009 Zaragoza, Spain; svicentea@salud.aragon.es\n* Correspondence: igurruchaga@salud.aragon.es\n25 6 2021\n8 2021\n28 4 23462350\n19 5 2021\n20 6 2021\n© 2021 by the authors.\n2021\nhttps://creativecommons.org/licenses/by/4.0/ Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).\nIn current clinical guidelines, such as those provided by the National Comprehensive Cancer Network (NCCN), evidence for treatment is based on a small clinical trial that included patients with HLRCC. They support the use of the combination of erlotinib and bevacizumab as the first therapeutic option in this rare condition. In the present study, we report a rare case of this condition in an 18-year-old male with a family history of kidney cancer whom we successfully treated with surgery and a novel drug treatment modality based on the combination of an immune check-point inhibitor (ICPI) and a tyrosine-kinase inhibitor (TKI) with excellent and promising results.\n\nhereditary leyomiomatosis\nrenal cell cancer\npembrolizumab\naxitinib\n==== Body\n1. Introduction\n\nHereditary leyomiomatosis and renal cell cancer (HLRCC) is an autosomal dominant genodermatosis of variable penetrance associated with a mutation of the gene encoding for fumarate hydratase (FH) at the level of 1q chromosome, in which missense mutations are the most common. This gene codes for an enzyme that catalyzes the reversible hydration/dehydration of fumarate to malate in the tricarboxylic acid cycle. Homozigous patients for the mutation may suffer fumaric aciduria, progressive encephalopathy, hypotonia and epileptic seizures, and do not survive beyond a few months of life.\n\nNevertheless, patients who are heterozygous for the mutation can develop multiple cutaneous piloleiomyomas, fibroids and have a 15% accumulated risk of type II papillary renal cell carcinoma (RCC). High concentrations of fumarate, secondary to the deficit of FH, leads to the inhibition of the hydroxylase of hypoxia inducible factors (HIF), therefore, an accumulation of HIF and an increase in downstream transcription factors related to cell proliferation, cell survival, and angiogenesis through the VEGF and GLUT1 pathways [1,2].\n\nUsing genomic mapping, Alam et al., described a minimum interval that contained the locus of the gene, which they called MCUL1 (multiple cutaneous and uterine leiomyomata), a region of 14 cM that can act as a tumor suppressor gene [3]. To date, three large series of cases have been reported and their mutation patterns have been analyzed [4,5,6]. Gardie’s study identified up to 32 mutations for the FH gene, including 21 mutations not previously described.\n\nRecently, Shuch et al. (2020) studied data sets from the 1000 Genomes Project (1000GP) and the Exome Aggregation Consortium (ExAC) containing sequencing data for the FH gene. They concluded that FH alterations are carried by 1 in 1000 patients with renal cell cancer and its penetrance varies between 1.7% and 5.8%, lower than estimated in other series [7].\n\nWe report a case of an intervened advanced RCC associated with HLRCC managed with a multimodal approach, combining surgery followed by systemic treatment that includes the combination of pembrolizumab and axitinib with promising results not described before in the literature and based on the pseudo-hypoxic status and a pro-inflammatory condition of the tumor.\n\n2. Case Report\n\nWe present an 18-year-old male with medical history of generalized epilepsy treated with lacosamide 100 mg twice a day and family history of a grandfather and an uncle diagnosed with and dead of renal cancer, both at the age of 40. The first presenting symptoms were haematuria and loss of 18 kg of weight in 3 months. The patient is diagnosed with a mass at the upper pole of the right kidney with a size of 10.5 × 6 × 9 cm, a retroperitoneal conglomerate of 7 × 3 cm with inferior vena cava infiltration, thrombus at the right renal artery, and an enlarged adenopathy in the aortic bifurcation of 4.6 × 2.8 cm (Figure 1).\n\nA stereotactic biopsy was performed with the result being papillary and tubular renal carcinoma. He underwent a radical right nephrectomy with extended retroperitoneal, retrocaval and periaortic lymphadenectomy. The pathological result shows a renal cell carcinoma with papillary, tubular, tubulocistyc, and solid pattern, with an affected vascular margin and with suspicion of fumarate hydratase (FH) loss of expression due to the presence of an eosinophilic nucleolus surrounded by a perinuclear halo (Figure 2a,b). TNM stage: pT3a pN1 (four out of seven lymph nodes affected).\n\nAfter recovery, a positron emission tomography/computed tomography.\n\n(PET/CT) scan was performed, showing disease persistence at lateroconal fascia, right psoas, peritoneum, retroperitoneum and a metastatic lesion in the hepatic VII segment (Figure 3). The patient was also submitted to genetic mapping and genetic counselling, identifying a deletion of 3.9 kB in the 1q43 chromosomal region, which includes exon 8 of the FH gen in heterozygosity, associated with hereditary leiomyomatosis and renal cell cancer (HLRCC).\n\nThe patient started biweekly bevacizumab (10 mg/m2) and erlotinib 150 mg QD. He developed grade 2 hypothyroidism, which was treated with levothyroxine oral supplementation and grade 3 acneiform rash requiring erlotinib interruption and topic treatment. At the two-month follow up visit, the patient presented radiological disease progression according to RECIST 1.1 criteria. A retroperitoneal node size increase of up to 32 × 24 mm and a new node at the anterior surface of the right psoas of 23 × 16 mm (Figure 4a). With ECOG (Eastern Cooperative Oncology Group) 1, mild abdominal pain and grade 1–2 rash, the patient started the second line of treatment with pembrolizumab 200 mg every 3 weeks combined with axitinib 5 mg BID. After 2 months, the patient’s abdominal pain resolved, and the CT scan revealed an important partial response to the therapy with a reduction of the retroperitoneal node and the disappearance of the other lesions (Figure 4b). Currently, the patient is undergoing the 11th cycle of treatment, with current toxicity being grade 1–2 diarrhea managed with loperamide and requiring temporary interruptions of axitinib. He has reached an overall survival of 20 months and a disease free survival of 15 months, with persistent good response and improved symptom control, since beginning treatment with pembrolizumab-axitinib.\n\nInvestigators obtained written consent from the patient for publishing this case report, including medical history, images, and treatments received.\n\n3. Discussion\n\nHLRCC is a rare hereditary condition with no more than 300 families reported worldwide. It is considered an orphan disease with no high-level evidence available or specific clinical trials designed for this disorder. The available treatment options for this condition in the metastatic setting are supported by the results of a few cases gathered from larger trials on kidney cancer. Based on the NCT01130519 clinical trial, where 42 out of 83 patients had HLRCC, NCCN guidelines recommend the combination of bevacizumab and erlotinib as the first line treatment for the metastatic scenario. This trial showed an overall response rate (ORR) of 64%, with progression free survival (PFS) of 21 months, and grade 3–4 toxicities of 47% [8].\n\nIn the Keynote426 clinical trial, the combination of axitinib and pembrolizumab in RCC has encouraging results with an ORR of 59.3% and a PFS of 15 months independent of PDL1 expression and International Metastatic Renal Cell Carcinoma Database Consortium risk groups [9]. For the use of the combination in the case reported, we relied on the pseudo-hypoxic status triggered by FH deficiency, as well as a pro-inflammatory condition demonstrated by a retrospective study in which a higher proportion of PDL1 overexpression was observed in the subgroup of patients with HLRCC, together with a greater number of PD1-expressing CD8 tumor-infiltrating lymphocytes at the tumor margins. The authors concluded that these patients could present a greater response to immune check-point inhibitors [ICPI] [10].\n\nRecently, the first two cases of stage IV HLRCC treated with a combination of ICPI and TKI have been published, using the combination of nivolumab-axitinib and sintilimab-axitinib, showing promising results with sustained partial responses [11,12].\n\n4. Conclusions\n\nThis case reports a young patient with a rare hereditary condition, HLRCC. It underlines the need to look for genetic alterations in young patients with kidney tumors (especially if they present a family history). Moreover, it highlights that adequate genetic profiling/counselling should be available in these cases in order to identify specific mutations and syndromes. Finally, this case report proposes a novel treatment strategy based on a combination of surgery, pembrolizumab, and axitinib, with promising results. The newly established European Reference Network (ERN) eUROGEN, is currently working on building online platforms to discuss rare urological diseases, such as the one presented here, update and adapt current guidelines, and offer physicians and patients a unique opportunity to manage complex and rare conditions with an specific workstream flow of rare urogenital tumors, such as HLRCC, with more than 4000 patients managed per year in those ERN eUROGEN centers [13].\n\nAuthor Contributions\n\nConceptualization, I.G.S. and C.S.L. Investigation, I.G.S. and C.S.L. Project administration I.G.S. Writing original draft I.G.S. and C.S.L. Writing review editing I.G.S. and A.N.A. Resources S.V.A. All authors have read and agreed to the published version of the manuscript.\n\nFunding\n\nThis research received no external funding.\n\nInstitutional Review Board Statement\n\nEthical review and approval were waived for this study, because the detailed management of the patient was made based on standard clinical practice, and he was not included in any clinical trials.\n\nInformed Consent Statement\n\nInformed consent was obtained from the subject involved in the case report.\n\nData Availability Statement\n\nThe data presented in this study are available in this article.\n\nConflicts of Interest\n\nThe authors declare no conflict of interest.\n\nFigure 1 CT at diagnosis. Mass at the upper pole of the right kidney.\n\nFigure 2 Biopsy showing papillary and tubular renal carcinoma (a): Histological section with hematoxylin-eosin stain showing renal cell carcinoma with eosinophilic nucleolus surrounded by perinuclear halo. (b): Histological section showing loss of expression of FH. Scale bar 100 µm.\n\nFigure 3 PET-CT confirming first progression, with locoregional lesions, hepatic and retroperitoneal metastasis.\n\nFigure 4 CT scans showing the evolution of the oncological disease. (a): CT confirming second progression. Increase of retroperitoneal node and a new node anterior to the right psoas. (b): CT with major partial response. Shows stable retroperitoneal node and resolution of the rest of metastatic disease.\n\nPublisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Maher E.R. Hereditary renal cell carcinoma syndromes: Diagnosis, surveillance and management World J. Urol. 2018 36 1891 1898 10.1007/s00345-018-2288-5 29680948\n2. Patel V.M. Handler M.Z. Schwartz R.A. Lambert W.C. Hereditary leiomyomatosis and renal cell cancer syndrome: An update and review J. Am. Acad. Dermatol. 2017 77 149 158 10.1016/j.jaad.2017.01.023 28314682\n3. Alam N.A. Barclay E. Rowan A.J. Tyrer J.P. Calonje E. Manek S. Kelsell D. Leigh I. Olpin S. Tomlinson I.P. Clinical features of multiple cutaneous and uterine leiomyomatosis: An underdiagnosed tumor syndrome Arch. Dermatol. 2005 141 199 206 10.1001/archderm.141.2.199 15724016\n4. Tomlinson I.P.M. Alam N.A. Rowan A.J. Barclay E. Jaeger E.E.M. Kelsell D. Leigh I. Gorman P. Lamlum H. Rahman S. Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer Nat. Genet. 2002 30 406 410 11865300\n5. Gardie B. Remenieras A. Kattygnarath D. Bombled J. Lefèvre S. Perrier-Trudova V. Rustin P. Barrois M. Slama A. Avril M.-F. Novel FH mutations in families with hereditary leiomyomatosis and renal cell cancer (HLRCC) and patients with isolated type 2 papillary renal cell carcinoma J. Med. Genet. 2011 48 226 234 10.1136/jmg.2010.085068 21398687\n6. Wei M.-H. Toure O. Glenn G.M. Pithukpakorn M. Neckers L. Stolle C. Choyke P. Grubb R. Middelton L. Turner M.L. Novel mutations in FH and expansion of the spectrum of phenotypes expressed in families with hereditary leiomyomatosis and renal cell cancer J. Med. Genet. 2006 43 18 27 10.1136/jmg.2005.033506 15937070\n7. Shuch B. Li S. Risch H. Bindra R.S. McGillivray P.D. Gerstein M. Estimation of the carrier frequency of fumarate hydratase alterations and implications for kidney cancer risk in hereditary leiomyomatosis and renal cancer Cancer 2020 126 3657 3666 10.1002/cncr.32914 32413184\n8. Srinivasan R. Gurram S. Al Harthy M. Singer E.A. Sidana A. Shuch B.M. Ball M.W. Friend J.C. Mac L. Purcell E. Results from a phase II study of bevacizumab and erlotinib in subjects with advanced hereditary leiomyomatosis and renal cell cancer (HLRCC) or sporadic papillary renal cell cancer J. Clin. Oncol. 2020 38 5004 10.1200/JCO.2020.38.15_suppl.5004\n9. Rini B.I. Plimack E.R. Stus V. Gafanov R. Hawkins R. Nosov D. Pouliot F. Alekseev B. Soulières D. Melichar B. Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma N. Engl. J. Med. 2019 380 1116 1127 10.1056/NEJMoa1816714 30779529\n10. Walter B. Gil S. Naizhen X. Kruhlak M.J. Linehan W.M. Srinivasan R. Merino M.J. Determination of the Expression of PD-L1 in the Morphologic Spectrum of Renal Cell Carcinoma J. Cancer 2020 11 3596 3603 10.7150/jca.35738 32284756\n11. Feng D. Yang Y. Han P. Wei X. The preliminary outcome of the combination of immunotherapy and targeted therapy after recurrence and metastasis for hereditary leiomyomatosis and renal cell cancer-a case report Transl. Androl. Urol. 2020 9 789 793 10.21037/tau.2019.12.37 32420185\n12. Yonese I. Ito M. Takemura K. Kamai T. Koga F. A Case of Metastatic Hereditary Leiomyomatosis and Renal Cell Cancer Syndrome-Associated Renal Cell Carcinoma Treated with a Sequence of Axitinib and Nivolumab Following Cytoreductive Nephrectomy J. Kidney Cancer VHL 2020 7 6 10 10.15586/jkcvhl.2020.148 32953419\n13. Oomen L. Leijte E. Shilhan D.E. Battye M. Members of ERN eUROGEN, Feitz WFJ. Rare and Complex Urology: Clinical Overview of ERN eUROGEN Eur. Urol. 2021 1 9 10.1016/j.eururo.2021.02.043\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1198-0052",
"issue": "28(4)",
"journal": "Current oncology (Toronto, Ont.)",
"keywords": "axitinib; hereditary leyomiomatosis; pembrolizumab; renal cell cancer",
"medline_ta": "Curr Oncol",
"mesh_terms": "D000293:Adolescent; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols; D000077784:Axitinib; D002292:Carcinoma, Renal Cell; D006801:Humans; D007680:Kidney Neoplasms; D008297:Male",
"nlm_unique_id": "9502503",
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"pages": "2346-2350",
"pmc": null,
"pmid": "34202275",
"pubdate": "2021-06-25",
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"title": "Response to Combination of Pembrolizumab and Axitinib in Hereditary Leyomiomatosis and Renal Cell Cancer (HLRCC).",
"title_normalized": "response to combination of pembrolizumab and axitinib in hereditary leyomiomatosis and renal cell cancer hlrcc"
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"activesubstancename": "ERLOTINIB HYDROCHLORIDE"
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"abstract": "Primary biliary cirrhosis (PBC), which predominantly affects women, has been associated with various autoimmune diseases. Although hypothyroidism accompanying PBC is well documented, the concomitance of PBC and hyperthyroidism is rare. Herein, we report the case of a 62-year-old man who was diagnosed with PBC several years after the development of Graves' disease. This is the first case of a male patient developing PBC with Graves' disease. Both serum alanine aminotransferase levels and serum thyroid hormone levels were normalized after the administration of thiamazole for Graves' disease. However, the cholestatic liver enzyme abnormalities continued, indicating that the PBC was actualized by the administration of thiamazole. After starting ursodeoxycholic acid treatment, cholestatic liver enzyme abnormalities improved. Taken together, when a cholestatic pattern of liver enzymes is observed during follow-up for Graves' disease, an association between Graves' disease and PBC should be considered as a differential diagnosis.",
"affiliations": "Division of Hepatology, Department of Internal Medicine, Iwate Medical University School of Medicine, 19-1 Uchimaru, Morioka, Iwate, 020-8505, Japan. yusuzuki@iwate-med.ac.jp.;Department of Molecular Diagnostic Pathology, Iwate Medical University School of Medicine, Morioka, Iwate, 020-8505, Japan.;Department of Gastroenterology, Iwate Prefectural Ninohe Hospital, 38-2 Horino Aza Ookawarake, Ninohe, Iwate, 028-6193, Japan.;Department of Gastroenterology, Iwate Prefectural Ninohe Hospital, 38-2 Horino Aza Ookawarake, Ninohe, Iwate, 028-6193, Japan.;Division of Hepatology, Department of Internal Medicine, Iwate Medical University School of Medicine, 19-1 Uchimaru, Morioka, Iwate, 020-8505, Japan.;Division of Hepatology, Department of Internal Medicine, Iwate Medical University School of Medicine, 19-1 Uchimaru, Morioka, Iwate, 020-8505, Japan.;Division of Hepatology, Department of Internal Medicine, Iwate Medical University School of Medicine, 19-1 Uchimaru, Morioka, Iwate, 020-8505, Japan.;Division of Hepatology, Department of Internal Medicine, Iwate Medical University School of Medicine, 19-1 Uchimaru, Morioka, Iwate, 020-8505, Japan.",
"authors": "Suzuki|Yuji|Y|;Ishida|Kazuyuki|K|;Takahashi|Hiroshi|H|;Koeda|Norihiko|N|;Kakisaka|Keisuke|K|;Miyamoto|Yasuhiro|Y|;Suzuki|Akiko|A|;Takikawa|Yasuhiro|Y|",
"chemical_list": "D002756:Cholagogues and Choleretics; D014580:Ursodeoxycholic Acid",
"country": "Japan",
"delete": false,
"doi": "10.1007/s12328-016-0635-x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1865-7265",
"issue": "9(2)",
"journal": "Clinical journal of gastroenterology",
"keywords": "Autoimmunity; Graves’ disease; Primary biliary cirrhosis",
"medline_ta": "Clin J Gastroenterol",
"mesh_terms": "D002756:Cholagogues and Choleretics; D006111:Graves Disease; D006801:Humans; D008105:Liver Cirrhosis, Biliary; D008297:Male; D008875:Middle Aged; D014580:Ursodeoxycholic Acid",
"nlm_unique_id": "101477246",
"other_id": null,
"pages": "99-103",
"pmc": null,
"pmid": "26935935",
"pubdate": "2016-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "2623321;18778710;24809534;24387726;1564300;6204905;17891696;16250040;10484012;11086105;20029462;16177252;21953406;3840820;6628157;8174893;12927435;12663229;3792920;16496080;25755537",
"title": "Primary biliary cirrhosis associated with Graves' disease in a male patient.",
"title_normalized": "primary biliary cirrhosis associated with graves disease in a male patient"
} | [
{
"companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2017R1-145529",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
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"activesubstancename": "METHIMAZOLE"
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"abstract": "Antiretroviral therapies prolong life expectancy and improve the quality of life of HIV-infected patients. Despite the documented benefits of antiretroviral drugs, its use is not without side effects. Here, we report cases of new onset diabetes mellitus after taking a dolutegravir (DTG)-based ART regimen.\nHIV-infected patients who had been on non-nucleoside reverse transcriptase inhibitor (NNRTI)-based ART regimens for more than a decade were shifted to integrase strand transfer inhibitors (dolutegravir)-based ART regimen as recommended by the National Comprehensive HIV Care Guideline. They were diagnosed to have diabetes mellitus with or without diabetic ketoacidosis (DKA) as evidenced by polyuria, polydipsia and fatigue, severe hyperglycemia (plasma glucose level >250 mg/dl) with or without ketonuria (3+) after 1-12 months of DTG-based ART regimen. Two of the patients who presented with DKA were treated with intravenous fluids and regular insulin. NPH insulin was started following recovery from DKA, which later shifted to metformin. One of the patients who presented with severe hyperglycemia without DKA was started with NPH insulin, which later shifted to metformin. Good glycemic control was obtained with metformin, while the DTG-based ART regimen was continued.\nHyperglycemia is a potential and noticed side effect of the DTG-based ART regimen. Baseline and periodic monitoring of plasma glucose might be required in ART regimens containing dolutegravir.",
"affiliations": "Department of Internal Medicine, University of Gondar, Gondar, North Gondar, Ethiopia.;Department of Internal Medicine, University of Gondar, Gondar, North Gondar, Ethiopia.;Department of Internal Medicine, University of Gondar, Gondar, North Gondar, Ethiopia.",
"authors": "Hailu|Workagegnehu|W|;Tesfaye|Tsebaot|T|;Tadesse|Abilo|A|",
"chemical_list": null,
"country": "New Zealand",
"delete": false,
"doi": "10.2147/IMCRJ.S323233",
"fulltext": "\n==== Front\nInt Med Case Rep J\nInt Med Case Rep J\nimcrj\nimcrj\nInternational Medical Case Reports Journal\n1179-142X\nDove\n\n323233\n10.2147/IMCRJ.S323233\nCase Series\nHyperglycemia After Dolutegravir-Based Antiretroviral Therapy\nHailu et al\nHailu et al\nHailu Workagegnehu 1\nTesfaye Tsebaot 1\nTadesse Abilo 1\n1 Department of Internal Medicine, University of Gondar, Gondar, North Gondar, Ethiopia\nCorrespondence: Abilo Tadesse Tel +251 911405144 Email abilo.tadesse@yahoo.com\n28 7 2021\n2021\n14 503507\n03 6 2021\n23 7 2021\n© 2021 Hailu et al.\n2021\nHailu et al.\nhttps://creativecommons.org/licenses/by-nc/3.0/ This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php).\nBackground\n\nAntiretroviral therapies prolong life expectancy and improve the quality of life of HIV-infected patients. Despite the documented benefits of antiretroviral drugs, its use is not without side effects. Here, we report cases of new onset diabetes mellitus after taking a dolutegravir (DTG)-based ART regimen.\n\nCase Presentation\n\nHIV-infected patients who had been on non-nucleoside reverse transcriptase inhibitor (NNRTI)-based ART regimens for more than a decade were shifted to integrase strand transfer inhibitors (dolutegravir)-based ART regimen as recommended by the National Comprehensive HIV Care Guideline. They were diagnosed to have diabetes mellitus with or without diabetic ketoacidosis (DKA) as evidenced by polyuria, polydipsia and fatigue, severe hyperglycemia (plasma glucose level >250 mg/dl) with or without ketonuria (3+) after 1–12 months of DTG-based ART regimen. Two of the patients who presented with DKA were treated with intravenous fluids and regular insulin. NPH insulin was started following recovery from DKA, which later shifted to metformin. One of the patients who presented with severe hyperglycemia without DKA was started with NPH insulin, which later shifted to metformin. Good glycemic control was obtained with metformin, while the DTG-based ART regimen was continued.\n\nConclusion\n\nHyperglycemia is a potential and noticed side effect of the DTG-based ART regimen. Baseline and periodic monitoring of plasma glucose might be required in ART regimens containing dolutegravir.\n\nKeywords\n\nINSTIs\ndolutegravir\nhyperglycemia\nno funding There is no funding to report.\n==== Body\nBackground\n\nAntiretroviral therapy (ART) restores immune function and reduces HIV-related adverse outcomes. Despite documented benefits of antiretroviral drugs, its use is not without side effects.1,2 Protease inhibitors (PIs), and to a lesser extent, nucleoside/tide reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs) were known to cause deranged glucose and lipid metabolism, leading to hyperglycemia, dyslipidemia and insulin resistance.5,6 In addition, insulin resistance might be worsened by immune activation and chronic inflammation due to HIV infection. Recently, there have been a few documented reports on deranged glucose metabolism with integrase strand transfer inhibitors (INSTIs) use.8–17 SAILING, SPRING-2, SINGLE and VIKING-3 clinical trials reported the incidence of moderate (plasma glucose, 126–250 mg/dl) and severe hyperglycemia (plasma glucose, >250 mg/dl) were 6–9% and 1–2%, respectively, after INSTIs therapy.8–11 This case series is the first of its kind in Ethiopia to report on new onset diabetes mellitus after dolutegravir-based ART use.\n\nCase Presentation\n\nCase-1\n\nA 48-year-old male patient was diagnosed with stage II HIV infection 11 years back after presenting with cutaneous fungal infections. He was treated with topical antifungals, and started on ART (AZT-3TC-EFV) and cotrimoxazole preventive therapy (CPT) with a baseline CD4+ count 175 cells/mm3. The patient achieved an undetected viral load after 6 months of ART initiation. The ART regimen was shifted to TDF-3TC-DTG after 10 years as recommended by the National Comprehensive HIV Care Guideline. His fasting blood sugar (FBS) level was 101 mg/dl at time of the DTG-based ART initiation. He was told to have hypertension on medical follow up and was prescribed amlodipine, 10 mg po daily, and advised on lifestyle modification. He was diagnosed to have diabetic ketoacidosis (DKA) with clinical evidence of polyuria, polydipsia and fatigue, severe hyperglycemia (RBS=320–466 mg/dl, HbA1c=9.3%), and ketonuria (3+)), which occurred after 7 months of DTG-based ART regimen (Table 1). No documented preceding infections. No personal or family history of diabetes mellitus or dyslipidemia. Serum C-peptide level, anti-insulin antibody or anti-glutamic acid decarboxylase (GAD) antibody were not determined due to limited clinical setup. He was treated with intravenous fluids, regular insulin and IV KCl, and recovered from DKA after 4 days of admission. NPH insulin 20/10 IU s/c daily was started, which later changed to metformin 850 mg/day. Good glycemic control (FBS=101–130 mg/dl, HbA1c=7.1%) was obtained with metformin, while the DTG-based ART regimen was continued.Table 1 Laboratory Profiles of HIV Infected Patients Taking Dolutegravir-Based ART Regimen at Initial Admission to Emergency Medical OPD, University of Gondar Hospital, Northwest Ethiopia\n\nParameters\tCase-1\tCase-2\tCase-3\tRef.\t\nHemogram\t\t\t\t\t\n WBC (x103 cells/mm3)\t10.6\t5.2\t6.4\t4.0–11.0\t\n Hgb (gm/dl)\t16.2\t14.2\t12.4\t12–16.5\t\n Platelets ((x103 cells/mm3)\t313\t158\t140\t150–450\t\nUrinalysis\t\t\t\t\t\n Glucosuria\t3+\t3+\t3+\t–ve\t\n Ketonuria\t3+\t–ve\t3+\t–ve\t\n Protein\tTrace\t1+\t–ve\t–ve\t\n Sediments\t–\t–\t–\t–ve\t\nLiver biochemical tests\t\t\t\t\t\n ALT (IU/L)\t–\t23\t–\t0–40\t\n AST (IU/L)\t–\t19\t–\t0–40\t\nRenal function tests\t\t\t\t\t\n Serum Cr (mg/dl)\t0.82\t0.77\t0.79\t0.6–1.2\t\n BUN (mg/dl)\t22\t27\t30\t5–30\t\nElectrolytes\t\t\t\t\t\n Serum Na+ (meq/L)\t133\t–\t–\t135–145\t\n Serum K+ (meq/L)\t4.4\t4.2\t3.9\t3.5–5.5\t\nBlood sugar profile\t\t\t\t\t\n RBS (mg/dl)\t320\t378\t350\t<180\t\n HbA1c (%)\t9.3\t–\t11.4\t4.0–6.0\t\nLipid profile\t\t\t\t\t\n Total cholesterol\t160.5\t180.1\t227\t<200\t\n HDL\t33.4\t34.1\t–\t40–60\t\n LDL\t127.0\t95.9\t–\t<130\t\n Triglycerides\t61.6\t250.2\t–\t<150\t\nAbbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; BUN, blood urea nitrogen; Cr, creatinine; Hgb, hemoglobin; HbA1c; hemoglobin A1c; HDL, high density lipoprotein; LDL, low density lipoprotein; RBS, random blood sugar; WBC, white blood cells.\n\nCase-2\n\nA 49-year-old female patient was diagnosed with stage III HIV infection 11 years back after presenting with smear negative pulmonary tuberculosis and oropharyngeal candidiasis with a baseline CD4+ count 74 cells/mm3. She was covered with fluconazole as antifungal therapy. She was treated with anti-tuberculosis treatment (ATT) for 6 months and declared treatment completed. ART (AZT-3TC-NVP) and CPT were started two weeks after ATT initiation. She had records of undetected viral load after 2 years of ART initiation. The ART regimen was shifted to TDF-3TC-DTG after 10 years as recommended by the National Comprehensive HIV Care Guideline. She was diagnosed with hypertension and dyslipidemia on follow-ups, and advised on lifestyle modification. She was diagnosed with type 2 diabetes after presenting with polyuria, polydipsia, fatigue and blurred vision, and hyperglycemia (RBS=313 g/dl) which occurred after 1 year of the DTG-based ART regimen (Table 1). No documented preceding infections. No personal or family history of diabetes mellitus. Serum C-peptide level, anti-insulin antibody or anti-GAD antibody were not determined due to limited clinical setup. No documented plasma glucose level prior to changing ART regimen. She was started on NPH insulin 24 IU s/c daily, which later changed to metformin 1 gm po daily. Good glycemic control (FBS=109–135 mg/dl) was achieved with metformin, while the DTG-based ART regimen was continued.\n\nCase-3\n\nA 46-year-old female patient was diagnosed with stage I HIV infection after voluntary counseling and testing (VCT) for HIV 13 years back. She was initiated on ART (AZT-3TC-NVP) and CPT 2 years later with a CD4+ count 119 cells/mm3. The ART regimen was shifted to TDF-3TC-DTG after 11 years as recommended by the National Comprehensive HIV Care Guideline. She was diagnosed to have DKA with clinical evidence of polyuria, polydipsia and fatigue, severe hyperglycemia (RBS=350–450 mg/dl, HbA1c=11.4%) and ketonuria (3+), which occurred after 1 month of the DTG-based ART regimen (Table 1). No documented preceding infections. No personal or family history of diabetes mellitus or dyslipidemia. Serum C-peptide level, anti-insulin antibody or anti-GAD antibody were not determined due to limited clinical setup. No documented plasma glucose level prior to changing ART regimen. She was treated with intravenous fluids, regular insulin and IV KCl, and recovered from diabetic ketoacidosis after 3 days of admission. NPH insulin 10/8 IU s/c daily was initiated, which later changed to metformin 750 mg po daily. Good glycemic control (FBS=106–140 mg/day, HbA1c=5.6%) was obtained with metformin, while the DTG-based ART regimen was continued.\n\nDiscussion\n\nAntiretroviral drugs have markedly reduced HIV-related morbidity and mortality. It has transformed HIV/AIDS from an inevitably fatal disease to a chronic, manageable illness. Combinations of antiretroviral drugs are required to achieve maximal viral suppression. The ART regimen comprises a combination of three drugs in two classes of antiretroviral drugs, ie, 2 NRTIs and 2 PIs, 1 NNRTIs, or 1 INSTIs.1,2 Second-generation INSTIs are currently the class of choice in ART regimens due to their high potency, good tolerability, low toxicity and high genetic barrier to resistance.1–3 The dolutegravir-based ART regimen was incorporated into the preferred regimen of choice in sub-Saharan Africa, including Ethiopia.2,4 INSTIs have been linked to weight gain and neuropsychiatric disorders.7 Recently, there is mounting evidence that INSTIs cause deranged glucose metabolism.8–17 Severe hyperglycemia (Plasma glucose level >250 mg/dl) with or without its life threatening acute complications (diabetic ketoacidosis or hyperosmolar hyperglycemia state) was recognized after INSTIs use in SAILING, SPRING-2, SINGLE, and VIKING-3 clinical trials.8–11 Similarly, severe (250–500mg/dl) or life threatening (>500 mg/dl) hyperglycemia were documented in case reports by Kamal et al, McLaughlin et al, Ntem-Mensah et al, Horikawa et al and Lamonde et al.12–15 INSTIs are believed to work by chelating mg2+ to prevent HIV from integrating into host DNA. Chelating mg2+ by INSTIs may lead to disorders of glucose metabolism, because mg2+ also serves as a cofactor in post-receptor insulin action.13–17 Two of the patients who presented with DKA were treated with intravenous fluids and regular insulin. NPH insulin was started following recovery from DKA, which later shifted to metformin. One of the patients who presented with severe hyperglycemia without DKA was started with NPH insulin, which later shifted to metformin. Good glycemic control was obtained with metformin, while the DTG-based ART regimen was continued. In conclusion, hyperglycemia is a potential and noticed side effect of the DTG-based ART regimen. Baseline and periodic monitoring of plasma glucose might be required in ART regimens containing dolutegravir.\n\nAcknowledgments\n\nWe are grateful to the medical personnel, who were caring for the patients.\n\nAbbreviations\n\nART, antiretroviral therapy; ATT, anti-tuberculosis treatment; AZT, zidovudine; DKA, diabetic ketoacidosis; DNA, deoxyribonucleic acid; DTG, dolutegravir; EFV, efavirenz; GAD, glutamic acid decarboxylase; HIV, human immunodeficiency virus; INSTIs, integrase strand transfer inhibitors; NVP, nevirapine; NRTIS, nucleoside/tide reverse transcriptase inhibitors; NNRTIs, non-nucleoside reverse transcriptase inhibitors; PIs, protease inhibitors; TBC, tuberculosis; TDF, tenofovir disoproxil fumarate; 3TC, lamivudine; VCT, voluntary counseling and testing.\n\nEthics Approval and Consent to Participate\n\nThe authors declare that ethics approval was not required for these case reports as we did not use any new procedures or any treatment, which was not approved for clinical use in our institution.\n\nConsent for Publication\n\nWritten informed consent was obtained from patients for publication of this case series and any accompanying laboratory reports. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nAuthor Contributions\n\nAll authors contributed to data analysis, drafting or revising the article, have agreed on the journal to which the article will be submitted, gave final approval of the version to be published, and agree to be accountable for all aspects of the work.\n\nDisclosure\n\nThe authors declare that they have no conflicts of interest for this work.\n==== Refs\nReferences\n\n1. WHO Clinical Guidelines. Antiretroviral therapy; 2020. Avaialble from: http://www.who.int. Accessed 723, 2021.\n2. Ethiopia national consolidated guidelines for comprehensive HIV prevention, care and treatment; 2018. Avaialble from: http://www.afro.who.int. Accessed 723, 2021.\n3. Magdalena DI, Carmen CR, Rugina S. Dolutegravir efficacy in HIV infected patients. ARS Medica Tomitana. 2015;1 (21 ):42–51.\n4. Phillips AN, Venter F, Havlir D, et al. Risks and benefits of dolutegravir-based antiretroviral drug regimens in Sub-Saharan Africa: a modeling study. Lancet. 2019;6 (2 ):e116–27. doi:10.1016/S2352-3018(18)30317-5\n5. American Diabetes Association. Diabetes care: standards of medical care in diabetes-2020. J Clin Appl Res Educ. 2020;43 (suppl–1 ):S1–S212.\n6. Thet D, Siritientong T. Antiretroviral therapy-associated metabolic complications. Review of the recent studies. HIV AIDS (Auckl). 2020;12 :507–524. doi:10.2147/HIV.S275314 33061662\n7. Kolakowska A, Maresca AF, Collins IJ, Cailhol J. Updates on adverse effects on HIV integrase inhibitors. Curr Treat Options Infect Dis. 2020;11 (4 ):372–87. doi:10.1007/S40506-019-00203-7\n8. Cahn P, Pozniak AL, Mingrone H, et al. Dolutegravir versus raltegravir in antiretroviral-experienced, integrase-inhibitor-naïve adults with HIV: week 48 results from the randomized, double blind, non-inferiority SAILING Study. Lancet. 2013;382 (9893 ):700–708. doi:10.1016/S0140-6736(13)61221-0 23830355\n9. Raffi F, Rachlis A, Stellbrink HJ, et al. Once-daily dolutegravir versus raltegravir in antiretroviral-naive adults with HIV-1 infection: 48 week results from the randomised, double-blind, non-inferiority SPRING-2 study. Lancet. 2013;381 (9868 ):735–743. doi:10.1016/S0140-6736(12)61853-4 23306000\n10. Walmsley SL, Antela A, Clumeck N, et al. Dolutegravir plus abacavirlamivudine for the treatment of HIV-1 infection. N Engl J Med. 2013;369 (19 ):1807–1818. doi:10.1056/NEJMoa1215541 24195548\n11. Castagna A, Maggiolo F, Penco G, et al. Dolutegravir in antiretroviralexperienced patients with raltegravir- and/or elvitegravir-resistant HIV-1: 24-week results of the Phase III VIKING-3 study. J Infect Dis. 2014;210 (3 ):354–362. doi:10.1093/infdis/jiu051 24446523\n12. Kamal P, Sharma S. SUN-187 dolutegravir causing diabetes. J Endocr Soc. 2019;3 (suppl1 ):SUN–187. doi:10.1210/js.2019-SUN-187\n13. McLaughlin M, Walsh S, Galvin S. Dolutegravir-induced hyperglycemia in a patient living with HIV. J Antimicrob Chemother. 2018;73 (1 ):253–260. doi:10.1093/jac/dkx365\n14. Ntem-Mensah AD, Millman N, Jakharia N, et al. Acute onset diabetic ketoacidosis/hyperosmolar hyperglycemic state in patients taking integrase strand transferase inhibitors. Available from: http://academic.oup.com/ofid/articles/6/supplement-2/s/183/5604152. Accessed 723, 2021.\n15. Horikawa M, Toyoda M, Saito N, et al. Raltegravir-associated diabetic ketoacidosis in a patient with HIV infection: a case report. Tokai J Exp Clin Med. 2018;43 (1 ):19–23.29637535\n16. Lamonde M, Atwiine M, Owarwo N, et al. Dolutegravir-associated hyperglycemia in patients with HIV. Lancet. 2020;7 (7 ):E461–E462. doi:10.1016/S2352-3018(20)30042-4\n17. Fong PS, Flynn DM, Evans CD, Korthuis PT. Integrase strand transfer inhibitor-associated diabetes: a case report. Int J STD AIDS. 2016;28 (6 ):626–8. doi:10.1177/0956462416675107 27733708\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1179-142X",
"issue": "14()",
"journal": "International medical case reports journal",
"keywords": "INSTIs; dolutegravir; hyperglycemia",
"medline_ta": "Int Med Case Rep J",
"mesh_terms": null,
"nlm_unique_id": "101566269",
"other_id": null,
"pages": "503-507",
"pmc": null,
"pmid": "34349567",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "33061662;29637535;32105626;24446523;24195548;27733708;33380904;30503325;23830355;23306000;29077869",
"title": "Hyperglycemia After Dolutegravir-Based Antiretroviral Therapy.",
"title_normalized": "hyperglycemia after dolutegravir based antiretroviral therapy"
} | [
{
"companynumb": "ET-VIIV HEALTHCARE LIMITED-ET2021GSK168849",
"fulfillexpeditecriteria": "1",
"occurcountry": "ET",
"patient": {
"drug": [
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"activesubstance": {
"activesubstancename": "LAMIVUDINE"
},
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{
"abstract": "Clozapine is considered to be more effective than other antipsychotic drugs for treating treatmentresistant schizophrenia. However, side effects of clozapine include agranulocytosis and, less commonly, cardiovascular disease, which is occasionally fatal. We describe a 56-year-old woman who developed clozapine-related paroxysmal supraventricular tachycardia during clozapine dose titration and had a recurrence despite being treated with verapamil. For treatment-resistant schizophrenia, a slow titration of the clozapine dose is necessary, and potential cardiac side-effects should be monitored.",
"affiliations": "Department of Psychiatry, College of Medicine, Inje University, Sanggye Paik Hospital, Seoul, Korea.;Department of Psychiatry, College of Medicine, Inje University, Sanggye Paik Hospital, Seoul, Korea.",
"authors": "Kim|S J|SJ|;Gim|M S|MS|",
"chemical_list": "D000889:Anti-Arrhythmia Agents; D014150:Antipsychotic Agents; D014700:Verapamil; D003024:Clozapine",
"country": "China",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2078-9947",
"issue": "28(2)",
"journal": "East Asian archives of psychiatry : official journal of the Hong Kong College of Psychiatrists = Dong Ya jing shen ke xue zhi : Xianggang jing shen ke yi xue yuan qi kan",
"keywords": "Clozapine; Schizophrenia; Tachycardia, supraventricular; Verapamil",
"medline_ta": "East Asian Arch Psychiatry",
"mesh_terms": "D000889:Anti-Arrhythmia Agents; D014150:Antipsychotic Agents; D003024:Clozapine; D005260:Female; D006801:Humans; D008875:Middle Aged; D012008:Recurrence; D013614:Tachycardia, Paroxysmal; D013617:Tachycardia, Supraventricular; D014700:Verapamil",
"nlm_unique_id": "101536416",
"other_id": null,
"pages": "68-70",
"pmc": null,
"pmid": "29921744",
"pubdate": "2018-06",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Clozapine-related Paroxysmal Supraventricular Tachycardia: a Case Report.",
"title_normalized": "clozapine related paroxysmal supraventricular tachycardia a case report"
} | [
{
"companynumb": "KR-TASMAN PHARMA, INC.-2018TSM00037",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "TRAZODONE HYDROCHLORIDE"
},
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{
"abstract": "Trichodysplasia spinulosa (TS) is a rare cutaneous condition associated with the TSPyV and characterized by skin-colored, folliculocentric papules with keratin spicule formation. TS is seen almost exclusively in immunosuppressed individuals, often presenting in patients with a history of solid organ transplantation or chemotherapy for a lymphoreticular malignancy. We report a case of widespread TS in a 9-year-old girl with a history of renal transplantation complicated by BK viremia, which is also caused by a polyomavirus, BKPyV. The clinical presentation of TS in this case morphologically resembled the more common, harmless skin condition known as \"lichen nitidus,\" and was more extensive than expected for TS, creating a diagnostic challenge. This case illustrates an important presentation of severe TS of which transplant teams, oncologists, primary care providers, and dermatologists should be aware.",
"affiliations": "University of New England College of Osteopathic Medicine, Biddeford, Maine.;Department of Dermatology, Oregon Health & Science University, Portland, Oregon.;Department of Dermatology, Oregon Health & Science University, Portland, Oregon.;Department of Pediatrics, Division of Kidney Services and Hypertension, Oregon Health & Science University, Portland, Oregon.;Department of Pediatrics, Division of Kidney Services and Hypertension, Oregon Health & Science University, Portland, Oregon.;Department of Dermatology, Oregon Health & Science University, Portland, Oregon.;Departments of Dermatology and Pediatrics, Oregon Health & Science University, Portland, Oregon.",
"authors": "Barone|Hope|H|0000-0002-6316-1747;Brockman|Ross|R|;Johnson|Luke|L|;Al-Uzri|Amira|A|0000-0001-6532-7117;Wright|Mary|M|;Mengden-Koon|Stephanie|S|;Funk|Tracy|T|",
"chemical_list": "D007166:Immunosuppressive Agents; D007633:Keratins",
"country": "Denmark",
"delete": false,
"doi": "10.1111/petr.13394",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1397-3142",
"issue": "23(4)",
"journal": "Pediatric transplantation",
"keywords": "antibody-mediated rejection; donor-specific antibodies; intravenous gamma globulin; polymerase chain reaction; trichodysplasia spinulosa; trichodysplasia spinulosa-associated polyomavirus",
"medline_ta": "Pediatr Transplant",
"mesh_terms": "D001739:BK Virus; D002648:Child; D000013:Congenital Abnormalities; D003937:Diagnosis, Differential; D005260:Female; D006801:Humans; D016867:Immunocompromised Host; D007166:Immunosuppressive Agents; D007633:Keratins; D007668:Kidney; D007674:Kidney Diseases; D016030:Kidney Transplantation; D017513:Lichen Nitidus; D011120:Polyomavirus; D027601:Polyomavirus Infections; D011183:Postoperative Complications; D012867:Skin; D012871:Skin Diseases; D014412:Tumor Virus Infections",
"nlm_unique_id": "9802574",
"other_id": null,
"pages": "e13394",
"pmc": null,
"pmid": "30916861",
"pubdate": "2019-06",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Trichodysplasia spinulosa mimicking lichen nitidus in a renal transplant patient.",
"title_normalized": "trichodysplasia spinulosa mimicking lichen nitidus in a renal transplant patient"
} | [
{
"companynumb": "US-TEVA-2020-US-1242149",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "PREDNISONE"
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{
"abstract": "Prolonged QTc intervals and life-threatening arrhythmias (LTA) are potential drug-induced complications previously reported with antimalarials, antivirals, and antibiotics. Our objective was to evaluate the prevalence and predictors of QTc interval prolongation and incidences of LTA during hospitalization for coronavirus disease 2019 (COVID-19) among patients with normal admission QTc.\n\n\n\nWe enrolled 110 consecutive patients in a multicenter international registry. A 12-lead electrocardiograph was performed at admission, after 7, and at 14 days; QTc values were analyzed.\n\n\n\nAfter 7 days, 15 (14%) patients developed a prolonged QTc (pQTc; mean QTc increase 66 ± 20 msec; +16%; P < .001); these patients were older and had higher basal heart rates, higher rates of paroxysmal atrial fibrillation, and lower platelet counts. The QTc increase was inversely proportional to the baseline QTc level and leukocyte count and directly proportional to the basal heart rate (P < .01).We conducted a multivariate stepwise analysis including age, male gender, paroxysmal atrial fibrillation, basal QTc values, basal heart rate, and dual antiviral therapy; age (odds ratio [OR], 1.06; 95% confidence interval [CI], 1.00-1.13; P < .05), basal heart rate (OR, 1.07; 95% CI, 1.02-1.13; P < .01), and dual antiviral therapy (OR, 12.46; 95% CI, 2.09-74.20; P < .1) were independent predictors of QT prolongation.The incidence rate of LTA during hospitalization was 3.6%. There was 1 patient who experienced cardiac arrest and 3 with nonsustained ventricular tachycardia. LTAs were recorded after a median of 9 days from hospitalization and were associated with 50% of the mortality rate.\n\n\n\nAfter 7 days of hospitalization, 14% of patients with COVID-19 developed pQTc; age, basal heart rate, and dual antiviral therapy were found to be independent predictors of pQTc. Life-threatening arrhythmias have an incidence rate of 3.6%, and were associated with a poor outcome.",
"affiliations": "Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy.;Emergency Cardiology Unit, University Hospital of Bari, Bari, Italy.;Section of Anesthesia and Intensive Care, Department of Emergency and Organ Transplantation, \"Aldo Moro\" University of Bari, Bari, Italy.;Department of Cardiology, San Carlo Hospital, Potenza, Italy.;Unit of Infectious Diseases, Hospital-University Polyclinic of Bari, Bari, Italy.;Department of Infectious Disease, San Carlo Hospital, Potenza, Italy.;Department of Cardiology, Vittorio Emanuele II Hospital, Bisceglie, Italy.;Department of Infectious Disease, Vittorio Emanuele II Hospital, Bisceglie, Italy.;Emergency Cardiology Unit, University Hospital of Bari, Bari, Italy.;Section of Anesthesia and Intensive Care, Department of Emergency and Organ Transplantation, \"Aldo Moro\" University of Bari, Bari, Italy.;University Mannheim, Mannheim, Germany.;University Mannheim, Mannheim, Germany.;Department of Infectious and Tropical Disease, San Giuseppe Moscati Hospital, Taranto, Italy.;Department of Cardiology, Santa Maria Degli Angeli Hospital, Putignano, Italy.;University Mannheim, Mannheim, Germany.;Unit of Infectious Diseases, Hospital-University Polyclinic of Bari, Bari, Italy.;Department of Cardiology, San Carlo Hospital, Potenza, Italy.;Department of Cardiology, Bonomo Hospital, Andria, Italy.;Unit of Infectious Diseases, Hospital-University Polyclinic of Bari, Bari, Italy.;Unit of Infectious Diseases, Hospital-University Polyclinic of Bari, Bari, Italy.;Department of Infectious Disease, Vittorio Emanuele II Hospital, Bisceglie, Italy.;Section of Anesthesia and Intensive Care, Department of Emergency and Organ Transplantation, \"Aldo Moro\" University of Bari, Bari, Italy.;Department of Medicine, Cardiology Division, Montefiore Medical Center, Bronx, New York, USA.;Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy.",
"authors": "Santoro|Francesco|F|0000-0001-9909-6513;Monitillo|Francesco|F|;Raimondo|Pasquale|P|;Lopizzo|Agostino|A|;Brindicci|Gaetano|G|;Gilio|Michele|M|;Musaico|Francesco|F|;Mazzola|Michele|M|;Vestito|Domenico|D|;Benedetto|Rossella Di|RD|;Abumayyaleh|Mohammad|M|;El-Battrawy|Ibrahim|I|;Santoro|Carmen Rita|CR|;Di Martino|Luigi Flavio Massimiliano|LFM|;Akin|Ibrahim|I|;De Stefano|Giulio|G|;Fiorilli|Rosario|R|;Cannone|Michele|M|;Saracino|Annalisa|A|;Angarano|Salvatore|S|;Carbonara|Sergio|S|;Grasso|Salvatore|S|;Di Biase|Luigi|L|;Brunetti|Natale Daniele|ND|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1093/cid/ciaa1578",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1058-4838",
"issue": "73(11)",
"journal": "Clinical infectious diseases : an official publication of the Infectious Diseases Society of America",
"keywords": "COVID-19; ECG; QTc prolongation; arrhythmia; risk prediction",
"medline_ta": "Clin Infect Dis",
"mesh_terms": null,
"nlm_unique_id": "9203213",
"other_id": null,
"pages": "e4031-e4038",
"pmc": null,
"pmid": "33098645",
"pubdate": "2021-12-06",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "QTc Interval Prolongation and Life-Threatening Arrhythmias During Hospitalization in Patients With Coronavirus Disease 2019 (COVID-19): Results From a Multicenter Prospective Registry.",
"title_normalized": "qtc interval prolongation and life threatening arrhythmias during hospitalization in patients with coronavirus disease 2019 covid 19 results from a multicenter prospective registry"
} | [
{
"companynumb": "IT-NOVARTISPH-NVSC2022IT051055",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "AZITHROMYCIN"
},
"drugadditional": "4",
... |
{
"abstract": "Primary hepatic functional paraganglioma is a rare form of extra-adrenal catecholamine-secreting tumor. Definitive treatment of functioning paraganglioma is challenging because of the critical location of the tumor frequently in close proximity to vital structures and risk of excessive catecholamine release during operative manipulation. We report the multidisciplinary management approach for a case of unresectable primary hepatic functional paraganglioma with invasion into the hepatic veins and suprahepatic vena cava. To our knowledge, this is the first report showing that orthotopic liver transplantation is curative for patients with unresectable primary hepatic paraganglioma. For locally advanced unresectable hepatic paraganglioma that involves the intrapericardial vena cava, a meticulous pre- and intraoperative medical management and transabdominal intrapericardial vascular control of the suprahepatic vena cava during orthotopic liver transplantation allows for complete extirpation of the tumor and achieves optimal outcome.",
"affiliations": "Division of Transplant Surgery, Medical College of Wisconsin and Children's Hospital of Wisconsin, Milwaukee, Wisconsin.;Department of Anesthesiology, Medical College of Wisconsin and Children's Hospital of Wisconsin, Milwaukee, Wisconsin.;Department of Anesthesiology, Medical College of Wisconsin and Children's Hospital of Wisconsin, Milwaukee, Wisconsin.;Division of Transplant Surgery, Medical College of Wisconsin and Children's Hospital of Wisconsin, Milwaukee, Wisconsin.;Division of Gastroenterology and Hepatology, Medical College of Wisconsin and Children's Hospital of Wisconsin, Milwaukee, Wisconsin.;Division of Hematology, Oncology, Bone Marrow Transplant, Medical College of Wisconsin and Children's Hospital of Wisconsin, Milwaukee, Wisconsin.;Division of Gastroenterology and Hepatology, Medical College of Wisconsin and Children's Hospital of Wisconsin, Milwaukee, Wisconsin.;Division of Gastroenterology and Hepatology, Medical College of Wisconsin and Children's Hospital of Wisconsin, Milwaukee, Wisconsin.;Department of Anesthesiology, Medical College of Wisconsin and Children's Hospital of Wisconsin, Milwaukee, Wisconsin.;Department of Anesthesiology, Medical College of Wisconsin and Children's Hospital of Wisconsin, Milwaukee, Wisconsin.;Division of Pediatric Radiology, Medical College of Wisconsin and Children's Hospital of Wisconsin, Milwaukee, Wisconsin.;Division of Transplant Surgery, Medical College of Wisconsin and Children's Hospital of Wisconsin, Milwaukee, Wisconsin.;Division of Transplant Surgery, Medical College of Wisconsin and Children's Hospital of Wisconsin, Milwaukee, Wisconsin. Electronic address: jhong@mcw.edu.",
"authors": "Kim|J|J|;Fons|R A|RA|;Scott|J P|JP|;Eriksen|C M|CM|;Lerret|S M|SM|;Browning|M B|MB|;Telega|G W|GW|;Vitola|B E|BE|;Hoffman|G M|GM|;North|P E|PE|;Vo|N N|NN|;Zimmerman|M A|MA|;Hong|J C|JC|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.transproceed.2018.02.189",
"fulltext": null,
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"issn_linking": "0041-1345",
"issue": "50(9)",
"journal": "Transplantation proceedings",
"keywords": null,
"medline_ta": "Transplant Proc",
"mesh_terms": "D034861:Abdominal Wall; D000293:Adolescent; D006503:Hepatic Veins; D006801:Humans; D008113:Liver Neoplasms; D016031:Liver Transplantation; D008297:Male; D009361:Neoplasm Invasiveness; D010235:Paraganglioma; D010496:Pericardium; D014684:Venae Cavae",
"nlm_unique_id": "0243532",
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"pages": "2630-2635",
"pmc": null,
"pmid": "30401364",
"pubdate": "2018-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
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"title": "Transabdominal Intrapericardial Approach in Liver Transplantation for Unresectable Primary Hepatic Functioning Paraganglioma With Invasion Into Hepatic Veins and Suprahepatic Vena Cava: A Surgical and Anesthesia Management Challenge.",
"title_normalized": "transabdominal intrapericardial approach in liver transplantation for unresectable primary hepatic functioning paraganglioma with invasion into hepatic veins and suprahepatic vena cava a surgical and anesthesia management challenge"
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"abstract": "As an emerging therapy with a promising efficacy, immunotherapy has been widely used in the treatment of solid tumors and hematologic malignancies. This clinical study compares the efficacy of tislelizumab, a domestic immune checkpoint inhibitor (ICI), to that of sorafenib when used as a first-line therapeutic option in hepatocellular carcinoma (HCC), and the concurrence of HCC and non-Hodgkin's lymphoma (NHL) is rare, especially in the treatment of ICIs.\n\n\n\nA 61-year-old patient presenting with primary HCC and indolent B-cell lymphoma had a partial clinical response to tislelizumab for his primary HCC. Besides, we described a phenomenon of pseudo-progression and delayed diagnosis of his lymphoma during a long course of treatment.\n\n\n\nTislelizumab, an immunotherapeutic option with a favorable efficacy and toxicity, can be used to manage double primary tumors. However, studies should aim to elucidate the probable mechanisms of this therapy. Pseudo-progression and separation remission make the treatment of double primary tumors even more challenging, which calls for additional caution in patients undergoing immunotherapy to avoid misdiagnosis and, therefore, begin early appropriate interventions.",
"affiliations": "Department of Medical Oncology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.;Department of Medical Oncology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.;Department of Medical Oncology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.;Department of Medical Oncology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.;Department of Medical Oncology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.",
"authors": "Li|Qijun|Q|;Dong|Yong|Y|;Pan|Yubin|Y|;Tang|Honglin|H|;Li|Da|D|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D000082082:Immune Checkpoint Inhibitors; C000707970:tislelizumab",
"country": "Switzerland",
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"doi": "10.3389/fimmu.2021.634559",
"fulltext": "\n==== Front\nFront Immunol\nFront Immunol\nFront. Immunol.\nFrontiers in Immunology\n1664-3224\nFrontiers Media S.A.\n\n10.3389/fimmu.2021.634559\nImmunology\nCase Report\nCase Report: Clinical Responses to Tislelizumab as a First-Line Therapy for Primary Hepatocellular Carcinoma With B-Cell Indolent Lymphoma\nLi Qijun †\n\nDong Yong †\n\nPan Yubin\n\nTang Honglin\nLi Da *\n\nDepartment of Medical Oncology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China\nEdited by: Jonathan Pol, Institut National de la Santé et de la Recherche Médicale (INSERM), France\n\nReviewed by: Alessandro Granito, University of Bologna, Italy; Yan Wang, Eastern Hepatobiliary Surgery Hospital, China\n\n*Correspondence: Da Li, lidaonconew@zju.edu.cn\n†These authors have contributed equally to this work and share first authorship\n\nThis article was submitted to Cancer Immunity and Immunotherapy, a section of the journal Frontiers in Immunology\n\n31 3 2021\n2021\n12 63455928 11 2020\n03 3 2021\nCopyright © 2021 Li, Dong, Pan, Tang and Li\n2021\nLi, Dong, Pan, Tang and Li\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\n\nAs an emerging therapy with a promising efficacy, immunotherapy has been widely used in the treatment of solid tumors and hematologic malignancies. This clinical study compares the efficacy of tislelizumab, a domestic immune checkpoint inhibitor (ICI), to that of sorafenib when used as a first-line therapeutic option in hepatocellular carcinoma (HCC), and the concurrence of HCC and non-Hodgkin’s lymphoma (NHL) is rare, especially in the treatment of ICIs.\n\nCase presentation\n\nA 61-year-old patient presenting with primary HCC and indolent B-cell lymphoma had a partial clinical response to tislelizumab for his primary HCC. Besides, we described a phenomenon of pseudo-progression and delayed diagnosis of his lymphoma during a long course of treatment.\n\nConclusion\n\nTislelizumab, an immunotherapeutic option with a favorable efficacy and toxicity, can be used to manage double primary tumors. However, studies should aim to elucidate the probable mechanisms of this therapy. Pseudo-progression and separation remission make the treatment of double primary tumors even more challenging, which calls for additional caution in patients undergoing immunotherapy to avoid misdiagnosis and, therefore, begin early appropriate interventions.\n\nimmune checkpoint inhibitors\ndouble primary tumors\nhepatocellular carcinoma\nB-cell indolent lymphoma\ntislelizumab\nmisdiagnosis\ncase report\nNSFC-Zhejiang Joint Fund for the Integration of Industrialization and Informatization10.13039/10001705481573003 Natural Science Foundation of Zhejiang Province10.13039/501100004731NO. LSY19H160005 Chinese Society of Clinical Oncology10.13039/501100009812Y-XD2019-243, Y-Roche2019/2-0042\n==== Body\nIntroduction\n\nGlobally, liver cancer is the sixth most prevalent malignant tumor, however, it is the second most common cause of tumor associated mortalities (1, 2). Due to its aggressive behavior and limited therapeutic options, hepatocellular carcinoma (HCC), a type of primary liver cancer, has a poor prognosis. Conversely, the nature of indolent non-Hodgkin’s lymphoma (NHL) is relatively mild, despite there being no effectively radical treatment during its long chronic process. Therapeutic resistance, multiple relapses, and biological characteristic transformations lead to poor clinical outcomes (3). Occurrence of double tumors, comprising HCC and NHL, is fairly rare, and treatment is based on individual experience rather than standard protocols. Immunotherapy has rapidly developed and become an efficient therapy for non-small cell lung cancer, malignant melanoma, and other diseases (4, 5). It is a promising option for treating drug-resistant HCC (6). Tislelizumab, a newly humanized IgG4 antibody against programmed cell death-1(PD-1), has been approved for the treatment of Hodgkin’s lymphoma (HL), and a large number of clinical studies, such as the Phase III clinical trial of sorafenib as a first-line treatment for HCC (NCT03412773), have been performed. We report a case of indolent B-cell lymphoma-complicated HCC, which was effectively controlled by tislelizumab as the first line treatment. Authors also reviewed current literature and discussed the possible interaction between HCC and B-cell lymphoma during the long course of treatment.\n\nCase Presentation\n\nIn April 2013, a 61-year-old man was found to have a liver mass by abdominal ultrasonography during regular physical examination. The patient did not exhibit gastrointestinal reactions or abdominal pain symptoms, and he was therefore referred to the Dongyang People’s Hospital for further examination. There was no significant personal or family history that could have aided the diagnosis. During hospitalization, he was diagnosed with chronic hepatitis B (no hepatitis C) with liver cirrhosis, and the level of HBV-DNA was 3.33x10^5 IU/ml. The levels of serum tumor markers such as AFP and CEA were found to be 48.32 ng/ml and 5.71 U/ml, respectively. Abdominal computed tomography (CT) revealed a left lateral segment lesion of the liver with multiple enlarged lymph nodes around the lesser peritoneal sac, porta hepatis, retroperitoneum, and right paracardiac regions, which was radiologically suspected for small HCC and lymphadenopathy of infectious etiology. He was subjected to the left lateral lobe hepatectomy and celiac lymphadenectomy for the clinical diagnosis of HCC. Intraoperative findings revealed that the diameter of the lump was 0.9 x 0.8 cm. Pathology indicated hepatocellular carcinoma ( Figure S1 ), while the two lymph nodes were negative. Therefore, his final diagnosis was HCC (pT1N0M0 stage I, BCLC 0). The patient was administered with entecavir (0.5 mg) once a day for antiviral treatment. Regular follow-up showed no tumor recurrence or active hepatitis for more than three years ( Table S1 ).\n\nUnfortunately, in July 2016, a new lesion in the right lobe segment was discovered by abdominal CT, without abnormal levels of serum liver function and tumor markers. However, the patient declined treatment with western medicines. In December 2016, the CT scan showed enlarged multiple liver nodules with vascular involvement, and he was hospitalized with HCC (cT3bN0M0 stage IIIB, BCLC B) in our hospital. Transarterial chemoembolization (TACE) was successively performed twice to downstage the tumor. After neoadjuvant therapy, he was histologically reassessed as HCC (ypT3N0M0 stage IIIB, BCLC B). Then, laparoscopic R0 resection of the right posterior liver lobe as well as the gall bladder was performed in April 2017 to eliminate residue lesions. Intraoperative findings revealed that lesion diameters were 9x8.5x10 cm with negative surgical margins. After partial liver resection, the patient’s HBV-DNA copies increased to 2.35x10^4 IU/ml, with mildly abnormal AST, ALT, and bilirubin levels. He was continuously administered with antiviral therapies and other medicines to protect liver functions. After successful management of the disease, he was discharged and regular follow-ups were performed thereafter. In December 2018, the patient was found to have hepatopulmonary metastases. CT scans showed multiple small nodules, the largest of which (in the lung) was about 8.6x6 mm, most possibly a result of HCC metastases, and about 18 mm in the liver. The patient was clinically diagnosed with HCC (cT3N0M1 stage IV, BCLC C). Notably, these enlarged lymph nodes in the peritoneum remained the same as before. Systemic therapies are available to treat patients with unresectable HCC. Multitargeted tyrosine kinase inhibitors (TKIs), such as sorafenib or lenvatinib, are first-line systemic therapies. The patient had not had a previous prescription of systemic treatments, and therefore, he met the inclusion criteria for BGB-A317-301(NCT03412773), a global study designed to compare the clinical efficacy as well as safety of tislelizumab and sorafenib (1:1 randomized) as a first-line systemic treatment for unresectable HCC, which was considered beneficially to the patient (clinical trial protocols are provided in the supplementary materials). After signing the informed consent, the patient was serially screened for confounding factors (exclusion criteria). On January 18th 2019, he was administered with tislelizumab 200 mg igtt q3w. To accurately evaluate immunotherapeutic efficacy, we used iRECIST to determine disease progression (7). Reductions in pseudo-progressions (PsPDs) during immunotherapy were recorded. During two cycles of tislelizumab, the patient developed multiple rashes with pruritus (grade 2, CTCAE 5.0), and on February 1st 2019, he was treated with loratadine, ebastin, and mometasone ointment. Since the rashes got worse (grade 3, CTCAE 5.0), the third cycle of therapy was suspended. From February 25th 2019, the patient was orally administered with 35 mg prednisolone tablet once a day, and the rash was gradually alleviated. Dosage of prednisolone was reduced stepwise by the order of 25 mg, 15 mg, and 10 mg, with the last dose on March 21st, 2019. Before the third immunotherapeutic cycle, CT scans indicated that pulmonary lesions almost disappeared while the liver lesions remained stable ( Figure 1B ). Moreover, before the seventh cycle, the liver lesions were significantly enlarged, without a corresponding enlargement of lymph nodes, evaluated as iuPD (immunity unconfirmed progressive disease). In the ninth cycle, lesions were similar to the seventh cycle and evaluated as icPD (immunity confirmed progressive disease). During the treatment, AFP reached the highest level (696.18 ng/ml) before the eighth treatment ( Figure 1A ). Given that the patient did not meet the exclusion criteria, it was considered that he could still benefit from tislelizumab, and therefore, his participation in the clinical trial was continued after deep consideration. CT scan before the tenth cycle showed that the lesion size was smaller than the last assessment, and simultaneously, AFP decreased to normal (21.14 ng/mL). Therefore, the researchers considered that the patient exhibited “false progression” in the previous treatment. Liver lesions remained stable until the thirteenth cycle. Before the sixteenth cycle, there was slow disease progression, while before the 22nd cycle (2020–4–2), liver lesions exhibited significant progression. Therefore, it was considered that tislelizumab was no longer beneficial to the patient, and he was withdrawn from the clinical trial. Disease progression is shown in Figure 2 , and except for the maculo-papule, all adverse events are described in Table 1 .\n\nFigure 1 Response evaluation during the clinical course including changes in imaging and quantitative data. iuPD (immunity unconfirmed progressive disease); icPD (immunity confirmed progressive disease). (A) Trends in the levels of tumor monitoring indicators, including AFP (left Y-axis) and tumor diameters (right Y-axis) corresponding to the treatment timeline. X-axis showing the date of the disease course. The frequency of imaging evaluations is less than that of AFP. (B) Representative images of the CT scan revealed the increasing and decreasing process of both primary and metastatic lesions in the liver and lung after PD-1 antibody (tislelizumab) and sorafenib treatment. Red arrows indicate tumor lesions.\n\nFigure 2 The whole clinical timeline of the patient, with major treatment and disease status. DFS, disease-free survival; PFS, progression-free survival.\n\nTable 1 Adverse events in the tislelizumab therapeutic course in the patient (graded by CTCAE 5.0).\n\nAdverse events\tBaseline\tMaximum grade\tDuration\tirAE\tTreatment\t\nPruritus\t0\tII\tC2-C3\tYes\tGlucocorticoid\t\nRash maculopapule\t0\tIII\tC2-C3\tYes\tGlucocorticoid\t\nLeukocytosis \t0\tIII\tC2-C5, C18-C21\tNo, may be unrelated\tNo\t\nLymphocyte count increased\tI\tIII\tC2-C5, C18-C21\tNo, may be related\tNo\t\nAlanine transaminase (ALT) levels increased\tI\tI\tC8\tMay be related\tMedicine\t\nAspartate aminotransferase (AST) levels increased\t0\tI\tC8\tMay be related\tMedicine\t\nBlood bilirubin levels increased\t0\tI\tC14-C15\tMay be related\tMedicine\t\nThe first screening indicators after the clinical trial as the baseline; CTCAE, Common Terminology Criteria for Adverse Events; C, cycle; irAE, immune-related adverse events.\n\nOutcomes and Follow-up\n\nAfter being discontinued from the clinical trial, the patient was treated with sorafenib. One month later, the liver tumor was found to be smaller and AFP decreased significantly. Meanwhile, the care team noticed that during treatment with tislelizumab, his lymph nodes did not exhibit any change, regardless the lesions were either enlarged or shrank, HBV was either well or poorly controlled. For further evaluation, we performed a lymph node biopsy. Histological examinations of axillary and inguinal lymph nodes revealed indolent B-cell lymphoma ( Figure 3 ). Retrospectively analyzed, his peritoneal sac, paracardiac regions, and superficial lymph nodes remained the same in size and unparallel to tumor progression, which supported that the patient had lymphoma seven years ago. It is unfortunate that a lymph node biopsy was not performed at that time, therefore, there is no definite pathological evidence to support our hypothesis. Currently, clinical follow-ups are still being performed and to date, the patient continues receiving sorafenib treatment and survives his double tumors. Under the treatment of ICIs, despite signs of “false progression”, his disease course showed his liver lesions were responsive to tislelizumab overall, but not his lymphoma. Recently, the patient was discovered to have an elevated lymphocyte count but without clinical symptoms, which may be correlated with the indolent lymphoma. Hematological assessments are shown in the Supplementary material ( Figure S2 ).\n\nFigure 3 Histopathology and immunohistochemistry (IHC) of the lymph node of this patient. Microscopic observation (10×) of H&E staining showed a dense diffuse lymphoid cells infiltration (A). Immunohistochemical staining of CD20 and Bcl-2 expression (20×) showed that tumor cells were positive for CD20 and Bcl-2, respectively (B, D). The Ki-67 proliferative index (20×) was low (C).\n\nDiscussion\n\nWarren’s definition of multiple primary tumors refers to the simultaneous or successive occurrence of two or more unrelated primary malignant tumors (8, 9). Patients with malignant tumors are more likely to develop a second malignant tumor, which may be due to the persistent effects of risk factors, radiotherapy, and chemotherapy (10). Currently, incidences of synchronous multiple primary cancer are increasing. Carson H. J. documented the reported cases of synchronous NHL with other cancers. The most common are colon cancer, prostate cancer, and lung cancer respectively, while the HCC, is penultimate (11). In case reports of HCC with lymphoma ( Table 2 ), the most common is HCC with invasive diffuse large B-cell lymphoma (DLBCL), while follicular lymphoma (FL) represents the majority of indolent NHL, which is consistent with the incidence of NHL (33). The overall survival (OS) of indolent NHL is high, with 70% of patients having more than 10 years of survival. However, in multiple malignant tumors, interactions between tumors may affect the OS. Retrospective studies have shown that the prognosis of gastric cancer patients complicated with lymphoma may depend more on gastric cancer (34), but Lee SI et al. documented that in patients with both HCC and hepatitis, delayed diagnosis of NHL, especially DLBCL, is associated with a poor prognosis (29). Therefore, it is crucial to identify multiple primary tumors early and precisely.\n\nTable 2 Clinical information of hepatocellular carcinoma with lymphoma patients.\n\nCase\tAge (year)\tGender\tHBV/HCV\tLymphoma\tHepatocellular adenocarcinoma\tOS (months)\t\nDiagnosis\tTreatment\tStaging\tTreatment\t\nTalamo T (12)\t67\tmale\tHBV\tmalignant lymphoma\tpalliative\tIV stage\tpalliative\t<1\t\nCavanna L (13)\t50\tmale\tNeither\tNHL\tchemotherapy\tpT1NxM0\toperation\t30\t\nOno T (14)\t59\tfemale\tHCV\tDLBCL\tNone\tT1NxM0\tTACE\t18\t\nShikuwa S (15)\t64\tmale\tHBV\tB cell\tNone\tTxNxM1\tchemotherapy and radiotherapy\t11\t\nMonarca R (16)\t66\tmale\tHBV\tchronic and indolent B-cell\tNot mentioned\tT1N0M0\tNot mentioned\tNot mentioned\t\nSuriawinata A (17)\t55\tmale\tHCV\tDLBCL\tNone\tT2NxM0\tliver transplantation\t>15\t\nShapira M (18)\t70\tmale\tHCV\tDLBCL\t/\tT2NxM0\t/\t/\t\nTakeshima F (19)\t65\tfemale\tHBV\tMALT\thepatic segmentectomy\tpT1N0M0\thepatic segmentectomy\t>10\t\nKataoka T (20)\t64\tmale\tNeither\tDLBCL\tconservative therapy\tT1NxM0\tconservative therapy\t1.5\t\nOthsubo K (21)\t66\tmale\tHCV\tDLBCL\tR-CHOP\tT2NxM0\tRFA\tNot mentioned\t\nHimoto T (22)\t63\tmale\tHCV\tDLBCL\tCHOP\tT1N0M0\tPEIT and RFA\tNot mentioned\t\nNonami A (23)\t73\tmale\tHBV\tDLBCL\tR-CHOP\tT2N0M0\thepatectomy\t>22\t\nLin A (24)\t70\tmale\tHCV\tDLBCL\tR-CHOP\tNot mentioned\tNot mentioned\t>5\t\nLin A (24)\t65\tfemale\tHCV\tMZL\tR-CHOP and radiotherapy\tT2NxMx\tNone\t14\t\nUtsunomiya T (25)\t70\tfemale\tHCV\tDLBCL\tNot mentioned\tpT2N0M0\tpartial hepatectomy\t4\t\nBecker D (26)\t68\tmale\tHCV\tSLL/CLL\tuntreated\tpT1N0M0\tRFA\tNot mentioned\t\nHeidecke S (27)\t70\tmale\tNeither\tCLL\tuntreated\tpT2NxMx\toperation\t>17\t\nTajiri H (28) \t75\tmale\tHCV\tDLBCL\tR-THP-COP\tpT1N0M0\thepatectomy and chemotherapy\t>12\t\nLee S (29)\t60\tmale\tHCV\tFL\tR-CVP\tT2NxM0\tTACE and RFA\t>20\t\nChan R (30)\t59\tmale\tHBV\tMALT\tRight hepatectomy\tpT1N0M0\tRight hepatectomy\t>48\t\nLee M (31)\t52\tmale\tHBV\tMCL\tCHOP\tT3N0M0\tRFA\t>12\t\nMeng J (32)\t58\tmale\tHBV\tDLBCL\tCHOP\tI stage\toperation\t>62\t\nHBV, chronic hepatitis B; HCV, chronic hepatitis B; NHL, non-Hodgkin’s lymphoma; DLBCL, diffuse large B-cell lymphoma; MALT, mantle cell lymphoma; SLL, small lymphocyte lymphoma; CLL, chronic lymphocytic leukemia; FL, follicular lymphoma; MZL, marginal zone lymphoma; MCL, mantle cell lymphoma; R-CHOP, a combination of rituximab, cyclophosphamide, adriamycin, vincristine and prednisone; R-THP-COP, a combination of rituximab, pirarubicin, cyclophosphamide, vincristine, and prednisolone; R-CVP, a combination of rituximab, cyclophosphamide, vincristine and prednisone; TACE, transarterial chemoembolization; RFA, radiofrequency ablation; PEIT, percutaneous ethanol injection therapy.\n\nIn our case, the patient with HCC was not diagnosed with B-cell indolent lymphoma until the lymph node biopsy was implemented at the later stage, so we made a retrospective analysis. Occurrence of both HCC and chronic hepatitis affects the diagnosis of multiple-lymphadenopathy, which is easily misdiagnosed as “reactive hyperplasia” or “lymph node metastasis of HCC”. Misdiagnoses resulted in delayed treatments. Therefore, NHL should be regarded as a differential diagnosis for HCC and chronic hepatitis patients (29). Compared to metachronous neoplasms, synchronous multiple neoplasms are perhaps tougher to identify. Next-generation sequencing (NGS) is effective in the identification of tumor-specific genes, which is important in the diagnosis of multifocal tumors and in informing clinical treatments (35). In our case, swollen lymph nodes were found in the initial treatment of HCC and were not parallel to the changes in HBV-DNA or tumor development. Therefore, if there is “separation remission” during the clinical treatment process, the possibility of double primary tumors should be ruled out. In our case, lymph node biopsy was negative for lymph node metastasis of liver cancer, so in the status of liver tumor progression with lung metastasis disappearance, local treatments of the liver can also be considered in the following treatments.\n\nAs mentioned in the treatment strategies, HCC is often diagnosed in the advanced stage, therefore, systemic treatment plays an essential role in its control. However, as the first-line treatment for advanced HCC, sorafenib does not show a dramatic benefit. The median survival time of sorafenib was only three months longer than placebo (36). Advances in immunotherapy have enhanced tumor treatment (5, 37), and some have shown good therapeutic effects in HCC. A phase III trial involving a combination of atezolizumab and bevacizumab as first-line treatment for unresectable HCC revealed a significant improvement, with a 12-month prolonged OS compared to sorafenib (38). Phase III randomized controlled trials comparing nivolumab (39) and tislelizumab (NCT03412773) with sorafenib as first-line therapeutic options for advanced HCC have been launched in succession. Unlike solid tumors, the decisive prognostic factor for patients with lymphoma is the pathological type rather than clinical stage. Even though the clinical course of indolent lymphoma is always stable or spontaneously relieved before progression (40), it is mostly incurable and has the probability of transforming to invasive lymphoma such as DLBCL (41), especially under the circumstance of immune disorders in patients with active tumor. Therefore, indolent lymphoma might require the same aggressive treatments under those scenarios. R-CHOP (a scheme including rituximab, which is an anti-CD20 monoclonal antibody, mAbs) is the first-line recommended treatment for indolent lymphoma at stages III and IV. In refractory HL, ICIs have shown good clinical outcomes (42). There are no clinical trials of tislelizumab for NHL, however, ICIs such as nivolumab (NCT02038946) have been used in the treatment of NHL, some case reports and small sample research studies of certain NHLs have displayed durable response under the treatment of ICIs (43, 44). At molecular and cytological levels, PD-1 positive expression was detected in DLBCL, FL and marginal zone lymphoma (MZL) (45). The density of PD-1 positive cells in FL is associated with the prognosis and possibility of transformation to DLBCL. However, expression levels of PD-1 vary from different studies (45–47). Most FLs have been shown to have a stronger immune escape (48), which may be due to the rich PD1+ γδ T lymphocytes. PD-1 regulates the immune components of γδ T cytotoxic cells, resulting in the hypofunction of γδ T lymphocytes which reduces antibody-dependent cell-mediated cytotoxicity (ADCC) (49). Therefore, ICIs have the ability to slow down FL development. Anti-CD20 mAbs can enhance intratumoral infiltration of γδ T cells (50), which provides the possibility to improve the efficacy of ICIs against immune desert tumors by rituximab. It is theoretically proven that a combination or bispecific antibodies of anti-CD20 mAbs and ICIs in the treatment of NHL complicated HCC can enhance the therapeutic effect.\n\nMoreover, both NHL and HCC are associated with hepatitis B or C viruses (51, 52), and NHL patients have higher odds for HCC development (53, 54). Activated NF-κB pathways have been simultaneously reported in a mantle cell lymphoma (MCL), renal cell carcinoma and stromal tumor tissue (55), suggesting that there may be a common pathway between lymphoma and solid tumors. Similarly, through different mechanisms such as cell proliferation and oxidative stress, Bccip, miR-29, and PI3K pathways can simultaneously induce NHL and HCC (56–59). Therefore, the correlation between NHL and HCC theoretically implies that multiple primary tumors of NHL and HCC have a higher incidence rate. Moreover, immunotherapy makes it possible to manage related multiple primary tumors at the same time.\n\nEven though we adopted tislelizumab instead of the standard first-line treatment of sorafenib when we treated the disease as primary HCC initially, treatment indications and the patient’s views were fully considered. The clinical trial provided the patient more treatment options, and the patient truly had clinical benefits from tislelizumab. Immunotherapy for HCC is promising and may also benefit indolent NHL patients that are resistant to chemotherapy. In our case, while lymphoma did not respond to tislelizumab, the influence of tislelizumab in NHL progression and histological transformation cannot be negated. The patient had no significant progression in lymph nodes and hematological indicators during treatment of tislelizumab, however, outcomes were different during sorafenib treatment. The natural course of NHL could not be excluded. Hematological tumors are often caused by multiple co-inhibitory signaling pathways (60), which suppress immune activation. Compared to chemotherapy, rituximab has been shown to reduce the risk of histological transformation in indolent lymphoma (2, 61). Treatments for asymptomatic indolent lymphoma are unnecessary, however reducing incidences of histological transformation in double or multiple primary tumors with indolent lymphoma may be a consideration for treatment options.\n\nOne of drawbacks of this case is the failure to identify lymphoma at the early stage, which made accurate parallel analysis along the treatment course impossible. In addition, detection of immune treatment resistance of HCC, such as the accumulation of β-catenin, was not completed in the later stage, and lacked the underlying relevant mechanism.\n\nConclusion\n\nThere are no standard therapeutic options for lymphoma and HCC, as well as for double primary tumors. Individualized treatments should be decided based on the behavior of tumor and patients’ overall conditions. Clinical management of HCC with indolent B-cell lymphoma has rarely been reported in previous studies. Among the described cases, most are early HCC with local therapy, while standard therapy is used to treat lymphoma. To our knowledge, there are no reports of advanced HCC complicated with lymphoma using systemic therapy and achieves a long survival in literature.\n\nFor double primary tumors, latent cancer may be misdiagnosed as the progression of the first primary tumor due to primary drug resistance of ICIs (62). Therefore, it is necessary to determine the pathology of abnormal lymph nodes through biopsy. NHL can infiltrate into other tumors, such as HCC and renal cell carcinoma, so when atypical lymphoid cells are detected in tumor tissues, attention should be paid to mixed pathological features (25) since diagnosis of a double tumor will substantially affect clinical management. Moreover, NHL invasion may lead to the occurrence of precancerous lesions and promote the development of HCC (12, 20). Therefore, early diagnosis of lymphoma and simultaneous treatment of lymphoma and HCC can theoretically prolong survival time. Pathological characteristics for HCC and NHL are different, therefore, when standard systemic therapy for both tumors is applied synchronously, there may be great toxicity and poor tolerability. Treatment of HCC in the remission stage of NHL may improve the cure rate. This study elucidates the correlation between NHL and HCC, and the necessity for treating both diseases at the same time. The synergistic effects of CD20 mAbs and ICIs might provide a potential therapeutic option for double primary tumors with NHL. However, this conclusion should be verified further.\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\nThe studies involving human participants were reviewed and approved by Sir Run Run Shaw Hospital, Zhejiang University School of Medicine. 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\nAll authors have contributed to the preparation of this manuscript. All authors contributed to the article and approved the submitted version.\n\nFunding\n\nThis work was financially supported by the National Natural Science Foundation of China (81573003), the Association Foundation of Zhejiang Natural Science Foundation-Zhejiang Society for Mathematical Medicine (NO. LSY19H160005), CSCO (Chinese society of clinical oncology) research foundation (Y-XD2019-243), and CSCO research foundation (Y-Roche2019/2-0042).\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\nAcknowledgments\n\nWe would like to thank the patient and his family for their assistance with the study.\n\nSupplementary Material\n\nThe Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fimmu.2021.634559/full#supplementary-material\n\nClick here for additional data file.\n==== Refs\nReferences\n\n1 Bray F Ferlay J Soerjomataram I Siegel RL Torre LA Jemal A . Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. 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"journal": "Frontiers in immunology",
"keywords": "B-cell indolent lymphoma; case report; double primary tumors; hepatocellular carcinoma; immune checkpoint inhibitors; misdiagnosis; tislelizumab",
"medline_ta": "Front Immunol",
"mesh_terms": "D061067:Antibodies, Monoclonal, Humanized; D006528:Carcinoma, Hepatocellular; D006801:Humans; D000082082:Immune Checkpoint Inhibitors; D008113:Liver Neoplasms; D016393:Lymphoma, B-Cell; D008297:Male; D008875:Middle Aged; D009378:Neoplasms, Multiple Primary; D016896:Treatment Outcome",
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"title": "Case Report: Clinical Responses to Tislelizumab as a First-Line Therapy for Primary Hepatocellular Carcinoma With B-Cell Indolent Lymphoma.",
"title_normalized": "case report clinical responses to tislelizumab as a first line therapy for primary hepatocellular carcinoma with b cell indolent lymphoma"
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"abstract": "Biological samples are an important part of investigating toxic exposures and disease outcomes. However, blood, urine, saliva, or hair can only reflect relatively recent exposures. Alternatively, deciduous teeth have served as a biomarker of early developmental exposure to heavy metals, but little has been done to assess organic toxic exposures such as pesticides, plastics, or medications. The purpose of our study was to determine if organic chemicals previously detected in a sample of typically developing children could be detected in teeth from a sample of children with autism. Eighty-three deciduous teeth from children with autism spectrum disorders (ASD) were chosen from our tooth repository. Organic compounds were assessed using liquid chromatography tandem mass spectrometry and gas chromatography methods. Consistent with a prior report from Camann et al., (2013), we have demonstrated that specific semivolatile organic chemicals relevant to autism etiology can be detected in deciduous teeth. This report provides evidence that teeth can be useful biomarkers of early life exposure for use in epidemiologic case-control studies seeking to identify differential unbiased exposures during development between those with and without specific disorders such as autism.",
"affiliations": "Department of Family and Community Medicine, University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900, USA.;Department of Family and Community Medicine, University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900, USA.;Department of Analytical and Environmental Chemistry, Southwest Research Institute, 6220 Culebra Road, San Antonio, TX 78238-5166, USA.;Department of Analytical and Environmental Chemistry, Southwest Research Institute, 6220 Culebra Road, San Antonio, TX 78238-5166, USA.;Department of Family and Community Medicine, University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900, USA.;Department of Family and Community Medicine, University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900, USA.;Department of Family and Community Medicine, University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900, USA.;Department of Family and Community Medicine, University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900, USA.;Department of Family and Community Medicine, University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900, USA.",
"authors": "Palmer|Raymond F|RF|;Heilbrun|Lynne|L|;Camann|David|D|;Yau|Alice|A|;Schultz|Stephen|S|;Elisco|Viola|V|;Tapia|Beatriz|B|;Garza|Noe|N|;Miller|Claudia|C|",
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"fulltext": "\n==== Front\nJ Environ Public HealthJ Environ Public HealthJEPHJournal of Environmental and Public Health1687-98051687-9813Hindawi Publishing Corporation 10.1155/2015/862414Research ArticleOrganic Compounds Detected in Deciduous Teeth: A Replication Study from Children with Autism in Two Samples Palmer Raymond F. \n1\n\n*\nhttp://orcid.org/0000-0002-3957-8809Heilbrun Lynne \n1\nCamann David \n2\nhttp://orcid.org/0000-0002-7681-3863Yau Alice \n2\nSchultz Stephen \n1\nElisco Viola \n1\nhttp://orcid.org/0000-0002-6537-4543Tapia Beatriz \n1\nGarza Noe \n1\nMiller Claudia \n1\n1Department of Family and Community Medicine, University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900, USA2Department of Analytical and Environmental Chemistry, Southwest Research Institute, 6220 Culebra Road, San Antonio, TX 78238-5166, USA*Raymond F. Palmer: palmerr@uthscsa.eduAcademic Editor: Chit Ming Wong\n\n2015 29 7 2015 2015 8624144 5 2015 2 7 2015 Copyright © 2015 Raymond F. Palmer 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.Biological samples are an important part of investigating toxic exposures and disease outcomes. However, blood, urine, saliva, or hair can only reflect relatively recent exposures. Alternatively, deciduous teeth have served as a biomarker of early developmental exposure to heavy metals, but little has been done to assess organic toxic exposures such as pesticides, plastics, or medications. The purpose of our study was to determine if organic chemicals previously detected in a sample of typically developing children could be detected in teeth from a sample of children with autism. Eighty-three deciduous teeth from children with autism spectrum disorders (ASD) were chosen from our tooth repository. Organic compounds were assessed using liquid chromatography tandem mass spectrometry and gas chromatography methods. Consistent with a prior report from Camann et al., (2013), we have demonstrated that specific semivolatile organic chemicals relevant to autism etiology can be detected in deciduous teeth. This report provides evidence that teeth can be useful biomarkers of early life exposure for use in epidemiologic case-control studies seeking to identify differential unbiased exposures during development between those with and without specific disorders such as autism.\n==== Body\n1. Introduction\nBiological samples are an important part of epidemiological investigations of toxic exposures and their disease outcomes. Blood, urine, saliva, or hair has often been utilized to assess risk factors for a specific disease by comparing the concentrations of some environmental toxic substances between affected and unaffected individuals. While this is a useful approach in some endeavors, these biosamples are only measures of recent exposure and cannot inform about distant past exposures. Therefore, the use of these types of biomarkers is limited.\n\nAlternatively, the use of deciduous teeth has served as a biomarker of early developmental exposure to heavy metals. The mineralization of primary teeth begins prenatally between 14-and 16-week gestation and concludes postnatally at 1.5 to 3 months for incisors, 9 months for canines, and 5.5 to 11 months for molars [1]. It has been demonstrated that metals in circulation, which are present during the period of tooth formation, become incorporated into forming dental tissue and are stored in the mineral component of teeth [2–4].\n\nDeciduous teeth have been used as biomarkers of heavy metal exposure in disease outcome studies for some time. Needleman et al. [5] demonstrated that lead measured in deciduous teeth was associated with lowered cognitive performance in children. Since that landmark study, the concentrations of lead in deciduous teeth have been widely used as a biomarker for lead exposure and body burden in a variety of other studies [6]. Along with lead, other heavy metals such as cadmium, zinc, and copper have also been measured in deciduous teeth [7].\n\nA major development in the assessment of heavy metals using deciduous teeth has been the use of Laser Ablation Electrospray Ionization (LAESI) methods [8]. These methods have been used to determine the timing of exposure during development by taking measurements along the developmental pathway of the tooth. In particular, identification of the perinatal line allows measurements to be assessed which correspond to pre- and postnatal periods. This has been demonstrated with metals such as chromium, iron, mercury, zinc, and antimony [9] and validated with lead, manganese, and other heavy metals [10–13].\n\nEnvironmental point sources of exposure have been shown to be related to tooth concentrations as a function of age and proximity to the source [14–16]. Further, physiological factors (i.e., gender, tooth type, and weight) as well as behavioral factors (i.e., socioeconomic status, home antiquity, and nail biting habits) have been shown to also explain levels of lead and cadmium in teeth [17, 18].\n\nThese studies demonstrate the advantage of analysis of primary teeth for determining early exposures that may be related to specific disease outcomes. Indeed, the conclusions from a recent NATO workshop on the effects of heavy metal pollution on child development recommend that depositions found in teeth can serve as an important tool in relating heavy metal pollution to childhood development outcomes [19]. For example, Adams et al. [20] used deciduous teeth to investigate differential mercury exposure between children with and without autism. Their study demonstrated that there was a higher concentration of mercury in baby teeth of children with autism compared to children without autism. However, a recent study by Abdullah et al. [21] failed to confirm these findings. Other applications of using deciduous teeth as biomarkers of exposure have been with radiation exposure and its relationship to cancer [22].\n\nThe majority of studies using deciduous teeth have been on investigating heavy metals and much less has been done to assess organic toxic exposures such as pesticides, plastics, or medications. While LAESI methods have been used to precisely determine the period of exposure when assessing metal concentrations, there is concern that heat produced by sectioning the tooth for analysis of semivolatile organic chemicals (SVOC) may vaporize or transform the SVOC on the surface so they will no longer be detectable by LAESI. Notwithstanding, researchers are currently working to overcome the obstacles with LAESI and other imaging methods for use with SVOC. \n\n\nDetection of Organic Chemicals in Teeth. Gas chromatography/mass spectrometry (GCMS) has been used to determine nicotine in deciduous teeth as a result of household exposure to cigarette smoking [23]. Recently, Camann et al. [24] identified additional semivolatile organic chemicals (SVOC) in deciduous teeth and hypothesized that organic chemicals or their metabolites circulating in the bloodstream during development may absorb into forming dental tissues and remain stored in the tooth thereafter. Chemicals detected by liquid chromatography/tandem mass spectrometry in molars of 21 typically developing children included the endocannabinoid anandamide (86% of children), acetaminophen (43%), and specific metabolites mono-2-ethylhexyl phthalate (MEHP, of plasticizer di-2-ethylhexyl phthalate, 29%), 3,5,6-trichloro-2-pyridinol (TCPy, of organophosphate (OP) insecticide chlorpyrifos, 10%), and 2-isopropyl-6-methyl-4-pyrimidinol (IMPy, of OP insecticide diazinon, 10%). None of these chemicals had previously been detected in teeth.\n\nThe use of deciduous teeth with GCMS methods to understand exposures to organic chemicals has great potential for use in epidemiological case-control studies for conditions of unknown etiology such as autism and other childhood disorders. However, unlike LAESI, which can precisely determine the timing of perinatal exposure, GCMS methods are limited to detection of cumulative exposures or at best approximate timing of exposure based on tooth type. Notwithstanding, GCMS methods currently offer a wider range of detectable SVOC that may be hypothesized to be associated with specific health conditions.\n\nThe purpose of this study was to replicate the findings of Camann et al. [24] using the deciduous teeth from two different samples of children with autism (in the United States and Mexico). Specifically, we investigated the replication of acetaminophen, arachidonic acid (ARA), 3,5,6-trichloro-2-pyridinol (TCPy, specific chlorpyrifos metabolite), 2-isopropyl-6-methyl-4-pyrimidinol (IMPy, specific diazinon metabolite), diethyl-m-toluamide (DEET), and five monoester phthalate metabolites (monoethyl phthalate (MEP), mono-n-butyl phthalate (MnBP), monoisobutyl phthalate (MiBP), monobenzyl phthalate (MBzP), and mono-2-ethylhexyl phthalate (MEHP).\n\nThe aforementioned chemicals are pertinent to autism research because several studies indicate that exposure to pesticides [25–27], acetaminophen [28, 29], plastics (Phthalates) [30, 31], and other chemicals [32] is biologically relevant to autism etiology. However, no studies have used objective measures of early life exposure such as deciduous teeth to identify these compounds.\n\nBefore future epidemiologic investigations ensue, replication studies are needed to determine whether SVOC concentrations can reliably be detected in diverse samples.\n\n\nPost Hoc Analysis. While this study was not designed to assess validity, mothers who donated their children's teeth also completed an exposure survey which included their reported exposures to acetaminophen, DEET, phthalates, and pesticides. We investigated if the mother's self-reported use or their child's exposure to these compounds would correspond to the concentrations found in their children's teeth.\n\n2. Methods\n2.1. Sample and Recruitment\nSeventy-one (71) deciduous teeth, primarily molars and canines (without cavities or fillings), from children with autism spectrum disorders (ASD) were chosen from our tooth repository consisting of 928 children's deciduous teeth. These teeth were obtained through ongoing recruitment efforts as part of our IRB-approved pilot studies on autism through the University of Texas Health Science Center (UTHSCSA). A component of our program involves an established biological tissue biorepository from families of children with and without autism. We have recently added the collection of deciduous teeth through collaborative efforts with the Interactive Autism Network (IAN) [33]. To control potential bias from using a mixed sample, we chose children recruited from the Interactive Autism Network (IAN) whose diagnoses of autism have been verified [33, 34].\n\nAs a cross-cultural comparison in a separate analysis, we also included 12 teeth from autistic children obtained through UTHSCSA collaborations with an autism parent group from Matamoros, Mexico.\n\n2.2. Laboratory Methods\n83 tooth crowns were pulverized, extracted in batches of approximately 20 samples, and analyzed for acetaminophen, ARA, DEET, TCPy, IMPy, and MEHP using modified methods from Camann et al. [24]. A dentist identified each deciduous tooth crown. The pulp and any fillings, attached roots, and/or cavities were removed with a scalpel, engraving tool, and/or heatless wheel. The tooth was gently swirled in dichloromethane (DCM), with the wash retained as a quality measure to evaluate external tooth contamination. Each prepared tooth crown (enamel + dentin) was pulverized with a mortar and pestle to a fine powder and weighed.\n\nPrior to extraction, a 50 mg pulverized tooth aliquot was spiked with acetaminophen-d\n4 and MEHP-13C4 and conditioned for 24 hours. The tooth aliquot was separately extracted under neutral and acidic conditions to enhance the extraction efficiency of the target analytes. The first extraction occurred through sonication with 0.5 mL acetonitrile. After removing the acetonitrile fraction, the tooth powder was acidified with glacial acetic acid and equilibrated overnight, with a second sonication extraction conducted using acetonitrile. Both acetonitrile extracts were concentrated to 50 μL prior to analysis. Electrospray ionization liquid chromatography tandem mass spectrometry (LC/MS/MS) in multiple-reaction monitoring mode was used to determine the concentrations of most targeted chemicals in the pulverized tooth samples. Acetaminophen and DEET were measured in positive mode, and TCPy, IMPy, and the phthalate metabolites in negative mode. A matrix blank with 50 mg of pulverized kiln-fired synthetic hydroxyapatite was extracted with each batch of tooth samples and analyzed to assess laboratory introduced contamination. A matrix spike of all target analytes, into a second 50 mg aliquot of two pulverized teeth, was extracted and analyzed to assess measurement accuracy (i.e., analyte extraction efficiency) in these teeth. The organic wash portion was analyzed as a QC measure to assess external contamination for specific samples containing high levels of detected target analytes.\n\nTo determine the concentration of ARA and other fatty acids (IAN sample only), a second 50 mg aliquot of each pulverized tooth was spiked with triheneicosanoin, decalcified with EDTA, and extracted three times with chloroform. Tridecanoic and tricosanoic acids were added as internal standards, and the extract was blown down to dryness, saponified, and methylated. The fatty acid methyl esters were extracted with saturated sodium chloride and isooctane, and the concentrated isooctane extract was analyzed for ARA by gas chromatography mass spectrometry in selected ion monitoring mode.\n\n2.3. Mothers Reported Use and Exposure to Acetaminophen\nSeven dichotomous items on the survey, indicating use (=1) or no use (=0) of acetaminophen, were summed to create a total exposure score. The items captured assessed (1) mother's use during pregnancy, (2) child's use from 0 to 6 months, (3) child's use from 7 to 12 months, (4) child's use from 13 to 18 months, and (5) around the time before or after Measles Mumps and Rubella (MMMR) vaccination (12–15 months). We also utilized information about the effectiveness of acetaminophen based on the mother's report of whether it works for her or her child (1 = works well versus 0 = works a little or not at all), reasoning that if this analgesic worked, then it would be used. Scores ranged from 0 to 7. A dichotomous variable was then formed using a median split roughly corresponding to a 50% split of the distribution (0 = lower half, n = 28 versus 1 = upper half, n = 43). This self-report exposure variable was submitted to a chi-square analysis, using Fisher's exact test, to determine if the two self-reported exposure groups had statistically different rates of acetaminophen detection in teeth.\n\n2.4. Mother Reported Use and Exposure to Insect Repellent (DEET)\nThis was constructed from five items asking the number of times insect repellant was used on their child at less than 1 years old, 1-2 years old, 2-3 years old, 3-4 years old, and 4-5 years old. Each response was scored 0 for no use during that time, 1 = 1–4 times, 2 = 5–9 times, and 3 = more than 10 times. Since 83 percent said they had used repellants sometime during their child's life, a sum score was used to reflect the frequency of repellant use summed over the five time frame items. This variable was also dichotomized based on a median split.\n\nThese self-reported insect repellant exposure variables were submitted to a chi-square analysis using Fisher's exact test to determine if the highest self-reported exposure group category had statistically different rates of DEET detection in teeth compared to the lowest reported exposure. We also used a Tobit regression (suitable for data that are left truncated due to laboratory detection limits) to assess the linear association between the continuous self-reported score and the continuous DEET tooth concentration, adjusted for parental age and gender.\n\n2.5. Mother Reported Use and Exposure to Pesticides\nThis was constructed from responses to three areas of usage. (1) Did anyone use sprays, dusts, powders, mothballs, or foggers (including a pest control service) in your home or place of work to kill bugs? (2) Did anyone use a lawn service or apply bug or weed killers on your yard, plants, or trees? (3) Did anyone use sprays, dusts, powders, soaps/shampoos, or skin applications for fleas or ticks on your pets? Each of the three questions had response options of 0 = not at all, 1 = once or twice, 2 = three to five times, and 3 = six or more times covering three developmental time periods: before pregnancy, during pregnancy, and from birth to six years old. A dichotomous summary variable based on a median split was formed to reflect high and low self-reported exposure. Chi-square analysis was performed with this dichotomous self-reported use and a dichotomous variable reflecting pesticide metabolites detection in teeth.\n\n2.6. Mothers Reported Use and Exposure to Phthalates\nCumulative self-reported exposure to phthalates was determined using questions asking whether or not the child was exposed to fumes/chemicals from new paint, new floors/cabinets (stains and paint strippers), new carpet, new walls/drywall, or carpet cleaning during three developmental periods: three months before pregnancy, during pregnancy, and during the child's life. Scores were summed to produce a total self-reported exposure score. A dichotomous variable was formed based on a median split and used as a predictor in a Tobit regression model with phthalates as an outcome.\n\n3. Results\n3.1. IAN Sample\n\nTable 1 describes the sample used for this study. The teeth from IAN children with autism are of parents who are largely middle class non-Hispanic white families. The Matamoros samples of children with autism are Hispanic families with comparably lower income and education.\n\n\nTable 2 shows the distribution of chemicals we sought to measure. There was a 44% detection rate for acetaminophen (31/71) and a 75% detection rate for DEET (53/71). The detection rate for both of the organophosphate insecticide metabolites TCPy and IMPy was 13%. Detection rates of the low molecular weight monoester phthalate metabolites were (monoethyl phthalate (MEP) (100%), mono-n-butyl phthalate (MnBP) (86%), and monoisobutyl phthalate (MiBP) (70%). Relatively smaller detection rates were found for monobenzyl phthalate (MBzP) (6%) and mono-2-ethylhexyl phthalate (MEHP) (36%). The detection rates of linoleic acid (LA) and arachidonic acid (ARA) were 100 and 85 percent, respectively. For alpha-linolenic acid (ALA) and docosahexaenoic acid (DHA), detection rates were much lower at 21 and 20 percent, respectively.\n\n3.2. Matamoros Sample\n\nTable 3 shows the distribution of chemicals from Matamoros. There was a 42% detection rate for acetaminophen (5/12) and a 100% detection rate for DEET. The detection rate for TCPy was zero and for IMPy was 17% (2/12).\n\nDetection rates of the low molecular weight monoester phthalate metabolites were (monoethyl phthalate (MEP) (100%), mono-n-butyl phthalate (MnBP) (66%), and monoisobutyl phthalate (MiBP) (100%). Detection rates were found for monobenzyl phthalate (MBzP) (0%) and mono-2-ethylhexyl phthalate (MEHP) (100%).\n\n3.3. Post Hoc Analysis: Mother Reported Use and Exposure to Acetaminophen\nAmong those self-reporting the highest cumulative exposures, 53.5 percent (n = 23/43) had detectable amounts of acetaminophen in teeth compared to 28.6 percent (n = 8/28) in the lower self-reported exposure group (Fisher exact test = p < .041). In a logistic regression model adjusting for age, gender, and tooth type, those reporting higher exposures were 3.18 times more likely to have a detection of acetaminophen than those with lower self-reported exposures (p < .03).\n\n3.4. Mother Reported Use and Exposure to Insect Repellant (DEET)\nThe distribution of DEET in teeth was highly skewed. A square root transformation greatly improved the distribution suitable for parametric tests. We also created a dichotomous variable where 1 = any detection and 0 = no detection of DEET.\n\nChi-square analysis showed that 90.9 percent of those in the higher self-reported use category had detectable amounts of DEET in teeth compared to 63.3 percent detection in the lower self-reported use group. This difference was statistically significant (Fisher exact test, p < .01). DEET tooth concentration was regressed on self-reported insect repellant use (on the children only) in three models: (a) self-reported use before 2 years old, (b) over 2 years old, and (c) across the entire developmental timespan. After adjustment for parental age, child age and gender, and tooth type, exposure under 2 years old yielded a .34 standardized regression coefficient (p < .01) (r-square = .18). Exposures after three years old yielded a .38 standardized regression coefficient (p < .001) (r-square = .21). Exposures during the entire developmental period yielded a .36 standardized regression coefficient (p < .005) (r-square = .20). Tobit regression reveals that the highest self-reported tertile level of exposure had 55.7 ng/g higher levels of DEET than the lowest one third (p = .01).\n\n3.5. Mother Reported Use and Exposure to Pesticides\nThe distribution of the organophosphate insecticide metabolites TCPy and IMPy in 71 teeth is shown in Table 2. The detection rate of both metabolites was 13% in the sample (9/71), with no detection in 62 of the teeth. Both variables were dichotomized to form a binary variable 0 = no detection (n = 62) and 1 = detection (n = 9). We also summed both insecticide metabolites to form another dichotomous variable, where 0 = no detection (n = 55) and 1 = detection (n = 16). There was no significant association between any of the self-reported pesticide usage variables and any of the chlorpyrifos and diazinon metabolite tooth measures.\n\n3.6. Mother Reported Use and Exposure to Phthalates\nThere was no significant association between self-reported fumes/chemicals exposure from listed products and measured phthalate metabolites in teeth for MnBP or MEP. There was, however, a significant association for MiBP. The Tobit regression results indicated that relative to the low self-reported group, the high self-reported group had 94 ng/g higher concentration of MiBP in teeth. When combining all phthalates together, the Tobit regression results indicated that relative to the low self-reported group the high self-reported group had 97 ng/g higher concentration of MiBP in teeth; however this was marginally significant (p < .08).\n\n4. Discussion\nConsistent with the prior report from Camann et al. [24], which used 21 deciduous teeth from typically developed children, we have demonstrated that specific SVOC can be detected in deciduous teeth from children with autism in two different populations. Despite demographic differences in the two samples, there were similar rates of detection for all chemicals with slightly higher detection rates of phthalates in the Matamoros sample.\n\nThis provides evidence that teeth are useful biomarkers of exposure to these SVOC compounds and therefore can be used in properly matched case-control studies to investigate potential differences in exposure between cases (e.g., children with autism) and controls (e.g., children without autism).\n\nThis method of assessing early life environmental exposures is relevant to a wide range of diseases suspected to involve environmental triggers. Prenatal exposures to polycyclic aromatic hydrocarbons, pesticides, secondhand smoke, diester phthalates, and polybrominated diphenyl ethers are linked to reduced fetal growth and developmental problems in young children [35–39]. Similarly, previous studies report a link between in utero organochlorine pesticide exposure and impaired neurodevelopment in childhood [40], and there is emerging evidence of neurobehavioral consequences for infants and children who have been exposed to even low levels pesticides [39, 41, 42]. Taken together, these studies suggest that there are multiple chemicals that may be associated with increased risks for ASD [43].\n\nChlorpyrifos has been shown to disrupt development of the serotonin neurotransmitter system; this is similar to serotonin system dysfunction which has been implicated in autism etiology [44–46]. Chlorpyrifos is widely used in agriculture and remains an exposure of concern for children through diet even though the EPA has restricted its indoor use. There are additional reports addressing established associations between ubiquitous environmental chemicals, including pesticides [47] with effects on neurodevelopment and/or immune system regulation [48]. For example, an elevated risk for ASD has been attributed to the commonly used pesticide permethrin, based on self-reports of exposure [49].\n\nGiven the male predominance in ASD, it is also relevant that phthalates are potential endocrine disruptors which can interfere with normal male development [50]. Diethylhexyl phthalate (DEHP), one of the most common phthalates present indoors, is often used as a plasticizer in polyvinylchloride (PVC) materials, such as PVC flooring and water pipes. Two recent small-scale studies have linked DEHP with autism [30, 51].\n\nPrenatal acetaminophen exposure has been associated with asthma symptoms at age five [52], while acetaminophen use within the first 18 months after birth may be associated with increased susceptibility to autism [53, 54]. Acetaminophen is an indirect agonist of the endocannabinoid system, affecting levels of the endocannabinoids anandamide and 2-arachidonoylglycerol. Anandamide, an endogenous activator of the endocannabinoid system, and 4-aminophenol, the active metabolite of acetaminophen, have similar toxic effects on developing cortical neurons [55].\n\nThe mode of action, metabolic activation, and detoxification of many ubiquitous environmental pesticides are well known and have been linked to the disruption of endocrine activity and to disruption in the function of the primarily inhibitory neurotransmitter, gamma-aminobutyric acid (GABA) [56, 57]. Various studies demonstrate abnormalities of the glutamate and GABA systems in the brain and serum of subjects with autism [58, 59]. For example, there is a significant decrease in GABA and various GABA subunit receptor-binding sites in brain tissues of subjects with autism when compared with controls [60]. Similarly, perinatal exposure to these environmental pesticide compounds appears to be associated with ASD through the disruption of GABA function; there are similar reports that pesticides interfere with development by disrupting thyroid function [25, 31].\n\nIn sum, there is a substantial amount of converging evidence to suggest that environmental chemicals may play a role in ASD risk and/or etiology by acting independently or through interactions with genetic vulnerabilities.\n\nThe post hoc analysis results indicate that mother's self-report of her child's usage/exposure to acetaminophen and products containing DEET and phthalates are consistent with detection and concentration levels in the child's deciduous tooth. While compelling, this provides limited support for concurrent validity. Until additional studies are completed, we can make no claim about the developmental timing of exposure to the aforementioned chemicals found in deciduous teeth using the laboratory methods described in this paper. It would therefore be useful for future validation studies to be performed involving laboratory experimental models that manipulate in vivo timing of exposures. While LAESI methods have been used to precisely determine the period of exposure when assessing metal concentrations, there is concern that heat produced by the necessary sectioning of the tooth may vaporize or transform the SVOC on the surface so they will no longer be detectable. However, “soft ionization” imaging techniques such as Matrix Assisted Laser Desorption Ionization Time-of-Flight (MALDI-TOF) mass spectrometry may circumvent this issue. Researchers are currently working to overcome the obstacles with sectioning methods for use with SVOC.\n\nThere are thousands of potential environmental chemicals in circulation to which humans are exposed [61]. Even within certain chemical classes, there are hundreds of structurally related chemicals that have potential relevance to ASD. Therefore, exploratory and targeted GC and LC/MS studies with pulverized teeth to identify candidate chemicals will be an important first step. Chemicals identified in these initial studies can then be targeted in future imaging studies to fine-tune the time period of exposure. We feel these initial investigations are important for informing future epidemiologic research that can more precisely identify the timing of exposures between cases and controls.\n\n\nLimitations. While we have demonstrated that chemicals relevant to ASD can be detected in deciduous teeth and are associated with mothers' self-reported exposures, our results are limited in generalizability—largely due to the sample consisting entirely of children with ASD. Future studies that include more diverse participants and neurotypical children as controls will allow case/control comparisons.\n\nFurther, until additional studies are completed, we make no claim about the developmental timing of exposure (pre- or postnatal) to the aforementioned chemicals found in deciduous teeth using the laboratory methods described in this paper. Studies incorporating both unbiased environmental exposure measures (e.g., deciduous teeth) and measures of individual variation in the ability to biologically detoxify specific toxins (e.g., gene expression assessments) would be the next step in understanding gene-environment interactions that could effectively inform various prevention efforts.\n\nAcknowledgments\nThis study was funded in part by Autism Speaks Grant no. 8426, the Suzanne and Bob Wright Trail Blazer award granted to the first author. Further support came from the Department of Family and Community Medicine at the University of Texas Health Science Center San Antonio and the UTHSCSA Hispanic Autism Research Center, Clinical Research Unit in Harlingen, TX.\n\nConflict of Interests\nThe authors declare that there is no conflict of interests regarding the publication of this paper.\n\nTable 1 Descriptive statistics of the study sample of children with ASD. \n\n \tMean (SD) or % IAN \n\nn = 71\tMean (SD) or % Matamoros \n\nn = 12 \t\nParent characteristics\t \t \t\n Mother's age1 in years\t43.6 (6.0)\t38.3 (8.9)\t\n Father's age∗ in years\t45.7 (6.0)\t41.9 (10.3)\t\n Mothers born in USA\t86.4%\t0%∗∗∗\n\t\n Fathers born in USA\t84.6%\t9%∗∗∗\n\t\n Married\t79.1%\t75%\t\n Four-year college degree or higher\t58.1%\t25%∗∗\n\t\n Household yearly income equal \n to or greater than $50,000\t73.4%\t0%∗∗∗\n\t\nChild characteristics\t \t \t\n Age1 (years)\t11.5 (4.4)\t11.1 (3.9)\t\n Non-Hispanic White \t82.1%\t0%∗∗∗\n\t\n Male\t71.1%\t92%∗\n\t\n\n1Age at tooth donation.\n\n\n∗\np < .05, ∗∗\np < .01, ∗∗∗\np < .001.\n\nTable 2 Detection frequency and concentration distributions of SVOC in a deciduous tooth crown of 71 IAN children with ASD. \n\nAnalyte (parent)\tMean (ng/g)\tNumber of teeth\tDetections\tConcentration (ng/g)\t\nNumber\tPercent\tP25\n\tP50\n\tP75\n\tP90\n\tP95\n\tMax\t\nLC/MS/MS-detected analytes\t \t \t \t \t \t \t \t \t \t \t\n Acetaminophen\t0.98\t71\t31\t44%\t<1.4\t<1.4\t5.1\t24.4\t52.5\t1050\t\n DEET\t82.2\t71\t53\t75%\t<4.3\t13.7\t47.5\t101\t198\t3270\t\n TCPy (chlorpyrifos)\t0.88\t71\t9\t13%\t<1.3\t<1.3\t<1.3\t1.9\t8.7\t18.5\t\n IMPy (diazinon)\t0.96\t71\t9\t13%\t<1.0\t<1.0\t<1.0\t0.4\t2.8\t56.7\t\n MEP∗ (DEP)\t268.6\t31\t31\t100%\t56.5\t138\t235\t870\t1290\t1720\t\n MnBP (DnBP, BzBP)\t229.0\t71\t61\t86%\t11.0\t34.0\t157\t730\t1270\t3250\t\n MiBP (DiBP)\t70.24\t71\t50\t70%\t<6.0\t19.7\t62.7\t186\t342\t790\t\n MBzP (BzBP)\t2.39\t71\t4\t6%\t<10.0\t<10.0\t<10.0\t<10.0\t25.4\t74.3\t\n MEHP (DEHP)\t47.0\t56\t20\t36%\t<10\t<10\t32.9\t214\t319\t715\t\n\n\n\t\nPolyunsaturated fatty acids\tMean μg/g\tNumber of teeth\tDetections\tConcentration (μg/g)\t\n\n\n\t\nLA, C18:2 n6\t14.1\t71\t71\t100%\t4.42\t7.58\t17.0\t34.3\t61.2\t92.1\t\nALA, C18:3 n3\t0.70\t71\t15\t21%\t<1.0\t<1.0\t<1.0\t1.96\t3.60\t15.4\t\nARA, C20:4 n6\t2.60\t71\t60\t85%\t1.29\t1.82\t3.49\t5.23\t8.66\t15.0\t\nDHA, C22:6 n3\t0.31\t71\t14\t20%\t<1.0\t<1.0\t<1.0\t1.52\t2.09\t2.41\t\n\n∗MEP reported after matrix blank subtraction.\n\nRecovery range of equilibrated spiked surrogates from the 71 teeth was 8–92% for acetaminophen-d\n4, 55–222% for MEHP-13C4, and 30–163% for C21:0.\n\nTable 3 Detection frequency and average concentrations of sVOC in deciduous tooth crowns of 12 children with ASD from Matamoros.\n\nAnalyte (parent)\tMean (ng/g)\tNumber of teeth\tDetections\tConcentration (ng/g)\t\nNumber\tPercent\tP25\n\tP50\n\tP75\n\tP90\n\tP95\n\tMax\t\nLC/MS/MS-detected analytes\t \t \t \t \t \t \t \t \t \t \t\n Acetaminophen\t1.69\t12\t5\t42%\t<0.4\t<0.4\t0.89\t1.04\t4.85\t4.85\t\n DEET\t39.3\t12\t12\t100%\t10.8\t16.7\t32.3\t58.5\t242.5\t242.5\t\n TCPy (chlorpyrifos)\t0\t12\t0\t0\t<1.3\t<1.3\t<1.3\t<1.3\t<1.3\t<1.3\t\n IMPy (diazinon)\t2.02∗\n\t12\t2\t17%\t<1.0\t<1.0\t<1.0\t1.85\t2.18\t2.18\t\n MEP∗ (DEP)\t115.0\t12\t12\t100%\t75.9\t115.1\t151.1\t176.5\t207.5\t207.5\t\n MnBP (DnBP, BzBP)∗\n\t22.92\t12\t8\t66%\t9.1\t9.7\t29.9\t42.2\t50.4\t50.4\t\n MiBP (DiBP)\t55.25\t12\t12\t100%\t11.43\t41.9\t85.3\t135.8\t144.6\t144.6\t\n MBzP (BzBP)\t0\t12\t0\t0\t<10.0\t<10.0\t<10.0\t<10.0\t<10.0\t<10.0\t\n MEHP (DEHP)\t198.5∗\n\t12\t2\t100%\t22.5\t67.6\t148.5\t383.8\t1347.4\t1347.4\t\n\n∗Significantly different (p < .01) than non-Hispanic White sample in Table 2.\n==== Refs\n1 Berkovitz B. K. B. Holland G. R. Moxham B. J. A Colour Atlas and Textbook of Oral Anatomy, Histology and Embryology 1992 London, UK Wolfe Publishing \n2 Rabinowitz M. B. Leviton A. Bellinger D. Relationships between serial blood lead levels and exfoliated tooth dentin lead levels: models of tooth lead kinetics Calcified Tissue International 1993 53 5 338 341 10.1007/bf01351840 2-s2.0-0027369027 8287322 \n3 Manea-Krichten M. Patterson C. Miller G. Settle D. Erel Y. Comparative increases of lead and barium with age in human tooth enamel, rib and ulna Science of the Total Environment 1991 107 179 203 10.1016/0048-9697(91)90259-h 2-s2.0-0025745050 1785049 \n4 Ericson J. E. Rinderknecht A. Gonzalez E. J. Crinella F. M. Kleinman M. T. Measurements of manganese with respect to calcium in histological enamel cross sections: toward a new manganese biomarker Environmental Research 2001 86 1 46 50 10.1006/enrs.2000.4240 2-s2.0-0034743648 11386740 \n5 Needleman H. L. Tuncay O. C. Shapiro I. M. Lead levels in deciduous teeth of urban and suburban American children Nature 1972 235 5333 111 112 10.1038/235111a0 2-s2.0-0015505330 4550400 \n6 Barbosa F. Jr. Tanus-Santos J. E. Gerlach R. F. Parsons P. J. A critical review of biomarkers used for monitoring human exposure to lead: advantages, limitations, and future needs Environmental Health Perspectives 2005 113 12 1669 1674 10.1289/ehp.7917 2-s2.0-29144437220 16330345 \n7 Attramadal A. Jonsen J. The content of lead, cadmium, zinc and copper in deciduous and permanent human teeth Acta Odontologica Scandinavica 1976 34 3 127 131 10.3109/00016357609002559 2-s2.0-0017107218 1067730 \n8 Lee K. M. Appleton J. Cooke M. Keenan F. Sawicka-Kapusta K. Use of laser ablation inductively coupled plasma mass spectrometry to provide element versus time profiles in teeth Analytica Chimica Acta 1999 395 1-2 179 185 10.1016/s0003-2670(99)00319-0 2-s2.0-0032793586 \n9 Lochner F. Appleton J. Keenan F. Cooke M. Multi-element profiling of human deciduous teeth by laser ablation-inductively coupled plasma-mass spectrometry Analytica Chimica Acta 1999 401 1-2 299 306 10.1016/s0003-2670(99)00476-6 2-s2.0-0032746040 \n10 Arora M. Kennedy B. J. Elhlou S. Spatial distribution of lead in human primary teeth as a biomarker of pre- and neonatal lead exposure Science of the Total Environment 2006 371 1–3 55 62 10.1016/j.scitotenv.2006.07.035 2-s2.0-33751029565 16950500 \n11 Arora M. Bradman A. Austin C. Determining fetal manganese exposure from mantle dentine of deciduous teeth Environmental Science and Technology 2012 46 9 5118 5125 10.1021/es203569f 2-s2.0-84860462222 22455722 \n12 Hare D. Austin C. Doble P. Arora M. Elemental bio-imaging of trace elements in teeth using laser ablation-inductively coupled plasma-mass spectrometry Journal of Dentistry 2011 39 5 397 403 10.1016/j.jdent.2011.03.004 2-s2.0-79955076184 21439345 \n13 Gunier R. B. Bradman A. Jerrett M. Determinants of manganese in prenatal dentin of shed teeth from CHAMACOS children living in an agricultural community Environmental Science & Technology 2013 47 19 11249 11257 10.1021/es4018688 2-s2.0-84885164900 24053404 \n14 Blanusa M. Ivicic N. Simeon V. Lead, iron, copper, zinc and ash in deciduous teeth in relation to age and distance from a lead smelter Bulletin of Environmental Contamination and Toxicology 1990 45 4 478 485 10.1007/bf01700618 2-s2.0-0025094081 2279110 \n15 Fergusson J. E. Jansen M. L. Sheat A. W. Lead in deciduous teeth in relation to environmental lead Environmental Technology Letters 1980 1 8 376 383 10.1080/09593338009383991 2-s2.0-0019127672 \n16 Kamberi B. Koçani F. Dragusha E. Teeth as indicators of environmental pollution with lead Journal of Environmental & Analytical Toxicology 2012 2, article 118 10.4172/2161-0525.1000118 \n17 Bayo J. Moreno-Grau S. Martinez M. J. 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"fulltext_license": "CC BY",
"issn_linking": "1687-9805",
"issue": "2015()",
"journal": "Journal of environmental and public health",
"keywords": null,
"medline_ta": "J Environ Public Health",
"mesh_terms": "D000293:Adolescent; D001321:Autistic Disorder; D015415:Biomarkers; D002648:Child; D002675:Child, Preschool; D004781:Environmental Exposure; D004785:Environmental Pollutants; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008800:Mexico; D009930:Organic Chemicals; D013781:Texas; D014094:Tooth, Deciduous",
"nlm_unique_id": "101516361",
"other_id": null,
"pages": "862414",
"pmc": null,
"pmid": "26290670",
"pubdate": "2015",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "11109179;20552678;8287322;15710174;15733932;16112323;16330345;16950500;17497416;18074303;18226068;18226078;18160196;18332717;18445737;18394707;18821008;19528057;19822263;19748189;11386740;11462151;11814263;12851273;14594624;14606691;2279110;19850963;20056561;21278053;20698709;21439345;21507777;21507778;21086189;21468770;21893441;22455722;21735299;22537663;22534084;22458970;22805989;24053404;24518398;24518932;25272369;21771276;4550400;1785049;20628445;1067730",
"title": "Organic Compounds Detected in Deciduous Teeth: A Replication Study from Children with Autism in Two Samples.",
"title_normalized": "organic compounds detected in deciduous teeth a replication study from children with autism in two samples"
} | [
{
"companynumb": "US-JNJFOC-20150901613",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ACETAMINOPHEN"
},
"drugadditional": null,
... |
{
"abstract": "Antibody-mediated rejection (AMR) is a major risk for renal allograft survival. Throughout decades, cyclophosphamide treatment has been proven to be effective in patients with antibody-associated autoimmune diseases. We investigated whether cyclophosphamide combined with plasmapheresis and intravenous immunoglobulins is an option for patients with AMR.\n\n\n\nBetween March 2013 and November 2015, we initiated treatment of 13 consecutive patients with biopsy-proven acute AMR with intravenous cyclophosphamide pulses (15 mg/kg adapted to age and renal function) at 3-week intervals, PPH (6×), and high-dose intravenous immunoglobulin (1.5 g/kg). Treatment was completed after 6 cyclophosphamide pulses or in case of return to baseline serum creatinine together with reduction of donor-specific HLA antibodies (DSA) below 500 mean fluorescence intensity.\n\n\n\nEleven of 13 patients completed treatment. Median follow-up was 18 (12-44) months. At the end of follow-up, graft survival was 77% (10/13). The 3 graft losses were caused at least in part by nonadherence and premature termination of treatment. Serum creatinine increased from 1.7±0.4 mg/dL at 3 months before diagnosis to 3.7±2.4 mg/dL at diagnosis (P = 0.01), and decreased to 2.1 ± 0.7 mg/dL at 3 months after diagnosis (P = 0.01). In 7 (64%) of 11 patients, who completed treatment, DSA decreased, in 4 (36%) of 11 DSA were below 500 mean fluorescence intensity after treatment. Dose reductions had to be performed in 3 of 13 patients for leukopenia. We observed 14 hospitalizations in 9 of 13 patients.\n\n\n\nTo our knowledge, this is the first systematic report on cyclophosphamide-based treatment of acute AMR based on modern diagnostics. Treatment was effective and relatively safe. Future studies will show, whether cyclophosphamide proves to be a valuable alternative for the treatment of AMR.",
"affiliations": "1 Medizinische Klinik mit Schwerpunkt Nephrologie, Charité Universitätsmedizin Berlin, Berlin, Germany. 2 Institut für Pathologie, Charité Universitätsmedizin Berlin, Berlin, Germany. 3 HLA-Labor, Zentrum für Tumormedizin, Charité Universitätsmedizin, Berlin, Germany.",
"authors": "Waiser|Johannes|J|;Duerr|Michael|M|;Budde|Klemens|K|;Rudolph|Birgit|B|;Wu|Kaiyin|K|;Bachmann|Friederike|F|;Halleck|Fabian|F|;Schönemann|Constanze|C|;Lachmann|Nils|N|",
"chemical_list": "D006680:HLA Antigens; D007166:Immunosuppressive Agents; D007518:Isoantibodies; D003520:Cyclophosphamide",
"country": "United States",
"delete": false,
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"issue": "101(10)",
"journal": "Transplantation",
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"mesh_terms": "D000208:Acute Disease; D000328:Adult; D003520:Cyclophosphamide; D004305:Dose-Response Relationship, Drug; D005260:Female; D005500:Follow-Up Studies; D006084:Graft Rejection; D006085:Graft Survival; D006680:HLA Antigens; D006801:Humans; D007166:Immunosuppressive Agents; D007275:Injections, Intravenous; D007518:Isoantibodies; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D014184:Transplantation, Homologous; D016896:Treatment Outcome",
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"pages": "2545-2552",
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"pubdate": "2017-10",
"publication_types": "D016428:Journal Article",
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"title": "Treatment of Acute Antibody-Mediated Renal Allograft Rejection With Cyclophosphamide.",
"title_normalized": "treatment of acute antibody mediated renal allograft rejection with cyclophosphamide"
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"abstract": "Ninety-four adults with newly diagnosed or relapsed/refractory acute myeloid leukemia (AML) were treated with fractionated doses of gemtuzumab ozogamicin (GO) at one-single French center over ten years. We attempted to define predictive factors for response and survival. The overall response rate was 70% (86% in newly diagnosed and 65% in relapsed/refractory AML). Mortality during induction was 6%. Disease-free survival (DFS) and overall survival at three years after GO treatment was 36% and 31%, respectively. Median DFS in relapsed/refractory patients was eight months with a 3-year DFS at 34%. Among remitters, allogeneic hematopoietic stem cell transplantation (HSCT) can be performed in 28 cases (42%), including two patients in first-line therapy and 26 in further line. In relapsed/refractory patients undergoing allogeneic HSCT after responding to GO therapy, the median DFS was not reached. Incidences of transplant-related mortality, grade ≥ 3 acute graft-versus-host (GvH) disease, and extensive chronic GvH disease were 11%, 14%, and 25%, respectively. No sinusoidal obstruction syndromes were reported among allografted patients as among the other patients in the studied cohort. GO-based chemotherapy is a viable option for the treatment of relapsed/refractory AML patients and is a feasible schedule as a bridge to allogeneic transplant.",
"affiliations": "Hospices Civils de Lyon, Department of Hematology, Lyon-Sud Hospital, Pierre Bénite, France.;Hospices Civils de Lyon, Department of Hematology, Lyon-Sud Hospital, Pierre Bénite, France.;Hospices Civils de Lyon, Department of Hematology, Lyon-Sud Hospital, Pierre Bénite, France.;Hospices Civils de Lyon, Department of Hematology, Lyon-Sud Hospital, Pierre Bénite, France.;Hospices Civils de Lyon, Department of Hematology, Lyon-Sud Hospital, Pierre Bénite, France.;Hospices Civils de Lyon, Department of Hematology, Lyon-Sud Hospital, Pierre Bénite, France.;Hospices Civils de Lyon, Department of Hematology, Lyon-Sud Hospital, Pierre Bénite, France.;Hospices Civils de Lyon, Department of Hematology, Lyon-Sud Hospital, Pierre Bénite, France.;Hospices Civils de Lyon, Department of Hematology, Lyon-Sud Hospital, Pierre Bénite, France.;Hospices Civils de Lyon, Department of Hematology, Lyon-Sud Hospital, Pierre Bénite, France.;Hospices Civils de Lyon, Department of Hematology, Lyon-Sud Hospital, Pierre Bénite, France.;Hospices Civils de Lyon, Department of Hematology, Lyon-Sud Hospital, Pierre Bénite, France.;Hospices Civils de Lyon, Department of Hematology, Lyon-Sud Hospital, Pierre Bénite, France.;Hospices Civils de Lyon, Department of Hematology, Lyon-Sud Hospital, Pierre Bénite, France.;Hospices Civils de Lyon, Department of Hematology, Lyon-Sud Hospital, Pierre Bénite, France.",
"authors": "Laurino|Marica|M|;Loron|Sandrine|S|;Larcher|Marie-Virginie|MV|;Fossard|Gaëlle|G|;Elhamri|Mohamed|M|;Deloire|Alexandre|A|;Balsat|Marie|M|;Barraco|Fiorenza|F|;Labussière|Hélène|H|;Ducastelle|Sophie|S|;Renault|Myriam|M|;Wattel|Eric|E|;Heiblig|Maël|M|;Salles|Gilles|G|;Thomas|Xavier|X|",
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"doi": "10.4084/MJHID.2020.020",
"fulltext": "\n==== Front\nMediterr J Hematol Infect Dis\nMediterr J Hematol Infect Dis\nMediterranean Journal of Hematology and Infectious Diseases\nMediterranean Journal of Hematology and Infectious Diseases\n2035-3006 Università Cattolica del Sacro Cuore \n\n10.4084/MJHID.2020.020\nmjhid-12-1-e2020020\nOriginal Article\nLyon-University Hospital Experience with Gemtuzumab Ozogamicin Therapy in Acute Myeloid Leukemia: a ‘Real-Life’ Study\nLaurino Marica 12 Loron Sandrine 1 Larcher Marie-Virginie 1 Fossard Gaëlle 1 Elhamri Mohamed 1 Deloire Alexandre 1 Balsat Marie 1 Barraco Fiorenza 1 Labussière Hélène 1 Ducastelle Sophie 1 Renault Myriam 1 Wattel Eric 1 Heiblig Maël 1 Salles Gilles 1 Thomas Xavier 1 \n1 Hospices Civils de Lyon, Department of Hematology, Lyon-Sud Hospital, Pierre Bénite, France\n\n2 Ematologia e Immunologia Clinica, Azienda Ospedaliera di Padova, Padova, Italy\nCorrespondence to: Xavier Thomas, Department of Hematology, Lyon-Sud Hospital, Bat. 1G, 165 chemin du Grand Revoyet, 69495 Pierre Bénite Cedex, France. Tel. (33)478862235; fax. (33)472678880; e-mail: xavier.thomas@chu-lyon.fr\n2020 \n01 5 2020 \n12 1 e202002006 1 2020 17 3 2020 2020This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by-nc/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Ninety-four adults with newly diagnosed or relapsed/refractory acute myeloid leukemia (AML) were treated with fractionated doses of gemtuzumab ozogamicin (GO) at one-single French center over ten years. We attempted to define predictive factors for response and survival. The overall response rate was 70% (86% in newly diagnosed and 65% in relapsed/refractory AML). Mortality during induction was 6%. Disease-free survival (DFS) and overall survival at three years after GO treatment was 36% and 31%, respectively. Median DFS in relapsed/refractory patients was eight months with a 3-year DFS at 34%. Among remitters, allogeneic hematopoietic stem cell transplantation (HSCT) can be performed in 28 cases (42%), including two patients in first-line therapy and 26 in further line. In relapsed/refractory patients undergoing allogeneic HSCT after responding to GO therapy, the median DFS was not reached. Incidences of transplant-related mortality, grade ≥ 3 acute graft-versus-host (GvH) disease, and extensive chronic GvH disease were 11%, 14%, and 25%, respectively. No sinusoidal obstruction syndromes were reported among allografted patients as among the other patients in the studied cohort. GO-based chemotherapy is a viable option for the treatment of relapsed/refractory AML patients and is a feasible schedule as a bridge to allogeneic transplant.\n\nAcute myeloid leukemiaGemtuzumab ozogamicinPrognosisTreatment\n==== Body\nIntroduction\nAcute myeloid leukemia (AML) is a life-threatening hematological disorder characterized by uncontrolled proliferation of abnormal blasts in the bone marrow, disturbing normal hematopoiesis. Over the past few years, several promising concepts have been introduced for the treatment of AML, of which one is based on the expression of CD33 on leukemic cells.1 Gemtuzumab ozogamicin (GO) (mylotarg®) is a humanized anti-CD33 monoclonal antibody conjugated to calicheamicin, a potent DNA-binding cytotoxic antibiotic that causes single and double-strand cuts. The bond between antibody and drug is stable in circulation and then dissolves, once intracellular, to allow the calicheamicin to bind with the DNA. GO spares the presumably normal precursors, so allowing for restoration of normal hematopoiesis.2 GO monotherapy has shown a 23% response rate in newly diagnosed AML patients not eligible for intensive chemotherapy.3 GO was initially approved by FDA, then subsequently withdrawn; it was reapproved combined with cytarabine and daunorubicin given as standard ‘7+3’ for newly diagnosed CD33-positive AML. Approval was obtained after the French ALFA-0701 trial randomizing newly diagnosed patients aged 50–70 years to receive ‘7+3’ ± GO with fractionated doses (3 mg/m2 on days 1, 4, and 7),4 and was based on prolongation of event-free survival (EFS) with, however, a benefit limited to patients with favorable or intermediate cytogenetics. Hepatotoxicity (including hepatic veno-occlusive disease) has been reported in association with the use of GO, especially in patients with underlying hepatic disease or abnormal liver function. Improved outcomes have also been reported in patients receiving low-dose GO combined with low-dose cytarabine compared with low-dose cytarabine alone (30% of responses versus 17%).5 In combination with azacitidine, GO produced a 44% CR rate with a median OS of 11 months in patients aged 60–69 years, and 35% CR rate with again a median OS of 11 months in patients aged ≥70 years.6\n\nIn this ‘real-life’ study, we report our experience with fractionated GO administration given as front-line therapy in combination with conventional chemotherapy according to the European recommendations, but also and above all given outside the official indications in the relapsed/refractory setting. The study aim was to evaluate its efficacy, especially in high-risk patients and its potential use as a bridge to transplant.\n\nPatients and Methods\nPatients\nA chart review of 94 AML patients receiving GO between January 2009 and January 2019 at the Lyon University Hospital (France) was retrospectively performed. All patients had Eastern Cooperative Oncology Group Performance Status (ECOG PS)<2 at the time of starting GO therapy. Diagnoses were established according to criteria proposed by the French-American-British (FAB) study group. In all patients, leukemic blasts CD33 expression was > 40%, and a majority of them expressed substantial amounts of CD33 (>70% in 60% of cases). All patients were classified according to the European LeukemiaNet (ELN) stratifications.7 Cytogenetic data were classified according to standard International System for Human Cytogenetic Nomenclature criteria into favorable-, intermediate-, or unfavorable-risk subgroups.\n\nThe screening for the following mutations was performed at diagnosis prospectively or retrospectively in 93 of the 94 patients: FMS-like tyrosine kinase 3 (Flt3) gene internal tandem mutation (ITD) or tyrosine kinase domain (TKD), the nucleophosmin gene (NPM1), the MLL partial tandem duplication (PTD), the CCAAT/enhancer-binding protein alpha (CEBPA) gene, the ectropic virus integration site 1 protein homolog (EVI1) gene (MECOM), and the isocitrate dehydrogenase (IDH1/2) genes.\n\nTreatment\nTwenty-two patients received GO as front-line therapy (group 1), while 72 patients received GO in second or further line of treatment of whom 13 were previously allografted. As a front-line treatment, GO (3 mg/m2/day on days 1, 4 and 7) was combined with a conventional ‘7+3’ induction chemotherapy, with cytarabine (200 mg/m2/day on days 1 to 7) and daunorubicin (60 mg/m2/day on days 1 to 3).4 The total dose of GO per infusion was not to exceed one 5 mg vial. Sixty-six patients in the relapsed/refractory setting (group 2) received the same treatment. Patients who achieved composite complete remission (CRc) can receive two courses of consolidation, including daunorubicin and cytarabine with GO (3 mg/m2/day on day 1). They could also be considered for allogeneic hematopoietic stem cell transplant (HSCT) according to age, Eastern Cooperative Oncology Group Performance Status (ECOG PS), genetic-risk profile, presence of a potential donor, and absence of prior transplantation. Six refractory patients (group 3) with an identified HLA compatible donor received GO (3 mg/m2/day on days 1, 4 and 7) combined with cytarabine (200 mg/m2/day on days 1 to 7) and daunorubicin (60 mg/m2/day on days 1 to 3) followed at day 15 by a FLAMSA sequential conditioning combining fludarabine, cytarabine, amsacrine, followed by cyclophosphamide, and/or either total body irradiation or busulfan, and allogeneic HSCT.8\n\nEthics statement\nAll treatments received approval from the institutional review board and were conducted in accordance with the Declaration of Helsinki. This observational and retrospective study did not require any specific, informed consent or ethics committee approval according to French legislation (articles L.1121-1 paragraph 1 and R1121-2, Public Health Code). However, the patients enrolled in a transplant protocol, and in any case of transplantation, signed informed consent. All data were collected and analyzed anonymously.\n\nStatistical analyses\nDescriptive statistics were used to characterize patients and their disease. Descriptive data were stratified by study cohorts. Associations between pretreatment characteristics and responses to induction were evaluated by the Pearson χ2 test. All tests were two-sided with statistical significance set at 0.05. CRc includes all patients who achieved CR, CRi (all CR criteria except for residual neutropenia or thrombocytopenia), and CRp (CR with incomplete platelet counts).9 CRc was defined as less than 5% blasts in bone marrow aspirates with no blasts with Auer rods and no extramedullary disease. Hematological relapse was considered when more than 5% blasts were seen in two bone marrow aspirates obtained at a 15-day interval. Overall survival (OS) was defined as the time from GO therapy to death or last patient contact. Disease-free survival (DFS) was defined from date of CRc following GO therapy to date of relapse or death, or last contact with patient in continuous CRc. DFS and OS distributions were estimated by the method of Kaplan and Meier. All treatment and subgroup comparisons were performed by the log-rank test. Simultaneous effects of multiple covariates were estimated with the maximum-likelihood logistic regression model for response to therapy and with the Cox’s proportional hazard model for DFS and OS and tested by the likelihood-ratio test, also used in univariate analyses for continuous variables. Regarding continuous variables the threshold chosen for the analyses was the median value. Estimated hazard ratios (HRs) are reported as relative risks (RR) with 95% confidence intervals (CI). All computations were made using BMDP software (BMDP Statistical Software, Los Angeles, CA).\n\nResults\nPopulation characteristics\nA total of 94 AML patients (53 males and 41 females) were treated with GO at the Lyon University Hospital between January 2009 and January 2019. At the time of analysis, the median follow-up was 3 years (95% CI: 1.8 – 3.3 years). Main characteristics at the time of treatment are summarized in Table 1. The median age was 56 years (18 – 75 years). Twenty-seven patients had secondary AML (6 with chronic myelomonocytic leukemia, 5 with prior myelodysplastic syndrome, 4 with prior chronic myeloproliferative syndrome, 4 with non-Hodgkin lymphoma, 2 with breast cancer, 2 with uterus cancer, 1 with mastocytosis, 1 with Hodgkin disease, 1 with colon cancer, and 1 following immunosuppressive treatment for renal transplantation). The patients were grouped into three study cohorts. Twenty-two patients received GO + chemotherapy as front-line therapy (group 1). Seventy-two patients received GO in the relapsed/refractory setting (49 in second line of treatment, 20 in third line, 2 in fourth line, and one in fifth line). Among them, 66 relapsed/refractory patients received GO + chemotherapy (group 2) and 6 very high-risk refractory patients received GO + chemotherapy 2 weeks prior starting conditioning regimen in the setting of allogeneic HSCT (group 3). Overall, 19 patients were classified as ‘favorable-risk’ according to the ELN classification, 42 as ‘intermediate-risk,’ and 33 as ‘unfavorable-risk.’ Molecular profiling of the studied patients included Flt3-ITD mutations in 20 patients (21.5%), Flt3-TKD in 6 (6.4%), NPM1 in 23 (24.7%), EVI1 in 15 (16.1%), MLL-PTD in 8 (8.6%), CEBPA in 4 (4.3%), IDH1 in 3 (3.2%), and IDH2 in 8 (8.6%).\n\nResponse rates\nOverall, the rate of CRc was 70% (66 of the 94 patients). CRc was achieved in 19 patients (86%) in group 1, 42 (63%) in group 2, and 5 (83%) in group 3.\n\nOverall, 28 patients (42% of morphological remitters) underwent allogeneic HSCT after achieving response with GO either in first remission (2 patients) or further remission (18 patients in second line and 8 in third line): 13 transplants from a mismatched unrelated donor, 6 from an identical unrelated donor, and 9 from an identical sibling. Conditioning regimens included amsacrine/cytarabine/fludarabine/anti-thymoglobulin (ATG)/busulfan or total body irradiation (TBI) (20 patients), fludarabine/busulfan/ATG (4 patients), cyclophosphamide/fludarabine/TBI (2 patients), busulfan/ATG/TBI (one patient), and cyclophosphamide/busulfan (one patient). Graft-versus-host (GvH) prophylaxis used ciclosporin ± methotrexate or mycophenolate mofetil or cyclophosphamide. Sources of cells were peripheral blood (23 patients), bone marrow (2 patients), and cord blood (3 patients). Six out of 20 patients (30%) evaluated for MRD before undergoing allogeneic HSCT were MRD-negative.\n\nThe other patients achieving any response received at least one subsequent consolidation therapy following GO treatment. Three patients not achieving CR with GO were allografted after a further line of treatment.\n\nWhen considering only relapsed/refractory patients (group 2 and group 3), factors influencing response in univariate analyses included AML subtype [78% (de novo AML) vs 36% (secondary AML); p =0.0006] and ELN classification [100% (favorable-risk) vs 60% (intermediate-risk) vs 48% (unfavorable); p =0.001]. In a multivariate analysis, only secondary AML [HR: 6.05; 95% CI: 2.01 – 17.8; p =0.001] remained of significant prognostic value (Table 2).\n\nDisease-free Survival\nAt the time of analysis, relapse has occurred in 33 of the 66 patients (50%) who responded to GO therapy. The median time from GO therapy to relapse was 5.3 months (1.5 – 53.6 months). Overall, median DFS was 10.5 months (95% CI: 6.0 – 22.6 months) with a 3-year DFS of 34% (Figure 1A). Median DFS was 19 months with a 3-year DFS of 36% in patients treated with GO as first-line therapy (group 1), and 7.7 months (3-year DFS: 33%) and 18.6 months (3-year DFS: 40%) in relapsed/refractory patients from group 2 and group 3, respectively (Figure 1B). Overall, median DFS in relapsed/refractory patients was 8 months with a 3-year DFS at 34%.\n\nIn relapsed/refractory patients (group 2 and group 3), factors predictive for DFS in the univariate analysis included allogeneic HSCT after achieving CRc with GO therapy (median DFS: not reached vs 1.5 months; p <0.0001) (Figure 1C) and the number of prior therapeutic lines [median DFS: 8.0 months (one prior line) vs 10.2 months (2 prior lines) vs 3.3 months (3 prior lines]. Adverse ELN stratification AML showed lower DFS than intermediate/favorable-risk AML (Figure 1D), as AML with prior history of hemopathy or cancer comparatively to de novo AML (Figure 1E), but differences were not statistically significant. In a multivariate analysis using a model including age (<55 vs ≥55 years), ELN stratification (favorable- and intermediate-risk vs unfavorable-risk), antecedents of hemopathy or cancer (secondary AML vs de novo AML), the number of prior therapeutic lines (one prior line vs > one prior line), Flt3-ITD, EVI1 and NPM1 mutation status, pre-treatment percentage of blasts in bone marrow (≤30% vs >30%), pre-treatment WBC count (<4 vs ≥4 × 109/L), antecedents of allogeneic\n\nHSCT, and allogeneic HSCT as consolidation treatment after GO therapy, only the number of prior therapeutic lines [HR: 2.55; 95% CI: 1.13 – 3.06; p =0.03] and allogeneic HSCT after GO therapy [HR: 5.88; 95% CI: 3.89 – 8.84; p <0.001] appeared of significant prognostic value (Table 2).\n\nOverall survival\nOverall median OS after GO therapy was 12.5 months (95% CI: 7.8 – 19.3 months) with a 3-year OS of 31%. Median OS was 25.9 months with a 3-year OS of 31% in group 1, and 8.4 months (3-year OS: 31%) and 2.4 months (3-year OS: 33%) in group 2 and group 3, respectively.\n\nIn relapsed/refractory patients (group 2 and group 3), factors predictive for OS in univariate analysis included ELN stratification [median OS: 19.1 months (favorable-risk) vs 9.4 (intermediate-risk) vs 3.5 months (adverse-risk); p =0.01], allogeneic HSCT prior to GO therapy [3.4 months (yes) vs 11.7 months (no); p =0.05), allogeneic HSCT after GO as consolidation therapy [58.8 months (yes) vs 4.7 months (no); p <0.0001], achievement of CRc with GP therapy [20.7 months (yes) vs 3.4 months (no); p <0.0001], EVI1 status [11.7 months (not mutated) vs 2 months (mutated); p =0.005], and the number of prior therapeutic lines [14.2 months (one prior line) vs 5.4 months (2 prior lines) vs 4.0 months (3 prior lines) vs 1.3 (4 prior lines); p =0.01]. In a multivariate Cox proportional hazard analysis including age, ELN stratification, WBC count before GO therapy, the line of treatment when receiving GO, Flt3-ITD, EVI1 and NPM1 mutation status, prior history of hemopathy or cancer, prior allogeneic HSCT, blast percentage in bone marrow before GO therapy, achievement of CRc with GO therapy, and use of allogeneic HSCT after GO therapy, the number of prior therapeutic lines (more than one line vs one prior line) [HR, 1.95; 95% CI: 1.06 – 3.52; p =0.03], NPM1 status [HR, 0.23; 95% CI: 0.10 – 0.54; p =0.02], EVI1 status [HR, 0.24; 95% CI: 0.11 – 0.52); p =0.02], prior allogeneic HSCT [HR, 0.29; 95% CI: 0.13 – 0.65; p =0.004], CRc achievement [HR, 3.63; 95% CI: 1.8 – 7.31; p =0.006], and allogeneic HSCT after GO therapy [HR, 3.86; 95% CI: 1.87 – 7.92; p <0.001] appeared of significant prognostic value (Table 2).\n\nToxicity\nOverall, GO therapy was well tolerated. All patients experienced severe myelosuppression. A total of 6 patients (6%) died during the period of induction (all patients in group 2). The causes of death were septic shock (2 patients), fungal infection (1 patient), pneumonia (1 patient), acute respiratory distress syndrome (1 patient), and hemorrhagic stroke (1 patient with progressive disease). In remitters, the median duration of aplasia in patients achieving response was 32.5 days (15 – 55 days) in group 1 and 30.5 days (8 – 93 days) in group 2. Severe prolonged thrombocytopenia (platelet count<50 × 109/L at day 45) was observed in 16% of cases.\n\nAmong the 28 responders to GO therapy who underwent allogeneic HSCT, 3 died from transplant-related toxicity: 2 from severe pulmonary infections and one from severe GvH disease. Severe acute GvH disease (grade ≥ 3) was observed in 4 cases (3 gut GvH and one liver GvH). Extensive and limited chronic GvH disease was observed in 7 and 3 cases, respectively. No sinusoidal obstruction syndromes were reported among allografted patients as among the other patients in the studied cohort.\n\nDiscussion\nIn initial publications, GO was used with an unfractionated dose of 9 mg/m2 on days 1 and 14 or 6 mg/m2 on day 4. In combination with chemotherapy, observed CR rates in relapsed/refractory patients were around 50% with a 2-year OS at 41%, but with the absence of full platelet recovery in roughly half of the responders and often early toxic deaths related to sinusoidal obstruction syndrome.10–16 In order to reduce toxicity while keeping efficacy, fractionated dosing was proposed, demonstrating in combination with chemotherapy a CR rate of 81% in older patients with untreated AML and 2-year event-free survival of 40.8% versus only 17.1% in a control group without GO.17 The benefit of fractionated dosing was then confirmed in first relapsed/refractory patients.18–20\n\nIn our study, we aimed at giving a realistic picture of patient outcomes during and after fractionated dosing GO therapy in newly diagnosed and relapsed/refractory AML patients. We, therefore, reported all AML cases seen in our department over 10 years with a specific interest for those treated outside the official indication of GO therapy in the relapsed/refractory setting. Despite improvements in the treatment of adult AML, the prognosis of relapsed/refractory AML patients remains particularly dismal.21 Prolonged survival is classically only observed in patients who underwent allogeneic HSCT.22 In relapsed/refractory patients, our goal with GO salvage therapy was, therefore, first to achieve a morphological CR, but secondly to go to transplantation with a leukemia cell burden as lowest as possible.\n\nAlthough suffering from several limitations, including the small number of patients, the high heterogeneity of patient characteristics, and the absence of comparator with results that cannot be entirely attributed to GO, our study has the advantage to describe the use of GO in a single-center ‘real-life.’ All our patients showed an expression of CD33. GO salvage therapy was assessed in 66 relapsed AML patients and in 6 refractory young adults as ‘last chance therapy’ in a sequential treatment with conditioning regimen followed by allogeneic HSCT. Results in the relapsed/refractory setting tended to be compared to those obtained over the same period with the same treatment in newly diagnosed AML.\n\nOverall, our study showed encouraging results for fractionated doses of GO therapy combined with a traditional ‘7+3’ induction chemotherapy in relapsed/refractory patients. Although the small size of our cohort underpowered subgroup analysis interpretations, this treatment yielded to achieve a promising\n\nCRc rate of 65% in relapsed/refractory patients and a 3-year DFS of 34%. These results were not significantly different from those obtained with the same treatment in front-line therapy patients. Furthermore, a sizeable proportion of patients were bridged to allogeneic HSCT, and an encouraging OS rate was observed. Our results were in accordance with those recently published showing a viable option for GO-based chemotherapy as salvage therapy, with similar survival rates and a feasible schedule as a bridge to allogeneic HSCT.23 Main prognostic factors appeared related to the intensity of prior therapy since a history of prior transplantation was of adverse influence and also related to leukemia cell characteristics such as the genetic profile. Overall, allogeneic HSCT performed after CR achievement following GO therapy remained the major prognostic factor for both DFS and OS. Analyses using transplant as a time-dependent covariate would have been suitable but were not relevant because of the small number of involved patients.\n\nSimilarly, the length of first remission, classically recognized as a major prognostic factor, was not taken into consideration because of the various number of prior therapeutic lines received by the patients. Although determined on small effectiveness, NPM1 mutation and EVI1 mutation emerged as prognostic factors of favorable and unfavorable impact on survival, respectively. On the contrary, Flt3-ITD presence did not appear to influence the prognosis, while it was associated with a high rate of CD33 expression.24 This unusual finding could be explained by a balance between the recognized unfavorable outcome of patients with Flt3 mutation and the high sensitivity of patients with Flt3 mutation to GO therapy. In these patients, the introduction of Flt3 inhibitors is going to be widely used. However, none of our patients received Flt3 inhibitors. Numerous studies have suggested the lack of efficacy of GO in case of low CD33 expression both in adults and children.25,26 Because CD33 expression of leukemic blasts was at least 40% in our series, CD33 expression was not introduced in prognostic models. On the other hand, previous therapy emerged as an important prognostic factor after GO treatment. Prior history of allogeneic HSCT was confirmed of poor outcome.27 This warrants trials using other novel therapeutic agents and strategies in case of relapse following allogeneic HSCT. Reversely, allogeneic HSCT of any type is regarded as the only therapeutic option with curative potential in high-risk AML, including relapsed/refractory patients.21 However, it represents the treatment of choice once a CR has been reached. Best results are generally achieved when transplantation is performed on a minimal leukemic burden generally estimated by a negative MRD determined either by molecular biology or by immunophenotyping.28 Based on this concept, our small series of refractory patients starting conditioning regimen at day 15 of GO plus chemotherapy reinduction showed encouraging results for a very high-risk AML population.\n\nWhile we always used GO in combination with intensive chemotherapy, GO could be combined with lower intensity treatments, such as hypomethylating agents, in patients considered unfit for standard chemotherapy.29 Such combinations might provide higher response rates in unfit patients. However, they can also generate higher hematological toxicity and potentially alter OS, which remains (with a sustained quality of life) the most important endpoints in the elderly AML population. In our study, GO combined with standard chemotherapy was well tolerated. Like all treatment using monoclonal antibodies, there is, however, always a significant risk of infusion-related reactions with IV administration of GO, which could be avoided by premedication with acetaminophen and methylprednisolone. In previous reports, a variable proportion of patients have been reported to develop clinically apparent sinusoidal obstruction syndrome.3–6,30–32 The cause is not really known, but it is likely due to the direct toxicity of the conjugate on Kuppfer cells.33 Endothelial lesions enhance vascular toxicity due to inflammatory state and high doses of reactive oxygen species into Kupffer cells, which express CD33. Symptoms usually arose within 5 to 20 days of the infusion and could be influenced by prior therapies and hepatic biological status. No sinusoidal obstruction syndromes were reported in our series after GO infusion or after allogeneic HSCT following GO therapy even when using conditioning regimen, including busulfan. The good tolerance observed in our series confirmed results reported by the MyloFrance-1 study20 and could potentially be explained by the use of GO at fractionated dosing. Toxicity was less than expected since sinusoidal obstruction syndrome was generally considered in 8.5% of cases.2 Patients receiving GO should nevertheless be carefully monitored before, during, and after each course of treatment.\n\nConclusions\nOverall, our study confirmed the efficacy and safety of GO-based chemotherapy in a real-life setting. Interestingly patients who received GO after relapse, assuming they did not previously receive allogeneic HSCT, showed no significant difference in terms of response to therapy and duration of response when compared to those who received GO as front-line therapy. In relapsed/refractory patients, this schedule should be used at the stage of the first relapse as a bridge to allogeneic transplant, which might be performed when possible after MRD negativization. These data need, however, to be confirmed in a larger cohort.\n\nCompeting interests: The authors declare no conflict of Interest.\n\nAuthor contributions. ML interpreted the data, drafted the manuscript, reviewed the manuscript, and gave final approval; ME, AL and MR collected the data and provided technical support; SL, MVL, FB, HL, SD and EW included patients; MH and GF included patients and reviewed the manuscript; GS reviewed the manuscript and gave final approval; XT included patients, collected the data, conducted the statistical analysis, interpreted the data, and wrote the manuscript.\n\nFigure 1 Kaplan-Meier analyses for DFS: (A) all remitters; (B) according to leukemia status (group 1: patients who received GO as front-line therapy; group 2: patients who received GO after one or further lines of therapy in the relapsed/refractory setting; group 3: very high-risk refractory patients who received GO 2 weeks prior starting conditioning regimen in the setting of allogeneic HSCT) (p values were given by Wald’s test, a HR value > 1 in the Cox model indicates that the outcome is worse in that category as compared with the baseline); (C) according to consolidation therapy after GO therapy (AlloHSCT or not) in relapsed/refractory patients (group 2 and group 3); (D) according to ELN stratification in relapsed/refractory patients (group 2 and group 3) (p values were given by Wald’s test, a HR value > 1 in the Cox model indicates that the outcome is worse in that category as compared with the baseline); (E) according to leukemia status (de novo AML or secondary AML).\n\nTable 1 Patient characteristics. Group 1: patients who received GO as front-line therapy; group 2: patients who received GO after one or further lines of therapy in the relapsed/refractory setting; group 3: very high-risk refractory patients who received GO 2 weeks prior starting conditioning regimen in the setting of allogeneic HSCT.\n\nCharacteristics\tGroup 1 (22pts)\tGroup 2 (66pts)\tGroup 3 (6pts)\tAll pts (94pts)\t\nM/F ratio\t2.14\t1.06\t2.00\t1.29\t\nAge (y)\t65* (18–75)**\t53 (24–71)\t49 (23–64)\t56 (18–75)\t\nSecondary AML\t5 (22%)\t20 (30%)\t2 (33%)\t27 (29%)\t\nPrior transplant\t0\t13 (20%)\t0\t13 (14%)\t\nELN 2017\t\nFavorable\t2 (9%)\t15 (23%)\t2 (33.3%)\t19 (20%)\t\nIntermediate\t12 (55%)\t28 (42%)\t2 (33.3%)\t42 (45%)\t\nUnfavorable\t8 (36%)\t23 (35%)\t2 (33.3%)\t33 (35%)\t\nBM blast count (%)\t40 (25–95)\t30 (20–90)\t20 (8–50)\t35 (8–95)\t\nWBC count (x 109/L)\t3.81 (1.1–54)\t5.20 (0.3–94)\t1.6 (0.6–69)\t4.42 (0.3–94)\t\nNb of lines\t\n1\t22\t-\t-\t22\t\n2\t-\t46\t3\t49\t\n>2\t-\t20\t3\t23***\t\n* median;\n\n** range;\n\n*** including 20 patients in third treatment line (17 in Group 2 and 3 in Group 3), 2 patients in fourth line (both in Group 2), and one patients in fifth line (in Group 2).\n\nAbbreviations: BM, bone marrow; ELN, European LeukemiaNet; FAB, French-American-British classification; M/F, male/female; Nb of lines, number of treatment lines; WBC, white blood cells; y, years.\n\nTable 2 Multivariate analyses in relapsed/refractory patients (group 2 and group 3).\n\nFactors\tHR\t95% CI\tp value\t\nAssociated with CRc\t\nSecondary AML (yes vs no)\t6.05\t2.01 – 17.8\t0.001\t\nAssociated with DFS\t\nNb of prior therapeutic lines (> 1 vs one)\t2.55\t1.13 – 3.06\t0.03\t\nAlloHSCT after GO (no vs yes)\t5.88\t3.89 – 8.84\t< 0.001\t\nAssociated with OS\t\nAlloHSCT after GO (no vs yes)\t3.86\t1.87 – 7.92\t< 0.001\t\nNb of prior therapeutic lines (> 1 vs one)\t1.95\t1.06 – 3.52\t0.03\t\nNPM1 mutation (yes vs no)\t0.23\t0.10 – 0.54\t0.02\t\nEVI1 mutation (no vs yes)\t0.24\t0.11 – 0.52\t0.02\t\nCRc achievement after GO (no vs yes)\t3.63\t1.80 – 7.31\t0.006\t\nPrior Allo HSCT (yes vs no)\t0.29\t0.13 – 0.65\t0.004\t\nAbbreviations: AlloHSCT, allogeneic hematopoietic stem cell transplantation; AML, acute myeloid leukemia; CI, confidence interval; CRc, composite complete response; DFS, disease-free survival; GO, gemtuzumab ozogamicin; HR, hazard ratio; Nb, number; OS, overall survival; WBC, white blood cell. A HR < 1 indicated a benefit for one factor over another.\n==== Refs\nReferences\n1 Sievers EL Larson RA Stadtmauer EA Mylotarg Study Group. Efficacy and safety of gemtuzumab ozogamicin in patients with CD33-positive acute myeloid leukemia in first relapse J Clin Oncol 2001 19 3244 3254 10.1200/JCO.2001.19.13.3244 11432892 \n2 Appelbaum FR Bernstein ID Gemtuzumab ozogamicin for acute myeloid leukemia Blood 2017 130 2373 2376 10.1182/blood-2017-09-797712 29021230 \n3 Amadori S Suciu S Selleslag D Randomized trial of two schedules of low-dose gemtuzumabozogamicin as induction monotherapy for newly diagnosed acute myeloid leukaemia in older patients not considered candidates for intensive chemotherapy. A phase II study of the EORTC and GIMEMA leukaemia groups (AML-19) Br J Haematol 2010 149 376 382 10.1111/j.1365-2141.2010.08095.x 20230405 \n4 Lambert J Pautas C Terré C Gemtuzumab ozogamicin for de novo acute myeloid leukemia: final efficacy and safety updates from the open-label, phase III ALFA-0701 trial Haematologica 2019 104 113 119 10.3324/haematol.2018.188888 30076173 \n5 Burnett AK Hills RK Hunter AE The addition of gemtuzumabozogamicin to low-dose AraC improves remission rate but does not significantly prolong survival in older patients with acute myeloid leukaemia: results from the LRF AML14 and NCRI AML16 pick-a-winner comparison Leukemia 2013 27 75 81 10.1038/leu.2012.229 22964882 \n6 Nand S Othus M Godwin JE A phase 2 trial of azacitidine and gemtuzumab ozogamicin therapy in older patients with acute myeloid leukemia Blood 2013 122 3432 3439 10.1182/blood-2013-06-506592 24092933 \n7 Döhner H Estey EH Amadori S Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet Blood 2010 115 453 474 10.1182/blood-2009-07-235358 19880497 \n8 Malard F Labopin M Stuhler G Sequential intensified conditioning regimen allogeneic hematopoietic stem cell transplantation in adult patients with intermediate- or high-risk acute myeloid leukemia in complete remission: a study from the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation Biol Blood Marrow Transplant 2017 23 278 284 10.1016/j.bbmt.2016.11.002 27816650 \n9 Medeiros BC Interpretation of clinical endpoints in trials of acute myeloid leukemia Leuk Res 2018 68 32 39 10.1016/j.leukres.2018.02.002 29524739 \n10 Stone RM Moser B Sanford B High dose cytarabine plus gemtuzumab ozogamicin for patients with relapsed or refractory acute myeloid leukemia: Cancer and Leukemia Group B study 19902 Leuk Res 2011 35 329 333 10.1016/j.leukres.2010.07.017 20688393 \n11 Specchia G Pastore D Carluccio P Gemtuzumab ozogamicin with cytarabine and mitoxantrone as a third-line treatment in a poor prognosis group of adult acute myeloid leukemia patients: a single-center experience Ann hematol 2007 86 425 428 10.1007/s00277-007-0272-z 17364181 \n12 Cortes J Tsimberidou AM Alvarez R Mylotarg combined with topotecan and cytarabine in patients with refractory acute myelogenous leukemia Cancer Chemother Pharmacol 2002 50 497 500 10.1007/s00280-002-0539-y 12451477 \n13 Fianchi L Pagano L Leoni F Gemtuzumab ozogamicin, cytosine arabinoside, G-CSF combination (G-AraMy) in the treatment of elderly patients with poor-prognosis acute myeloid leukemia Ann Oncol 2008 19 128 134 10.1093/annonc/mdm451 17906298 \n14 Piccaluga PP Martinelli G Rondoni M Gemtuzumab ozogamicin for relapsed and refractory acute myeloid leukemia and myeloid sarcomas LeukLymphoma 2004 45 1791 1795 10.1080/1042819042000219485 15223637 \n15 Apostolidou E Cortes J Tsimberidou A Pilot study of gemtuzumab ozogamicin, liposomal daunorubicin, cytarabine and cyclosporine regimen in patients with refractory acute myelogenous leukemia Leuk Res 2003 27 887 891 10.1016/S0145-2126(03)00021-3 12860007 \n16 Petersdorf SH Kopecky KJ Slovak M A phase 3 study of gemtuzumab ozogamicin during induction and postconsolidation therapy in younger patients with acute myeloid leukemia Blood 2013 121 4854 4860 10.1182/blood-2013-01-466706 23591789 \n17 Castaigne S Pautas C Terré C Effect of gemtuzumab ozogamicin on survival of adult patients with de-novo acute myeloid leukaemia (ALFA-0701): a randomized, open-label, phase 3 study Lancet 2012 379 1508 1516 10.1016/S0140-6736(12)60485-1 22482940 \n18 Pilorge S Rigaudeau S Rabian F Fractionated gemtuzumab ozogamicin and standard dose cytarabine produced prolonged second remissions in patients over the age of 55 years with acute myeloid leukemia in late relapse Am J Hematol 2014 89 399 403 10.1002/ajh.23653 24375467 \n19 Chantepie SP Reboursiere E Mear JB Gemtuzumab ozogamicin with intensive chemotherapy in relapsed or refractory acute myeloid leukemia Leuk Lymphoma 2015 56 2326 2330 10.3109/10428194.2014.986478 25393676 \n20 Taksin AL Legrand O Raffoux E High efficacy and safety profile of fractionated doses of Mylotarg as induction therapy in patients with relapsed acute myeloblastic leukemia: a prospective study of the ALFA group Leukemia 2007 21 61 71 10.1038/sj.leu.2404434 17109024 \n21 Breems DA Van Putten WL Huijgens PC Prognostic index for adult patients with acute myeloid leukemia in first relapse J ClinOncol 2005 23 1969 1978 10.1200/JCO.2005.06.027 15632409 \n22 Biggs JC Horowitz MM Gale RP Bone marrow transplants may cure patients with acute leukemia never achieving remission with chemotherapy Blood 1992 80 1090 1093 10.1182/blood.V80.4.1090.bloodjournal8041090 1498326 \n23 Debureaux PE Labopin M Mamez AC Fractionated gemtuzumab ozogamicin in association with high dose chemotherapy: a bridge to allogeneic stem cell transplantation in refractory and relapsed acute myeloid leukemia Bone Marrow Transplant 2019 10.1038/s41409-019-0690 [Epub ahead of print] 10.1038/s41409-019-0690-2 31554931 \n24 Tarlock K Alonzo TA Gerbing RB Gemtuzumab ozogamicin reduces relapse risk in FLT3/ITD acute myeloid leukemia: a report from the Children’s Oncology Group Clin Cancer Res 2016 22 1951 1957 10.1158/1078-0432.CCR-15-1349 26644412 \n25 Pollard JA Alonzo TA Loken M Correlation of CD33 expression level with disease characteristics and response to gemtuzumab ozogamicin containing chemotherapy in childhood AML Blood 2012 119 3705 3711 10.1182/blood-2011-12-398370 22378848 \n26 Khan N Hills RK Virgo P Expression of CD33 is a predictive factor for effect of gemtuzumab ozogamicin at different doses in adult AML Leukemia 2017 31 1059 1068 10.1038/leu.2016.309 27795558 \n27 Thomas X Raffoux E Renneville A Outcome of treatment after first relapse in younger adults with acute myeloid leukemia initially treated by the ALFA-9802 trial LeukRes 2012 36 1112 1118 10.1016/j.leukres.2012.04.020 22647869 \n28 Craddock C Labopin M Pillai S Factors predicting outcome after unrelated donor stem cell transplantation in primary refractory acute myeloid leukemia Leukemia 2011 25 808 813 10.1038/leu.2011.13 21339758 \n29 Daver N Kantarjian H Ravandi F A phase II study of decitabine and gemtuzumab ozogamicin in newly diagnosed and relapsed acute myeloid leukemia and high-risk myelodysplastic syndrome Leukemia 2016 30 268 273 10.1038/leu.2015.244 26365212 \n30 Giles FJ Kantarjian HM Kornblau SM Mylotarg (gemtuzumab ozogamicin) therapy is associated with hepatic venoocclusive disease in patients who have not received stem cell transplantation Cancer 2001 92 406 413 10.1002/1097-0142(20010715)92:2<406::AID-CNCR1336>3.0.CO;2-U 11466696 \n31 Tack DK Letendre L Kamath PS Tefferi A Development of hepatic veno-occlusive disease after Mylotarg infusion for relapsed acute myeloid leukemia Bone Marrow Transplant 2001 28 895 897 10.1038/sj.bmt.1703242 11781652 \n32 Rajvanshi P Shulman HM Sievers EL Hepatic sinusoidal obstruction after gemtuzumab ozogamicin (Mylotarg) therapy Blood 2002 99 2310 2314 10.1182/blood.V99.7.2310 11895761 \n33 McKoy JM Angelotta C Bennett CL Gemtuzumab ozogamicin-associated sinusoidal obstruction syndrome (SOS): an overview from the research on adverse drug events and reports (RADAR) project Leuk Res 2007 31 599 604 10.1016/j.leukres.2006.07.005 16959316\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2035-3006",
"issue": "12(1)",
"journal": "Mediterranean journal of hematology and infectious diseases",
"keywords": "Acute myeloid leukemia; Gemtuzumab ozogamicin; Prognosis; Treatment",
"medline_ta": "Mediterr J Hematol Infect Dis",
"mesh_terms": null,
"nlm_unique_id": "101530512",
"other_id": null,
"pages": "e2020020",
"pmc": null,
"pmid": "32395209",
"pubdate": "2020",
"publication_types": "D016428:Journal Article",
"references": "16959316;12860007;1498326;11895761;24375467;17051246;11781652;27816650;11432892;29524739;26365212;22647869;24092933;31554931;20230405;30076173;23591789;25393676;19880497;22964882;20688393;12451477;15632409;15223637;17906298;22378848;29021230;27795558;17364181;22482940;26644412;21339758;11466696",
"title": "Lyon-University Hospital Experience with Gemtuzumab Ozogamicin Therapy in Acute Myeloid Leukemia: a 'Real-Life' Study.",
"title_normalized": "lyon university hospital experience with gemtuzumab ozogamicin therapy in acute myeloid leukemia a real life study"
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"abstract": "We herein report a case of chemical meningitis that developed after cervical transforaminal steroid injection. A 49-year-old man presented with symptoms of meningitis (severe headache and neck stiffness) after cervical transforaminal steroid injection at the right C5-6 level. The injection solution was a mixture of lidocaine (0.3 mL), hyaluronidase (1 mL), placenta hydrolysate (2 mL), and normal saline (1 mL). The patient developed symptoms of meningitis 2.5 hours after the cervical epidural injection. Cerebrospinal fluid (CSF) analysis was performed 1 day after the injection, and the results showed an elevated white blood cell count at 7106 cells/µL. The patient's CSF analysis findings and symptoms did not differ from those of bacterial meningitis. However, considering that his symptoms developed 2.5 hours after the epidural injection, we believe that the patient developed chemical meningitis; therefore, he was symptomatically treated with an analgesic. Three days after the cervical transforaminal epidural injection, the patient experienced complete relief from the headache and neck stiffness. A Gram stain of the CSF revealed no organisms. Hence, the diagnosis of chemical meningitis was confirmed. Clinicians should be knowledgeable about the risk of this complication.",
"affiliations": "Department of Physical Medicine and Rehabilitation, College of Medicine, Yeungnam University, Namku, Taegu, Republic of Korea.;Department of Physical Medicine and Rehabilitation, College of Medicine, Yeungnam University, Namku, Taegu, Republic of Korea.",
"authors": "Lee|Min Young|MY|;Chang|Min Cheol|MC|https://orcid.org/0000-0002-7629-7213",
"chemical_list": "D013256:Steroids",
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"doi": "10.1177/0300060521993974",
"fulltext": "\n==== Front\nJ Int Med Res\nJ Int Med Res\nIMR\nspimr\nThe Journal of International Medical Research\n0300-0605\n1473-2300\nSAGE Publications Sage UK: London, England\n\n33616459\n10.1177/0300060521993974\n10.1177_0300060521993974\nCase Report\nChemical meningitis after cervical transforaminal epidural steroid injection: a case report\nLee Min Young\nhttps://orcid.org/0000-0002-7629-7213\nChang Min Cheol\nDepartment of Physical Medicine and Rehabilitation, College of Medicine, Yeungnam University, Namku, Taegu, Republic of Korea\nMin Cheol Chang, Department of Physical Medicine and Rehabilitation, College of Medicine, Yeungnam University, 317-1 Daemyungdong, Namku, Taegu 705-717, Republic of Korea. Email: wheel633@gmail.com\n22 2 2021\n2 2021\n49 2 030006052199397417 8 2020\n20 1 2021\n© The Author(s) 2021\n2021\nSAGE Publications\nCreative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) 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 pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).\nWe herein report a case of chemical meningitis that developed after cervical transforaminal steroid injection. A 49-year-old man presented with symptoms of meningitis (severe headache and neck stiffness) after cervical transforaminal steroid injection at the right C5–6 level. The injection solution was a mixture of lidocaine (0.3 mL), hyaluronidase (1 mL), placenta hydrolysate (2 mL), and normal saline (1 mL). The patient developed symptoms of meningitis 2.5 hours after the cervical epidural injection. Cerebrospinal fluid (CSF) analysis was performed 1 day after the injection, and the results showed an elevated white blood cell count at 7106 cells/µL. The patient’s CSF analysis findings and symptoms did not differ from those of bacterial meningitis. However, considering that his symptoms developed 2.5 hours after the epidural injection, we believe that the patient developed chemical meningitis; therefore, he was symptomatically treated with an analgesic. Three days after the cervical transforaminal epidural injection, the patient experienced complete relief from the headache and neck stiffness. A Gram stain of the CSF revealed no organisms. Hence, the diagnosis of chemical meningitis was confirmed. Clinicians should be knowledgeable about the risk of this complication.\n\nChemical meningitis\nepidural injection\nheadache\ncomplication\ncerebrospinal fluid analysis\nGram stain\ntypesetterts2\n==== Body\nIntroduction\n\nIn pain clinics, epidural injection is widely used to manage axial neck and back pain and radicular pain.1,2 Previous studies have shown that epidural injection is effective for treatment of radicular pain or axial pain induced by spinal stenosis or herniated discs.1,2 However, adverse effects such as neural injury, infection, cord or cerebral infarction, hematoma, and lidocaine-induced seizure can occasionally occur.3–5 Moreover, chemical meningitis is a potential adverse effect of epidural injection.6–8 This condition can cause several symptoms, such as headache, neck stiffness, fever, nausea/vomiting, and an altered mental status.6–8 In all reported cases, chemical meningitis occurred after interlaminar lumbar epidural injection.\n\nWe herein describe a patient who developed chemical meningitis after cervical transforaminal epidural steroid injection (TFESI).\n\nCase report\n\nA 49-year-old man underwent TFESI in the right C6 nerve root under C-arm fluoroscopic guidance for control of radicular pain induced by right C5–6 foraminal stenosis due to spondylosis in a local pain clinic. The injected solution was a mixture of lidocaine (0.3 mL), hyaluronidase (1 mL), placenta hydrolysate (2 mL), and normal saline (1 mL). Prior to the TFESI, 0.3 mL of contrast medium had been injected to determine whether the needle tip was placed at the proper location. The patient had a history of avascular necrosis of both femoral heads. In addition, he had undergone left total hip replacement for avascular necrosis of the left femoral head 3 years previously. He had undergone a single TFESI procedure of the right C6 nerve root with the same injection material 3 months previously. However, he developed no adverse effects after the previous TFESI.\n\nAbout 2 hours 30 minutes after the cervical TFESI, the patient developed a severe headache. He visited the emergency department of a university hospital around 2:00 am the day after the epidural injection. Upon arrival, the patient’s body temperature was 37.7°C, and his blood pressure, pulse rate, and respiratory rate were normal. Laboratory tests showed that his white blood cell (WBC) count was elevated to 18,390 cells/µL (reference range, 4,000–10,000 cells/µL) with a neutrophil count of 80.8%, and his C-reactive protein level was elevated to 0.897 mg/dL (reference range, 0.0–0.5 mg/dL). The patient was admitted at the physical medicine and rehabilitation department. Using a numeric rating scale (0 indicating no pain and 10 indicating the worst pain imaginable), the patient gave a rating of 9 for his headache, which was aggravated in the supine position and relieved in the sitting and standing positions. The patient had also developed neck stiffness. His mental status was normal, and no motor or sensory deficits were observed. The deep tendon reflexes in the bilateral upper and lower limbs were normal. Brudzinski’s and Kernig’s signs were negative. Brain computed tomography (CT) and magnetic resonance imaging revealed no abnormalities (Figure 1). In addition, cervical spine magnetic resonance imaging revealed no specific abnormal findings other than right C5–6 foraminal stenosis. Considering the patient’s history, symptoms, and physical examination and imaging findings, we believe that he developed meningitis. Cerebrospinal fluid (CSF) analysis was performed around 1:00 pm (about 11 hours after arriving at the emergency room), revealing an elevated WBC count at 7106 cells/μL (polymorphonuclear cells, 93%; lymphocytes, 6%). Moreover, the patient’s protein and glucose concentrations were 293.95 mg/dL (reference range, 15–45 mg/dL) and 52 mg/dL (reference range, 40–70 mg/dL), respectively. The CSF was cloudy. The patient’s CSF analysis findings and symptoms did not differ from those of bacterial meningitis. However, considering that the symptoms developed 2.5 hours after the epidural injection, we believe that the patient most likely developed chemical meningitis. Dexamethasone was not administered for the treatment of chemical meningitis because the patient had a history of avascular necrosis of the femoral head; instead, only intravenous propacetamol (1 mg) was administered every 4 to 6 hours for 2 days for symptomatic treatment. If the symptoms became aggravated, we planned to start intravenous antibiotic treatment. However, the symptoms were gradually relieved. Three days after the cervical TFESI, the patient experienced complete relief from the headache and neck stiffness. A Gram stain of the CSF revealed no organisms. Additionally, fungal infection was ruled out by the CSF culture result. A follow-up CSF evaluation was conducted 6 days after the epidural injection. The following results were obtained: WBC count, 193 cells/μL (polymorphonuclear cells, 3%; lymphocytes, 73%); protein concentration, 65.38 mg/dL; and glucose concentration, 53 mg/dL. Based on the course of the patient’s symptoms and the CSF analysis findings, the diagnosis of chemical meningitis due to cervical TFESI was confirmed. The patient was discharged on the seventh day after the epidural injection.\n\nFigure 1. Non-contrast brain computed tomography revealed no abnormalities.\n\nDiscussion\n\nWe have herein described a patient who developed chemical meningitis after TFESI. Although dexamethasone and antibiotics were not administered for treatment of the meningitis, the patient experienced complete relief from the symptoms of meningitis 3 days after the epidural injection.\n\nThe mechanism underlying the occurrence of chemical meningitis has not been clearly elucidated. However, it might be caused by allergic or hypersensitivity reactions.9 Although several reports have described chemical meningitis caused by local anesthetics after spinal anesthesia or intrathecal anesthetics and/or steroid injection,10–13 only three cases of chemical meningitis after epidural injection for pain management have been reported.6–8 In 1987, Gutknecht6 reported a case of chemical meningitis after interlaminar epidural injection at the L12–1, L4–5, and L5–S1 levels with methylprednisolone for treatment of lower back pain and lumbar radicular pain. The patient’s symptoms developed 4 hours after the epidural injection, and brain CT revealed air droplets in the subarachnoid space. In 2016, Shah et al.8 reported a case of chemical meningitis with pneumocephalus. The symptoms developed 1.5 hours after the epidural injection of lidocaine, methylprednisolone, and betamethasone. The patient’s symptoms completely resolved 48 hours after the onset of meningitis symptoms. In 2020, Koo and Cho7 reported a case of chemical meningitis with pneumocephalus. The symptoms developed 30 minutes after lumbar interlaminar epidural injection with mepivacaine and dexamethasone. Brain CT revealed multiple small foci of air in the subarachnoid space and ventricle. Two days after initiating symptomatic treatment, the patient’s symptoms completely resolved. Because pneumocephalus was observed in these three cases,6–8 inadvertent dural puncture might have occurred during the procedure. Although there were no findings indicative of pneumocephalus in our case, there was a high risk of unintended intrathecal entry of the injected solution. In addition, a mixture of lidocaine, hyaluronidase, and placenta hydrolysate was used for cervical TFESI. Therefore, which component of the injected solution induced the chemical meningitis remains unclear.\n\nChemical and bacterial meningitis cannot be easily differentiated because their symptoms and laboratory findings are similar. Moreover, the CSF culture results are available after a few days.14 A previous study showed that the symptoms of bacterial meningitis usually develop 2 to 10 days after the procedure, and those of chemical meningitis develop within a few hours.15 The only significant difference between the two disorders is the duration from epidural injection to onset of symptoms. In our case, because the patient’s meningitis symptoms appeared about 2 hours 30 minutes after the cervical TFESI, we considered that our patient had chemical meningitis and therefore did not administer antibiotics. However, because the course of each disorder is not fully elucidated, clinicians should initiate empirical treatment with broad-spectrum antibiotics until the CSF culture results are available.8\n\nIn summary, we have herein reported a case of chemical meningitis that developed after TFESI. Intrathecal injection might have been conducted inadvertently. Hence, clinicians should be knowledgeable about the risk of this complication. In addition, the sensitivity and specificity of physical signs of meningeal inflammation, such as Brudzinski’s and Kernig’s signs, are not high enough to accurately rule in or rule out meningitis. Therefore, when patients complain of meningitis symptoms such as headache, neck stiffness, and nausea/vomiting after epidural injection, the occurrence of chemical meningitis should be considered even in the absence of physical signs of meningeal irritation, and CSF analysis with empirical antibiotic treatment should be initiated as soon as possible.\n\nEthics: The study protocol was approved by the Institutional Review Board of Yeungnam University Hospital. The patient provided written informed consent.\n\nDeclaration of conflicting interest: The authors declare that there is no conflict of interest.\n\nFunding: This work was supported by a National Research Foundation of Korea grant funded by the Korean government (grant no. NRF-2019M3E5D1A02068106).\n\nORCID iD: Min Cheol Chang https://orcid.org/0000-0002-7629-7213\n==== Refs\nReferences\n\n1 Kim MS Lee DG Chang MC. Outcome of transforaminal epidural steroid injection according to severity of cervical foraminal stenosis. World Neurosurg 2018; 110 : e398–e403.29138074\n2 Lee JH Shin KH Park SJ , et al Comparison of clinical efficacy between transforaminal and interlaminar epidural injections in lumbosacral disc herniation: a systematic review and meta-analysis. Pain Physician 2018; 21 : 433–448.30282389\n3 Boudier-Revéret M Chang MC. Segmental spinal myoclonus following a cervical transforaminal epidural steroid injection: a case report [published online ahead of print, 2020 Mar 6]. Am J Phys Med Rehabil 2020; 10.1097/PHM.0000000000001414.\n4 Chang MC. Spinal cord injury by direct damage during CT-guided C7 transforaminal epidural steroid injection. Am J Phys Med Rehabil 2018; 97 : e62–e64.29116946\n5 Shukla AB Vu TN Vorobeychik Y. Permanent paraplegia as a complication of injection of contrast media at L2-L3 vertebral level. Pain Med 2020; 21 : 261–265.31578563\n6 Gutknecht DR. Chemical meningitis following epidural injections of corticosteroids. Am J Med 1987; 82 : 570.\n7 Koo J Cho KT. Pneumocephalus and chemical meningitis after inadvertent dural puncture during lumbar epidural injection. Korean J Neurotrauma 2020; 16 : 67–72.32395453\n8 Shah AK Bilko A Takayesu JK. Epidural steroid injection complicated by intrathecal entry, pneumocephalus, and chemical meningitis. J Emerg Med 2016; 51 : 265–268.27381953\n9 Jha P Stromich J Cohen M , et al A rare complication of trimethoprim-sulfamethoxazole: drug induced aseptic meningitis. Case Rep Infect Dis 2016; 2016 : 3879406.27579194\n10 Besocke AG Santamarina R Romano LM , et al . Bupivacaine induced aseptic meningitis. Neurologia 2007; 22 : 551–552.17641986\n11 Doghmi N Meskine A Benakroute A , et al Aseptic meningitis following a bupivacaine spinal anesthesia. Pan Afr Med J 2017; 27 : 192.28904717\n12 Santos MC De Albuquerque BC Monte RL , et al Outbreak of chemical meningitis following spinal anesthesia caused by chemically related bupivacaine. Infect Control Hosp Epidemiol 2009; 30 : 922–924.19653822\n13 Tateno F Sakakibara R Kishi M , et al Bupivacaine-induced chemical meningitis. J Neurol 2010; 257 : 1327–1329.20306069\n14 Brown EM De Louvois J Bayston R , et al Distinguishing between chemical and bacterial meningitis in patients who have undergone neurosurgery. Clin Infect Dis 2002; 34 : 556–558.11797188\n15 The Korean Society of Infectious Diseases, The Korean Society for Chemotherapy, The Korean Neurological Association, The Korean Neurosurgical Society, and The Korean Society of Clinical Microbiology. Clinical practice guidelines for the management of bacterial meningitis in adults in Korea. Infect Chemother 2012; 44 : 140–163.\n16 Waghdhare S Kalantri A Joshi R , et al Accuracy of physical signs for detecting meningitis: a hospital-based diagnostic accuracy study. Clin Neurol Neurosurg 2010; 112 : 752–757.20615607\n\n",
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"title": "Chemical meningitis after cervical transforaminal epidural steroid injection: a case report.",
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"abstract": "BACKGROUND\nTargeted therapies may impact the natural history of bladder cancer based upon their pharmacokinetics. The Her2/neu receptor tyrosine kinase, overexpressed by half of all primary urothelial carcinomas, has recently been examined as a therapeutic target in bladder cancer in a prospective phase II multicenter trial (NCI-198) that enrolled 109 patients with advanced bladder carcinomas for treatment with trastuzumab in combination with paclitaxel, carboplatin, and gemcitabine. We report on documented isolated Her2/neu positive carcinomatous meningitis in a patient treated with trastuzumab.\n\n\nMETHODS\nA 61-year-old Caucasian man with metastatic bladder cancer was treated with neoadjuvant chemotherapy in combination with trastuzumab with a partial response that was followed by a complete response after surgery. He relapsed with isolated Her2/neu positive carcinomatous meningitis.\n\n\nCONCLUSIONS\nCarcinomatous meningitis in bladder cancer is extremely rare. This is the first case reported of Her2/neu positive carcinomatous meningitis. Disease recurred solely at a sanctuary site, demonstrating that despite the systemic efficacy of trastuzumab in combination with chemotherapy, its inability to enter the central nervous system potentially contributes to the unusual site of disease recurrence.",
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"fulltext": "\n==== Front\nJ Med Case ReportsJournal of Medical Case Reports1752-1947BioMed Central 1752-1947-0003-00000091101991828910.4076/1752-1947-3-9110Research articleCarcinomatous meningitis in a patient with Her2/neu expressing bladder cancer following trastuzumab and chemotherapy: a case report and review of the literature Goodman Oscar B Jr1Milowsky Matthew I 2Kaplan Jodi 2Hussain Maha 3Nanus David M 2dnanus@med.cornell.edu1 Division of Clinical Oncology, Nevada Cancer Institute, Las Vegas, NV 89135, USA2 Division of Hematology and Medical Oncology, Department of Medicine, Weill Medical College of Cornell University – New York Presbyterian Hospital, New York, NY 10021, USA3 Division of Hematology and Medical Oncology, Department of Medicine, University of Michigan, Ann Arbor, MI 48109, USA2009 15 9 2009 3 9110 9110 18 8 2008 8 4 2009 Copyright ©2009 licensee BioMed Central Ltd.2009licensee BioMed Central Ltd.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.Introduction\nTargeted therapies may impact the natural history of bladder cancer based upon their pharmacokinetics. The Her2/neu receptor tyrosine kinase, overexpressed by half of all primary urothelial carcinomas, has recently been examined as a therapeutic target in bladder cancer in a prospective phase II multicenter trial (NCI-198) that enrolled 109 patients with advanced bladder carcinomas for treatment with trastuzumab in combination with paclitaxel, carboplatin, and gemcitabine. We report on documented isolated Her2/neu positive carcinomatous meningitis in a patient treated with trastuzumab.\n\nCase presentation\nA 61-year-old Caucasian man with metastatic bladder cancer was treated with neoadjuvant chemotherapy in combination with trastuzumab with a partial response that was followed by a complete response after surgery. He relapsed with isolated Her2/neu positive carcinomatous meningitis.\n\nConclusion\nCarcinomatous meningitis in bladder cancer is extremely rare. This is the first case reported of Her2/neu positive carcinomatous meningitis. Disease recurred solely at a sanctuary site, demonstrating that despite the systemic efficacy of trastuzumab in combination with chemotherapy, its inability to enter the central nervous system potentially contributes to the unusual site of disease recurrence.\n==== Body\nIntroduction\nThe Her2/neu receptor tyrosine kinase is overexpressed by the majority of all primary invasive urothelial carcinomas [1]. The epidermal growth factor receptor (EGFR) tyrosine kinase family comprises four members (erbB-1 through erbB-4), with erbB-1 (EGFR) and erbB-2 (Her2/neu) expressed in urothelial carcinoma [2]. Following ligand activation, the receptors dimerize resulting in stimulation of multiple signaling pathways, leading to increased cell growth and survival [3]. Her2/neu-mediated signaling activates important oncogenic signaling cascades such as the ras-mitogen activated protein (MAP)-kinase pathway, phospholipase C-gamma (PLC-γ) and phosphatidylinositol-3 (PI-3) kinase [4]. Overexpression of Her2/neu is associated with higher tumor grade and decreased disease-related survival [5], suggesting a specific role for Her2/neu in bladder cancer progression. Gene amplification is rarely observed, in contrast to breast cancer where gene amplification is seen in about 25% of cases and correlates with Her2/neu protein overexpression [6]. Although the mechanism for gene overexpression is not well understood, most evidence points to a transcriptional mechanism mediated by the transcription factor OB2-1 [7]. We report the case of a patient who had a complete response to surgery but relapsed with isolated Her2/neu positive carcinomatous meningitis. Advances in multimodality therapies including neoadjuvant chemotherapy in bladder cancer may alter the natural history of this disease.\n\nThis case represents the first report of Her2/neu positive urothelial carcinomatous meningitis. Several recent studies have implicated Her2/neu overexpression in the progression of urothelial carcinoma. Overexpression of Her2/neu is associated with higher tumor grade and decreased disease-related survival [5]. A cohort study of 245 patients revealed that 45% of the tumors expressed Her2/neu protein and expression correlated with higher grade, tumor recurrence, and decreased survival, especially when co-expressed with ErbB1 or ErbB3 [8]. In a series of 80 consecutive cases of muscle-invasive urothelial bladder carcinomas, Jimenez and colleagues showed that 45% of Her2/neu negative primary disease had Her2/neu positive metastatic nodal disease, while only one case (8%) of Her2/neu positive primary disease manifested with Her-2/neu negative nodal metastatic disease [9]. Collectively, these data indicate that Her2/neu expression may be predictive of tumor aggressiveness and contribute to metastasis.\n\nThe phase II NCI-198 (NCT00005831) trial prospectively evaluated the safety and efficacy of open label trastuzumab in combination with chemotherapy in patients with documented Her2/neu positive advanced urothelial carcinoma. Eligible patients received paclitaxel (200 mg/m2 day 1), carboplatin (AUC 5 day 1), gemcitabine (800 mg/m2 days 1, 8) and trastuzumab (4 mg/kg loading dose, then 2 mg/kg days 1, 8, 15) every 21 days. Of 109 patients screened for the study, 57 (52%) were Her2/neu positive and of these, 44 were eligible for protocol therapy. Her2/neu positive patients had a greater mean number of metastatic sites (2 versus 1, p = 0.014). The overall response rate was 31/44 (70%), with a median time to progression of 9.3 months and a median survival of 14.1 months [10]. These findings compared favorably with historical controls, for example, gemcitabine/cisplatin-treated patients had an overall response rate of 49%, a median progression-free survival of 7.7 months and a median survival of 14.0 months [11,12]. Notably, however, nearly one-third of these patients had tumors that were not metastatic, possibly explaining the similar median survival between the two groups [10].\n\nCase presentation\nA 61-year-old Caucasian man with a history of benzidine exposure and tobacco use presented with intermittent gross hematuria over the previous 2 months. Cystoscopy and transurethral resection of the bladder revealed a 2 cm high grade muscle invasive urothelial carcinoma. A staging computed tomography (CT) scan identified extensive retroperitoneal lymphadenopathy with a conglomerate of nodes at the aortic bifurcation measuring 7.6 × 3.5 cm and with the largest individual node found at the level of the right common iliac bifurcation measuring 2.7 × 3.9 cm. Biopsy of this lymph node confirmed metastatic urothelial carcinoma. Immunohistochemical analysis of the primary tumor revealed 3+ Her2/neu positivity, while fluorescence in situ hybridization (FISH) analysis revealed no Her2/neu gene amplification. The patient was enrolled on the NCI-198 trial with paclitaxel (200 mg/m2 day 1), carboplatin (AUC 5 day 1), gemcitabine (800 mg/m2 days 1, 8) and trastuzumab (4 mg/kg loading dose, then 2 mg/kg days 1, 8, 15) every 21 days. After six cycles, a CT scan demonstrated a partial response in the retroperitoneum, with the right common iliac node measuring 1.2 × 0.8 cm, corresponding to a >95% decrease in volume [13]. He then underwent a radical cystectomy and extensive lymph node dissection with removal of 69 nodes, revealing pT2aN0M0 high grade disease and resulting in a surgically rendered complete response.\n\nTwo weeks postoperatively, the patient developed paresthesia and proprioceptive deficits in his hands and feet that were attributed to nerve compression that occurred during prolonged surgery. Nerve conduction studies revealed an axonal sensorimotor polyradicular neuropathy with demyelinating features. Neurologic symptoms did not improve with gabapentin therapy and a lumbar puncture five months postoperatively revealed carcinoma cells. Immunohistochemical analysis of the cerebrospinal fluid (CSF) revealed 2+ Her2/neu expression (Figure 1). Magnetic resonance imaging (MRI) of the brain confirmed diffuse leptomeningeal enhancement along with cerebellar metastases (Figure 2). A CT scan of the chest, abdomen and pelvis revealed no evidence of systemic recurrence. An Ommaya reservoir was placed and the patient received four weeks of biweekly intrathecal methotrexate therapy, resulting in negative repeat cytologic CSF evaluations after two weeks of therapy. After week four, intrathecal therapy was stopped due to urosepsis, and a repeat cytologic evaluation one week later revealed recurrent carcinomatous meningitis. The patient refused further chemotherapy and died two weeks later.\n\nFigure 1 Immunohistochemical staining of cerebrospinal fluid revealing a 2+ Her2/neu positive malignant cell (arrow).\n\nFigure 2 T1-weighted brain magnetic resonance imaging demonstrating both leptomeningeal enhancement (arrowheads) and a cerebellar metastasis (arrow).\n\nDiscussion\nFollowing treatment, our patient relapsed with isolated Her2/neu positive carcinomatous meningitis. Carcinomatous meningitis is rare in bladder cancer [14]-[16]. Trastuzumab does not cross the blood–brain barrier [17], suggesting that targeting Her2/neu positive systemic disease may alter the natural history of bladder carcinoma metastasis predisposing to the onset and progression of central nervous system (CNS) disease. Her2/neu expression in breast cancer CNS metastases is highly concordant with systemic disease status, with 93% of patients with Her2/neu positive primary tumors also expressing Her2/neu in CNS metastatic disease [18]. Given similar concordance in bladder cancer [9] as well as the fact that Her2/neu expression is more common in bladder cancer than in breast cancer [5], it remains to be seen if the incidence of carcinomatous meningitis due to leptomeningeal bladder metastases will increase in the setting of trastuzumab therapy as a consequence of systemic therapeutic efficacy and poor CNS bioavailability.\n\nDespite the presence of Her2/neu positive disease, it is possible that the initial clinical response and subsequent CNS relapse in our patient was not due to trastuzumab but to carboplatin, gemcitabine and paclitaxel. Of the chemotherapeutic drugs, carboplatin has the highest CNS penetration with a peak CSF/plasma ratio of 28% but with significant interpatient variability (range 17-46%) [19], while gemcitabine and paclitaxel have markedly lower CNS penetration, with CSF:plasma ratios of 6.7% [20] and less than 1.8% (the limit of detection) [21], respectively. Thus, it is likely that the combination of paclitaxel, carboplatin and gemcitabine (TCG) has little if any therapeutic efficacy for CNS disease, while TCG in combination with trastuzumab may augment the systemic disease response, thereby predisposing to CNS relapse.\n\nConclusions\nCarcinomatous meningitis is exceedingly rare in bladder cancer, with only a few cases reported. Trastuzumab may alter the natural history of bladder carcinoma metastasis predisposing to CNS relapse. This likely reflects the potential efficacy of the therapy as well as an inability of chemobiologic therapy to penetrate the CNS. As a consequence of its systemic therapeutic efficacy and poor CNS bioavailability, trastuzumab may alter the natural history of bladder carcinoma resulting in an unusual presentation of metastatic disease.\n\nAbbreviations\nCNS: central nervous system; CSF: cerebrospinal fluid; EGFR: epidermal growth factor receptor; FISH: fluorescence in situ hybridization; MAP: mitogen activated protein; MRI: magnetic resonance imaging; NCI: National Cancer Institute; PI-3: phosphatidylinositol-3; PLC-γ: phospholipase C-gamma; TCG: paclitaxel, carboplatin and gemcitabine.\n\nConsent\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\nCompeting interests\nThe authors declare that they have no competing interests.\n\nAuthors' contributions\nOG assisted in the acquisition and analysis of the data, and in drafting the manuscript. MM analyzed the data and assisted in drafting the manuscript. JK assisted in the acquisition and analysis of the data. MH aided in the conception and design of this study, and in the acquisition and analysis of the data. DN assisted in the acquisition and analysis of the data, as well as drafting the manuscript. All authors have read and approved the final manuscript.\n\nAcknowledgements\nThe authors acknowledge John Crapanzano, M.D. for his assistance in data acquisition. We acknowledge the patient and his family for his courageous participation on a clinical trial and fight against cancer. This work was supported by the Cancer Therapy Evaluation Program (CTEP), Cancer Center Core Grant 5P30CA046592-17, the John & Suzanne Munn Endowed Research Fund, and Genentech.\n==== Refs\nLatif Z Watters AD Dunn I Grigor K Underwood MA Bartlett JM HER2/neu gene amplification and protein overexpression in G3 pT2 transitional cell carcinoma of the bladder: a role for anti-HER2 therapy? Eur J Cancer 2004 40 56 63 10.1016/j.ejca.2003.08.027 14687790 \nRajjayabun PH Keegan PE Lunec L Mellon JK erbB receptor expression patterns in human bladder cancer Urology 2005 66 196 200 10.1016/j.urology.2005.01.046 15992892 \nSebastian S Settleman J Reshkin SJ Azzariti A Bellizzi A Paradiso A The complexity of targeting EGFR signalling in cancer: From expression to turnover Biochim Biophys Acta 2006 1766 120 139 16889899 \nReese DM Slamon DJ HER-2/neu signal transduction in human breast and ovarian cancer Stem Cells 1997 15 1 8 10.1002/stem.150001 9007217 \nKruger S Weitsch G Buttner H Matthiensen A Bohmer T Marquardt T Sayk F Feller AC Bohle A HER2 overexpression in muscle-invasive urothelial carcinoma of the bladder: prognostic implications Int J Cancer 2002 102 514 518 10.1002/ijc.10731 12432555 \nCoogan CL Estrada CR Kapur S Bloom KJ HER-2/neu protein overexpression and gene amplification in human transitional cell carcinoma of the bladder Urology 2004 63 786 790 10.1016/j.urology.2003.10.040 15072912 \nHollywood DP Hurst HC Targeting gene transcription: a new strategy to down-regulate c-erbB-2 expression in mammary carcinoma Br J Cancer 1995 71 753 757 7710940 \nChow NH Chan SH Tzai TS Ho CL Liu HS Expression profiles of ErbB family receptors and prognosis in primary transitional cell carcinoma of the urinary bladder Clin Cancer Res 2001 7 1957 1962 11448910 \nJimenez RE Hussain M Bianco FJ JrVaishampayan U Tabazcka P Sakr WA Pontes JE Wood DP JrGrignon DJ Her-2/neu overexpression in muscle-invasive urothelial carcinoma of the bladder: prognostic significance and comparative analysis in primary and metastatic tumors Clin Cancer Res 2001 7 2440 2447 11489824 \nHussain M MacVicar GR Petrylak D Dunn R Vaishampayan U Lara PN Chatta G Nanus DM Glode LM Trump D Chen H Smith DC National Cancer Institute Trastuzumab, paclitaxel, carboplatin, and gemcitabine in advanced Her2/neu positive urothelial carcinoma: Results of a multi-center phase II NCI trial J Clin Oncol 2007 25 2218 2224 10.1200/JCO.2006.08.0994 17538166 \nvon der Maase H Hansen SW Roberts JT Dogliotti L Oliver T Moore MJ Bodrogi I Albers P Knuth A Lippert CM Kerbrat P Sanchez Rovira P Wersall P Cleall SP Roychowdhury DF Tomlin I Visseren-Grul CM Conte PF Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large, randomized, multinational, multicenter, phase III study J Clin Oncol 2000 18 3068 3077 11001674 \nvon der Maase H Sengelov L Roberts JT Ricci S Dogliotti L Oliver T Moore MJ Zimmermann A Arning M Long-term survival results of a randomized trial comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin, plus cisplatin in patients with bladder cancer J Clin Oncol 2005 23 4602 4608 10.1200/JCO.2005.07.757 16034041 \nTherasse P Arbuck SG Eisenhauer EA Wanders J Kaplan RS Rubinstein L Verweij J Van Glabbeke M van Oosterom AT Christian MC Gwyther SG New guidelines to evaluate the response to treatment in solid tumors European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada J Natl Cancer Inst 2000 92 205 216 10.1093/jnci/92.3.205 10655437 \nEng C Cunningham D Quade BJ Schwamm L Kantoff PW Skarin AT Meningeal carcinomatosis from transitional cell carcinoma of the bladder Cancer 1993 72 553 557 10.1002/1097-0142(19930715)72:2<553::AID-CNCR2820720236>3.0.CO;2-Z 8319186 \nHara Y Kobayashi Y Goto K Tozuka K Tokue A Mochizuki M [A case of carcinomatous meningitis from transitional cell carcinoma of the urinary bladder] Hinyokika Kiyo 1994 40 1113 1117 7863865 \nMatsushita M Kawasaki Y Okada Y [Carcinomatous meningitis from urothelial carcinoma of bladder and ureter: case report] Nippon Hinyokika Gakkai Zasshi 2004 95 817 819 15624493 \nPestalozzi BC Brignoli S Trastuzumab in CSF J Clin Oncol 2000 18 2349 2351 10829059 \nFuchs IB Loebbecke M Buhler H Stoltenburg-Didinger G Heine B Lichtenegger W Schaller G HER2 in brain metastases: issues of concordance, survival, and treatment J Clin Oncol 2002 20 4130 4133 10.1200/JCO.2002.04.016 12351617 \nRiccardi R Riccardi A Di Rocco C Carelli G Tartaglia RL Lasorella A Servidei T Mastrangelo R Cerebrospinal fluid pharmacokinetics of carboplatin in children with brain tumors Cancer Chemother Pharmacol 1992 30 21 24 10.1007/BF00686480 1586976 \nKerr JZ Berg SL Dauser R Nuchtern J Egorin MJ McGuffey L Aleksic A Blaney S Plasma and cerebrospinal fluid pharmacokinetics of gemcitabine after intravenous administration in nonhuman primates Cancer Chemother Pharmacol 2001 47 411 414 10.1007/s002800000253 11391856 \nRowinsky EK Burke PJ Karp JE Tucker RW Ettinger DS Donehower RC Phase I and pharmacodynamic study of taxol in refractory acute leukemias Cancer Res 1989 49 4640 4647 2568175\n\n",
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"title": "Carcinomatous meningitis in a patient with Her2/neu expressing bladder cancer following trastuzumab and chemotherapy: a case report and review of the literature.",
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"abstract": "CONCLUSIONS\nThe concomitant use of weekly nab-paclitaxel and carboplatin with concurrent radiotherapy was demonstrated to be a safe therapeutic approach in this phase I trial of 10 evaluable patients with stage III NSCLC.Despite the lack of systemic glucocorticoids, there were no reported infusion reactions or cases of peripheral neuropathy in this trial, both of which are known to occur with the use of paclitaxel.\n\n\nBACKGROUND\nUnresectable stage III non-small cell lung cancer (NSCLC) has a 5-year survival rate of 20%, and concurrent chemoradiotherapy results in significant toxicity with the use of current chemotherapeutic agents. nab-Paclitaxel was approved by the U.S. Food and Drug Administration in October 2012 for use along with carboplatin in advanced NSCLC. This study was undertaken to determine the maximum tolerated dose and dose-limiting toxicities (DLTs) of weekly nab-paclitaxel given in combination with carboplatin and concurrent radiotherapy in patients with unresectable stage III NSCLC.\n\n\nMETHODS\nEscalating doses of once-weekly nab-paclitaxel were given along with once-weekly carboplatin area under the plasma concentration time curve (AUC) of 2 and concurrent radiotherapy 66 Gy in 33 fractions, followed by 2 cycles of carboplatin and nab-paclitaxel consolidation chemotherapy.\n\n\nRESULTS\nEleven patients were enrolled and received treatment per protocol, with 10 evaluable for efficacy and toxicity. At dose level 1 (nab-paclitaxel 60 mg/m(2)), 2 DLTs were observed: esophagitis and radiation dermatitis. Six patients were enrolled at dose level 0 (nab-paclitaxel 40 mg/m(2)) with no DLTs. Nine of 10 evaluable patients had a partial response.\n\n\nCONCLUSIONS\nConcurrent chemoradiotherapy with nab-paclitaxel 40 mg/m(2) and carboplatin AUC 2 is a safe and well-tolerated therapeutic regimen in patients with stage III NSCLC. A separate phase I/II study to evaluate the efficacy of this regimen is under way.",
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"abstract": "Older men, particularly those with low serum testosterone (T) levels, might benefit from T therapy to improve bone mineral density (BMD) and reduce fracture risk. Concerns exist, however, about the impact of T therapy on the prostate in older men. We hypothesized that the combination of T and finasteride (F), a 5 alpha-reductase inhibitor, might increase BMD in older men without adverse effects on the prostate. Seventy men aged 65 yr or older, with a serum T less than 12.1 nmol/liter on two occasions, were randomly assigned to receive one of three regimens for 36 months: T enanthate, 200 mg im every 2 wk with placebo pills daily (T-only); T enanthate, 200 mg every 2 wk with 5 mg F daily (T+F); or placebo injections and pills (placebo). Low BMD was not an inclusion criterion. We obtained serial measurements of BMD of the lumbar spine and hip by dual x-ray absorptiometry. Prostate-specific antigen (PSA) and prostate size were measured at baseline and during treatment to assess the impact of therapy on the prostate. Fifty men completed the 36-month protocol. By an intent-to-treat analysis including all men for as long as they contributed data, T therapy for 36 months increased BMD in these men at the lumbar spine [10.2 +/- 1.4% (mean percentage increase from baseline +/- SEM; T-only) and 9.3 +/- 1.4% (T+F) vs. 1.3 +/- 1.4% for placebo (P < 0.001)] and in the hip [2.7 +/- 0.7% (T-only) and 2.2 +/- 0.7% (T+F) vs. -0.2 +/- 0.7% for placebo, (P < or = 0.02)]. Significant increases in BMD were seen also in the intertrochanteric and trochanteric regions of the hip. After 6 months of therapy, urinary deoxypyridinoline (a bone-resorption marker) decreased significantly compared with baseline in both the T-only and T+F groups (P < 0.001) but was not significantly reduced compared with the placebo group. Over 36 months, PSA increased significantly from baseline in the T-only group (P < 0.001). Prostate volume increased in all groups during the 36-month treatment period, but this increase was significantly less in the T+F group compared with both the T-only and placebo groups (P = 0.02). These results demonstrate that T therapy in older men with low serum T increases vertebral and hip BMD over 36 months, both when administered alone and when combined with F. This finding suggests that dihydrotestosterone is not essential for the beneficial effects of T on BMD in men. In addition, the concomitant administration of F with T appears to attenuate the impact of T therapy on prostate size and PSA and might reduce the chance of benign prostatic hypertrophy or other prostate-related complications in older men on T therapy. These findings have important implications for the prevention and treatment of osteoporosis in older men with low T levels.",
"affiliations": "Department of Medicine, Veterans Affairs-Puget Sound Health Care System, Seattle, WA 98195, USA.",
"authors": "Amory|John K|JK|;Watts|Nelson B|NB|;Easley|Kirk A|KA|;Sutton|Paul R|PR|;Anawalt|Bradley D|BD|;Matsumoto|Alvin M|AM|;Bremner|William J|WJ|;Tenover|J Lisa|JL|",
"chemical_list": "D004791:Enzyme Inhibitors; D013739:Testosterone; D018120:Finasteride; C004648:testosterone enanthate; D017430:Prostate-Specific Antigen",
"country": "United States",
"delete": false,
"doi": "10.1210/jc.2003-031110",
"fulltext": null,
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"issn_linking": "0021-972X",
"issue": "89(2)",
"journal": "The Journal of clinical endocrinology and metabolism",
"keywords": null,
"medline_ta": "J Clin Endocrinol Metab",
"mesh_terms": "D000368:Aged; D015519:Bone Density; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors; D018120:Finasteride; D006801:Humans; D008297:Male; D009929:Organ Size; D011467:Prostate; D017430:Prostate-Specific Antigen; D013739:Testosterone",
"nlm_unique_id": "0375362",
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"pages": "503-10",
"pmc": null,
"pmid": "14764753",
"pubdate": "2004-02",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D016449:Randomized Controlled Trial; D013487:Research Support, U.S. Gov't, P.H.S.",
"references": null,
"title": "Exogenous testosterone or testosterone with finasteride increases bone mineral density in older men with low serum testosterone.",
"title_normalized": "exogenous testosterone or testosterone with finasteride increases bone mineral density in older men with low serum testosterone"
} | [
{
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"activesubstancename": "TESTOSTERONE ENANTHATE"
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"abstract": "Pulmonary artery (PA) leiomyosarcoma (PAL) is a rare but extremely malignant tumor of the cardiovascular system, which is often misdiagnosed as pulmonary thromboembolism. Although the early detection and surgical resection improves patient survival, the benefits of adjuvant therapy are not well understood. The current study presents the case of a patient with primary PAL who underwent surgical resection along with three courses of chemotherapy. Despite these interventions, the patient experienced recurrence of the PAL within four months following treatment. The patient received localized radiotherapy and subsequently achieved a stable disease state. This case indicates that radiotherapy may offer a benefit to PAL patients, particularly those who do not respond to chemotherapy.",
"affiliations": "Department of Radiotherapy, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China.;Department of Radiotherapy, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China.;Department of Radiotherapy, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China.;Department of Radiotherapy, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China.",
"authors": "Lv|Yin|Y|;Wang|Fan|F|;Qian|Wenchuan|W|;Sun|Guoping|G|",
"chemical_list": null,
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"doi": "10.3892/ol.2015.2957",
"fulltext": "\n==== Front\nOncol LettOncol LettOLOncology Letters1792-10741792-1082D.A. Spandidos 10.3892/ol.2015.2957ol-09-04-1545ArticlesTreatment of a recurrent pulmonary artery leiomyosarcoma with a combination of surgery, chemotherapy, and radiotherapy: A case report and literature review LV YIN WANG FAN QIAN WENCHUAN SUN GUOPING Department of Radiotherapy, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. ChinaCorrespondence to: Dr Guoping Sun, Department of Radiotherapy, The First Affiliated Hospital of Anhui Medical University, 281 Jixi Road, Hefei, Anhui 230022, P.R. China, E-mail: sunguoping@ahmu.edu.cn4 2015 11 2 2015 11 2 2015 9 4 1545 1548 14 4 2014 12 12 2014 Copyright © 2015, Spandidos Publications2015This is an open-access article licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported License. The article may be redistributed, reproduced, and reused for non-commercial purposes, provided the original source is properly cited.Pulmonary artery (PA) leiomyosarcoma (PAL) is a rare but extremely malignant tumor of the cardiovascular system, which is often misdiagnosed as pulmonary thromboembolism. Although the early detection and surgical resection improves patient survival, the benefits of adjuvant therapy are not well understood. The current study presents the case of a patient with primary PAL who underwent surgical resection along with three courses of chemotherapy. Despite these interventions, the patient experienced recurrence of the PAL within four months following treatment. The patient received localized radiotherapy and subsequently achieved a stable disease state. This case indicates that radiotherapy may offer a benefit to PAL patients, particularly those who do not respond to chemotherapy.\n\npulmonary arteryleiomyosarcomaradiotherapypulmonary thromboembolis\n==== Body\nIntroduction\nPulmonary artery leiomyosarcoma (PAL) is an extremely rare primary sarcoma of the pulmonary artery with an incidence rate of ~0.001–0.03% (1,2). Due to its low incidence, PAL is often undetected and frequently misdiagnosed as chronic pulmonary embolism (3,4). However, the majority of PAL tumors are highly malignant, highlighting the requirement for improved methods of detecting and treating these tumors (2). Early detection and surgical resection of the primary PAL lesion have been demonstrated to improve patient survival; the median survival time of all patients was 1.5 months, but this was prolonged to 10 months with surgery such as pneumonectomy or mere excision of the tumor from the vascular bed (5). However recurrence of PAL often occurs following surgical resection (6). The benefits of adjuvant therapy for PAL tumors have not been clearly defined, particularly in the case of recurrent tumors. A previous report showed that a patient with primary leiomyosarcoma, who was receiving adjuvant therapy, survived for as long as 20 months (7). The current study presents the case of a patient with recurrent PAL. Written informed consent was obtained from the patient.\n\nCase report\nA 42-year-old male presented to The First Affiliated Hospital of Anhui Medical University (Hefei, China) with repeated and progressive dizziness and chest pain for the previous five months, and with one occurrence of syncope in this period. The patient was admitted to the Department of Cardiac Surgery on 25th October 2012. Upon physical examination the patient’s blood pressure was 100/70 mmHg (normal range, 100–140/60–90 mmHg; 1 mmHg=0.133 kPa) and his heart rate was 78 beats/minute. No cyanosis was detectable when the patient was in a supine position. The patient’s jugular vein filling time was normal, and a slightly enlarged left heart border was observed. A grade III systolic murmur was identified between the second and third left intercostal space. Cardiac exam indicated that the patient’s pulmonary valve closing (P2) was normal, with no signs of hyperactivity. The liver was not accessible for examination. Blood tests revealed no abnormalities in the patient’s blood cell counts or blood chemistry. Echocardiography (ECG) indicated that the right atrium and right ventricle had significantly increased in size. ECG also revealed abnormal Q waves of and ST-T changes in the II, III and aVF leads. The pulmonary trunk and left distal pulmonary artery were filled by light reflection. The patient experienced severe tricuspid regurgitation, with estimated pulmonary artery pressure of 126 mmHg (normal range, 12–18 mmHg).\n\nBased on these symptoms, an initial diagnosis of pulmonary thromboembolism with severe pulmonary hypertension and a minor pericardial effusion was determined. A computed tomography (CT) angiogram revealed thrombosis of the pulmonary artery, left pulmonary artery, and the right pulmonary artery branch. The diameters of ascending aortic and descending aortic were 28.9×30.9 mm and 23.5×23.4 mm, respectively (normal diameters, <35×35 mm) (Figs. 1A and 2A). A vascular ultrasound indicated that the portal vein, splenic vein, inferior vena cava, and bilateral iliac vein of the patient were all normal.\n\nBased on the initial diagnosis of pulmonary thromboembolism, the patient was scheduled to undergo a pulmonary embolectomy in combination with tricuspid valvuloplasty under extracorporeal circulation. However, during surgery, a mass predominantly involving the right pulmonary artery and its branches was observed. No similar mass was identified in the left pulmonary artery. Tissue samples of the mass were extracted from the patient and frozen for subsequent analysis. Analysis of the frozen tissue section indicated that the mass was a malignant emboli of unknown origin. Therefore, tumor cystectomy and tricuspid valvuloplasty was performed.\n\nUpon postoperative pathological analysis, the mass was identified as a spindle cell sarcoma, indicating that the mass was a PAL tumor (Fig. 1B). Immunohistochemical analysis showed that the cells of the mass were positive for CD117 and negative for cytokeratin (CK) 7, CK20, Villln, CD34, DOG-1, CK10 and CD10. Proliferation analysis by Ki-67 staining indicated that 40% of the cells were actively proliferating in the tumor. Following the removal of the tumor, the patient’s dizziness and chest pain were eliminated and no abnormal lesions were detected in the right pulmonary artery under enhanced CT examination on 30th November 2012 (Fig. 2B). Following surgery, the patient received three cycles of chemotherapy with 100 mg epirubicin and 20 mg cisplatin under a d1-5 regimen on 11th December 2012, 12th January 2013, and 19th February 2013, respectively.\n\nOn 20th March 2013, the patient returned to the hospital presenting with dizziness and congestion. Enhanced chest CT examination revealed a soft tissue mass of 3.5×3.4×3.6 cm in size in the right pulmonary artery (Fig. 3A). The mass was diagnosed as a recurrent PAL tumor. The patient’s Karnofsky Performance Score (KPS) was 60, indicating that the quality of life was compromised (8). The patient was subsequently treated with intensity modulated conformal radiotherapy (diffusion-tensor; 32 Gy/16 f) at the right pulmonary artery between 28th March and 16th April 2013. Following therapy, the patient reported relief of dizziness and congestion. Enhanced chest CT examination revealed that the tumor mass had reduced in size to 3.1×3.2×3.3 cm (Fig. 3B). The patient received additional radiotherapy (30 sessions) with a dosage each time of 2 Gy administered five times a week for six weeks until May 2, 2013 (Fig. 5). During the course of radiotherapy, the patient reported chest pain when swallowing food, which was due to radiation esophagitis; this was relieved following symptomatic treatment (160,000 units gentamicin, three times a day, orally). The patient did not receive any additional chemotherapy after radiotherapy. By 27th May 2013, enhanced chest CT examination indicated that the mass had further reduced in size to 3.0×3.2×2.7 cm (Fig. 4A). Following this course of radiotherapy, the patient reported relatively good health with minor tightness of the chest after climbing stairs quickly, and had regained the ability to perform mild to moderate physical labor. Enhanced chest CT examination on 8th August 2013 showed further reduction of the PAL mass to a size of 2.5×2.2×2.4 cm (Fig. 4B). Bronchial ultrasound examination of the patient’s abdomen revealed no further abnormalities. The patient was followed up four times over a period of eight months. The tumor appeared to be stable for the first three sessions. However, at the fourth follow-up tumor growth was observed. At this time, the patient’s quality of life was substantially improved, with a KPS of 90.\n\nDiscussion\nPrimary leiomyosarcoma of the pulmonary artery is an extremely rare tumor, and the majority of PAL patients present with non-specific symptoms including dyspnea, chest pain, coughing and hemoptysis (5,9). As a result, many PAL patients are initially misdiagnosed with pulmonary thromboembolism (10–13), as demonstrated in the present case. However, as PAL is an extremely aggressive tumor, more thorough diagnoses must be considered when patients present with such symptoms, so as to minimize the risk of misdiagnosing a malignant PAL lesion. In particular, the diagnosis of a tumor must be considered in the absence of predisposing factors for thromboembolism, in cases were the patient’s symptoms persist or recur despite adequate anticoagulation, and also in cases with a unilateral distribution of a massive perfusion defect (14).\n\nIn the current study, PAL was diagnosed incidentally during surgery and the tumor was subsequently resected, which potentially contributed to the favorable prognosis of this patient, as early detection and surgical resection has been shown to improve PAL survival rates (6). Patients typically develop PAL between the ages of 40 and 60 years. Thus patients within this age range should be subjected to a thorough clinical examination, and diagnoses including PAL, thromboembolism and lung cancer must be considered. For maximal benefit, definitive diagnostic methods must be employed to differentiate between these possibilities, and immediate surgical intervention must be performed in cases of cancer.\n\nThe diagnosis of PAL is frequently delayed due to the nonspecific symptoms, therefore, these neoplasms are often well developed before they are clinically diagnosed (2,9,15,16). If the tumor is detected early and can be completely resected, surgery offers the best opportunity to eliminate PAL without residual disease. However, despite aggressive surgical intervention, the mean patient survival time of 1.5 months has been shown to improve by only a few months, to 10 months, due to the aggressive nature of advanced PAL lesions (5,17). Another study showed that the median survival time of all patients was 1.5 months, but this was prolonged to 10 months following surgery such as pneumonectomy or mere excision of the tumor from the vascular bed (5). This is also shown in the current study, as the PAL recurred within four months of surgical resection, indicating that the patient’s disease had already reached an aggressive state at the time of diagnosis.\n\nTo date, little evidence is available indicating that adjuvant therapies, such as chemotherapy or radiotherapy, are beneficial for patients with recurrent PAL (6,18–20). Furthermore, only a few reports have demonstrated the successful treatment of recurrent PAL, primarily through surgery or stenting (6,19,20). Notably, in the current study, radiotherapy was found to effectively inhibit and control the development of PAL in the patient. This case suggests that radiotherapy may benefit PAL patients, including those who have failed to respond to surgery and/or chemotherapy. However, why radiotherapy was effective in this case, but ineffective in previous reports, remains unclear. A more extensive analysis of the factors that influenced the present patient’s response to radiotherapy may aid in informing future treatment strategies for recurrent PAL.\n\nChemotherapy and radiotherapy are two major adjuvant therapeutic methods for the treatment of malignancies (21,22). The therapeutic efficacy of these two methods varies depending on the specific tumor. In the present case, the patient did not respond well to chemotherapy, however, did respond to radiotherapy. This is in contrast to the majority of reports describing PAL, in which adjuvant therapies had been largely ineffective, as PAL is considered not sensitive to radiotherapy and chemotherapy. Therefore, there is insufficient evidence to conclude that radiotherapy is more efficient than chemotherapy in treating recurrent PAL. Nonetheless, the clinical results presented in this case report indicate that the use of radiotherapy to treat PAL warrants further investigation to better assess the efficacy of this therapeutic strategy.\n\nFigure 1 (A) Major vascular reconstruction was performed by Computed tomography angiography (10/27/2012). (B) Representative pathological image following surgery on 11/14/2012. Tissue was stained using hematoxylin and eosin.\n\nFigure 2 A representative computed tomography image (A) prior to surgery (10/27/2012), and (B) following surgery (11/30/2012). Arrows indicate the location of the pulmonary artery leiomyosarcoma tumor prior to surgery.\n\nFigure 3 (A) Representative CT image (3/20/2013) showing recurrence of the pulmonary artery leiomyosarcoma tumor (arrow). (B) Representative CT image during radiotherapy (04/16/2013) showing a slight reduction in the size of the tumor (arrow). CT, computed tomography.\n\nFigure 4 (A) Representative CT image after 25 days of radiotherapy at 5/27/2013. (B) Representative CT image recorded during follow up three months following radiotherapy (8/08/2013), illustrating further reduction of the tumor mass (arrow). CT, computed tomography.\n\nFigure 5 The planning of radiotherapy. (A) The target delineation and (B) the iso-dose curves of clinical target volume.\n==== Refs\nReferences\n1 Hoffmeier A Semik M Fallenberg EM Scheld HH Leiomyosarcoma of the pulmonary artery - a diagnostic chameleon Eur J Cardiothorac Surg 20 1049 1051 2001 10.1016/S1010-7940(01)00939-3 11675204 \n2 Dumont P Diot P Aupart MR Toumieux B Leiomyosarcoma of the pulmonary artery Ann Thorac Surg 66 2089 2091 1998 10.1016/S0003-4975(98)01070-4 9930499 \n3 Adeli SH Nemati B Jandaghi M Riahi MM Hosseinzadeh F Salarvand F Pulmonary Hypertension due to a Pulmonary Artery Leiomyosarcoma: A Case Report Case Rep Pulmonol 2013 160619 2013 23607029 \n4 Widera E Sulica R Pulmonary artery sarcoma misdiagnosed as chronic thromboembolic pulmonary hypertension Mt Sinai J Med 72 360 364 2005 16358159 \n5 Krüger I Borowski A Horst M de Vivie ER Theissen P Gross-Fengels W Symptoms, diagnosis, and therapy of primary sarcomas of the pulmonary artery Thorac Cardiovasc Surg 38 91 95 1990 10.1055/s-2007-1014001 2190350 \n6 Okada K Okada M Yamamoto S Successful resection of a recurrent leiomyosarcoma of the pulmonary trunk Ann Thorac Surg 55 1009 1012 1993 10.1016/0003-4975(93)90139-9 8466316 \n7 Kashima K1 Yamashita E Mataki H Yotsumoto G Nomoto M Sonoda M Hanada S Primary leiomyosarcoma of the pulmonary artery: a case of a 20-month survivor after incomplete surgical resection Intern Med 51 75 78 2012 10.2169/internalmedicine.51.6259 22214627 \n8 Milstein JM Cohen ME Sinks LF The influence and reliability of neurologic assessment and Karnofsky performance score on prognosis Cancer 56 7 Suppl 1834 1836 1985 10.1002/1097-0142(19851001)56:7+<1834::AID-CNCR2820561323>3.0.CO;2-A 4027921 \n9 Mayer E Kriegsmann J Gaumann A Surgical treatment of pulmonary artery sarcoma J Thorac Cardiovasc Surg 121 77 82 2001 10.1067/mtc.2001.111423 11135162 \n10 Allen S Todd J Copley S Al-Nahhas A F-18 FDG uptake in bilateral pulmonary artery leiomyosarcomata, one mimicking a pulmonary embolus Clin Nucl Med 30 418 419 2005 10.1097/01.rlu.0000162964.84907.3f 15891297 \n11 Minakata K Konishi Y Matsumoto M Aota M Nonaka M Yamada N Primary leiomyosarcoma of the pulmonary artery mimicking massive pulmonary thromboembolism Jpn Circ J 64 783 784 2000 10.1253/jcj.64.783 11059620 \n12 Mazzucco A Luciani GB Bertolini P Faggian G Morando G Ghimenton C Primary leiomyosarcoma of the pulmonary artery: diagnostic and surgical implications Ann Thorac Surg 57 222 225 1994 10.1016/0003-4975(94)90407-3 8279900 \n13 Myerson PJ Myerson DA Katz R Lawson JP Gallium imaging in pulmonary artery sarcoma mimicking pulmonary embolism: case report J Nucl Med 17 893 895 1976 966057 \n14 Eng J Murday AJ Leiomyosarcoma of the pulmonary artery Ann Thorac Surg 53 905 906 1992 10.1016/0003-4975(92)91468-O 1570996 \n15 Babatasi G Massetti M Galateau F Khayat A Leiomyosarcoma of the pulmonary veins extending into the left atrium or left atrial leiomyosarcoma: multimodality therapy J Thorac Cardiovasc Surg 116 665 667 1998 10.1016/S0022-5223(98)70186-2 9766605 \n16 Rafal RB Nichols JN Markisz JA Pulmonary artery sarcoma: diagnosis and postoperative follow-up with gadolinium-diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging Mayo Clin Proc 70 173 176 1995 10.4065/70.2.173 7845042 \n17 Tanaka I Masuda R Inoue M Primary pulmonary-artery sarcoma. Report of a case with complete resection and graft replacement and review of 47 surgically treated cases reported in the literature Thorac Cardiovasc Surg 42 64 68 1994 10.1055/s-2007-1016459 8184399 \n18 Yamada N Kamei S Yasuda F Isaka N Yada I Nakano T Primary leiomyosarcoma of the pulmonary artery confirmed by catheter suction biopsy Chest 113 555 556 1998 10.1378/chest.113.2.555 9498986 \n19 Omura A Tobe S Yoshida K Yamaguchi M Surgical treatment for recurrent pulmonary artery sarcoma Gen Thorac Cardiovasc Surg 56 28 31 2008 10.1007/s11748-007-0183-x 18213469 \n20 Meckel S Buitrago-Téllez C Herrmann R Jacob AL Stenting for pulmonary artery stenosis due to a recurrent primary leiomyosarcoma J Endovasc Ther 10 141 146 2003 10.1583/1545-1550(2003)010<0141:SFPASD>2.0.CO;2 12751946 \n21 Zaric B Stojsic V Tepavac A Adjuvant chemotherapy and radiotherapy in the treatment of non-small cell lung cancer (NSCLC) J Thorac Dis 5 Suppl 4 S371 S377 2013 24102009 \n22 Chaulagain CP Ng J Goodman MD Saif MW Adjuvant therapy of pancreatic cancer JOP 14 119 122 2013 23474550\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1792-1074",
"issue": "9(4)",
"journal": "Oncology letters",
"keywords": "leiomyosarcoma; pulmonary artery; pulmonary thromboembolis; radiotherapy",
"medline_ta": "Oncol Lett",
"mesh_terms": null,
"nlm_unique_id": "101531236",
"other_id": null,
"pages": "1545-1548",
"pmc": null,
"pmid": "25788998",
"pubdate": "2015-04",
"publication_types": "D016428:Journal Article",
"references": "15891297;11135162;11675204;23607029;2190350;4027921;966057;7845042;16358159;8279900;8466316;22214627;24102009;9930499;12751946;9498986;9766605;23474550;18213469;8184399;11059620;1570996",
"title": "Treatment of a recurrent pulmonary artery leiomyosarcoma with a combination of surgery, chemotherapy, and radiotherapy: A case report and literature review.",
"title_normalized": "treatment of a recurrent pulmonary artery leiomyosarcoma with a combination of surgery chemotherapy and radiotherapy a case report and literature review"
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"activesubstancename": "EPIRUBICIN"
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{
"abstract": "Hepatosplenic T cell lymphoma (HSTCL) is a rare subtype of peripheral non-Hodgkin lymphoma, of which 20% of cases are associated with chronic immunosuppression. It often occurs in patients with inflammatory bowel disease treated with immunomodulating medications such a thiopurines or TNF-alpha inhibitors. Cytopenias are commonly seen but autoimmune hemolytic anemia (AIHA) is rare. Here we present a young male with longstanding ulcerative colitis on chronic azathioprine, exhibiting several rare features of HSTCL. He initially presented with refractory AIHA, thrombocytopenia, and massive splenomegaly, requiring splenectomy. Histologic examination of his spleen confirmed diagnosis of HSTCL. Approximately 3 months after diagnosis, he was found to have leukemic transformation, representing a secondary malignancy.",
"affiliations": "Department of Medicine, University of Connecticut, 263 Farmington Ave, Farmington, CT, 06030, USA. mmavilia@uchc.edu.;Department of Medicine, University of Connecticut, 263 Farmington Ave, Farmington, CT, 06030, USA.;Department of Pathology, Hartford Hospital, Hartford, CT, USA.;Department of Gastroenterology and Hepatology, University of Connecticut, Farmington, CT, USA.",
"authors": "Mavilia|Marianna|M|;McAuliffe|Agnes|A|;Hafeez|Safina|S|;Vaziri|Haleh|H|",
"chemical_list": "D007166:Immunosuppressive Agents; D001379:Azathioprine",
"country": "Japan",
"delete": false,
"doi": "10.1007/s12328-018-0869-x",
"fulltext": null,
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"issn_linking": "1865-7265",
"issue": "11(5)",
"journal": "Clinical journal of gastroenterology",
"keywords": "Autoimmune hemolytic anemia; Inflammatory bowel disease; Lymphoma; TNF alpha inhibitor; Thiopurines",
"medline_ta": "Clin J Gastroenterol",
"mesh_terms": "D000328:Adult; D000743:Anemia, Hemolytic; D001379:Azathioprine; D001706:Biopsy; D002908:Chronic Disease; D003093:Colitis, Ulcerative; D017809:Fatal Outcome; D006801:Humans; D016867:Immunocompromised Host; D007166:Immunosuppressive Agents; D008107:Liver Diseases; D008113:Liver Neoplasms; D016399:Lymphoma, T-Cell; D008279:Magnetic Resonance Imaging; D008297:Male; D000072078:Positron Emission Tomography Computed Tomography; D013160:Splenic Neoplasms; D013163:Splenomegaly; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "101477246",
"other_id": null,
"pages": "364-370",
"pmc": null,
"pmid": "29766398",
"pubdate": "2018-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "22527855;23083012;21122554;23826928;26680795;27099586;8314255;10716161;21941193;26688667;23876844;11921021;11957154;17710549;22047938;24621284;21082951;23032984;19070390;24399013;26317456;19837455;9295981;29114832;12803128;9111428;19749141",
"title": "Hepatosplenic T cell lymphoma: a unifying entity in a patient with hemolytic anemia, massive splenomegaly, and liver dysfunction.",
"title_normalized": "hepatosplenic t cell lymphoma a unifying entity in a patient with hemolytic anemia massive splenomegaly and liver dysfunction"
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"abstract": "Ileitis and colitis are known complications of capecitabine when used in patients with gastrointestinal cancers. However, to our knowledge, pneumatosis intestinalis (PI) has not previously been reported with this medication. We present a patient with breast cancer, without any metastases to the gastrointestinal tract, who presented with persistent diarrhea 4 weeks after discontinuing adjuvant capecitabine, which was found to be due to PI. As she had no other risk factors or identifiable causes, her PI was attributed to a delayed reaction to capecitabine. This case highlights the need to consider PI earlier in the differential diagnosis in patients with breast cancer who present with unexplained diarrhea after recent discontinuation of capecitabine.",
"affiliations": "Department of Medicine, Jersey Shore University Medical Center, Hackensack Meridian Health, Neptune, NJ 07753, USA.;Department of Medicine, Jersey Shore University Medical Center, Hackensack Meridian Health, Neptune, NJ 07753, USA.;Department of Medicine, Jersey Shore University Medical Center, Hackensack Meridian Health, Neptune, NJ 07753, USA.;Department of Medicine, Jersey Shore University Medical Center, Hackensack Meridian Health, Neptune, NJ 07753, USA.;Department of Medicine, Jersey Shore University Medical Center, Hackensack Meridian Health, Neptune, NJ 07753, USA.",
"authors": "Khan|Taimoor|T|;Mujtaba|Mohamed|M|;Flores|Marcus S|MS|;Nahum|Kenneth|K|;Carson|Michael P|MP|",
"chemical_list": null,
"country": "Canada",
"delete": false,
"doi": "10.14740/wjon1186",
"fulltext": "\n==== Front\nWorld J OncolWorld J OncolElmer PressWorld Journal of Oncology1920-45311920-454XElmer Press 10.14740/wjon1186Case ReportA Case of Pneumatosis Intestinalis With Pneumoperitoneum as a Potential Delayed Adverse Effect of Capecitabine Pneumotosis Intestinalis With CapecitabineKhan Taimoor aMujtaba Mohamed aFlores Marcus S. aNahum Kenneth aCarson Michael P. aba Department of Medicine, Jersey Shore University Medical Center, Hackensack Meridian Health, Neptune, NJ 07753, USAb Corresponding Author: Michael P. Carson, Department of Medicine, Jersey Shore University Medical Center, Hackensack Meridian Health, 1945 Route 33, Neptune, NJ 07753, USA. Email: Michael.carson@hackensackmeridian.org6 2019 29 6 2019 10 3 151 152 28 1 2019 18 4 2019 Copyright 2019, Khan et al.2019This article is distributed under the terms of the Creative Commons Attribution Non-Commercial 4.0 International License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Ileitis and colitis are known complications of capecitabine when used in patients with gastrointestinal cancers. However, to our knowledge, pneumatosis intestinalis (PI) has not previously been reported with this medication. We present a patient with breast cancer, without any metastases to the gastrointestinal tract, who presented with persistent diarrhea 4 weeks after discontinuing adjuvant capecitabine, which was found to be due to PI. As she had no other risk factors or identifiable causes, her PI was attributed to a delayed reaction to capecitabine. This case highlights the need to consider PI earlier in the differential diagnosis in patients with breast cancer who present with unexplained diarrhea after recent discontinuation of capecitabine.\n\nCapecitabinePneumatosis intestinalisIntestinal perforation\n==== Body\nIntroduction\nCapecitabine is an oral pyrimidine analog prodrug used for the treatment of metastatic breast cancer as a single agent or in combination. Ileitis, colitis, and bowel perforation have been reported as complications of capecitabine in patients with gastrointestinal (GI) malignancies while actively receiving the medication [1-4]. However, to our knowledge, pneumatosis intestinalis (PI) has not previously been reported with this medication. Herein, we present what to our knowledge is the first case of PI as a delayed adverse reaction after therapy with capecitabine for breast cancer.\n\nCase Report\nA woman in her 70’s was diagnosed with right-sided, intraductal grade 3 triple-negative stage III breast cancer and treated with neoadjuvant chemotherapy consisting of doxorubicin, cyclophosphamide, and paclitaxel. Five months after beginning her neoadjuvant therapy, she underwent a mastectomy, and adjuvant therapy with capecitabine was initiated 3 months after her surgery. One week after the end of the first 21-day cycle, she presented to her oncologist with nausea and severe watery diarrhea. Her outpatient evaluation included stool ova and parasites, C. difficile stool antigen, and colonoscopy, all of which were negative. Based on her apparent intolerance, capecitabine was discontinued. It was decided that she would not receive additional adjuvant therapy, and because of that decision, genetic testing for dihydropyrimidine dehydrogenase (DPD) mutations was not ordered. DPD is the principle enzyme required for 5-flourouracil (5-FU) metabolism and 3-5% of patients have a mutation leading to partial deficiency that can lead to acute and early-onset toxicity, which would need to be considered if she relapsed and required additional chemotherapy.\n\nFour weeks after discontinuing capecitabine, the patient presented to the emergency department due to continued diarrhea. Her vital signs were: blood pressure (BP) 115/66 mm Hg; heart rate 89/min; respiratory rate 18/min; temperature 97.8 F; and pulse ox 98% on room air. Her physical examination was unremarkable, and her abdomen was normal. Due to prerenal azotemia she was admitted to the hospital and treated with intravenous fluids and anti-diarrheal medications. The morning after admission, she noted abdominal discomfort and a computed tomography (CT) scan of the abdomen/pelvis was ordered, which revealed extensive PI and free intraperitoneal air. She was taken to the operating room that night, and when the surgeons entered the abdomen, they were met with a rush of air consistent with pneumoperitoneum. PI and thickening were present in 4 feet of the jejunum, and there was a 1 cm area of inflamed jejunum that was presumed to be the site of perforation. No bowel was resected as there was no obvious perforation, her post-operative course was unremarkable, and her diarrhea resolved.\n\nDiscussion\nPI is the presence of gas within the wall of the bowel and has multiple synonyms, including pseudopneumatosis, intestinal emphysema, and bullous emphysema of intestine [5]. In a study of ninety-seven patients with a CT diagnosis of PI, the location of pneumatosis was as follows: 46% colon, 27% small bowel, 5% stomach, and 7% both small and large bowel [6]. PI is classified as either primary (idiopathic) or secondary, with the latter making up about 85% of all PI cases. Causes of secondary PI classically include: 1) Mechanical irritation or increased intra-abdominal pressure such as surgery, trauma, colonoscopy; 2) Respiratory disease such as chronic obstructive pulmonary disease (COPD); 3) Bacterial overgrowth producing gas in the intestine lumen, which penetrates the luminal wall through damaged mucosa; and 4) Chemotherapy, as the associated mucositis causes distortion of the bowel wall integrity and increases permeability. Patients with PI may be asymptomatic, but common symptoms include abdominal pain (53%), distention (42%), nausea and vomiting (14%), and bloody stool (13%) [7].\n\nIn general, the diagnosis of PI can be made via endoscopy or radiography. On plain radiographs of the abdomen, the classic finding is grape-like clusters or honeycomb-shaped radiolucencies along the wall of the intestine [7]. CT scans, as used in our patient, can also establish the diagnosis, determine the underlying etiology, and evaluate for associated complications. The management of PI depends upon the severity. Emergent laparotomy is indicated for PI presenting with any one of the following: signs of peritonitis, acidosis with PH < 7.3, lactate > 2.0 mg/dL, or portal venous gas. Conservative management is recommended for asymptomatic patients.\n\nCase reports associate PI with patients actively receiving chemotherapy including vincristine, fluorouracil, and platinum alkylating agents, but it has not been reported as a delayed reaction [8, 9]. In our case, the patient received capecitabine, an oral pyrimidine analog prodrug that is hepatically metabolized to 5-FU and commonly used to treat multiple malignancies including breast cancer. Diarrhea is a common adverse effect, and while it has been reported to continue for up to 5 days after discontinuation, capecitabine typically poses little risk for continued toxicity beyond this point. In patients with colon cancer, capecitabine-associated ileitis and colitis have been reported, but to our knowledge capecitabine-associated large bowel perforation has not [1-4]. This case is unique because, to our knowledge, it is the first to associate capecitabine with PI and breast cancer, and only the third case of capecitabine associated bowel perforation in a patient treated for breast cancer. Our patient did not have any tumor burden on the bowel, and the previous reports of perforation were during active treatment with the drug, whereas our patient presented nearly 4 weeks after discontinuing the medication [10]. This late presentation is unexpected based on the mechanism and half-life of less than 1 h. This case demonstrates the need to consider PI in patients treated with capecitabine within the past month who present with persistent diarrhea without other apparent clinical causes.\n\nWe have no acknowledgement.\n\nFinancial Disclosure\nWe have received no financial support in developing this manuscript.\n\nConflict of Interest\nWe have no conflict of interest or relationship to disclose.\n\nInformed Consent\nNot applicable.\n\nAuthor Contributions\nAll authors contributed to the preparation, review, and submission of this article.\n==== Refs\nReferences\n1 Temel T Meric Ozgenel S Canaz F Arik D Tokmak S Harmanci Ozakyol A A case report of ulcerative colitis induced by therapy of colorectal carcinoma Euroasian J Hepatogastroenterol 2015 5 2 115 117 10.5005/jp-journals-10018-1148 29201706 \n2 Lee SF Chiang CL Lee AS Wong FC Tung SY Severe ileitis associated with capecitabine: Two case reports and review of the literature Mol Clin Oncol 2015 3 6 1398 1400 10.3892/mco.2015.635 26807255 \n3 Maggo G Grover SC Grin A Capecitabine induced colitis Pathol Res Pract 2014 210 9 606 608 10.1016/j.prp.2014.05.005 24947412 \n4 Radwan R Namelo WC Robinson M Brewster AE Williams GL Ileitis secondary to oral capecitabine treatment? Case Rep Med 2012 2012 154981 10.1155/2012/154981 23251164 \n5 Hanna P Kassir R Tarek D Bassile B Saint-Eve P Elias B Pneumatosis cystoidis intestinalis presenting as bowel perforation, a rare entity Int J Surg Case Rep 2016 20 7 9 10.1016/j.ijscr.2015.12.047 26774416 \n6 Morris MS Gee AC Cho SD Limbaugh K Underwood S Ham B Schreiber MA Management and outcome of pneumatosis intestinalis Am J Surg 2008 195 5 679 682 discussion 682-673 10.1016/j.amjsurg.2008.01.011 18424288 \n7 Wu LL Yang YS Dou Y Liu QS A systematic analysis of pneumatosis cystoids intestinalis World J Gastroenterol 2013 19 30 4973 4978 10.3748/wjg.v19.i30.4973 23946603 \n8 Groninger E Hulscher JB Timmer B Tamminga RY Broens PM Free air intraperitoneally during chemotherapy for acute lymphoblastic leukemia: consider pneumatosis cystoides intestinalis J Pediatr Hematol Oncol 2010 32 2 141 143 10.1097/MPH.0b013e3181ced397 20147849 \n9 Kirmanidis M Boulas KA Paraskeva A Kariotis I Barettas N Kariotis S Keskinis C et al Extensive colonic pneumatosis in a patient on adjuvant chemotherapy after right colectomy for primary terminal ileum lymphoma: A decision-making process between surgical and non-surgical management Int J Surg Case Rep 2018 52 84 88 10.1016/j.ijscr.2018.09.050 30336386 \n10 Cowman S Stebbing J Tuthill M Large bowel perforation associated with capecitabine treatment for breast cancer Ann Oncol 2008 19 8 1510 1511 10.1093/annonc/mdn397 18562326\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1920-4531",
"issue": "10(3)",
"journal": "World journal of oncology",
"keywords": "Capecitabine; Intestinal perforation; Pneumatosis intestinalis",
"medline_ta": "World J Oncol",
"mesh_terms": null,
"nlm_unique_id": "101564097",
"other_id": null,
"pages": "151-152",
"pmc": null,
"pmid": "31312282",
"pubdate": "2019-06",
"publication_types": "D002363:Case Reports",
"references": "18424288;18562326;20147849;23251164;23946603;24947412;26774416;26807255;29201706;30336386",
"title": "A Case of Pneumatosis Intestinalis With Pneumoperitoneum as a Potential Delayed Adverse Effect of Capecitabine.",
"title_normalized": "a case of pneumatosis intestinalis with pneumoperitoneum as a potential delayed adverse effect of capecitabine"
} | [
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"companynumb": "US-HIKMA PHARMACEUTICALS USA INC.-US-H14001-19-46562",
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"activesubstancename": "CAPECITABINE"
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"... |
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"abstract": "BACKGROUND\nRomosozumab reportedly increases bone mineral density (BMD) potently but might adversely affect cardiovascular disease (CVD). We evaluated the efficacy of romosozumab in osteoporotic HD patients with a high risk of fracture.\n\n\nMETHODS\nThis was a single-center 1-year study in Japanese HD patients. Among 96 HD romosozumab-treated HD patients with high risk of fracture, 76 HD patients completed 1 year of subcutaneous administration of romosozumab (210 mg/4 weeks) for 1 year. Romosozumab-untreated HD patients (n = 55) were also included. Changes in BMD and serum markers, together with fracture occurrence, and CVD events, were monitored.\n\n\nRESULTS\nDuring romosozumab treatment of 76 HD patients, BMD time-dependently increased significantly by 15.3% ± 12.9% at the lumbar spine (L1-4), and 7.2% ± 8.3% at the femoral neck at 1 year. Serum BAP and total P1NP increased significantly and serum TRACP-5b decreased at 4 weeks. Fragility fractures occurred in three (3.8%) patients. Hypocalcemia occurred at 4-48 weeks despite the increased dosing of active vitamin-D derivatives, but without any symptom. New CVD events occurred in 5.2% of romosozumab-treated HD patients and10.9% in romosozumab-untreated HD patients.\n\n\nCONCLUSIONS\nBMD was increased significantly during romosozumab treatment at the lumbar spine, and the femoral neck, respectively, at 1 year in HD patients. Hypocalcemia occurred but without any intolerable event. There was no apparent increase in CVD events during 1 year of study, suggesting romosozumab as a promising agent for HD patients with severe osteoporosis.",
"affiliations": "Department of Orthopedics, Inoue Hospital, Osaka, Japan.;Renal Center, Ohno Memorial Hospital, 1-26-10, Minami-Horie, Nishi-ku, Osaka, Osaka, 550-0015, Japan. m-inaba@ohno.or.jp.;Department of Metabolism, Endocrinology, and Molecular Medicine, Osaka City University Medical School, Osaka, Japan.;Department of Metabolism, Endocrinology, and Molecular Medicine, Osaka City University Medical School, Osaka, Japan.;Renal Center, Ohno Memorial Hospital, 1-26-10, Minami-Horie, Nishi-ku, Osaka, Osaka, 550-0015, Japan.;Renal Center, Inoue Hospital, Osaka, Japan.",
"authors": "Sato|Motohiko|M|;Inaba|Masaaki|M|;Yamada|Shinsuke|S|;Emoto|Masanori|M|;Ohno|Yoshiteru|Y|;Tsujimoto|Yoshihiro|Y|",
"chemical_list": "D000911:Antibodies, Monoclonal; D050071:Bone Density Conservation Agents; C557282:romosozumab",
"country": "Japan",
"delete": false,
"doi": "10.1007/s00774-021-01253-y",
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"issn_linking": "0914-8779",
"issue": "39(6)",
"journal": "Journal of bone and mineral metabolism",
"keywords": "Bone mineral density; Hemodialysis; Osteoporosis; Romosozumab; TRACP-5b",
"medline_ta": "J Bone Miner Metab",
"mesh_terms": "D000911:Antibodies, Monoclonal; D015519:Bone Density; D050071:Bone Density Conservation Agents; D006801:Humans; D007564:Japan; D010024:Osteoporosis; D006435:Renal Dialysis",
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"pmid": "34324082",
"pubdate": "2021-11",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": "33409990",
"title": "Efficacy of romosozumab in patients with osteoporosis on maintenance hemodialysis in Japan; an observational study.",
"title_normalized": "efficacy of romosozumab in patients with osteoporosis on maintenance hemodialysis in japan an observational study"
} | [
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"companynumb": "JP-AMGEN-JPNSP2021187916",
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... |
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"abstract": "A number of recent articles have reviewed the problem of hypoprothrombinemia and bleeding associated with antibiotic therapy. We report three cases in which bleeding is believed to be related to a prolonged prothrombin time secondary to cefoperazone therapy. Reports of coagulopathies such as these are increasing in number and call attention to the need to monitor the prothrombin time during cefoperazone therapy.",
"affiliations": null,
"authors": "Freedy|H R|HR|;Cetnarowski|A B|AB|;Lumish|R M|RM|;Schafer|F J|FJ|",
"chemical_list": "D002438:Cefoperazone",
"country": "United States",
"delete": false,
"doi": "10.1177/106002808602000413",
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"issn_linking": "0012-6578",
"issue": "20(4)",
"journal": "Drug intelligence & clinical pharmacy",
"keywords": null,
"medline_ta": "Drug Intell Clin Pharm",
"mesh_terms": "D000368:Aged; D001778:Blood Coagulation Disorders; D002438:Cefoperazone; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011517:Prothrombin Time",
"nlm_unique_id": "0212457",
"other_id": null,
"pages": "281-3",
"pmc": null,
"pmid": "3698824",
"pubdate": "1986-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Cefoperazone-induced coagulopathy.",
"title_normalized": "cefoperazone induced coagulopathy"
} | [
{
"companynumb": "US-PFIZER INC-2016203658",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
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{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "METRONIDAZOLE"
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... |
{
"abstract": "OBJECTIVE\nThe authors aimed to determine the prevalence of drug-induced long QT at admission to a public psychiatric hospital and to document the associated factors using a cross-sectional approach.\n\n\nMETHODS\nAll ECG recordings over a 5-year period were reviewed for drug-induced long QT (heart-rate corrected QT ≥500 ms and certain or probable drug imputability) and associated conditions. Patients with drug-induced long QT (N=62) were compared with a sample of patients with normal ECG (N=143).\n\n\nRESULTS\nAmong 6,790 inpatients, 27.3% had abnormal ECG, 1.6% had long QT, and 0.9% qualified as drug-induced long QT case subjects. Sudden cardiac death was recorded in five patients, and torsade de pointes was recorded in seven other patients. Relative to comparison subjects, patients with drug-induced long QT had significantly higher frequencies of hypokalemia, hepatitis C virus (HCV) infection, HIV infection, and abnormal T wave morphology. Haloperidol, sertindole, clotiapine, phenothiazines, fluoxetine, citalopram (including escitalopram), and methadone were significantly more frequent in patients with drug-induced long QT. After adjustment for hypokalemia, HCV infection, HIV infection, and abnormal T wave morphology, the effects of haloperidol, clotiapine, phenothiazines, and citalopram (including escitalopram) remained statistically significant. Receiver operating characteristic curve analysis based on the number of endorsed factors per patient indicated that 85.5% of drug-induced long QT patients had two or more factors, whereas 81.1% of patients with normal ECG had fewer than two factors.\n\n\nCONCLUSIONS\nDrug-induced long QT and arrhythmia propensity substantially increase when specific psychotropic drugs are administered to patients with hypokalemia, abnormal T wave morphology, HCV infection, and HIV infection.",
"affiliations": null,
"authors": "Girardin|François R|FR|;Gex-Fabry|Marianne|M|;Berney|Patricia|P|;Shah|Dipen|D|;Gaspoz|Jean-Michel|JM|;Dayer|Pierre|P|",
"chemical_list": "D014150:Antipsychotic Agents; D015283:Citalopram; D008691:Methadone",
"country": "United States",
"delete": false,
"doi": "10.1176/appi.ajp.2013.12060860",
"fulltext": null,
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"issn_linking": "0002-953X",
"issue": "170(12)",
"journal": "The American journal of psychiatry",
"keywords": null,
"medline_ta": "Am J Psychiatry",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D014150:Antipsychotic Agents; D016022:Case-Control Studies; D015283:Citalopram; D003430:Cross-Sectional Studies; D016757:Death, Sudden, Cardiac; D004562:Electrocardiography; D005260:Female; D006801:Humans; D007297:Inpatients; D008133:Long QT Syndrome; D008297:Male; D001523:Mental Disorders; D008691:Methadone; D008875:Middle Aged; D015995:Prevalence; D012307:Risk Factors; D013557:Switzerland; D016171:Torsades de Pointes",
"nlm_unique_id": "0370512",
"other_id": null,
"pages": "1468-76",
"pmc": null,
"pmid": "24306340",
"pubdate": "2013-12",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Drug-induced long QT in adult psychiatric inpatients: the 5-year cross-sectional ECG Screening Outcome in Psychiatry study.",
"title_normalized": "drug induced long qt in adult psychiatric inpatients the 5 year cross sectional ecg screening outcome in psychiatry study"
} | [
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"companynumb": "CH-CIPLA LTD.-2015CH07453",
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"patient": {
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ESCITALOPRAM OXALATE"
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"drugadditional": nu... |
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"abstract": "Pulmonary Arterial Hypertension (PAH), a rare complication of HHT is associated with poor outcome. There are no trials to date that have investigated whether pulmonary vasodilator therapy improves hemodynamics or survival in this disease.\n\n\n\nTo determine whether pulmonary vasodilator therapy improves survival, exercise capacity, or hemodynamics in HHT patients with pre-capillary PH.\n\n\n\nWe performed a before-and-after observational study on a multicenter cohort of subjects with HHT-PAH who received intravenous prostanoid therapy. We then conducted a systematic review, searching Medline and EMBASE through December 2019. Studies that enrolled HHT-PAH subjects and reported treatment outcomes were selected. PROSPERO #158179.\n\n\n\nTwenty-one articles were selected. Studies were before-and-after observational studies, case reports, and case series. Among all subjects with HHT-PAH, both mPAP (65 ± 19 pre-treatment vs 51 ± 16 mmHg post-treatment p = 0.04) and PVR (12 ± 6 pre-treatment vs 8 ± 4 WU post-treatment p = 0.01) improved with treatment. The mPAP improved with either oral (57 ± 17 pre-treatment versus 44 ± 13 mmHg post-treatment, p = 0.03) or intravenous (80 ± 15 pre-treatment versus 64 ± 16 mmHg post-treatment, p = 0.017) therapy. PVR also improved with either oral (10 ± 4 pre-treatment versus 6 ± 3 WU post-treatment, p = 0.004) or intravenous (17 ± 5 pre-treatment versus 10 ± 4 WU post-treatment, p = 0.04) therapy. Survival among HHT-PAH patients who received oral or intravenous therapy was not different (p = 0.2). Unadjusted survival among HHT-PAH patients was longer than that of IPAH patients (p = 0.008). There was no difference in side effects among HHT-PAH patient who received oral or intravenous therapy (p = 0.1).\n\n\n\nPulmonary vasodilator therapy is effective in improving hemodynamics of subjects with HHT-PAH and was not associated with increased risk of side effects.",
"affiliations": "Division of Allergy, Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, Boston University School of Medicine, Boston, MA, USA; Center for Thoracic Cancers, Division of Thoracic Surgery, Department of Surgery, Massachusetts General Hospital, Boston, MA, USA. Electronic address: ericdabston@gmail.com.;Division of Allergy, Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, Boston University School of Medicine, Boston, MA, USA; Division of Pulmonary, Critical Care, And Sleep Medicine, Department of Medicine, Tufts Medical Center, Boston, MA, USA.;Division of Pulmonary and Critical Care Medicine, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.;Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, MA, USA.;Center for Thoracic Cancers, Division of Thoracic Surgery, Department of Surgery, Massachusetts General Hospital, Boston, MA, USA.;Division of Pulmonary, Critical Care, And Sleep Medicine, Department of Medicine, Tufts Medical Center, Boston, MA, USA.;Division of Allergy, Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, Boston University School of Medicine, Boston, MA, USA.",
"authors": "Abston|Eric|E|;Hon|Stephanie|S|;Rodriguez-Lopez|Josanna|J|;Moll|Matt|M|;Lanuti|Michael|M|;Farber|Harrison W|HW|;Wilson|Kevin C|KC|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1016/j.pupt.2021.102033",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1094-5539",
"issue": "68()",
"journal": "Pulmonary pharmacology & therapeutics",
"keywords": null,
"medline_ta": "Pulm Pharmacol Ther",
"mesh_terms": "D065627:Familial Primary Pulmonary Hypertension; D006439:Hemodynamics; D006801:Humans; D006976:Hypertension, Pulmonary; D015337:Multicenter Studies as Topic; D064887:Observational Studies as Topic; D000081029:Pulmonary Arterial Hypertension; D013683:Telangiectasia, Hereditary Hemorrhagic",
"nlm_unique_id": "9715279",
"other_id": null,
"pages": "102033",
"pmc": null,
"pmid": "33895318",
"pubdate": "2021-06",
"publication_types": "D016428:Journal Article; D000078182:Systematic Review",
"references": null,
"title": "Treatment of pulmonary hypertension in patients with Hereditary Hemorrhagic Telangiectasia - A case series and systematic review.",
"title_normalized": "treatment of pulmonary hypertension in patients with hereditary hemorrhagic telangiectasia a case series and systematic review"
} | [
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"companynumb": "US-GLAXOSMITHKLINE-US2021GSK208438",
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"actiondrug": "5",
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"activesubstancename": "EPOPROSTENOL SODIUM"
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"abstract": "Understanding why some multidrug-resistant tuberculosis cases are not detected by rapid phenotypic and genotypic routine clinical tests is essential to improve diagnostic assays and advance toward personalized tuberculosis treatment. Here, we combine whole-genome sequencing with single-colony phenotyping to identify a multidrug-resistant strain that had infected a patient for 9 years. Our investigation revealed the failure of rapid testing and genome-based prediction tools to identify the multidrug-resistant strain. The false-negative findings were caused by uncommon rifampicin and isoniazid resistance mutations. Although whole-genome sequencing data helped to personalize treatment, the patient developed extensively drug-resistant tuberculosis, highlighting the importance of coupling new diagnostic methods with appropriate treatment regimens.",
"affiliations": "Instituto de Biomedicina de Valencia-Consejo Superior de Investigaciones Científicas.;Instituto de Biomedicina de Valencia-Consejo Superior de Investigaciones Científicas.;Instituto de Biomedicina de Valencia-Consejo Superior de Investigaciones Científicas.;Instituto de Biomedicina de Valencia-Consejo Superior de Investigaciones Científicas.;Instituto de Biomedicina de Valencia-Consejo Superior de Investigaciones Científicas.;Unidad Mixta \"Infección y Salud Pública,\" Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunitat Valenciana (FISABIO)-Conselleria de Sanitat Universal i Salut Pública.;Genomics and Health Unit, FISABIO Public Health, Consorci Hospital General Universitari de València, Valencia, Spain.;Departamento de Neumología, Consorci Hospital General Universitari de València, Valencia, Spain.;Servicio de Microbiología, Consorci Hospital General Universitari de València, Valencia, Spain.;Instituto de Biomedicina de Valencia-Consejo Superior de Investigaciones Científicas.",
"authors": "Cancino-Muñoz|Irving|I|;Moreno-Molina|Miguel|M|;Furió|Victoria|V|;Goig|Galo A|GA|;Torres-Puente|Manuela|M|;Chiner-Oms|Álvaro|Á|;Villamayor|Luis M|LM|;Sanz|Francisco|F|;Guna-Serrano|María Remedio|MR|;Comas|Iñaki|I|",
"chemical_list": "D000995:Antitubercular Agents; D001426:Bacterial Proteins; D007538:Isoniazid; D012293:Rifampin",
"country": "United States",
"delete": false,
"doi": "10.1093/infdis/jiz104",
"fulltext": "\n==== Front\nJ Infect DisJ. Infect. DisjidThe Journal of Infectious Diseases0022-18991537-6613Oxford University Press US 10.1093/infdis/jiz104jiz104Major Articles and Brief ReportsBacteriaCryptic Resistance Mutations Associated With Misdiagnoses of Multidrug-Resistant Tuberculosis Cancino-Muñoz Irving 13Moreno-Molina Miguel 1Furió Victoria 1Goig Galo A 1Torres-Puente Manuela 1Chiner-Oms Álvaro 2Villamayor Luis M 3Sanz Francisco 4Guna-Serrano María Remedio 5Comas Iñaki 161 Instituto de Biomedicina de Valencia–Consejo Superior de Investigaciones Científicas2 Unidad Mixta “Infección y Salud Pública,” Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunitat Valenciana (FISABIO)–Conselleria de Sanitat Universal i Salut Pública3 Genomics and Health Unit, FISABIO Public Health, Consorci Hospital General Universitari de València, Valencia, Spain4 Departamento de Neumología, Consorci Hospital General Universitari de València, Valencia, Spain5 Servicio de Microbiología, Consorci Hospital General Universitari de València, Valencia, Spain6 Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública, Madrid, SpainCorrespondence: I. Comas, PhD, Unidad de Genómica de la Tuberculosis, Instituto de Biomedicina de Valencia, Jaume Roig 11, 46010, Valencia, Spain (icomas@ibv.csic.es).15 7 2019 15 4 2019 15 4 2019 220 2 316 320 19 11 2018 11 3 2019 © The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America.2019This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.comAbstract\nUnderstanding why some multidrug-resistant tuberculosis cases are not detected by rapid phenotypic and genotypic routine clinical tests is essential to improve diagnostic assays and advance toward personalized tuberculosis treatment. Here, we combine whole-genome sequencing with single-colony phenotyping to identify a multidrug-resistant strain that had infected a patient for 9 years. Our investigation revealed the failure of rapid testing and genome-based prediction tools to identify the multidrug-resistant strain. The false-negative findings were caused by uncommon rifampicin and isoniazid resistance mutations. Although whole-genome sequencing data helped to personalize treatment, the patient developed extensively drug-resistant tuberculosis, highlighting the importance of coupling new diagnostic methods with appropriate treatment regimens.\n\nWhole-genome sequencing identified a case of multidrug-resistant tuberculosis missed by routine culture and molecular susceptibility tests. Rare rifampin and isoniazid resistance mutations were behind the false-negative results. Whole-genome sequencing helped manage the case despite its further progression to extensively drug-resistant tuberculosis.\n\nTuberculosisdrug resistancewhole-genome sequencingindividualized treatmentcryptic mutationsEuropean Research Council10.13039/100010663638553-TB-ACCELERATEMinisterio de Economía y Competitividad10.13039/501100003329SAF2016-77346-R\n==== Body\nPersonalized treatment in tuberculosis can be achieved in the next few years if we are able to implement rapid, cost-effective, and comprehensive drug susceptibility tests (DSTs). However, the prospects for this personalization deeply depend on our ability to identify drug resistance–associated mutations and to interpret their clinical role during management of the cases [1]. Current methods to identify and manage drug resistance are based on rapid liquid culture systems and/or molecular amplification tests [2]. Both approaches have limitations. For rifampicin (RIF), some mutations, termed “disputed” mutations [3], are systematically missed by rapid automatic liquid culture methods, such as the Bactec–Mycobacteria Growth Indicator Tube (Bactec-MGIT) system, which is used in this study. These noncanonical RIF resistance mutations are involved in low-level resistance and associated with relapse [2, 4]. Likewise, the number of mutations screened by nucleic acid amplifications tests is limited [3]. Until now, no case has been reported in which both the Bactec-MGIT system and genotypic assays failed to identify multidrug-resistant strains. Here, we report a multidrug-resistant strain with cryptic mutations not detected by rapid routine clinical methods or whole-genome prediction tools. Prospective whole-genome sequencing (WGS) helped to track additional resistance mutations, but failure to provide an appropriate treatment regimen led to extensively drug-resistant tuberculosis. Despite limited therapeutic options, the patient was declared cured in 2018.\n\nMETHODS\nClinical and microbiological data, together with a more-detailed description of the methods, are included in the Supplementary Data.\n\nClinical Case, Isolate Collection, and Routine DST Procedures\nThe study case was a Spanish-born patient with no common tuberculosis risk factors whose first episode of tuberculosis occurred in 2009. Findings of sputum and culture analyses became negative within 2 months after treatment initiation, and the patient was considered cured 4 months later, based on World Health Organization guidelines. However, relapse occurred in 2013 despite no risk factor for relapse during the initial episode [5]. Two years later, the patient was not responding to therapy despite compliance with treatment, close monitoring, and infection with a drug-susceptible strain, based on results of the hospital’s routine rapid phenotypic DST and genotypic testing. We analyzed 16 serial clinical isolates recovered from the patient during 2009–2018 by the clinical microbiology unit of the Hospital Universitario General de Valencia (Valencia, Spain).\n\nRoutine phenotypic DST for the first-line antituberculosis drugs (and linezolid in 1 isolate) was performed on all clinical samples collected during the study period, using the Bactec-MGIT 960 system (Becton Dickinson, Franklin Lakes, NJ). For second-line drugs, the Sensititre MycoTB MIC plate (Trek Diagnostics System, Cleveland, OH) was used. Ranges of the critical concentrations for all drugs are specified in the Supplementary Data.\n\nWGS Analysis\nExtracted DNA from diagnostic cultures was sequenced on the MiSeq platform, using standard procedures. We used Kraken [6] to identify reads belonging to Mycobacterium tuberculosis complex. For mapping and variant calling, we used a previously described pipeline [7]. For details, see the Supplementary Data.\n\nIdentification of Candidate Drug Resistance Variants\nWe identified candidate drug resistance variants by mapping them to known drug resistance–associated genes and confirming that they had not previously been described as phylogenetic markers (Supplementary Table 1). In addition, we screened any new variant that arose during the course of treatment in any part of the genome and reached a minimal frequency of 15% in ≥1 sample, to evaluate their potential role in drug resistance. Our in-house results were compared to data from 3 publically genomic resistance databases (accessed April 2018) [8–10]. The global frequencies of these candidate mutations were evaluated against an in-house database of 4762 genomes collected worldwide.\n\nIsolation of Single Clones, Amplicon Sequencing, and Minimum Inhibitory Concentration (MIC) Validation for Resistance Mutations\nAfter we identified mutations in genes or genomic regions associated with drug resistance to INH and RIF, we tested whether those variants conferred resistance, by characterizing a series of single-colony isolates. Twenty-two single clones with different genotypes, obtained from complex diagnostic cultures at different time points, were selected and isolated. Each clone was tested twice for susceptibility to INH, using the resazurin microtiter assay with 2-fold dilutions for 9 different concentrations (range, 0.06–32 μg/mL). We also confirmed that the I491F mutation conferred resistance to RIF, using the proportions method with 2-fold dilutions for 10 different concentrations (range, 0.06–64 μg/mL). Before DST, we performed ultra-deep amplicon sequencing of the regions of interest (rpoB, katG, and the ahpC promoter) to confirm the genotype of each clone, as well as to discount the presence of any unnoticed mutation with a frequency of ≥0.1%, the lower limit of detection (Supplementary Methods and Supplementary Table 6).\n\nRESULTS\nCryptic Variants behind an Unnoticed Multidrug-Resistant Tuberculosis Case\nA total of 16 isolates from the patient were available and sequenced during the study period (2009–2017). It is important to note that the first genome sequence was analyzed in 2015, after the patient had received standard first-line treatment for 2 years without a response (Supplementary Figure 1). Reconstruction of a phylogeny from WGS data strongly supported a scenario in which the relapse infection (which began in 2013) was caused by the strain from the first episode (which began in 2009; Supplementary Figure 2).\n\nInspection of candidate variants only revealed likely mutations in known drug resistance genes (a complete list is shown in Supplementary Table 2). We found the rpoB mutation I491F, which is a noncanonical but known RIF resistance–associated variant. I491F is systematically missed by the Bactec-MGIT system because of an unfortunate combination of slow mycobacterial growth and the system’s switch to an automated readout after 20 days.\n\nWGS analysis of previous isolates revealed that the I491F variant appeared to be fixed in the isolate initially cultured during the relapse episode (in September 2013) but not in the isolate from the first episode (in 2009). Thus, during the relapse episode, the mycobacteria were already resistant to RIF at the time the first positive culture result was obtained (Figure 1). Knowing this, we looked for INH resistance variants in the first isolate from the relapse episode, but we did not detect any putative mutation. However, in later isolates we identified 2 new noncanonical, mutually exclusive candidate INH resistance mutations, in katG (G249del and G273R). The G249del variant appeared as early as January 2014 but with highly variable frequency across samples, although it dominated the last mycobacteria-positive cultures (from June 2016 onward). In contrast, the G273R mutation appeared for the first time in March 2014, disappearing by December 2015. As expected for noncanonical katG mutations, screening of the ahpC gene and promoter region identified multiple ahpC promoter mutations whose presence fluctuated through time (Figure 1).\n\nFigure 1. \nA, All drug resistance mutations detected during treatment. Grey scales and symbols indicate drug resistance variants associated with different genes. Solid lines denote mutations detected at a frequency of 100% in the patient’s last mycobacteria-positive culture, whereas dashed lines indicate transitory variants over time. B, Relevant clinical findings of the case study, including antibiotic therapy, sputum and culture status, results of drug susceptibility testing (DST) in the hospital, and predicted whole-genome sequencing–based resistance profile. Plus signs denote that higher doses of isoniazid were added. AMK, amikacin; CM, capreomycin; DS, drug susceptible; EMB, ethambutol; INH, isoniazid; LZD, linezolid; MDR, multidrug-resistant; MFX, moxifloxacin; PZA, pyrazinamide; RIF, rifampicin; RR, rifampicin resistant; XDR, extensively drug-resistant. aPhenotypic analysis was performed using the Bactec-MGIT 960 system (Becton Dickinson, Franklin Lakes, NJ), and genotypic analysis was performed using the GenoType MTBDR plus system (Hain Lifescience, Nehren, Germany). bPredicted DST-based resistance, based on mutations detected in genomic regions associated with RIF and INH resistance. cPredicted whole-genome sequencing–based drug susceptibility profile.\n\nSwitching treatment from a first-line regimen to a multidrug-resistant tuberculosis regimen is a major clinical decision. Thus, resistance variants detected by our genomic analyses needed validation. We selected 22 single clones from secondary cultures of specimens obtained at different time points during treatment and performed DST with alternative methods (Figure 2). Furthermore, we performed ultra-deep amplicon sequencing in specific RIF and INH resistance regions (Supplementary Methods). First, we confirmed that all 19 clones harboring the rpoB I491F mutation were RIF resistant (MIC, > 1 µg/mL) as compared to the 3 clones from 2009 with no mutation (MIC, < 1 µg/mL), which had an MIC higher than that for H37Rv but similar to that for other RIF-susceptible strains described elsewhere [11]. In the case of INH resistance, clones from 2009 and 2013 had a low MIC for INH (< 0.25 μg/mL), consistent with the fact that no putative katG mutations were found in these isolates. In contrast, all clones from 2014 had either the katG G273R or the G249del mutation fixed and no other alternative candidate mutation at a frequency of ≥0.1%, as revealed by amplicon sequencing (Figure 2). All of these clones were highly resistant to INH (MIC, > 32 μg/mL), based on the resazurin microtiter assay. In addition, clone haplotype analysis established a link between specific ahpC mutations and the 2 specific katG variants (Figure 2).\n\nFigure 2. Percentage of the different mutations associated with resistance to isoniazid (INH) and rifampin (RIF). Percentages are given for the frequency among diagnostic cultures, as well as among individual isolated clones (identified with a “C”). DST, drug susceptibility testing; MIC, minimum inhibitory concentration; PM, proportions methods; REMA, resazurin microtiter assay. aPhenotypic DST results for RIF and INH from individual clones. bPhenotypic DST results for RIF and INH from clinical isolates.\n\nThus, multiple lines of evidence suggested that the 2 katG mutations were likely involved in INH resistance: (1) genomic analyses identified the variants as mutually exclusive, suggesting selection for different resistant populations; (2) a single-clone phenotypic assay identified that these mutations were associated with high-level INH resistance; and (3) ahpC mutations were associated with noncanonical katG mutations (Supplementary Table 3).\n\nAdditionally, genomic analysis detected 3 different ethambutol-associated mutations, beginning April 2015, including 2 in the embB genomic region (G328Y and M306V) and 1 in the ubiA region (G165S; Figure 1).\n\nProspective Case Management Aided by WGS Data\nAfter validation of RIF and INH resistance, we used WGS as a primary tool for detecting resistance. Given the newly discovered multidrug-resistant tuberculosis profile of the patient and their lack of response to treatment, the clinical team decided to change the drug regimen in December 2015. Moxifloxacin (MFX) and capreomycin were added, and RIF was removed. Despite the patient’s adherence to the new treatment regimen, sputum smear results were positive in June 2016, followed by another positive culture result in October 2016. Rapid sequencing of this isolate revealed that it had acquired a related MFX resistance mutation (E540D, in gyrB) and a likely capreomycin resistance mutation (L16R, in tlyA). In parallel, a microdilution-based assay (the Sensititre MycoTB MIC Plate) confirmed resistance to MFX (MIC, < 4 µg/mL) but revealed amikacin susceptibility (MIC, ≤ 1 µg/mL). Accordingly, drug therapy was adjusted, removing MFX and adding linezolid and amikacin. Unfortunately, bedaquiline and delamanid were not available to the hospital. With this new treatment, the last positive culture result was in February 2017, and after 18 months of culture negativity the patient made a satisfactory recovery. All resistance variants detected are in Supplementary Table 4.\n\nNotably, none of the publically available genomic resistance prediction databases classified any of the isolates as a multidrug-resistant or extensively drug-resistant strain (Supplementary Table 5). In agreement with this, an extensive analysis of 4762 genomes revealed that strains with noncanonical RIF resistance mutations were depleted of known katG resistance mutations (7.6% vs 36%; P < .001, by the χ2 test). A deeper analysis of katG in those strains revealed 7 mutations not described before, all of them leading to an amino acid change and some with a phylogenetic convergence signal (Supplementary Data).\n\nDISCUSSION\nHere we described the use of WGS data to diagnose a case of multidrug-resistant tuberculosis that was missed by the commonly used Bactec-MGIT system. An uncommon RIF resistance mutation (I491F, in rpoB) led to a systematic negative test result. Notably, this outcome affected INH DST with the Bactec-MGIT system; in contrast, our investigation clearly demonstrated the presence of high-level INH resistance at different time points. The resistance profile undetected by the Bactec-MGIT system before genomic data were available explains why the patient remained culture positive and the infecting mycobacteria acquired additional resistance mutations between 2013 and 2015. In the absence of a fully reliable Bactec-MGIT result, we decided to use WGS data to aid in the clinical management of the case.\n\nHowever, clinical decisions based on WGS data are not straightforward. The higher resolution of next-generation sequencing approaches, combined with our increasing knowledge of drug resistance–associated mutations, provide evidence for the usefulness of designing individualized drug regimens [12]. Nevertheless, this work also reveals additional layers of complexity in clinical decision making; for example, INH-susceptible subpopulations were still present after 2.5 years of treatment (Supplementary Figure 3). These results suggest that personalized treatment will require serial sequencing over time, preferably instead of sputum culture, to avoid culture bias and track the dynamics of susceptible and resistant subpopulations. Furthermore, rigorous standardized statistical approaches such as those developed by Miotto et al [13] should identify highly likely drug resistance mutations, to avoid false-positive predictions and adverse downstream clinical consequences. In this particular case, WGS aided care management, but despite access to WGS data, treatment decisions led to the development of extensively drug-resistant tuberculosis.\n\nThe poor treatment outcome in this patient is in line with previous reports that RIF monoresistance is associated with relapse and with the acquisition of additional resistance mutations [2, 14]. Furthermore, it is also noteworthy that most of the variants described are epidemiologically rare and that none of the canonical mutations were found. Uncommon drug resistance–conferring mutations are likely more common in high-burden countries [15], and, thus, personalized treatment approaches based on WGS data in those countries may be compromised. Evidence from this patient adds to the view that we need to integrate different layers of heterogeneity to understand the emergence of and predict drug resistance in a patient. Those layers include strain, lesion, pharmacodynamics, and drug penetration heterogeneity.\n\nSupplementary Data\nSupplementary materials are available at The Journal of Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.\n\njiz104_suppl_Supplementary_Material Click here for additional data file.\n\n Notes\n\nAcknowledgments. We thank Dr Ana Gil-Brusola (Hospital Universitario y Politécnico de La Fe, Valencia, Spain) for her corrections and feedback during manuscript preparation.\n\n\nFinancial support. This work was supported by the European Research Council (638553-TB-ACCELERATE to I. C.) and the Ministerio de Economía y Competitividad (SAF2016-77346-R to I. C.).\n\n\nPotential conflicts of interest. All authors: No reported conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.\n==== Refs\nReferences\n1. \nCox H , Hughes J , Black J , Nicol MP \nPrecision medicine for drug-resistant tuberculosis in high-burden countries: is individualised treatment desirable and feasible? Lancet Infect Dis 2018 ; 18 :e282 –7 .29548923 \n2. \nVan Deun A , Aung KJ , Bola V , et al. \nRifampin drug resistance tests for tuberculosis: challenging the gold standard . J Clin Microbiol 2013 ; 51 :2633 –40 .23761144 \n3. \nMiotto P , Cabibbe AM , Borroni E , Degano M , Cirillo DM \nRole of disputed mutations in the rpoB gene in interpretation of automated liquid MGIT culture results for rifampin susceptibility testing of Mycobacterium tuberculosis . J Clin Microbiol 2018 ; 56 :e01599 –17 .29540456 \n4. \nHo J , Jelfs P , Sintchencko V \nPhenotypically occult multidrug-resistant Mycobacterium tuberculosis: dilemmas in diagnosis and treatment . J Antimicrob Chemother 2013 ; 68 :2915 –20 .23838950 \n5. \nRomanowski K , Balshaw RF , Benedetti A , et al \nPredicting tuberculosis relapse in patients treated with the standard 6-month regimen: an individual patient data meta-analysis . Thorax 2019 ; 74 :291 –7 .30420407 \n6. \nWood DE , Salzberg SL \nKraken: ultrafast metagenomic sequence classification using exact alignments . Genome Biol 2014 ; 15 :R46 .24580807 \n7. \nComas I , Coscolla M , Luo T , et al. \nOut-of-Africa migration and Neolithic coexpansion of Mycobacterium tuberculosis with modern humans . Nat Genet 2013 ; 45 :1176 –82 .23995134 \n8. \nFeuerriegel S , Schleusener V , Beckert P , et al \nPhyResSE: a web tool delineating mycobacterium tuberculosis antibiotic resistance and lineage from whole-genome sequencing data . J Clin Microbiol 2015 ; 53 :1908 –14 .25854485 \n9. \nBradley P , Gordon NC , Walker TM , et al \nRapid antibiotic-resistance predictions from genome sequence data for Staphylococcus aureus and Mycobacterium tuberculosis. \nNat Commun \n2015 ; 6 .\n10. \nColl F , McNerney R , Preston MD , et al \nRapid determination of anti-tuberculosis drug resistance from whole-genome sequences . Genome Med 2015 ; 7 .\n11. \nSchön T , Juréen P , Giske CG , et al. \nEvaluation of wild-type MIC distributions as a tool for determination of clinical breakpoints for Mycobacterium tuberculosis . J Antimicrob Chemother 2009 ; 64 :786 –93 .19633001 \n12. \nMetcalfe JZ , Streicher E , Theron G , et al. \nCryptic microheteroresistance explains Mycobacterium tuberculosis phenotypic resistance . Am J Respir Crit Care Med 2017 ; 196 :1191 –201 .28614668 \n13. \nMiotto P , Tessema B , Tagliani E , et al \nA standardised method for interpreting the association between mutations and phenotypic drug resistance in Mycobacterium tuberculosis . Eur Respir J 2017 ; 50 :1701354 .29284687 \n14. \nRidzon R , Whitney CG , McKenna MT , et al. \nRisk factors for rifampin mono-resistant tuberculosis . Am J Respir Crit Care Med 1998 ; 157 :1881 –4 .9620922 \n15. \nManson AL , Abeel T , Galagan JE , et al. \n\nMycobacterium tuberculosis whole genome sequences from southern india suggest novel resistance mechanisms and the need for region-specific diagnostics . Clin Infect Dis 2017 ; 64 :1494 –501 .28498943\n\n",
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"issn_linking": "0022-1899",
"issue": "220(2)",
"journal": "The Journal of infectious diseases",
"keywords": "Tuberculosis; cryptic mutations; drug resistance; individualized treatment; whole-genome sequencing",
"medline_ta": "J Infect Dis",
"mesh_terms": "D000995:Antitubercular Agents; D001426:Bacterial Proteins; D003951:Diagnostic Errors; D024901:Drug Resistance, Multiple, Bacterial; D054908:Extensively Drug-Resistant Tuberculosis; D016680:Genome, Bacterial; D005838:Genotype; D006801:Humans; D007538:Isoniazid; D008826:Microbial Sensitivity Tests; D009154:Mutation; D009169:Mycobacterium tuberculosis; D012293:Rifampin; D017422:Sequence Analysis, DNA; D018088:Tuberculosis, Multidrug-Resistant; D000073336:Whole Genome Sequencing",
"nlm_unique_id": "0413675",
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"pages": "316-320",
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"pmid": "30875421",
"pubdate": "2019-06-19",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
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"title": "Cryptic Resistance Mutations Associated With Misdiagnoses of Multidrug-Resistant Tuberculosis.",
"title_normalized": "cryptic resistance mutations associated with misdiagnoses of multidrug resistant tuberculosis"
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"abstract": "OBJECTIVE\nTo report a case of a testosterone deficient man desiring maintenance of spermatogenesis converting from clomiphene citrate (CC) to Natesto, who had a decrease in gonadotropins and semen parameter values after making this medication change. The data on men maintaining gonadotropins and semen parameter values after converting from CC to Natesto is also reported.\n\n\nMETHODS\nA retrospective chart review was performed. Baseline hormones prior to treatment, and again on CC and Natesto, as well as semen parameters on CC and on Natesto were assessed.\n\n\nRESULTS\nA 32-year-old testosterone deficient man desiring to maintain future fertility potential who had a poor symptomatic response to CC despite an adequate serum testosterone response was converted to Natesto 11 mg twice daily. His gonadotropins diminished as did his semen parameter values but with dose titration of Natesto to 11 mg in the morning and 5.5 mg in the evening he had normalization of gonadotropins and a rise in semen parameter values back towards his values on CC with a continued satisfactory symptomatic response. The remainder of the 49 men to date converting from CC to Natesto revealed stability in gonadotropins and semen parameter values.\n\n\nCONCLUSIONS\nTestosterone deficient men interested in maintaining spermatogenesis who convert from CC to Natesto seeking a more robust symptomatic response should be followed closely with repeat serum gonadotropins and semen parameters to confirm that spermatogenesis is not being suppressed. Dose titration of Natesto may be effective at optimizing gonadotropins, semen parameter values, testosterone levels, and symptomatic response to treatment.",
"affiliations": "Austin Fertility & Reproductive Medicine/Westlake IVF, Austin, Texas. Electronic address: pkavoussi@hotmail.com.",
"authors": "Kavoussi|Parviz K|PK|",
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"pubdate": "2021-08-30",
"publication_types": "D016428:Journal Article",
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"title": "Men Converting from Clomiphene Citrate to Natesto with a Desire to Maintain Spermatogenesis Should Be Followed Closely.",
"title_normalized": "men converting from clomiphene citrate to natesto with a desire to maintain spermatogenesis should be followed closely"
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"abstract": "A 56-year-old Japanese man diagnosed with acquired immunodeficiency syndrome, Pneumocystis jirovecii pneumonia and cytomegalovirus infection presented with thrombocytopenia after starting antiretroviral therapy, which included dolutegravir (DTG). Although good control of the human immunodeficiency virus and cytomegalovirus infections was achieved, the patient's thrombocytopenia persisted. The patient's platelet count decreased to ≤50,000/μL even after the cessation of valganciclovir, which can cause bone marrow suppression. At five months after starting antiretroviral therapy, DTG was replaced by ritonavir-boosted darunavir. Soon after, his platelet count improved and was maintained at a level of >100,000/μL. This is the first reported case of severe thrombocytopenia during DTG-containing antiretroviral therapy.",
"affiliations": "Department of Infectious Diseases and Infection Control, Jikei University School of Medicine, Japan.;Department of Infectious Diseases and Infection Control, Jikei University School of Medicine, Japan.;Department of Infectious Diseases and Infection Control, Jikei University School of Medicine, Japan.;Department of Infectious Diseases and Infection Control, Jikei University School of Medicine, Japan.;Department of Infectious Diseases and Infection Control, Jikei University School of Medicine, Japan.;Department of Infectious Diseases and Infection Control, Jikei University School of Medicine, Japan.;Department of Infectious Diseases and Infection Control, Jikei University School of Medicine, Japan.",
"authors": "Nakaharai|Kazuhiko|K|;Miyajima|Makiko|M|;Kobayashi|Hiroaki|H|;Shimizu|Akihiro|A|;Hosaka|Yumiko|Y|;Horino|Tetsuya|T|;Hori|Seiji|S|",
"chemical_list": "D019428:HIV Integrase Inhibitors; D006575:Heterocyclic Compounds, 3-Ring; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; C562325:dolutegravir",
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"doi": "10.2169/internalmedicine.8377-16",
"fulltext": "\n==== Front\nIntern MedIntern. MedInternal Medicine0918-29181349-7235The Japanese Society of Internal Medicine 2878131010.2169/internalmedicine.8377-16Case ReportSevere Thrombocytopenia During Dolutegravir-containing Antiretroviral Therapy Nakaharai Kazuhiko 1Miyajima Makiko 1Kobayashi Hiroaki 1Shimizu Akihiro 1Hosaka Yumiko 1Horino Tetsuya 1Hori Seiji 1\n1 Department of Infectious Diseases and Infection Control, Jikei University School of Medicine, JapanCorrespondence to Dr. Kazuhiko Nakaharai, nakaharai@jikei.ac.jp\n\n1 8 2017 15 8 2017 56 16 2229 2232 7 10 2016 24 1 2017 Copyright © 2017 by The Japanese Society of Internal Medicine2017The Internal Medicine is an Open Access article 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 56-year-old Japanese man diagnosed with acquired immunodeficiency syndrome, Pneumocystis jirovecii pneumonia and cytomegalovirus infection presented with thrombocytopenia after starting antiretroviral therapy, which included dolutegravir (DTG). Although good control of the human immunodeficiency virus and cytomegalovirus infections was achieved, the patient's thrombocytopenia persisted. The patient's platelet count decreased to ≤50,000 /μL even after the cessation of valganciclovir, which can cause bone marrow suppression. At five months after starting antiretroviral therapy, DTG was replaced by ritonavir-boosted darunavir. Soon after, his platelet count improved and was maintained at a level of >100,000 /μL. This is the first reported case of severe thrombocytopenia during DTG-containing antiretroviral therapy. \n\ndolutegravirHIVthrombocytopeniaplateletadverse drug reaction\n==== Body\nIntroduction\nDolutegravir (DTG) is a recently approved, easy-to-take, and highly active integrase strand transfer inhibitor (INSTI) that offers a high genetic barrier to resistance and which has few drug interactions (1). Thus, the usage of DTG as a treatment for human immunodeficiency virus (HIV) infection has been increasing worldwide. As with other INSTIs, DTG has been regarded as a well-tolerated drug; however, there is insufficient information about the incidence and type of adverse drug reactions (ADRs) associated with DTG. The most commonly reported ADRs include headache, nausea, diarrhea, and some biochemical disturbances (e.g. elevation of the creatinine, transaminase and creatine kinase levels); these are typically reported as mild ADRs and do not require the treatment to be discontinued or changed. There are few published reports on the association between DTG and blood cell disorders. We encountered a case of an HIV-infected Japanese man who developed severe thrombocytopenia during DTG-containing antiretroviral therapy. To the best of our knowledge, this is the first report of this ADR. We herein report the case and review the literature on the subject.\n\nCase Report\nA 56-year-old Japanese man presenting with prolonged fever and dyspnea was admitted to Jikei University Hospital, Tokyo, Japan. He had a comorbidity of hyperuricemia, which was treated with febuxostat. His height and body weight were 1.58 m, and 54 kg, respectively. Chest computed tomography revealed diffuse ground-glass opacity in both lungs. Following detailed examinations, he was diagnosed with acquired immunodeficiency syndrome (AIDS), Pneumocystis jirovecii pneumonia (PCP), and cytomegalovirus (CMV) infection with no evidence of organ involvement. With the exception of PCP and CMV infection, he had no active co-infections (such as hepatitis virus, Helicobacter pylori, or other opportunistic organisms). At the time of his diagnosis, the patient's CD4 cell count was 10 cells/mm3 and the viral load of HIV was 97,000 copies/mL. Induction therapies for PCP and CMV infection were successfully completed, and secondary prevention for each disease was initiated using inhaled pentamidine (300 mg, once a month) and valganciclovir (VGCV). VGCV was appropriately administered as secondary prevention based on the estimated glomerular filtration rate (eGFR) (as an indicator of kidney function) adjusted for Japanese patients (2). The patient received VGCV (450 mg/day) for secondary prevention because his eGFR remained at approximately 50 mL/min/1.73 m2. In addition, azithromycin (1,200 mg, once a week) was started to prevent disseminated nontuberculous mycobacterial disease after the diagnosis of AIDS (CD4 cell count: ≤ 50 cells/mm3).\n\nAt four weeks after starting induction therapy for PCP and CMV infection, combination antiretroviral therapy (cART) for HIV infection was started with DTG (50 mg/day), tenofovir (TDF; 300 mg/day), and emtricitabine (FTC; 200 mg/day). The patient's biochemical data at the start of cART are shown in Table. Approximately two months after the start of cART, the patient's platelet count began to gradually decrease. We suspected an adverse reaction to VGCV and discontinued drug; however, the patient's platelet count continued to decrease and reached <50,000 /μL. At four weeks after the discontinuation of VGCV, the reactivation of CMV occurred with no evidence of organ involvement, and three-week induction therapy with VGCV (900 mg/day) was restarted. After the induction therapy, VGCV was continued at a dose of 450 mg/day as secondary prevention. During that period, thrombocytopenia remained. At its lowest, the platelet count decreased to 31,000 /μL without bleeding symptoms. After starting cART, the patient's HIV viral load decreased rapidly, and virological suppression was successfully achieved; however, the patient presented severe thrombocytopenia.\n\nTable. The Patient’s Biochemical Data at the Start of cART.\n\nWBC (/µL)\t1,900\tβ-D-glucan (pg/mL)\t6.2\t\nRBC (×104 /µL)\t360\tCandida antigen\t(-)\t\nHb (g/dL)\t11.3\tAspergillus antigen\t(-)\t\nHt (%)\t33.8\tCryptococcus antigen\t(-)\t\nPLT (×103 /µL)\t186\tCMV pp65 AG (positive cell/leukocyte)\t4/50,000\t\nRet (%)\t2.8\tAnti-Toxoplasma gondii IgG\t(-)\t\nAST (U/L)\t43\t\nHelicobacter\npylori IgG\t(-)\t\nALT (U/L)\t108\tIGRA (T-SPOT®)\t(-)\t\nLDH (U/L)\t205\tAnti-HAV IgM\t(-)\t\nT-BIL (mg/dL)\t0.3\tHBs antigen\t(-)\t\nALP (U/L)\t402\tAnti-HBs\t(+)\t\nγ-GTP (U/L)\t205\tAnti-HBc\t(+)\t\nTP (g/dL)\t7.2\tHBV-DNA\tUndetectable\t\nALB (g/dL)\t3.2\tAnti-HCV\t(-)\t\nCK (U/L)\t28\tHCV-RNA\tUndetectable\t\nBUN (mEq/L)\t18\tTPHA\t×320\t\nCr (mg/dL)\t0.89\tRPR\t×1\t\neGFR (mL/min/1.73m2)\t69\t\t\t\nTG (mg/dL)\t192\tCD4 (/µL)\t27\t\nHDL-C (mg/dL)\t33\tHIV-RNA (copy/mL)\t3.3×105\t\nLDL-C (mg/dL)\t116\t\t\t\nHbA1c (%)\t6.0\t\t\t\nCRP (mg/dL)\t0.85\t\t\t\nPT-INR\t1.1\t\t\t\nAPTT (sec)\t41.7\t\t\t\nFibrinogen (mg/dL)\t830\t\t\t\nFDP (µg/mL)\t6\t\t\t\nD-dimer (µg/mL)\t1.6\t\t\t\nAG: antigemenia, ALB: albumin, ALP: alkaline phosphatase, ALT: alanine aminotransferase, APTT: activated partial thromboplastin time, AST: aspartate aminotransferase, BUN: blood urea nitrogen, cART: combination antiretroviral therapy, CK: creatine kinase, CMV: cytomegalovirus, Cr: creatinine, CRP: C-reactive protein, eGFR: estimated glomerular filtration rate, FDP: fibrinogen degradation product, γ-GTP: gamma-glutamyl transpeptidase, HAV: hepatitis A virus, Hb: hemoglobin, HBV: hepatitis B virus, HCV: hepatitis C virus, HDL-C: high-density lipoprotein cholesterol, HIV: human immunodeficiency virus, Ht: hematocrit, IGRA: interferon-gamma release assay, LDH: lactate dehydrogenase, LDL-C: low-density lipoprotein cholesterol, PLT: platelet, PT-INR: international normalized ratio of prothrombin time, RBC: red blood cell, Ret: reticulocyte, RPR: rapid plasma reagin, T-BIL: total bilirubin, TP: total protein, TPHA: treponema pallidum hemagglutination assay, TG: triglyceride, WBC: white blood cell\n\nConsidering the clinical course, we hypothesized that the patient's thrombocytopenia was likely drug-related, and that an antiretroviral drug(s) was most likely responsible. First, TDF and FTC were replaced by abacavir and lamivudine at approximately 18 weeks after the start of cART; however, the patient's platelet count did not improve. At five weeks after the replacement, DTG was switched to ritonavir-boosted darunavir, which is a highly active protease inhibitor with a high genetic barrier. Thereafter, the patient's platelet count promptly improved by >100,000 /μL. At four months after the cessation of DTG, the patient's platelet count remained at >100,000 /μL. The clinical course is summarized in Figure. Inhaled pentamidine, azithromycin, and febuxostat were not changed after the start of cART. In addition, the patient did not take any drugs (other than those listed in Figure), supplements, or Chinese herbs after starting cART.\n\nFigure. The Clinical course. 3TC: lamivudine, ABC: abacavir, AG: antigemenia, ALT: alanine aminotransferase, AST: aspartate aminotransferase, CK: creatine kinase, CMV: cytomegalovirus, DTG: Dolutegravir, DRV/r: ritonavir-boosted darunavir, FDP: fibrinogen degradation product, Hb: hemoglobin, NE: not evaluated, PT-INR: international normalized ratio of prothrombin time, sCr: serum creatinine, TDF: tenofovir, FTC: emtricitabine, VGCG: valganciclovir, VL: viral load of human immunodeficiency virus, WBC: white blood cell\n\nDiscussion\nThis is the first reported case of severe thrombocytopenia during DTG-containing antiretroviral therapy. DTG is one of the newest antiretroviral drugs, and was approved in the United States and Japan in August 2013 and March 2014, respectively. The efficacy of DTG has been demonstrated in several clinical trials (3-7), and DTG is currently recommended as a first-line agent for the treatment of HIV infection. In a recent safety review of DTG, the most commonly reported ADRs were headache, nausea, and diarrhea; these ADRs were typically mild and did not require discontinuation or a change of treatment (1). The main reported biochemical disturbances have been the elevation of the creatinine, transaminase, and creatine kinase levels. There have been no reports of thrombocytopenia, leukopenia, or anemia. Some older antiretroviral drugs, such as zidovudine, have the potential to cause thrombocytopenia due to bone marrow suppression; however, new-generation agents, including DTG, have rarely been associated with thrombocytopenia.\n\nThrombocytopenia is a relatively common complication in patients with HIV infection. Many factors, such as HIV-associated immune disorders, co-infection with another virus (e.g. CMV or hepatitis virus) or Helicobacter pylori, malignancy, or drugs can cause thrombocytopenia. Consequently, it is not easy to identify the causative factor. In particular, the diagnosis of drug-induced thrombocytopenia is usually made in complicated situations because patients with HIV infection often take several drugs at the same time. Among the drugs that are frequently used in the treatment of HIV infection and opportunistic diseases, trimethoprim-sulfamethoxazole, ganciclovir (GCV)/VGCV, and rifampicin have been reported to cause secondary thrombocytopenia (8,9). In the present case, with the exception of PCP and CMV infection, the patient did not have active co-infections such as hepatitis virus, Helicobacter pylori, or other opportunistic organisms. The patient required long-term VGCV as induction therapy and secondary prevention for CMV infection. During a period in which DTG and VGCV were concomitantly used, leukopenia and anemia were also observed, along with thrombocytopenia. These blood cell disorders are well known ADRs resulting from bone marrow suppression due to GCV/VGCV (10). Although VGCV could have contributed to the patient's thrombocytopenia, we suspected that DTG was more likely to be the major causative agent because the platelet count recovered after the cessation of DTG, despite the continuous use of VGCV.\n\nThe diagnosis of DTG-associated thrombocytopenia is associated with several limitations. We did not evaluate the patient's bone marrow and hence the mechanism of thrombocytopenia remains unclear (e.g. megakaryocytic hypoplasia, or platelet destruction due to immune responses). The possibility of malignancy cannot be completely ruled out for the same reason. In addition, the patient's serum concentration of DTG was not measured; the patient took a normal dose of DTG. Thus, the association between the dose of DTG and the ADR observed in the present case is also unclear. Despite these limitations, we believe that the severe thrombocytopenia was more likely associated with the use of DTG than other potentially influential factors in the present case (e.g. VGCV or viremia due to HIV and CMV) for the following reasons: a) despite the successful suppression of HIV and CMV, the patient's platelet count continued to decrease, and during this period, DTG-containing cART and VGCV (450 mg/day), which can cause bone marrow suppression, were administered; b) after the replacement of DTG, the patient's platelet count rapidly improved; and c) despite the continuous use of VGCV (450 mg/day), the patient's platelet count remained at >100,000 /μL after the replacement of DTG, which suggested that VGCV (450 mg/day) was not responsible for the severe thrombocytopenia. To the best of our knowledge, there are no published reports on this ADR in patients receiving DTG.\n\nIn conclusion, we encountered a case of severe thrombocytopenia during DTG-containing antiretroviral therapy. Although several potentially influential factors were present at the same time, we suspected that DTG was the cause of the patient's severe thrombocytopenia, based on the clinical course. DTG has generally been regarded as a well-tolerated drug; however, the information on DTG-associated ADRs remains insufficient. Clinicians should carefully observe patients to detect the signs of ADRs in patients who are treated with DTG. The further accumulation of clinical experience in relation to the administration of DTG is needed.\n\n\nAuthor's disclosure of potential Conflicts of Interest (COI).\n\nSeiji Hori: Advisory role, Kyorin Pharmaceutical; Fees for promotional materials, Daiichi-Sankyo.\n\nAcknowledgement\nThe authors would like to thank the nurses, clerks, laboratory technicians, pharmacists, and resident doctors of our hospital for their vigorous contribution to our practice.\n==== Refs\n1. \nKandel CE , Walmsley SL \nDolutegravir - a review of the pharmacology, efficacy, and safety in the treatment of HIV . Drug Des Devel Ther \n9 : 3547 -3555 , 2015 .\n2. \nMatsuo S , Imai E , Horio M , et al \nRevised equations for estimated GFR from serum creatinine in Japan . Am J Kidney Dis \n53 : 982 -992 , 2009 .19339088 \n3. \nWalmsley SL , Antela A , Clumeck N , et al \nDolutegravir plus abacavir-lamivudine for the treatment of HIV-1 infection . N Engl J Med \n369 : 1807 -1818 , 2013 .24195548 \n4. \nvan Lunzen J , Maggiolo F , Arribas JR , et al \nOnce daily dolutegravir (S/GSK1349572) in combination therapy in antiretroviral-naive adults with HIV: planned interim 48 week results from SPRING-1, a dose-ranging, randomised, phase 2b trial . LnID \n12 : 111 -118 , 2012 .\n5. \nRaffi F , Jaeger H , Quiros-Roldan E , et al \nOnce-daily dolutegravir versus twice-daily raltegravir in antiretroviral-naive adults with HIV-1 infection (SPRING-2 study): 96 week results from a randomised, double-blind, non-inferiority trial . LnID \n13 : 927 -935 , 2013 .\n6. \nCahn P , Pozniak AL , Mingrone H , et al \nDolutegravir versus raltegravir in antiretroviral-experienced, integrase-inhibitor-naive adults with HIV: week 48 results from the randomised, double-blind, non-inferiority SAILING study . Lancet \n382 : 700 -708 , 2013 .23830355 \n7. \nClotet B , Feinberg J , van Lunzen J , et al \nOnce-daily dolutegravir versus darunavir plus ritonavir in antiretroviral-naive adults with HIV-1 infection (FLAMINGO): 48 week results from the randomised open-label phase 3b study . Lancet \n383 : 2222 -2231 , 2014 .24698485 \n8. \nArnold DM , Nazi I , Warkentin TE , et al \nApproach to the diagnosis and management of drug-induced immune thrombocytopenia . Transfus Med Rev \n27 : 137 -145 , 2013 .23845922 \n9. \nDanziger-Isakov L , Mark Baillie G \nHematologic complications of anti-CMV therapy in solid organ transplant recipients . Clin Transplant \n23 : 295 -304 , 2009 .19191800 \n10. \nJabs DA , Ahuja A , Van Natta M , Dunn JP , Yeh S \nComplications of AIDS Research Group: Comparison of treatment regimens for cytomegalovirus retinitis in patients with AIDS in the era of highly active antiretroviral therapy . Ophthalmology \n120 : 1262 -1270 , 2013 .23419804\n\n",
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"issue": "56(16)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": "HIV; adverse drug reaction; dolutegravir; platelet; thrombocytopenia",
"medline_ta": "Intern Med",
"mesh_terms": "D023241:Antiretroviral Therapy, Highly Active; D015658:HIV Infections; D019428:HIV Integrase Inhibitors; D006575:Heterocyclic Compounds, 3-Ring; D006801:Humans; D008297:Male; D008875:Middle Aged; D010078:Oxazines; D010879:Piperazines; D010976:Platelet Count; D011728:Pyridones; D013921:Thrombocytopenia",
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"title": "Severe Thrombocytopenia During Dolutegravir-containing Antiretroviral Therapy.",
"title_normalized": "severe thrombocytopenia during dolutegravir containing antiretroviral therapy"
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"abstract": "A 72-year-old female patient who was admitted for ischaemic stroke had developed ascending cholangitis. Percutaneous transhepatic cholangiogram was performed to drain the infected bile, but this was complicated by haemorrhagic shock and hepatic haematoma. Mesenteric angiogram showed right hepatic artery (RHA) pseudoaneurysm which was embolised, there by stopping her bleeding. RHA is normally located posterior to common bile duct (CBD). An uncommon location of RHA is anterior to CBD, which can lead to haemorrhagic complications during percutaneous cholangiogram.",
"affiliations": "Department of Internal Medicine, Unity Hospital, Rochester, New York, USA.;Department of Internal Medicine, Universidad Autonoma Metropolitana, Coyoacan, Mexico.;Department of Internal Medicine, Unity Hospital, Rochester, New York, USA.;Department of Internal Medicine, Unity Hospital, Rochester, New York, USA.",
"authors": "Tirumanisetty|Pratyusha|P|http://orcid.org/0000-0001-7497-9870;Sotelo|Jose William|JW|;Rander|Aditya|A|;Syed|Taussif|T|",
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"keywords": "biliary intervention; interventional radiology; ultrasonography",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000368:Aged; D017541:Aneurysm, False; D002758:Cholangiography; D002761:Cholangitis; D003135:Common Bile Duct; D004621:Embolization, Therapeutic; D005260:Female; D005704:Gallbladder; D006499:Hepatic Artery; D006801:Humans; D014057:Tomography, X-Ray Computed",
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"references": "1627884;21140174;19679454;1871548;25409968;14564553;17661249;28270883;4685873;21875851;27803558;20209691",
"title": "Hepatic artery pseudoaneurysm following percutaneous transhepatic cholangiogram: an extremely rare complication.",
"title_normalized": "hepatic artery pseudoaneurysm following percutaneous transhepatic cholangiogram an extremely rare complication"
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"abstract": "BACKGROUND\nin Brazil, chronic hepatitis C in patients coinfected with the human immunodeficiency virus (HIV) is treated with pegylated interferon (Peg-IFN) and ribavirin (RBV). However, few studies have evaluated the effectiveness of this treatment in this particular population. The identification of the factors that predict sustained virological response (SVR) under current clinical practice would enable clinicians to more accurately estimate the probability of achieving an SVR and therefore utilize the appropriate therapeutics, especially in the era of direct-acting antiviral (DAA) agents.\n\n\nOBJECTIVE\nthe primary aim of our study was to determine the SVR rate under current clinical practice. The secondary aims were as follows: (1) to determine the factors before and during treatment that predict SVR; and (2) to identify the causes of treatment interruption.\n\n\nMETHODS\nwithin a cohort of HIV/hepatitis C virus (HCV)-coinfected patients in Brazil, we performed a retrospective analysis of those individuals treated with Peg-IFN and RBV.\n\n\nRESULTS\namong the 382 analyzed patients, SVR was observed in 118 [30.9% (95% confidence interval (CI): 26.3-35.8)], which included 25.9% (75/289) of the patients with genotypes 1 and 4 and 48.2% (41/85) of those with genotypes 2 and 3. After multivariate analyses the independent positive predictors for SVR after treatment for chronic hepatitis C with Peg-IFN and RBV were: absence of an AIDS-defining illness (p=0.001), HCV viral load lower than 600,000IU/mL at the onset of treatment (p=0.003), higher liver enzyme levels (p=0.039) at baseline, infection with genotypes 2 or 3 (p=0.003), and no transient treatment interruption (p=0.001). The treatment was interrupted in 25.6% (98/382) of the patients because of adverse events (11.3%, 43/382), virologic failure (7.8%, 30/382), and dropout (6.5%, 43/382). The main adverse events were cytopenia and psychiatric disorders.\n\n\nCONCLUSIONS\nin our Brazilian case series, the SVR rate under current clinical practice conditions was similar to that reported in other studies. There was a correlation between an SVR and being infected by genotypes 2 and 3, low viral load, high ALT levels at the onset of treatment, and absence of an AIDS-defining illness. Cytopenia and psychiatric disorders were the major causes of treatment interruption. Efforts should be focused on optimizing management of side effects and counseling to improve adherence and to keep patients on treatment.",
"affiliations": "Disciplina de Infecologia Universidade Federal de São Paulo - UNIFESP, São Paulo, Brazil. Electronic address: paulo.abrao.ferreira@gmail.com.;Centro de Referência e Tratamento DST-AIDS de São Paulo, São Paulo, Brazil; Clínica de Especialidades de São Bernardo do Campo, São Paulo, Brazil.;Universidade Federal do Estado do Rio de Janeiro - UNIRIO, Rio de Janeiro, Brazil.;Centro de Especialidades - Ambulatório de Hepatites, Secretaria Municipal de Saúde de Ribeirão Preto, São Paulo, Brazil.;Instituto de Infectologia Emilio Ribas, São Paulo, Brazil.;Disciplina de Infectologia - Universidade Federal do Espírito Santo - UFES, Vitória, Brazil.;Unidade Mista de Saúde - Unimista 508/509, SES-DF, Brasília, Brazil.;Laboratório de Investigação Médica em Epidemiologia e Estatística, Faculdade de Medicina da Universidade de São Paulo - FMUSP, São Paulo, Brazil.;Divisão de Gastroenterologia da Faculdade de Medicina da Universidade de São Paulo, Ribeirão Preto, Brazil.;Departamento de Doenças Infecciosas e Parasitárias da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.",
"authors": "Ferreira|Paulo Roberto Abrão|PR|;Silva|Mariliza Henrique da|MH|;Brandão-Melo|Carlos Eduardo|CE|;Rezende|Rosamar Eulira|RE|;Gonzalez|Mário|M|;Reuter|Tânia|T|;Urbaez|Jose David|JD|;Gianini|Reinaldo Jose|RJ|;Martinelli|Ana|A|;Mendes-Correa|Maria Cássia|MC|",
"chemical_list": "D000998:Antiviral Agents; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D012367:RNA, Viral; D011994:Recombinant Proteins; D011092:Polyethylene Glycols; D012254:Ribavirin; C417083:peginterferon alfa-2b",
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"fulltext": "\n==== Front\nBraz J Infect Dis\nBraz J Infect Dis\nThe Brazilian Journal of Infectious Diseases\n1413-8670\n1678-4391\nElsevier\n\nS1413-8670(14)00166-4\n10.1016/j.bjid.2014.08.002\nOriginal Article\nThe clinical effectiveness of pegylated interferon and ribavirin for the treatment of chronic hepatitis C in HIV-infected patients in Brazil: a multicentric study\nFerreira Paulo Roberto Abrão paulo.abrao.ferreira@gmail.com\na⁎\nda Silva Mariliza Henrique bc\nBrandão-Melo Carlos Eduardo d\nRezende Rosamar Eulira e\nGonzalez Mário f\nReuter Tânia g\nUrbaez Jose David h\nGianini Reinaldo Jose i\nMartinelli Ana j\nMendes-Correa Maria Cássia k\na Disciplina de Infecologia Universidade Federal de São Paulo – UNIFESP, São Paulo, Brazil\nb Centro de Referência e Tratamento DST-AIDS de São Paulo, São Paulo, Brazil\nc Clínica de Especialidades de São Bernardo do Campo, São Paulo, Brazil\nd Universidade Federal do Estado do Rio de Janeiro – UNIRIO, Rio de Janeiro, Brazil\ne Centro de Especialidades – Ambulatório de Hepatites, Secretaria Municipal de Saúde de Ribeirão Preto, São Paulo, Brazil\nf Instituto de Infectologia Emilio Ribas, São Paulo, Brazil\ng Disciplina de Infectologia – Universidade Federal do Espírito Santo – UFES, Vitória, Brazil\nh Unidade Mista de Saúde – Unimista 508/509, SES-DF, Brasília, Brazil\ni Laboratório de Investigação Médica em Epidemiologia e Estatística, Faculdade de Medicina da Universidade de São Paulo – FMUSP, São Paulo, Brazil\nj Divisão de Gastroenterologia da Faculdade de Medicina da Universidade de São Paulo, Ribeirão Preto, Brazil\nk Departamento de Doenças Infecciosas e Parasitárias da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil\n⁎ Corresponding author at: Federal University of São Paulo – UNIFESP, Division of Infectious Disease, Outpatient Clinic to HIV and Viral Hepatitis, Rua Loefgreen, 1588, Vila Clementino, São Paulo-SP, CEP 04040-002, Brazil. paulo.abrao.ferreira@gmail.com\n01 9 2014\nJan-Feb 2015\n01 9 2014\n19 1 1522\n26 5 2014\n1 8 2014\n© 2014 Elsevier Editora Ltda. Este é um artigo Open Access sob a licença de CC BY-NC-ND.\n2014\nElsevier Editora Ltda.\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).\nIntroduction\n\nin Brazil, chronic hepatitis C in patients coinfected with the human immunodeficiency virus (HIV) is treated with pegylated interferon (Peg-IFN) and ribavirin (RBV). However, few studies have evaluated the effectiveness of this treatment in this particular population. The identification of the factors that predict sustained virological response (SVR) under current clinical practice would enable clinicians to more accurately estimate the probability of achieving an SVR and therefore utilize the appropriate therapeutics, especially in the era of direct-acting antiviral (DAA) agents.\n\nAims\n\nthe primary aim of our study was to determine the SVR rate under current clinical practice. The secondary aims were as follows: (1) to determine the factors before and during treatment that predict SVR; and (2) to identify the causes of treatment interruption.\n\nMethods\n\nwithin a cohort of HIV/hepatitis C virus (HCV)-coinfected patients in Brazil, we performed a retrospective analysis of those individuals treated with Peg-IFN and RBV.\n\nResults\n\namong the 382 analyzed patients, SVR was observed in 118 [30.9% (95% confidence interval (CI): 26.3–35.8)], which included 25.9% (75/289) of the patients with genotypes 1 and 4 and 48.2% (41/85) of those with genotypes 2 and 3. After multivariate analyses the independent positive predictors for SVR after treatment for chronic hepatitis C with Peg-IFN and RBV were: absence of an AIDS-defining illness (p = 0.001), HCV viral load lower than 600,000 IU/mL at the onset of treatment (p = 0.003), higher liver enzyme levels (p = 0.039) at baseline, infection with genotypes 2 or 3 (p = 0.003), and no transient treatment interruption (p = 0.001).\n\nThe treatment was interrupted in 25.6% (98/382) of the patients because of adverse events (11.3%, 43/382), virologic failure (7.8%, 30/382), and dropout (6.5%, 43/382). The main adverse events were cytopenia and psychiatric disorders.\n\nConclusions\n\nin our Brazilian case series, the SVR rate under current clinical practice conditions was similar to that reported in other studies. There was a correlation between an SVR and being infected by genotypes 2 and 3, low viral load, high ALT levels at the onset of treatment, and absence of an AIDS-defining illness. Cytopenia and psychiatric disorders were the major causes of treatment interruption. Efforts should be focused on optimizing management of side effects and counseling to improve adherence and to keep patients on treatment.\n\nKeywords\n\nInterferon\nRibavirin\nHCV\nHIV\n==== Body\npmcIntroduction\n\nTherapeutic decisions regarding the treatment of hepatitis C with pegylated interferon (Peg-IFN) and ribavirin (RBV) in patients coinfected with the human immunodeficiency virus (HIV) are complex. Numerous factors must be considered, such as the status of the HIV infection, the stage of liver fibrosis, the probability of attaining sustained virologic response (SVR), potential treatment risks, and any comorbidities. The treatment regimen consisting of Peg-IFN and RBV has a high rate of ineligibility,1 an increased frequency of adverse events, lower rates of SVR, and more relapses among the HIV/hepatitis C virus (HCV)-coinfected population compared with HCV mono-infected patients.2 The development and utilization of direct-acting antiviral (DAA) agents should advance the treatment paradigms.\n\nCurrently, Peg-IFN and RBV, in combination with new oral DAA agents, remain the basis of the therapeutic regimens utilized to treat HCV genotype 1 and the other genotypes. Treating chronic hepatitis C with DAA agents against HCV in HIV/HCV-coinfected patients faces many challenges, including drug interactions with antiretroviral (ARV) agents,3, 4 increased toxicity due to the combination therapy with ARVs, rapid selection of HCV-resistant mutants, treatment compliance with multiple medications, and excessive pill burden.5 HCV protease inhibitors are approved for clinical use in HCV-mono-infected patients.6, 7, 8, 9 Recently published data reported that HIV/HCV-coinfected patients treated with first wave protease inhibitors (telaprevir and boceprevir),10, 11 second wave protease inhibitors (simeprevir and faldaprevir)12, 13 and polymerase inhibitor (sofosbuvir)14, 15 had higher SVR rates compared with those treated with Peg-IFN and RBV. Based on these data, the international guidelines recommend new DAA for the treatment of HIV/HCV-coinfected patients.16, 17, 18, 19\n\nSeveral studies have analyzed the efficacy and safety of combining Peg-IFN and RBV to treat hepatitis C in HIV-coinfected patients. Although in randomized studies the SVR rate varied from 26 to 55%,20, 21, 22, 23 the response rate reported in observational studies was lower, ranging from 12 to 21%.24, 25, 26, 27\n\nThe current recommendations for the treatment of chronic hepatitis C with Peg-IFN and RBV are based on the above-mentioned randomized studies, which included highly selective cohorts of patients without clinically significant comorbidities and with supervised adherence, such as assistance at reference centers, and experienced physicians. The aim of this study was to assess the effectiveness of treatment with Peg-IFN and RBV under typical conditions, i.e., not as part of a research protocol and in a population of patients treated at several Brazilian centers, by determining the SVR rate and the related factors, and the frequency and causes of treatment interruption.\n\nMethods\n\nDesign and selection of patients\n\nThis study was a retrospective, observational, and non-probabilistic sampling study based on a cohort that included 12 centers at various locations in Brazil. All the HIV/HCV-coinfected patients who were treated with at least one dose of Peg-IFN and RBV (48-week regimen) between January 2005 and June 2008 and were assisted at these centers were included (intention-to-treat analysis). The treatment decisions at the centers were based on the guidelines of the Brazilian Health Ministry (which followed the international recommendations at the time) and were at the discretion of the attending physicians. This study was approved by the research ethics committees at all of the participating centers.\n\nAssessment of effectiveness\n\nEffectiveness was determined based on virological response at the end of the treatment (HCV-RNA undetectable or <50 IU/mL) and on SVR (HCV-RNA undetectable or <50 IU/mL 24 weeks after the end of the treatment). Only intention-to-treat analysis was considered.\n\nAnalyzed variables\n\nThe variables selected for analysis were grouped into several categories: variables related to the patients (age, gender, and weight), variables related to HCV infection [level of alanine transaminase (ALT) before treatment, quantitative HCV-RNA measurements before treatment, HCV genotype, and pattern of liver fibrosis], variables related to HCV treatment [number of treatments received; type, dose, and length of Peg-IFN and RBV treatment; and frequency and causes of transient interruption (interruption of RBV and/or Peg-IFN, up to a maximum of two weeks) and treatment discontinuation (interruption of RBV and/or Peg-IFN treatment prior to the completion of the scheduled 48 weeks)], and variables related to HIV infection [history of acquired immunodeficiency syndrome (AIDS)-defining illness, length of antiretroviral therapy (ART), use of zidovudine (AZT), number of CD4+ T cells before treatment, and number of nadir CD4+ T cells].\n\nWe reported the liver biopsy results (the degree of inflammatory activity and the stage of fibrosis) as defined by the METAVIR Cooperative Study Group.28 In addition, the degree of steatosis and siderosis were determined by histological examination of the liver.\n\nStatistical analysis\n\nThe qualitative variables were expressed as frequencies and percentages, and the quantitative variables were reported as measures of central tendency. For the binary outcomes, the correlation between exposure and outcome was estimated using the prevalence ratio (PR).29, 30 The variables with a p-value < 0.25 by univariate analysis were selected for a multiple analysis of variance using a Cox regression model with robust variance.31 The variables with a p-value < 0.05 in the multiple analysis remained in the final model. Finally, the PR of each such variable was estimated together with the corresponding confidence interval (95% CI) at a 5% descriptive level.\n\nResults\n\nCharacterization of the population sample\n\nThis study included 382 HIV-HCV-coinfected patients from 12 different Brazilian institutions. Most of the patients were male (72.5%), 40 years old or older (64.2%), had no history of AIDS-defining illness (50.3%), were on ART (92.3%) for at least five years (63.6%), and had 500 or more CD4+ T cells/mm3 in the peripheral blood before treatment (58.2%) (Table 1). The average weight of the patients was 68.4 kg [standard deviation (SD) = 12.4 kg].Table 1 Baseline characteristics of the study subjects.\n\nVariables\tn/N\t%\t\nMale gender\t277/382\t72.5\t\nAge (years)\t\n <35\t42/371\t11.3\t\n 35–39\t91/371\t24.5\t\n 40–44\t91/371\t24.5\t\n 45–49\t82/371\t22.1\t\n ≥50\t65/371\t17.5\t\n Mean (SD); median (min–max) 42.9 (7.7); 42 (23–78)\t\n\n\n\t\nNadir CD4+ (cells/mm3)\t\n <200\t126/307\t41.0\t\n 200–349\t98/307\t31.9\t\n 350–499\t47/307\t15.3\t\n ≥500\t36/307\t11.7\t\n Mean (SD); median (min–max) 275.7 (205.0); 249 (1–1140)\t\n\n\n\t\nAids-defining illness\t176/354\t49.7\t\nCurrent use of ART\t335/363\t92.3\t\n\n\n\t\nLength of ART (years)\t\n <5\t87/239\t36.4\t\n 5–9\t104/239\t43.5\t\n ≥10\t48/239\t20.1\t\n Mean (SD); median (min–max) 6.8 (3.5); 7 (0–19)\t\n\n\n\t\nUse of AZT\t141/303\t46.5\t\nCD4+ before treatment (cells/mm3)\t\n <350\t57/376\t15.2\t\n 350–499\t100/376\t26.6\t\n ≥500\t219/376\t58.2\t\n Mean (SD); median (min–max) 600.0 (287.2); 538 (134–2473)\t\n\n\n\t\nHCV genotype\t\n 1 or 4\t293/374\t76.7\t\n 2 or 3\t81/374\t23.3\t\nHCV viral load (IU/mL) ≥600,000\t164/239\t68.6\t\nALT levels\t\n Normal\t77/367\t21.0\t\n Above the ULNRa\t290/367\t79.0\t\nMETAVIR fibrosis stage\t\n 0\t13/357\t3.6\t\n 1\t101/357\t28.3\t\n 2\t126/357\t35.3\t\n 3\t72/357\t20.2\t\n 4\t45/357\t12.6\t\nMETAVIR score of inflammatory activity\t\n 0\t8/353\t2.3\t\n 1\t79/353\t22.4\t\n 2\t152/353\t43.1\t\n 3\t114/353\t32.3\t\nCirrhosis\t43/364\t11.8\t\nSteatosis\t115/264\t43.6\t\nSiderosis\t64/254\t25.2\t\nType of pegylated interferon\t\n Alpha-2b\t169/382\t44.2\t\n Alpha-2a\t213/382\t55.8\t\nLength of HCV treatment (weeks)\t\n <48\t132/274\t48.2\t\n ≥48\t142/274\t51.8\t\n Mean (SD); median (min–max) 42.1 (15.4); 48 (1–111)\t\n\n\n\t\nUse of filgrastim\t71/382\t18.6\t\n\n\n\t\nUse of erythropoietin\t67/382\t17.5\t\nTransient interruption\t99/382\t25.9\t\nTreatment discontinuation\t98/382\t25.6\t\na ULNR: upper limit of the normal range.\n\nRegarding the HCV infection, 76.7% of the patients had genotypes 1 or 4, 68.6% presented with a viral load >600,000 IU/mL, and 79.0% exhibited ALT levels above the upper limit of the normal range (Table 1).\n\nAccording to liver histopathological assessment before treatment, the cohort included patients with advanced fibrosis (F3) (20.2%), cirrhosis (12.6%), moderate or intense inflammatory activity (75.4%), some degree of steatosis (43.6%), and some degree of siderosis (25.2%).\n\nIt is noteworthy that 77 (21.5%) patients had previously received anti-HCV treatment consisting of conventional interferon and RBV.\n\nFor the current anti-HCV treatment, most patients were given Peg-IFN-alpha-2a (55.8%), and the median length of treatment was 48 weeks (n = 274). Overall, 18.6% of the patients received filgrastim, and 17.5% took erythropoietin.\n\nTransient interruption or early treatment discontinuation occurred among 99 (25.9%) and 98 (25.6%) patients, respectively.\n\nIn 25.6% of the patients (98/382), the treatment was discontinued prematurely because of adverse events (11.3%, 43/382), virologic failure (7.8%, 30/382), and dropout (6.5%, 25/382). The most frequent reasons for early treatment discontinuation among 98 patients were as follows: nonresponse to treatment (n = 30; 30.6%), anemia (n = 23; 23.5%), dropout (n = 23; 23.5%), intolerance to the medication (n = 21; 21.4%), and psychiatric illness that contra-indicated treatment (n = 17; 17.3%). The most frequent reasons for transient interruption included the following: anemia (n = 47; 47.5%), neutropenia (n = 47; 35.4%), and poor adherence (n = 10; 10.1%) (Table 2). Some patients had more than one cause of interruption.Table 2 Reasons for transient interruption or early treatment discontinuation.\n\nReasona\tTreatment discontinuation (N = 98)\tTransient interruption (N = 99)\t\n\tN\t%\tN\t%\t\nAnemia\t23\t23.5\t47\t47.5\t\nNeutropenia\t20\t20.4\t35\t35.4\t\nDropout\t23\t23.5\t\t\t\nNon-responders\t30\t30.6\t–\t–\t\nPsychiatric illness\t21\t21.4\t7\t7.1\t\nThrombocytopenia\t7\t7.1\t6\t6.1\t\nIntolerance to medication\t21\t21.4\t5\t5.1\t\nIncorrect use of medication\t1\t1.0\t3\t3.0\t\nLack of medication\t1\t1.0\t–\t–\t\nLiver decompensation\t6\t6.1\t2\t2.0\t\nNeoplasia\t2\t2.0\t1\t1.0\t\nMyalgia\t–\t–\t1\t1.0\t\nWeight loss\t–\t–\t1\t1.0\t\nOpportunistic disease\t5\t5.1\t–\t–\t\nDVT (deep vein thrombosis)\t3\t3.1\t–\t–\t\nThyroid disorder\t2\t2.0\t–\t–\t\nCD4 reduction\t1\t1.0\t–\t–\t\nPancreatitis\t1\t1.0\t–\t–\t\nKidney failure (proteinuria)\t1\t1.0\t–\t–\t\nDrug-induced skin disorders\t1\t1.0\t–\t–\t\nDeath\t1\t1.0\t–\t–\t\nOthers\t–\t–\t1\t1.0\t\na Some patients exhibited more than one reason.\n\nAmong the 382 analyzed patients, 118 patients achieved SVR [30.9% (95% CI: 26.3–35.8)]. Among them 25.9% (75/289) had genotypes 1 or 4 and 48.2% (41/85) had genotypes 2 or 3.\n\nUnivariate analysis\n\nWe conducted a univariate analysis to test the association of each variable and SVR. SVR was associated to: absence of AIDS-defining illness (p < 0.001), no current use of AZT (p = 0.029), HCV genotypes 2 or 3 (p < 0.001), baseline HCV viral load lower than 600,000 IU/mL (p = 0.017), higher ALT level at baseline (p = 0.024, use of Peg-IFN-alpha-2a (p = 0.044), 48-week treatment duration (p = 0.008), and no treatment interruption (p = 0.005) or discontinuation (p < 0.001) (Table 3).Table 3 Univariate analysis of the factors associated with SVR.\n\nVariables\tWith SVR, n (%)\tWithout SVR, n (%)\tPR\t95% CI\tp-value\t\nGender\t\t\t\t\t0.077\t\n Female\t80 (76.2)\t25 (23.8)\t1\t\t\t\n Male\t184 (66.4)\t93 (33.6)\t1.41\t0.96–2.06\t\t\nAge*\t\t\t\t\t0.442\t\n <35\t27 (64.3)\t15 (35.7)\t1\t\t\t\n 35–39\t62 (68.1)\t29 (31.9)\t0.89\t0.54–1.48\t\t\n 40–44\t67 (73.6)\t24 (26.4)\t0.74\t0.43–1.26\t\t\n 45–49\t52 (63.4)\t30 (36.6)\t1.02\t0.62–1.68\t\t\n 50 or +\t49 (75.4)\t16 (24.6)\t0.69\t0.38–1.24\t\t\nNadir CD4**\t0.403\t\n < 200\t80 (63.5)\t46 (36.5)\t1\t\t\t\n 200–349\t71 (72.5)\t27 (27.5)\t0.75\t0.51–1.12\t\t\n 350–499\t28 (59.6)\t19 (40.4)\t1.11\t0.73–1.68\t\t\n 500 or +\t24 (66.7)\t12 (33.3)\t0.91\t0.54–1.53\t\t\nOpportunistic infection***\t<0.001\t\n Yes\t137 (77.8)\t39 (22.2)\t1\t\t\t\n No\t106 (59.6)\t72 (40.4)\t1.83\t1.31–2.54\t\t\nUse of ARV+\t0.599\t\n No\t18 (64.3)\t10 (35.7)\t1\t\t\t\n Yes\t231 (69.0)\t104 (31.0)\t0.87\t0.52–1.47\t\t\nLength of ARV++(years)\t0.350\t\n <5\t57 (65.5)\t30 (35.5)\t1\t\t\t\n 5–9\t68 (65.4)\t36 (34.6)\t1.00\t0.68–1.49\t\t\n 10 or +\t37 (77.1)\t11 (22.9)\t0.66\t0.37–1.21\t\t\nUse of AZT+++\t0.029\t\n Yes\t108 (76.6)\t33 (23.4)\t1\t\t\t\n No\t105 (64.8)\t57 (35.2)\t1.50\t1.04–2.17\t\t\nPretreatment CD4\t0.441\t\n <350\t39 (68.4)\t18 (31.6)\t1\t\t\t\n 350–499\t74 (74.0)\t26 (26.0)\t0.82\t0.50–1.37\t\t\n 500 or +\t146 (66.7)\t73 (33.3)\t1.06\t0.69–1.62\t\t\nHCV Genotype@\t< 0.001\t\n 1–4\t214 (74.1)\t75 (25.9)\t1\t\t\t\n 2–3\t44 (51.8)\t41 (48.2)\t1.86\t1.38–2.49\t\t\nHCV RNA@@\t0.017\t\n ≥ 600.000\t121 (73.8)\t43 (26.2)\t1\t\t\t\n < 600.000\t44 (58.7)\t31 (41.3)\t1.58\t1.09–2.29\t\t\nALT@@@\t0.024\t\n Normal\t48 (62.3)\t29 (37.7)\t1\t\t\t\n ULNR\t208 (71.7)\t82 (28.3)\t0.50\t0.30–0.83\t\t\nFibrosis stage+\t0.141\t\n 3 or 4\t89 (76.1)\t28 (23.9)\t1\t\t\t\n 0, 1 or 2\t164 (68.3)\t76 (31.7)\t1.32\t0.91–1.92\t\t\nInflammatory activity++\t0.065\t\n 2 or 3\t195 (73.3)\t71 (26.7)\t1\t\t\t\n 0 or 1\t55 (63.2)\t32 (36.8)\t1.38\t0.98–1.94\t\t\nCirrhosis+++\t0.335\t\n Yes\t33 (76.7)\t10 (23.3)\t1\t\t\t\n No\t223 (69.2)\t99 (30.8)\t1.32\t0.75–2.33\t\t\nSteatosis++++\t0.644\t\n Yes\t78 (67.8)\t37 (32.2)\t1\t\t\t\n No\t105 (70.5)\t44 (29.5)\t0.92\t0.64–1.32\t\t\nSiderosis+++++\t0.340\t\n Yes\t47 (73.4)\t17 (26.6)\t1\t\t\t\n No\t127 (68.8)\t63 (33.2)\t1.25\t0.79–1.97\t\t\nRetreatment&\t0.753\t\n Yes\t52 (67.5)\t25 (32.5)\t1\t\t\t\n No\t195 (69.4)\t86 (30.6)\t0.94\t0.65–1.36\t\t\nType of Peg interferon\t0.044\t\n Alpha 2b\t126 (74.6)\t43 (25.4)\t1\t\t\t\n Alpha 2a\t138 (64.8)\t75 (35.2)\t1.38\t1.01–1.90\t\t\nLength of HCV treatment (weeks)&&&\t0.008\t\n <48\t102 (77.3)\t30 (22.7)\t1\t\t\t\n ≥48\t88 (62.0)\t54 (38.0)\t1.67\t1.15–2.44\t\t\nUse of filgrastim\t0.589\t\n Yes\t51 (71.8)\t20 (28.2)\t1\t\t\t\n No\t213 (68.5)\t98 (31.5)\t1.12\t0.74–1.68\t\t\nUse of erythropoetin\t0.840\t\n Yes\t47 (70.1)\t20 (29.9)\t1\t\t\t\n No\t217 (68.9)\t98 (31.1)\t1.04\t0.70–1.56\t\t\nWeight (kg)&&&\t0.149\t\n < 70\t157 (72.3)\t60 (27.7)\t1\t\t\t\n ≥ 70\t102 (65.4)\t54 (34.6)\t1.25\t0.92–1.70\t\t\nTransient interruption&&&\t0.005\t\n Yes\t80 (80.8)\t19 (19.2)\t1\t\t\t\n No\t176 (64.2)\t98 (35.8)\t1.86\t1.21–2.88\t\t\nTreatment discontinuation&&&&\t<0.001\t\n Yes\t89 (90.8)\t9 (9.2)\t1\t\t\t\n No\t172 (62.1)\t105 (37.9)\t4.13\t2.17–7.84\t\t\nMissing values: (*)11; (**)75; (***)28; (****)19; (#)143; (##)79; (###)6; (@)8; (@@)143; (@@@)15; (+)25; (++)29; (+++)17; (++++)118; (+++++)128; (&)24; (&&)108; (&&&)9; (&&&&)7.\n\nPR: prevalence ratio; AZT: zidovudine.\n\nMultivariate analysis\n\nAccording to the multivariate analysis the following variables correlated with SVR: absence of AIDS-defining illness (p = 0.001), HCV viral load lower than 600,000 IU/mL at the onset of treatment (p = 0.003), higher liver enzyme levels (p = 0.039), infection with genotypes 2 or 3 (p < 0.003), and no transient treatment interruption (p = 0.001) (Table 4).Table 4 Variables elected from uni- to multivariate analyses of the factors associated with SVR.\n\nVariables\tUnivariate\tMultivariate\t\n\tPR\t95% CI\tp value\tPRadj\t95% CI\tp value\t\nPrevious opportunistic infection (yes vs. no)\t1.83\t1.31–2.54\t<0.001\t2.06\t1.36–3.12\t0.001\t\nUse of AZT (yes vs. no)\t1.50\t1.04–2.17\t0.029\t\t–\t\t\nHCV genotype (1 or 4 vs. 2 or 3)\t1.86\t1.38–2.49\t<0.001\t1.84\t1.22–2.78\t<0.003\t\nHCV viral load (≥600,000 vs. <600,000 IU/mL)\t1.58\t1.09–2.29\t0.017\t1.76\t1.20–2.58\t0.004\t\nIncreased ALT ULNR vs. normal ALT\t0.50\t0.30–0.83\t0.024\t0.53\t0.29–0.96\t0.039\t\nType of Peg-IFN (alpha-2b vs. alpha-2a)\t1.38\t1.01–1.90\t0.044\t\t–\t\t\nLength of anti-HCV treatment (<48 vs. ≥48 weeks)\t1.67\t1.15–2.44\t0.008\t\t–\t\t\nTransient interruption (yes vs. no)\t1.86\t1.21–2.88\t0.005\t3.32\t1.59–6.90\t0.001\t\nPR: prevalence ratio; PRadj: adjusted prevalence ratio.\n\nDiscussion\n\nAccording to our data, infection with genotypes 2 or 3, low pre-treatment HCV viral load, and higher transaminases at baseline were independent positive predictors of SVR. These factors were identified in previous studies, and our study confirms their relevance in clinical practice.32, 33, 34, 35, 36 In addition, a previous history of opportunistic infections and transient treatment interruption robustly correlated with treatment failure, which possibly reflects previous more intense impairment of immune system and problems with adverse events and adherence, respectively. The identification of these factors is important to estimate the chance of SVR before and during treatment.\n\nAnemia was the primary cause for interrupting anti-HCV treatment (23.5%) and also stood out as the main cause of transient treatment interruption (47.5%). Interestingly, 46.5% of the patients included in our study took zidovudine (AZT) at some point of treatment. Currently, AZT is not recommended to be used in combination with RBV because of the high risk of anemia, which necessitates reducing or interrupting RBV. Along with previously published data, our results corroborate the evidence indicating that the combination of AZT and RBV is not appropriate.\n\nOur study also identified psychiatric disorder as an important cause of treatment interruption (17.3%), which highlights the need for more adequate and specific interventions concerning the mental health of the target population to improve treatment adherence. Other important reasons for discontinuation of treatment were neutropenia (20.4%), thrombocytopenia (7.1%), liver decompensation (6.1%), and opportunistic disease (5.1%).\n\nThe high rate of treatment interruption in our study is a particular concern in DAAs era. Even with important increase of SVR rates with these new drugs, interferon and ribavirin will be used, particularly in resource-poor settings due to higher costs of interferon free regimens. Using telaprevir or boceprevir will increase the incidence of severe adverse events. This situation can impact on adherence and effectiveness, especially in real-life HCV/HIV coinfected patients, where cases tend to be more severe. It is clear that we need more affordable regimens with interferon and without interferon to increase the access of patients to treatment.\n\nAccording to results of univariate analysis, premature treatment interruption and duration of anti-HCV treatment correlated with SVR. Nevertheless, we opted not to include those variables in the multivariate analysis because we considered them to be co-linear and a reflection of transient treatment interruptions stemming from virologic failure, adverse events, or dropout. It is clear that the probability of curing chronic hepatitis C is reduced under these circumstances.\n\nOur study was a retrospective, multicenter cohort of HIV/HCV-coinfected patients followed in clinical practice settings at 12 Brazilian centers. Although retrospective studies cannot replace prospective randomized studies, they represent an important source of data on treatments in realistic settings. In particular, such studies provide an opportunity to establish whether the success rates, SVR in this case (efficacy), reported in randomized clinical trials extend to typical treatment scenarios where the patients are exposed to factors that are not assessed in randomized clinical trials (effectiveness). This information is important in pinpointing the probability of therapeutic success for each patient and guiding the population-based decision-making by the health authorities. Therefore, observational studies should be conducted immediately following the conclusion of randomized clinical trials to extend the results obtained under ideal conditions to typical settings.37\n\nOur study had several limitations. First, we were not able to establish how many HIV/HCV-coinfected patients were originally screened, i.e., were considered to be eligible for treatment, or refused treatment. This consideration is critical because we cannot rule out the occurrence of selection bias, which may have favored the inclusion of patients with higher probability of achieving SVR.\n\nSecond, because our study was retrospective, we did not have access to all of the patients’ clinical data regarding the analyzed variables. The missing data may have impacted the results. To minimize the effect of this bias on our results, the loss of data was not higher than 10% for any of the variables included in the analysis. This fact reflects the difference between randomized clinical trials, where several parameters are systematically collected, and typical conditions, where only the most relevant parameters needed to monitor treatments are routinely collected.\n\nThird, because our study was retrospective, treatment adherence could not be monitored. However, retrospective studies have the advantage of assessing realistic clinical practice (effectiveness) without the potential bias created by changes in behavior that occur in prospective studies because of the awareness of being under observation (Hawthorne effect).38\n\nIn conclusion, in our study patients were treated with Peg-IFN and RBV, and the following were identified as predictors of SVR: HCV genotypes 2 or 3, low HCV viral load, high ALT levels at the onset of treatment, no previous history of an AIDS-defining illness and no transient treatment interruption. The identification of these factors may help clinicians to estimate the probability of achieving an SVR and therefore make more appropriate therapeutic decisions. The use of HCV new DAA in HIV/HCV-coinfected patients is currently indicated. With these new drugs, the efficacy of treating HIV/HCV-coinfected patients should increase and with less contra-indications and best tolerance, we will enhance the access to treatment final effectiveness. The potential repercussions in realistic treatment settings are unknown, as the pharmacoeconomic impact, particularly in resource limited situation. In many cases, success will certainly depend on the appropriate management of the basic Peg-IFN and RBV combination therapy.\n\nConflicts of interest\n\nThe authors have no conflict of interest to declare.\n==== Refs\nReferences\n\n1 Mendes-Corrêa M.C. Ferreira P.R.A. Martins L.G. Barriers to the treatment of hepatitis C in HIV/HCV-coinfected adults in Brazil Braz J Infect Dis 14 2010 237 241 20835506\n2 Adeyemi O.M. Hepatitis C in HIV-positive patients – treatment and liver disease outcomes J Clin Gastroenterol 41 2007 75 87 17198069\n3 Seden K. Back D. Shoo S. New direct-acting antivirals for hepatitis C: potential for interaction with antiretrovirals J Antimicrob Chemother 65 2010 1079 1085 20335191\n4 Jiménez-Nácher I. Alvarez E. Morello J. Approaches for understanding and predicting drug interactions in HIV-infected patients Expert Opin Drug Metab Toxicol 7 2011 457 477 21342079\n5 Soriano V. Sherman K.E. Rockstroh J. Challenges and opportunities for hepatitis C drug development in HIV/hepatitis C virus-coinfected patients AIDS 25 2011 2197 2208 21866039\n6 Jacobson I.M. McHutchison J.G. Dusheiko G. Telaprevir for previously untreated chronic hepatitis C virus infection N Engl J Med 364 2011 2405 2416 21696307\n7 Zeuzem S. Andreone P. Pol S. Telaprevir for the retreatment of HCV infection N Engl J Med 364 2011 2417 2428 21696308\n8 Poordad F. McCone J. Jr. Bacon B.R. Boceprevir for untreated chronic HCV genotype 1 infection N Engl J Med 364 2011 1195 1206 21449783\n9 Bacon B.R. Gordon S.C. Lawitz E. Boceprevir for previously treated chronic HCV genotype 1 infection N Engl J Med 364 2011 1207 1217 21449784\n10 Sulkowski M. Pol S. Mallolas J. Boceprevir versus placebo with pegylated interferon alfa-2b and ribavirin for treatment of hepatitis C virus genotype 1 in patients with HIV: a randomised, double-blind, controlled phase 2 trial Lancet Infect Dis 13 2013 597 605 23768747\n11 Sulkowski M.S. Sherman K.E. Dieterich D.T. Combination therapy with telaprevir for chronic hepatitis C virus genotype 1 infection in patients with HIV: a randomized trial Ann Intern Med 159 2013 86 96 23685940\n12 Dieterich D. Tural C. Nelson M. Faldaprevir plus pegylated interferon alfa-2a/ribavirin in HIV/HCV coinfection: STARTVerso4 Conference on Retroviruses and Opportunistic Infections (CROI 2014) Boston, March 3–6 2014 Abstract 23\n13 Dieterich D. Rockstroh J.K. Orkin C. Simeprevir (TMC435) plus PegIFN/ribavirin in HCV genotype-1/HIV-1 coinfection (Study C212) 21st Conference on Retroviruses and Opportunistic Infections (CROI 2014) Boston, March 3–6 2014 Abstract 24\n14 Naggie S. Sulkowski M.S. Lalezari J. Sofosbuvir plus ribavirin for HCV genotype 1–3 infection in HIV coinfected patients (PHOTON-1) 21st Conference on Retroviruses and Opportunistic Infections (CROI 2014) Boston, March 3–6, 2014 2014 Abstract 26\n15 Rodriguez-Torres M. Rodriguez-Orengo J.F. Gaggar A. Sofosbuvir and peginterferon alfa-2a/ribavirin for treatment-naïve genotype 1–4 HCV-infected patients who are coinfected with HIV 53rd ICAAC 2013 Denver, CO, Sept 10–13, 2013 2013\n16 http://www.aidsinfo.nih.gov/guidelines/html/1/adult-and-adolescent-treatment-guidelines/26/hepatitis-c--hcv--hiv-coinfection [accessed 30.3.14].\n17 Thompson M.A. Aberg J.A. Hoy J.F. Antiretroviral treatment of adult HIV infection 2012 recommendations of the international antiviral society – USA panel JAMA 308 2012 387 402 22820792\n18 http://www.europeanaidsclinicalsociety.org/index.php?option=com_content&view=article&id=59&Itemid=41 [accessed 28.7.12].\n19 http://www.hcvguidelines.org/full-report/unique-patient-populations [accessed 30.3.14].\n20 Torriani F.J. Rodriguez-Torres M. Rockstroh J.K. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection in HIV-infected patients N Engl J Med 351 2004 438 450 15282351\n21 Laguno M. Murillas J. Blanco J.L. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for the treatment of HIV/HCV-coinfected patients AIDS 18 2004 27 36\n22 Chung R.T. Andersen J. Volberding P. Interferon alfa-2a plus ribavirin for chronic hepatitis C in HIV-coinfected persons N Engl J Med 351 2004 451 459 15282352\n23 Carrat F. Bani-Sadr F. Pol S. Pegylated interferon alfa-2b vs standard interferon alfa-2b, plus ribavirin, for chronic hepatitis C in HIV-infected patients: a randomized controlled trial JAMA 292 2004 2839 2848 15598915\n24 Moreno L. Quereda C. Moreno A. Pegylated interferon a2b plus ribavirin for the treatment of chronic hepatitis C in HIV-infected patients AIDS 18 2004 67 73 15090831\n25 Moreno A. Bárcena R. García-Garzón S. HCV clearance and treatment outcomes in genotype 1 HCV-monoinfected, HIV-coinfected and liver transplant patients on peg-IFN-a-2b/ribavirin J Hepatol 43 2005 783 790 16084622\n26 Pérez-Olmeda M. Núñez M. Romero M. Pegylated IFNalpha 2b plus ribavirin as a treatment for chronic hepatitis C in HIV-infected patients AIDS 17 2003 1023 1028 12700452\n27 Voigt E. Schulz C. Klausen G. Pegylated interferon alfa-2b plus ribavirin for the treatment of chronic hepatitis C J Infect 53 2006 36 42 16269184\n28 Bedossa P. Poynard T. An algorithm for the grading of activity in chronic hepatitis C. The METAVIR Cooperative Study Group Hepatology 24 1996 289 293 8690394\n29 Barros A.J. Hirakata V.N. Alternatives for logistic regression in cross-sectional studies: an empirical comparison of models that directly estimate the prevalence ratio BMC Med Res Methodol 3 2003 21 14567763\n30 Davies H.T. Crombie I.K. Tavakoli M. When can odds ratios mislead? BMJ 316 1998 989 991 9550961\n31 Lin D.Y. Wei L.J. The robust inference for the Cox Proportional Hazards Model J Am Stat Assoc 84 1989 1074 1078\n32 Berenguer J. González-García J. López-Aldeguer J. Pegylated interferon alfa-2a plus ribavirin versus pegylated interferon alfa-2b plus ribavirin for the treatment of chronic hepatitis C in HIV-infected patients J Antimicrob Chemother 63 2009 1256 1263 19363085\n33 Righi E. Beltrame A. Bassetti M. Therapeutic aspects of and outcomes for HIV/HCV-coinfected patients treated with pegylated interferon plus ribavirin in an Italian cohort Infection 36 2008 358 361 18642111\n34 Righi E. Beltrame A. Bassetti M. The efficacy and safety of pegylated-interferon plus ribavirin in HIV-infected patients coinfected with hepatitis C virus in clinical practice: a 32 case observational follow-up Rev Med Interne 26 2005 280 287 15820563\n35 Tural C. Galeras J.A. Planas R. Differences in the virological response to pegylated interferon and ribavirin between hepatitis C virus (HCV)-monoinfected and HCV/HIV-coinfected patients Antivir Ther 13 2008 1047 1055 19195330\n36 Laguno M. Cifuentes C. Murillas J. A randomized trial comparing pegylated interferon alfa-2b to pegylated interferon alfa-2a, both plus ribavirin, to treat chronic hepatitis C in human immunodeficiency virus patients Hepatology 49 2009 22 31 19085908\n37 Seale J.P. Gebski V.J. Keech A.C. Generalizing the results of trials to clinical practice Med J Aust 181 2004 558 560 15540970\n38 De Amici D. Klersy C. Ramajoli F. Impact of the Hawthorne effect in a longitudinal clinical study: the case of anesthesia Control Clin Trials 21 2000 103 104 10715508\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "1413-8670",
"issue": "19(1)",
"journal": "The Brazilian journal of infectious diseases : an official publication of the Brazilian Society of Infectious Diseases",
"keywords": "HCV; HIV; Interferon; Ribavirin",
"medline_ta": "Braz J Infect Dis",
"mesh_terms": "D000328:Adult; D000998:Antiviral Agents; D018791:CD4 Lymphocyte Count; D015331:Cohort Studies; D004359:Drug Therapy, Combination; D005260:Female; D005838:Genotype; D016174:Hepacivirus; D019698:Hepatitis C, Chronic; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D008297:Male; D008875:Middle Aged; D011092:Polyethylene Glycols; D012367:RNA, Viral; D011994:Recombinant Proteins; D012189:Retrospective Studies; D012254:Ribavirin; D016896:Treatment Outcome; D019562:Viral Load",
"nlm_unique_id": "9812937",
"other_id": null,
"pages": "15-22",
"pmc": null,
"pmid": "25181403",
"pubdate": "2015",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": null,
"title": "The clinical effectiveness of pegylated interferon and ribavirin for the treatment of chronic hepatitis C in HIV-infected patients in Brazil: a multicentric study.",
"title_normalized": "the clinical effectiveness of pegylated interferon and ribavirin for the treatment of chronic hepatitis c in hiv infected patients in brazil a multicentric study"
} | [
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"abstract": "Six cases involving the antidepressant mirtazapine were analyzed in detail at the San Diego County Medical Examiner's Office from 2004 to 2005. Mirtazapine was initially detected and confirmed in each of these cases by a liquid-liquid gas chromatography (GC)-MS basic drug screen. Following another liquid-liquid basic extraction, mirtazapine was quantitated by GC with nitrogen-phosphorus detection. For each case, mirtazapine concentrations in peripheral blood (pb), central blood (cb), vitreous (vit), and liver were determined against matrix specific calibration curves (limit of detection 0.01 mg/L; linear range 0.025-1.0 mg/L). In contrast with earlier studies of postmortem distribution of mirtazapine, we found concentrations in liver that were significantly higher. Mirtazapine was identified in the cause of death by the pathologist in three cases. In the drug-related deaths, mirtazapine concentrations (mean +/- S.D.) were 2.0 +/- 1.5 mg/L (pb), 1.6 +/- 1.0 mg/L (cb), 0.78 +/- 0.56 mg/L (vit), and 10 +/- 7.4 mg/kg (liver). Alternatively, concentrations considered therapeutic (three non-drug-related deaths) were (mean +/- S.D.) 0.18 +/- 0.22 mg/L (pb), 0.16 +/- 0.17 mg/L (cb), 0.12 +/- 0.16 mg/L (vit), and 0.73 +/- 0.68 mg/kg (liver). Although mirtazapine concentrations were elevated in blood and liver in three cases, it should be noted that other drugs were also found in toxic concentrations in each case. These data may further support the fact that mirtazapine is a relatively safe drug with respect to overdose.",
"affiliations": "San Diego County Medical Examine's Office, 5555 Overland Ave., Suite 1411, San Diego, California 92123-1245, USA.",
"authors": "Kirkton|Carrie|C|;McIntyre|Iain M|IM|",
"chemical_list": "D000929:Antidepressive Agents, Tricyclic; D008803:Mianserin; D000078785:Mirtazapine",
"country": "England",
"delete": false,
"doi": "10.1093/jat/30.9.687",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0146-4760",
"issue": "30(9)",
"journal": "Journal of analytical toxicology",
"keywords": null,
"medline_ta": "J Anal Toxicol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000929:Antidepressive Agents, Tricyclic; D003863:Depression; D062787:Drug Overdose; D005260:Female; D006801:Humans; D008099:Liver; D008297:Male; D008803:Mianserin; D008875:Middle Aged; D000078785:Mirtazapine; D011180:Postmortem Changes; D013405:Suicide",
"nlm_unique_id": "7705085",
"other_id": null,
"pages": "687-91",
"pmc": null,
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"pubdate": "2006",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Therapeutic and toxic concentrations of mirtazapine.",
"title_normalized": "therapeutic and toxic concentrations of mirtazapine"
} | [
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"companynumb": "US-PFIZER INC-2017236667",
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"activesubstancename": "HYDROCODONE"
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... |
{
"abstract": "The management of severe late-onset hemorrhagic cystitis (LO-HC) after allogeneic hematopoietic stem cell transplantation (HSCT) is still challenging. Because mesenchymal stromal cells (MSCs) possess anti-inflammatory and tissue repair-promoting properties, we retrospectively analyzed the efficacy and safety of MSC infusions in 7 of 33 patients with severe LO-HC after allogeneic HSCT. During treatment, each patient received at least one MSC infusion of Wharton's jelly derived from the umbilical cord of a third-party donor. In 6 patients, MSC treatment was initiated within 3 days of gross hematuria onset, while the 7th patient received an infusion 40 days later. The median dose was 1.0 (0.8-1.6) × 10(6)/kg. Five of 7 patients responded to treatment. Notably, gross hematuria promptly disappeared in 3 patients after 1 infusion, with a time to remission not seen in patients without MSC infusion. Two patients showed no response even after several infusions. No acute or late complications were recorded. Our findings indicate that MSC transfusion might be a feasible and safe supplemental therapy for patients with severe LO-HC after allogeneic HSCT.",
"affiliations": "Jiangsu Institute of Hematology, Key Laboratory of Thrombosis and Hemostasis, Ministry of Health, The First Affiliated Hospital of Soochow University, Suzhou, PR China.",
"authors": "Wang|Ying|Y|;Chen|Feng|F|;Gu|Bing|B|;Chen|Guanghua|G|;Chang|Huirong|H|;Wu|Depei|D|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000362530",
"fulltext": null,
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"issn_linking": "0001-5792",
"issue": "133(1)",
"journal": "Acta haematologica",
"keywords": null,
"medline_ta": "Acta Haematol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D002648:Child; D003556:Cystitis; D005260:Female; D006086:Graft vs Host Disease; D018380:Hematopoietic Stem Cell Transplantation; D006470:Hemorrhage; D006566:Herpesviridae Infections; D006801:Humans; D015994:Incidence; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells; D012189:Retrospective Studies; D012720:Severity of Illness Index; D014184:Transplantation, Homologous; D055815:Young Adult",
"nlm_unique_id": "0141053",
"other_id": null,
"pages": "72-7",
"pmc": null,
"pmid": "25139500",
"pubdate": "2015",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Mesenchymal stromal cells as an adjuvant treatment for severe late-onset hemorrhagic cystitis after allogeneic hematopoietic stem cell transplantation.",
"title_normalized": "mesenchymal stromal cells as an adjuvant treatment for severe late onset hemorrhagic cystitis after allogeneic hematopoietic stem cell transplantation"
} | [
{
"companynumb": "PHHY2014CN104989",
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"activesubstancename": "CYCLOSPORINE"
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"abstract": "Genetic defects causing dysfunction in bile salt export pump (BSEP/ABCB11) lead to liver diseases. ABCB11 mutations alter the bile acid metabolome. We asked whether profiling plasma bile acids could reveal compensatory mechanisms and track genetic and clinical status.\n\n\n\nWe compared plasma bile acids in 17 ABCB11-mutated patients, 35 healthy controls and 12 genetically undiagnosed cholestasis patients by ultra-high-performance liquid chromatography/multiple-reaction monitoring-mass spectrometry (UPLC/MRM-MS). We developed an index to rank bile acid hydrophobicity, and thus toxicity, based on LC retention times. We recruited 42 genetically diagnosed hereditary cholestasis patients, of whom 12 were presumed to have impaired BSEP function but carried mutations in genes other than ABCB11, and 8 healthy controls, for further verification.\n\n\n\nThe overall hydrophobicity indices of total bile acids in both the ABCB11-mutated group (11.89 ± 1.07 min) and the undiagnosed cholestasis group (11.46 ± 1.07 min) were lower than those of healthy controls (13.69 ± 0.77 min) (both p < 0.005). This was owing to increased bile acid modifications. Secondary bile acids were detected in patients without BSEP expression, suggesting biliary bile acid secretion through alternative routes. A diagnostic panel comprising lithocholic acid (LCA), tauro-LCA, glyco-LCA and hyocholic acid was identified that could differentiate the ABCB11-mutated cohort from healthy controls and undiagnosed cholestasis patients (AUC=0.946, p < 0.0001) and, in non-ABCB11-mutated cholestasis patients, could distinguish BSEP dysfunction from normal BSEP function (9/12 vs 0/38, p < 0.0000001).\n\n\n\nProfiling of plasma bile acids has provided insights into cholestasis alleviation and may be useful for the clinical management of cholestatic diseases.",
"affiliations": "Department of Pediatrics, Jinshan Hospital of Fudan University, Shanghai, China.;BC Cancer Agency, Vancouver, BC, Canada.;University of Victoria-Genome BC Proteomics Centre, University of Victoria, Victoria, BC, Canada.;Department of Pediatrics, Shanghai Medical College, Fudan University, Shanghai, China.;Department of Pediatrics, Shanghai Medical College, Fudan University, Shanghai, China.;Department of Pediatrics, Jinshan Hospital of Fudan University, Shanghai, China.;Department of Pediatrics, Shanghai Medical College, Fudan University, Shanghai, China.;Department of Pediatrics, Jinshan Hospital of Fudan University, Shanghai, China.;Department of Pediatrics, Jinshan Hospital of Fudan University, Shanghai, China.;Department of Pediatrics, Shanghai Medical College, Fudan University, Shanghai, China.;Department of Pediatrics, Jinshan Hospital of Fudan University, Shanghai, China.;Department of Pediatrics, Shanghai Medical College, Fudan University, Shanghai, China.;University of Victoria-Genome BC Proteomics Centre, University of Victoria, Victoria, BC, Canada.;Department of Pediatrics, Jinshan Hospital of Fudan University, Shanghai, China.;Department of Pediatrics, Jinshan Hospital of Fudan University, Shanghai, China.;Institut für Pathologie, Medizinische Universität Graz, Graz, Österreich/Austria.;University of Victoria-Genome BC Proteomics Centre, University of Victoria, Victoria, BC, Canada.;BC Cancer Agency, Vancouver, BC, Canada.;Department of Pediatrics, Shanghai Medical College, Fudan University, Shanghai, China.",
"authors": "Liu|Teng|T|0000-0002-0858-2151;Wang|Ren-Xue|RX|;Han|Jun|J|;Hao|Chen-Zhi|CZ|;Qiu|Yi-Ling|YL|;Yan|Yan-Yan|YY|;Li|Li-Ting|LT|0000-0003-1165-4360;Wang|Neng-Li|NL|0000-0001-6967-9873;Gong|Jing-Yu|JY|;Lu|Yi|Y|;Zhang|Mei-Hong|MH|;Xie|Xin-Bao|XB|;Yang|Jun-Cong|JC|;You|Yi-Jie|YJ|;Li|Jia-Qi|JQ|;Knisely|A S|AS|;Borchers|Christoph H|CH|;Ling|Victor|V|;Wang|Jian-She|JS|",
"chemical_list": "C093491:ABCB11 protein, human; D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D001647:Bile Acids and Salts",
"country": "United States",
"delete": false,
"doi": "10.1111/liv.13714",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1478-3223",
"issue": "38(9)",
"journal": "Liver international : official journal of the International Association for the Study of the Liver",
"keywords": "\nABCB11\n; PFIC2; bile salt export pump; liquid chromatography-mass spectrometry",
"medline_ta": "Liver Int",
"mesh_terms": "D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D001647:Bile Acids and Salts; D016022:Case-Control Studies; D002675:Child, Preschool; D002681:China; D002780:Cholestasis, Intrahepatic; D002851:Chromatography, High Pressure Liquid; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D009154:Mutation",
"nlm_unique_id": "101160857",
"other_id": null,
"pages": "1676-1685",
"pmc": null,
"pmid": "29412511",
"pubdate": "2018-09",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Comprehensive bile acid profiling in hereditary intrahepatic cholestasis: Genetic and clinical correlations.",
"title_normalized": "comprehensive bile acid profiling in hereditary intrahepatic cholestasis genetic and clinical correlations"
} | [
{
"companynumb": "CN-ALLERGAN-1844995US",
"fulfillexpeditecriteria": "1",
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"patient": {
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"actiondrug": "6",
"activesubstance": {
"activesubstancename": "URSODIOL"
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{
"abstract": "The pandemic of SARS-CoV-2 is a serious global challenge affecting millions of people worldwide. Cancer patients are at risk for infection exposure and serious complications. A prompt diagnosis of SARS-CoV-2 infection is crucial for the timely adoption of isolation measures and the appropriate management of cancer treatments. In lung cancer patients the symptoms of infection 19 may resemble those exhibited by the underlying oncologic condition, possibly leading to diagnostic overlap and delays. Moreover, cancer patients might display a prolonged positivity of nasopharyngeal RT-PCR assays for SARS-CoV-2, causing long interruptions or delay of cancer treatments. However, the association between the positivity of RT-PCR assays and the patient's infectivity remains uncertain. We describe the case of a patient with non-small cell lung cancer, and a severe ab extrinseco compression of the trachea, whose palliative radiotherapy was delayed because of the prolonged positivity of nasopharyngeal swabs for SARS-CoV-2. The patient did not show clinical symptoms suggestive of active infection, but the persistent positivity of RT-PCR assays imposed the continuation of isolation measures and the delay of radiotherapy for over two months. Finally, the negative result of SARS-CoV-2 viral culture allowed us to verify the absence of viral activity and to rule out the infectivity of the patient, who could finally continue her cancer treatment.",
"affiliations": "Infectious Diseases Unit, Azienda Ospedale Università di Padova, 35128 Padova, Italy.;Infectious Diseases Unit, Azienda Ospedale Università di Padova, 35128 Padova, Italy.;Infectious Diseases Unit, Azienda Ospedale Università di Padova, 35128 Padova, Italy.;Medical Oncology 2, Istituto Oncologico Veneto IRCCS, 35128 Padova, Italy.;Department of Medicine, Geriatric Clinic, Università di Padova, 35128 Padova, Italy.;Microbiology Department, Azienda Ospedale Università di Padova, 35128 Padova, Italy.;Infectious Diseases Unit, Azienda Ospedale Università di Padova, 35128 Padova, Italy.;Infectious Diseases Unit, Azienda Ospedale Università di Padova, 35128 Padova, Italy.",
"authors": "Ferrari|Anna|A|0000-0001-6924-6306;Trevenzoli|Marco|M|;Sasset|Lolita|L|;Di Liso|Elisabetta|E|;Tavian|Toni|T|;Rossi|Lucia|L|;Di Meco|Eugenia|E|;Cattelan|Anna Maria|AM|0000-0003-2869-2945",
"chemical_list": "D012367:RNA, Viral",
"country": "Switzerland",
"delete": false,
"doi": "10.3390/curroncol28010083",
"fulltext": "\n==== Front\nCurr Oncol\nCurr Oncol\ncurroncol\nCurrent Oncology\n1198-0052\n1718-7729\nMDPI\n\n33567626\n10.3390/curroncol28010083\ncurroncol-28-00083\nCase Report\nProlonged SARS-CoV-2-RNA Detection from Nasopharyngeal Swabs in an Oncologic Patient: What Impact on Cancer Treatment?\nhttps://orcid.org/0000-0001-6924-6306\nFerrari Anna 1*\nTrevenzoli Marco 1\nSasset Lolita 1\nDi Liso Elisabetta 2\nTavian Toni 3\nRossi Lucia 4\nDi Meco Eugenia 1\nhttps://orcid.org/0000-0003-2869-2945\nCattelan Anna Maria 1\n1 Infectious Diseases Unit, Azienda Ospedale Università di Padova, 35128 Padova, Italy; marco.trevenzoli@aopd.veneto.it (M.T.); lolita.sasset@aopd.veneto.it (L.S.); edm1984@gmail.com (E.D.M.); annamaria.cattelan@aopd.veneto.it (A.M.C.)\n2 Medical Oncology 2, Istituto Oncologico Veneto IRCCS, 35128 Padova, Italy; elisabetta.diliso@ioveneto.it\n3 Department of Medicine, Geriatric Clinic, Università di Padova, 35128 Padova, Italy; toni.tavian@gmail.com\n4 Microbiology Department, Azienda Ospedale Università di Padova, 35128 Padova, Italy; lucia.rossi@aopd.veneto.it\n* Correspondence: anna.ferrari@aopd.veneto.it; Tel.: +39-049-8213765\n08 2 2021\n2 2021\n28 1 847852\n13 11 2020\n26 1 2021\n© 2021 by the authors.\n2021\nLicensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).\nThe pandemic of SARS-CoV-2 is a serious global challenge affecting millions of people worldwide. Cancer patients are at risk for infection exposure and serious complications. A prompt diagnosis of SARS-CoV-2 infection is crucial for the timely adoption of isolation measures and the appropriate management of cancer treatments. In lung cancer patients the symptoms of infection 19 may resemble those exhibited by the underlying oncologic condition, possibly leading to diagnostic overlap and delays. Moreover, cancer patients might display a prolonged positivity of nasopharyngeal RT-PCR assays for SARS-CoV-2, causing long interruptions or delay of cancer treatments. However, the association between the positivity of RT-PCR assays and the patient’s infectivity remains uncertain. We describe the case of a patient with non-small cell lung cancer, and a severe ab extrinseco compression of the trachea, whose palliative radiotherapy was delayed because of the prolonged positivity of nasopharyngeal swabs for SARS-CoV-2. The patient did not show clinical symptoms suggestive of active infection, but the persistent positivity of RT-PCR assays imposed the continuation of isolation measures and the delay of radiotherapy for over two months. Finally, the negative result of SARS-CoV-2 viral culture allowed us to verify the absence of viral activity and to rule out the infectivity of the patient, who could finally continue her cancer treatment.\n\nnon-small cell lung cancer\nSARS-CoV-2 RNA\nCOVID-19\nviral culture\ncancer treatment\n==== Body\n1. Introduction\n\nSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic is a complex global challenge affecting millions of people worldwide [1]. Cancer patients are at high risk for serious complications and the infection itself may compromise the continuation of cancer therapies and supportive care [2,3,4]. Moreover, the frequent visits to the hospital for treatment and monitoring represent for cancer patients a major risk factor for exposure to SARS-CoV-2 [5]. In order to optimize the cancer care pathway and improve the clinical outcomes during the pandemic, a large, international and multidisciplinary consortium reviewed and discussed the clinical evidence in cancer management. In this current situation, the risk of infection must be individualized taking into consideration the primary tumor type, stage, age, and sex. In addition, cancer treatment must be patient tailored [6]. Thus far, the gold standard test for the diagnosis of COVID-19 has been the RT-PCR test performed on nasopharyngeal swabs or other upper respiratory tract specimens. However, a “positive” PCR result reflects the detection of viral RNA and does not necessarily prove the presence of active viral replication. To ascertain the infectivity of RT-PCR positive patients, several diagnostic methods such as the viral culture, the viral RNA measured by the cycle threshold (Ct), the antigen rapid test, and the detection of sub-genomic RNAs (sg-RNAs) have been recently introduced in clinical care. All these tests, when correlated with the time course of disease, may help define the contagiousness of patients diagnosed with SARS-CoV-2 infection [7,8,9,10]. We describe the case of a cancer patient whose palliative radiotherapy treatment was delayed because of the prolonged positivity of RT-PCR assays for SARS-CoV-2 on nasopharyngeal swabs, despite the absence of acute signs of infection. Eventually, the negative viral culture result allowed the physicians to continue the treatment.\n\n2. Case Report\n\nOn 1 April 2020, a 72-year-old Caucasian woman affected by non-small cell lung cancer of the upper right lobe, was referred to the Istituto Oncologico Veneto (IOV) of Padua, Italy, for the acute onset of progressive shortness of breath and dry cough. Her past medical history was relevant for glaucoma, depression, and Parkinson disease. The patient had undergone a right upper lobe lung resection with ilo-mediastinic lymph node dissection in 2015; the histo-pathological examination revealed an EGFR exon19 deletion mutated adenocarcinoma. After four courses of adjuvant chemotherapy (cisplatin plus gemticitabine), due to disease progression, in 2018 targeted therapy with osimertinib was started with partial response according to RECIST (response evaluation criteria in solid tumors version 1.1).\n\nAt hospital admission, the physical examination revealed moderate inspiratory retraction and diffuse inspiratory wheezing; the body temperature was 36.8 °C; heart rate 68 bpm; blood pressure 125/80 mm Hg; respiratory rates 25 per minute; oxygen saturation 98% with 3 L/min oxygen supplement. Her ECOG PS (Eastern Cooperative Oncology Group performance status) was 2.\n\nLaboratory investigations were all within the normal range, including lactate dehydrogenase (LDH), C-reactive protein (CRP), and procalcitonin. The nasopharyngeal swab for the detection of SARS-CoV-2 RNA by RT-PCR [11] was negative. A computed tomography (CT) scan of the thorax showed progressive disease in the superior mediastinum with significant reduction of the tracheal lumen (Figure 1). Palliative mediastinal radiotherapy was planned in order to reduce the tracheal compression, and methylprednisolone 40 mg bid was initiated obtaining a slight reduction of dyspnea.\n\nDuring the hospital stay, the patient was exposed to an asymptomatic SARS-CoV-2 virus carrier. On 6 April 2020, she underwent screening nasopharyngeal swab for detection of SARS-CoV-2, which was positive. The scheduled radiotherapy was postponed and the patient was transferred to the infectious diseases unit. At admission she presented with mild inspiratory retraction but all the vital signs were normal. Blood examinations showed a moderate elevation of CRP (91 mg/L, normal value 0–6). Because of the high-risk condition, she was treated with the therapy currently recommended: hydroxychloroquine (HCQ) (400 mg bid for 24 h, then 200 mg bid) and azithromycin (AZI) (500 mg qd) [12]. Both drugs were stopped after two days because of QTc prolongation. Tapered steroidal therapy, osimertinib, and subcutaneous enoxaparin were continued.\n\nThe patient did not develop any coronavirus disease 2019 (COVID-19)-related symptoms, but nasopharyngeal swabs were persistently positive for SARS-CoV-2 for over one month. On 13 May after two consecutive negative swabs, she was transferred to the oncology ward to start radiotherapy treatment. Her ECOG PS was 3. Unfortunately, on May 19, the nasopharyngeal swab for SARS-CoV-2 RNA was positive. Once again the radiotherapy was postponed and the patient was isolated in the infectious diseases ward. The clinical conditions remained stable and the nasopharyngeal swabs were repeated at regular intervals with alternating results (Figure 2). On 30 May, a viral culture with Vero cells [13] was performed and resulted negative. The same result was achieved also 15 days later, despite the occurrence of new positive swabs.\n\nInterestingly, serological tests showed the presence of high levels of anti-SARS-CoV-2 IgG [75,400 kAU/L (Positive: >1100 kAU/L)] and high titers persisted during the whole observation period; IgM title was persistently negative (Figure 2).\n\nOn the basis of these results, a single-fraction radiotherapy was performed on 4 June and the patient continued her regular follow-up with no need of oxygen supplementation. The last total body CT scan performed in July 2020 confirmed stable disease.\n\n3. Discussion\n\nSARS-CoV-2 pandemic caught clinicians and health authorities unprepared to manage cancer patients. Diagnostic and treatment guidelines were lacking at the beginning of the outbreak. Clinicians were challenged to manage COVID-19 disease with clinical characteristics which might be partly masked or confounded by coexisting cancer conditions. Moreover, the risk of nosocomial transmission of SARS-CoV-2 and the need for isolation contributed to the risk of progression of the malignant disease because of cancer treatments’ delays [14,15,16].\n\nAfter the detection of SARS-CoV-2 our patient did not show any acute signs of infection and her symptoms could be attributed to her lung cancer. However SARS-CoV-2 swabs remained positive for more than 90 days, showing alternating results: in five occasions they turned out positive after one or two consecutive negative tests. It has been described that, after clinical resolution, some COVID-19 patients may experience a prolonged nucleic acid conversion [17,18]. Xiao and colleagues, from Wuhan, reported 21.4% of patients experiencing a “turn positive” of nucleic acid detection by RT-PCR test after two consecutive negative results [18]. In addition, it is still to be determined whether these patients are able to transmit the infection. However, relevant recent studies have shown that COVID-19 patients with mild-to-moderate illness are highly unlikely to be infectious longer than 10 days after symptom onset [19]. The molecular detection of SARS-CoV-2 by RT-PCR is a rapid and highly sensitive diagnostic method, but its ability to determine the duration of infectivity of patients is quite limited [20]. Viral culture is a more accurate tool to demonstrate the “in vitro” infectivity, giving surrogate information on viral transmission [9]. It is a complex diagnostic tool that needs expertise and biosafety level 3 laboratories, but it could be of crucial importance to define viral transmission and the infectivity of patients in particular conditions, such as the oncological setting [21]. Aside from viral culture, other diagnostic methods such as the threshold cycle (Ct) of RT-PCR and antigen-tests have been reported to be able to determine patients’ contagiousness. It has been demonstrated that infectivity is significantly reduced when Ct values are >24; for every unit increase in Ct, the odds ratio for infectivity decreases by 32%, suggesting that Ct values >24, along with the duration of symptoms >8 days may be used in combination to rule out patients’ contagiousness. Similar results are reported by La Scola et al. who showed a strong correlation between Ct value and sample infectivity in a cell culture model. Based on their data, they inferred that patients with Ct values equal or above 34 do not excrete infectious viral particles [22]. Rapid antigen tests may also have a role in this setting. They have a lower sensitivity compared to the standard RT-PCR test, but may be sensitive enough to detect cases with a high viral load (i.e., low RT-PCR cycle threshold (Ct) value <25), which likely account for a significant proportion of transmissions [8,23]. In addition, as reported in 68 respiratory specimens from 35 COVID patients in Hong Kong, the detection of subgenomic viral RNA (sgRNA) strongly correlated with the presence of active virus replication, with sgRNA being rarely detectable 8 days after the onset of the illness [7]. On the contrary, there is no consensus yet on the significance of the dynamic profile of SARS-CoV-2-specific antibody response. In our case the persistent positivity of RT-PCR assays coexisted with a strong serologic response, and none of the diagnostic procedures could prove or rule out the infectivity of the patient [24]. Unfortunately, in the first half of 2020, when our patient was hospitalized, viral load estimation by threshold cycle of RT-PCR and antigen-based tests were still under investigation, and the detection of sub-genomic RNAs was not available. Furthermore, the World Health Organization guidelines for releasing COVID-19 patients from isolation (i.e., ten days after symptom onset and at least three additional days without symptoms) were not yet amended. Nevertheless these guidelines do not specifically address immunocompromised individuals [25].\n\nAn Italian group has recently proposed an algorithm for the management of oncologic patients who need radiation therapy. Their recommendation is to delay or discontinue the radiation treatment in symptomatic and asymptomatic patients diagnosed with COVID-19 and to carefully start the treatment only when the patients are declared no longer exhibiting infection by the infectious diseases specialist [26].\n\nIn line with this recommendation we could discontinue hospital isolation owing to the repeatedly negative cell culture results, which allowed us to verify the absence of viral activity despite the persistent positivity of nasopharyngeal swabs. In this way the patient could finally undergo palliative radiotherapy for airway obstruction with a delay of eight weeks from the initial scheduled time. Although it is unlikely that the delayed palliative radiotherapy affected the short-term poor prognosis, it surely prolonged the length of hospitalization and negatively affected the patient’s quality of life.\n\n4. Conclusions\n\nThis clinical case emphasizes the multifaceted and challenging approach to SARS-CoV-2 infection in the oncological setting. Clinicians must protect the vulnerable cancer population from a potentially severe infection without jeopardizing cancer care and support. The development of diagnostic tests able to determine the activity of the disease and patients’ infectivity may contribute to the fight against SARS-CoV-2, limiting the number of COVID-19-related deaths and the excess indirect mortality and morbidity in patients suffering from cancer.\n\nAuthor Contributions\n\nA.F.—Conceptualization, writing original draft. M.T.—Writing review & editing, supervision. L.S.—Writing review & editing. E.D.L.—Writing original draft. T.T.—Data curation. L.R.—Case analysis. E.D.M.—Writing review & editing. A.M.C.—Conceptualization, writing review and editing. All authors have read and agreed to the published version of the manuscript.\n\nFunding\n\nThis research received no external funding.\n\nInformed Consent Statement\n\nVerbal informed consent for this report was obtained from the patient involved in the study.\n\nConflicts of Interest\n\nWe have read and understood Current Oncology’s policy on conflicts of interest disclosure and declare that we have none.\n\nFigure 1 Chest computed tomography (CT) scan: axial lung image showing huge reduction (arrow) of the trachea lumen (2 mm) due to mediastinal pathological tissue.\n\nFigure 2 Timeline of SARS-CoV-2 nucleic acid testing results from nasopharyngeal swabs along with the anti-SARS-CoV-2 serology and viral culture testing.\n\nPublisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. European Centre for Disease Prevention and Control COVID-19 Situation Update Worldwide, as of 12 October 2020 ECDC Solna, Sweden 2020 Available online: https://www.ecdc.europa.eu/en/geographical-distribution-2019-ncov-cases (accessed on 12 October 2020)\n2. Tian J. Yuan X. Xiao J. Zhong Q. Yang C. Liu B. Cai Y. Lu Z. Wang J. Wang Y. Clinical characteristics and risk factors associated with COVID-19 disease severity in patients with cancer in Wuhan, China: A multicentre, retrospective, cohort study Lancet Oncol. 2020 21 893 903 10.1016/S1470-2045(20)30309-0 32479790\n3. Yang F. Shi S. Zhu J. Shi J. Dai K. Chen X. Clinical characteristics and outcomes of cancer patients with COVID-19 J. Med. Virol. 2020 92 2067 2073 10.1002/jmv.25972 32369209\n4. Calabrò L. Peters S. Soria J.-C. Di Giacomo A.M. Barlesi F. Covre A. Altomonte M. Vegni V. Gridelli C. Reck M. Challenges in lung cancer therapy during the COVID-19 pandemic Lancet Respir. Med. 2020 8 542 544 10.1016/S2213-2600(20)30170-3 32278368\n5. Yu J. Ouyang W. Chua M.L.K. Xie C. SARS-CoV-2 Transmission in Patients with Cancer at a Tertiary Care Hospital in Wuhan, China JAMA Oncol. 2020 6 1108 1110 10.1001/jamaoncol.2020.0980 32211820\n6. Lamarre J. Banerjee S. Cervantes A. Garassino M. Garrido P. Girard N. Haanen J. Jordan K. Lordick F. Machiels J. Managing cancer patients during the COVID-19 pandemic: An ESMO multidisciplinary expert consensus Ann. Oncol. 2020 31 1320 1335 10.1016/j.annonc.2020.07.010 32745693\n7. Perera R.A.P.M. Tso E. Tsang O.T.Y. Tsang D.N.C. Fung K. Leung Y.W.Y. Chin A.W.H. Chu D.K.W. Cheng S.M.S. Poon L.M.L. SARS-CoV-2 Virus Culture and Subgenomic RNA for Respiratory Specimens from Patients with Mild Coronavirus Disease Emerg. Infect. Dis. 2020 26 2701 2704 10.3201/eid2611.203219 32749957\n8. World Health Association Antigen-Detection in the Diagnosis of SARS-CoV-2 Infection Using Rapid Immunoassays. Interim Guidance 11 9 2020 Available online: https://www.who.int/publications/i/item/antigen-detection-in-the-diagnosis-of-sars-cov-2infection-using-rapid-immunoassays (accessed on 10 January 2021)\n9. Bullard J. Dust K. Funk D. Strong J.E. Alexander D. Garnett L. Boodman C. Bello A. Hedley A. Schiffman Z. Predicting Infectious Severe Acute Respiratory Syndrome Coronavirus 2 from Diagnostic Samples Clin. Infect. Dis. 2020 71 2663 2666 10.1093/cid/ciaa638 32442256\n10. Avanzato V.A. Matson M.J. Seifert S.N. Pryce R. Williamson B.N. Anzick S.L. Barbian K. Judson S.D. Fischer E.R. Martens C. Case Study: Prolonged Infectious SARS-CoV-2 Shedding from an Asymptomatic Immunocompromised Individual with Cancer Cell 2020 183 1901 1912.e9 10.1016/j.cell.2020.10.049 33248470\n11. Corman V.M. Landt O. Kaiser M. Molenkamp R. Meijer A. Chu D.K. Bleicker T. Brünink S. Schneider J. Schmidt M.L. Detection of 2019 novel coronavirus (2019-nCoV) by real-time RT-PCR Eurosurveillance 2020 25 2000045 10.2807/1560-7917.ES.2020.25.3.2000045\n12. Gautret P. Lagier J.C. Parola P. Hoang V.T. Meddeb L. Mailhe M. Doudier B. Courjon J. Giordanengo V. Vieira V.E. Hydroxychloroquine and azithromycin as a treatment of COVID-19: Results of an open-label non-randomized clinical trial Int. J. Antimicrob. Agents 2020 56 105949 10.1016/j.ijantimicag.2020.105949 32205204\n13. Ramakrishnan M.A. Determination of 50% endpoint titer using a simple formula World J. Virol. 2016 5 85 86 10.5501/wjv.v5.i2.85 27175354\n14. Moujaess E. Kourie H.R. Ghosn M. Cancer patients and research during COVID-19 pandemic: A systematic review of current evidence Crit. Rev. Oncol. 2020 150 102972 10.1016/j.critrevonc.2020.102972 32344317\n15. Addeo A. Friedlaender A. Cancer and COVID-19: Unmasking their ties Cancer Treat. Rev. 2020 88 102041 10.1016/j.ctrv.2020.102041 32516704\n16. Weinkove R. McQuilten Z.K. Adler J. Agar M.R. Blyth E. Cheng A.C. Conyers R. Haeusler G.M. Hardie C. Jackson C. Managing haematology and oncology patients during the COVID -19 pandemic: Interim consensus guidance Med. J. Aust. 2020 212 481 489 10.5694/mja2.50607 32401360\n17. Sun J. Xiao J. Sun R. Tiang X. Liang C. Lin H. Zeng L. Hu J. Yuan R. Zhou P. Prolonged Persistence of SARS-CoV-2 RNA in Body Fluids Emerg. Infect. Dis. 2020 26 e1834 e1838 10.3201/eid2608.201097\n18. Xiao A.T. Tong Y.X. Zhang S. False negative of RT-PCR and prolonged nucleic acid conversion in COVID-19: Rather than recurrence J. Med. Virol. 2020 92 1755 1756 10.1002/jmv.25855 32270882\n19. Walsh K.A. Spillane S. Comber L. Cardwell K. Harrington P. Connell J. Teljeur C. Broderick N. de Gascun C.F. Sith S.M. The duration of infectiousness of individuals infected with SARS-CoV-2 J. Infect. 2020 81 847 856 10.1016/j.jinf.2020.10.009 33049331\n20. Strong J.E. Feldmann H. The Crux of Ebola Diagnostics J. Infect. Dis. 2017 216 1340 1342 10.1093/infdis/jix490 29029148\n21. Gosain R. Abdou Y. Singh A. Rana N. Puzanov I. Ernstoff M.S. COVID-19 and Cancer: A Comprehensive Review Curr. Oncol. Rep. 2020 22 53 10.1007/s11912-020-00934-7 32385672\n22. La Scola B. Le Bideau M. Andreani J. Hoang V.T. Grimaldier C. Colson P. Gautret P. Raoult D. Viral RNA load as determined by cell culture as a management tool for discharge of SARS-CoV-2 patients from infectious disease wards Eur. J. Clin. Microbiol. Infect. Dis. 2020 39 1059 1061 10.1007/s10096-020-03913-9 32342252\n23. European Centre for Disease Prevention and Control Options for the Use of Rapid Antigen Tests for COVID-19 in the EU/EEA and the UK ECDC Stockholm, Sweden 2020 11 2020 Available online: https://www.ecdc.europa.eu/sites/default/files/documents/Options-use-of-rapid-antigen-tests-for-COVID-19_0.pdf (accessed on 10 January 2021)\n24. Yongchen Z. Shen H. Wang X. Shi X. Li Y. Yan J. Chen Y. Gu B. Different longitudinal patterns of nucleic acid and serology testing results based on disease severity of COVID-19 patients Emerg. Microbes Infect. 2020 9 833 836 10.1080/22221751.2020.1756699 32306864\n25. World Health Organization Criteria for releasing COVID-19 patients from isolation. Scientific brief 17 6 2020 Available online: https://apps.who.int/iris/bitstream/handle/10665/332451/WHO-2019-nCoV-Sci_Brief-Discharge_From_Isolation-2020.1-eng.pdf (accessed on 10 January 2021)\n26. Filippi A.R. Russi E. Magrini S.M. Corvò R. Letter from Italy: First practical indications for radiation therapy departments during COVID-19 outbreak Int. J. Radiat. Oncol. Biol. Phys. 2020 107 597 599 10.1016/j.ijrobp.2020.03.007 32199941\n\n",
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"journal": "Current oncology (Toronto, Ont.)",
"keywords": "COVID-19; SARS-CoV-2 RNA; cancer treatment; non-small cell lung cancer; viral culture",
"medline_ta": "Curr Oncol",
"mesh_terms": "D000368:Aged; D000086382:COVID-19; D002289:Carcinoma, Non-Small-Cell Lung; D002353:Carrier State; D005260:Female; D006801:Humans; D008175:Lung Neoplasms; D009305:Nasopharynx; D012367:RNA, Viral; D000086402:SARS-CoV-2; D061665:Time-to-Treatment",
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"title": "Prolonged SARS-CoV-2-RNA Detection from Nasopharyngeal Swabs in an Oncologic Patient: What Impact on Cancer Treatment?",
"title_normalized": "prolonged sars cov 2 rna detection from nasopharyngeal swabs in an oncologic patient what impact on cancer treatment"
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"abstract": "Association of statins with autoimmune disorders is rarely reported. We report a case of an apparently healthy 76-year-old woman who was on long-term statin therapy presenting with severe rhabdomyolysis, autoimmune hepatitis, and positive lupus antibodies. Patient presented with complaints of worsening fatigue, leg cramps, and progressive weakening of lower extremities over 3 weeks. The patient was on simvastatin daily for several years. Clinical examination on admission included muscle tenderness, lower extremity edema, and ascites. Her laboratory values on admission showed elevated creatine kinase and transaminases. Immunologic workup revealed positive ANA, anti-dsDNA and anti-SSA antibodies. F-actin antibody was also positive at high titer. Magnetic resonance imaging of the lower extremities showed findings consistent with myositis. Patient underwent biopsy of the thigh muscles, which showed inflammatory myositis. Liver biopsy was characteristic of autoimmune hepatitis. Patient responded well to immunosuppressive therapy with azathioprine and prednisone. Although statins are generally considered safe, recent data from long-term follow-up on patients who are on statins for long duration suggest that prolonged exposure to statins may trigger autoimmune reactions. The exact mechanism of statin-induced autoimmune reaction is unclear. Statins, as proapoptotic agents, release nuclear antigen into the circulation and may induce the production of pathogenic autoantibodies. The role of statins in inducing an endoplasmic reticular stress response with associated upregulation of major histocompatibility complex-1 expression and antigen presentation by muscle fibers has also been reported. Systemic immunosuppressive therapy has proven to be effective in many reported cases.",
"affiliations": "Departments of 1Medicine and 2Pathology, University of Arizona, Tucson, AZ.",
"authors": "John|Santhosh G|SG|;Thorn|Jennifer|J|;Sobonya|Richard|R|",
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"title": "Statins as a potential risk factor for autoimmune diseases: a case report and review.",
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"abstract": "BACKGROUND\nHemodynamic instability is a common occurrence during liver transplantation (LT). Hypotension and hemodynamic instability during graft reperfusion are most commonly consequences of the postreperfusion syndrome (PRS).\n\n\nMETHODS\nIn this report, we present a case of severe cardiovascular collapse leading to cardiac arrest which occurred in the course of graft reperfusion during LT. Persistent hypotension, non-responsive to regular measures such as volume filling and the use of vasopressors, yielded the question of whether other mechanisms were involved in causing it. Diffuse redness of the face and body, swelling of the face, lips and tongue with tongue prolapse, accompanied with severe cardiovascular collapse indicated that it was an anaphylactic reaction. This caused a dilemma as to what instigated the reaction. The trigger may have been the pharmacological substance administered during the graft reperfusion, or the one administered immediately prior to the reperfusion.The substances in question would most likely be either the University of Wisconsin preservation solution (UW), which was administered during the reperfusion, or Hepatect, which the patient received immediately prior to reperfusion.\n\n\nCONCLUSIONS\nThe clinical syndrome resulting from degranulation of mast cells and basophils in anaphylaxis is very similar to the PRS in LT. Clinical features play the most important role in establishing a timely diagnosis and early treatment of anaphylaxis. Swift administration of epinephrine reduces the chances of a fatal outcome. Better information on both donor and recipient can improve the efficiency of therapy and prophylaxis for anaphylaxis.",
"affiliations": null,
"authors": "Andjelić|Nada|N|;Erdeljan|Svetlana|S|;Popović|Radmila|R|;Božić|Teodora|T|",
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"mesh_terms": "D000707:Anaphylaxis; D017809:Fatal Outcome; D006323:Heart Arrest; D006801:Humans; D016031:Liver Transplantation; D015427:Reperfusion Injury",
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"title": "Anaphylaxis on Graft Reperfusion during Orthotopic Liver Transplantation: A Case Study.",
"title_normalized": "anaphylaxis on graft reperfusion during orthotopic liver transplantation a case study"
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"abstract": "Cardiovascular disease is the most common cause of sickness and death for long-term kidney transplant recipients, and dyslipidemia is an important risk factor for developing cardiovascular disease. Lipid-lowering strategies, with the use of statins, have been shown to reduce the cardiovascular risks related to dyslipidemia, but concomitant use of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors and immunosuppressive agents may increase the risk of rhabdomyolysis owing to a drug-drug interaction. We report a case of simvastatin-induced rhabdomyolysis and acute kidney injury triggered by addition of sirolimus and cisplatin-based chemotherapy to a kidney transplant recipient who had previously tolerated chronic statin therapy.",
"affiliations": "From the Division of Nephrology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea.",
"authors": "Hong|Yu Ah|YA|;Kim|Hyung Duk|HD|;Jo|Kwanhoon|K|;Park|Yun Kyung|YK|;Lee|Jonghoon|J|;Sun|In O|IO|;Chung|Byung Ha|BH|;Park|Cheol Whee|CW|;Yang|Chul Woo|CW|;Choi|Bum Soon|BS|",
"chemical_list": "D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007166:Immunosuppressive Agents; D019821:Simvastatin; D002945:Cisplatin; D020123:Sirolimus",
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"mesh_terms": "D058186:Acute Kidney Injury; D000971:Antineoplastic Combined Chemotherapy Protocols; D002945:Cisplatin; D004347:Drug Interactions; D050171:Dyslipidemias; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007166:Immunosuppressive Agents; D016030:Kidney Transplantation; D008175:Lung Neoplasms; D008875:Middle Aged; D006435:Renal Dialysis; D012206:Rhabdomyolysis; D012307:Risk Factors; D012720:Severity of Illness Index; D019821:Simvastatin; D020123:Sirolimus; D013997:Time Factors; D016896:Treatment Outcome",
"nlm_unique_id": "101207333",
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"references": null,
"title": "Severe rhabdomyolysis associated with concurrent use of simvastatin and sirolimus after cisplatin-based chemotherapy in a kidney transplant recipient.",
"title_normalized": "severe rhabdomyolysis associated with concurrent use of simvastatin and sirolimus after cisplatin based chemotherapy in a kidney transplant recipient"
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"abstract": "BACKGROUND\nCREST (calcinosis, Raynaud phenomenon, oesophageal dysmotility, sclerodactyly, and telangiectasia) syndrome comprising calcinosis cutis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly and telangiectasia and primary sclerosing cholangitis are both chronic fibrotic diseases but the association between them is extremely rare. While primary sclerosing cholangitis has been associated with diffuse cutaneous scleroderma, the association with limited cutaneous scleroderma or CREST has not been previously reported in the literature. This case report illustrates the association between CREST and primary sclerosing cholangitis.\n\n\nMETHODS\nWe report the case of an 84-year-old Asian woman with a long history of CREST who was admitted with abdominal pain, fatigue and progressive derangement of her liver enzymes. This was initially thought to be secondary to her bosentan therapy for pulmonary hypertension but it persisted despite bosentan being ceased. Primary sclerosing cholangitis was subsequently diagnosed on magnetic resonance cholangiopancreatography and she was referred to a hepatologist for treatment.\n\n\nCONCLUSIONS\nThis case highlights the need to consider primary sclerosing cholangitis in patients with CREST who present with abdominal symptoms and deranged liver enzymes when other causes have been excluded. Relevant differential diagnoses for this presentation, which can be difficult to exclude, include immunoglobulin G4-associated cholangitis and antimitochondrial antibody negative primary biliary cirrhosis. It is of particular significance to rheumatologists and gastroenterologists but has broader relevance to all medical specialists involved in the care of patients with CREST.",
"affiliations": "The Queen Elizabeth Hospital, Adelaide, SA, Australia. alice.c.powell@gmail.com.;University Department of Medicine, Modbury Hospital, Adelaide, SA, Australia. julian.mcneil@adelaide.edu.au.",
"authors": "Powell|Alice|A|;McNeil|Julian|J|",
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"doi": "10.1186/s13256-015-0747-9",
"fulltext": "\n==== Front\nJ Med Case RepJ Med Case RepJournal of Medical Case Reports1752-1947BioMed Central London 74710.1186/s13256-015-0747-9Case ReportPrimary sclerosing cholangitis associated with CREST (calcinosis, Raynaud phenomenon, oesophageal dysmotility, sclerodactyly and telangiectasia) in an elderly woman: a case report Powell Alice alice.c.powell@gmail.com McNeil Julian julian.mcneil@adelaide.edu.au The Queen Elizabeth Hospital, Adelaide, SA Australia University Department of Medicine, Modbury Hospital, Adelaide, SA Australia 25 11 2015 25 11 2015 2015 9 2723 5 2015 26 10 2015 © Powell and McNeil. 2015\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.Introduction\nCREST (calcinosis, Raynaud phenomenon, oesophageal dysmotility, sclerodactyly, and telangiectasia) syndrome comprising calcinosis cutis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly and telangiectasia and primary sclerosing cholangitis are both chronic fibrotic diseases but the association between them is extremely rare. While primary sclerosing cholangitis has been associated with diffuse cutaneous scleroderma, the association with limited cutaneous scleroderma or CREST has not been previously reported in the literature. This case report illustrates the association between CREST and primary sclerosing cholangitis.\n\nCase presentation\nWe report the case of an 84-year-old Asian woman with a long history of CREST who was admitted with abdominal pain, fatigue and progressive derangement of her liver enzymes. This was initially thought to be secondary to her bosentan therapy for pulmonary hypertension but it persisted despite bosentan being ceased. Primary sclerosing cholangitis was subsequently diagnosed on magnetic resonance cholangiopancreatography and she was referred to a hepatologist for treatment.\n\nConclusions\nThis case highlights the need to consider primary sclerosing cholangitis in patients with CREST who present with abdominal symptoms and deranged liver enzymes when other causes have been excluded. Relevant differential diagnoses for this presentation, which can be difficult to exclude, include immunoglobulin G4-associated cholangitis and antimitochondrial antibody negative primary biliary cirrhosis. It is of particular significance to rheumatologists and gastroenterologists but has broader relevance to all medical specialists involved in the care of patients with CREST.\n\nKeywords\nBosentanCholestasisCRESTLiver toxicityPrimary sclerosing cholangitisissue-copyright-statement© The Author(s) 2015\n==== Body\nIntroduction\nPrimary sclerosing cholangitis (PSC) is a rare idiopathic chronic progressive liver disease resulting in fibro-obliterative inflammation of the hepatic bile ducts and ultimately cirrhosis and liver failure [1]. It is more frequent in men and strongly associated with inflammatory bowel disease [1, 2]. The liver disease usually associated with scleroderma is primary biliary cirrhosis (PBC) with approximately 15 % of patients with PBC reported to have scleroderma [3]. The association was first made by Murray-Lyon et al. in the 1970s [4]. In contrast, the relationship between PSC and scleroderma is extremely rare [3] with only one case report, to the best of our knowledge, of PSC and diffuse cutaneous scleroderma [2]. We describe a case of PSC occurring in a patient with CREST (calcinosis cutis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly and telangiectasia) syndrome, which is a type of limited cutaneous scleroderma.Fig. 1 Magnetic resonance cholangiopancreatography demonstrating prominent common bile duct and prominent irregular hepatic ducts\n\n\n\nCase presentation\nAn 84-year-old Asian woman was electively admitted to our hospital for investigation of a 6-month history of liver function test (LFT) derangement, abdominal pain, fatigue and weight loss. The results of her LFTs were as follows: alkaline phosphatase 953 U/L, gamma glutamyl transpeptidase 1164 U/L, alanine aminotransferase 81 U/L, aspartate aminotransferase 89 U/L, bilirubin 13 μmol/L and albumin 33 g/L. She had experienced Raynaud’s phenomenon for 50 years and had a confirmed diagnosis of CREST complicated by pulmonary hypertension, for which she had been treated with bosentan for the past 7 years. Her abdominal pain was initially attributed to esophageal dysmotility associated with her CREST and had improved with pantoprazole.\n\nThe most frequent severe side effect of bosentan is liver toxicity, typically manifested by a transaminasemia [5]. Of interest, animal models have demonstrated that bosentan may also cause cholestatic liver injury through inhibition of the bile salt export pump (BSEP) [6]. Our patient’s LFT derangement was initially attributed to bosentan and this was decreased and then changed to macitentan which does not interfere with BSEP [6]. However, her LFT derangement gradually worsened despite these measures and therefore other causes were sought. There were no other new medications, her hepatitis serology was negative and there was no evidence of cholecystitis, cholelithiasis or biliary obstruction on ultrasound. Computed tomography (CT) of her abdomen was also unremarkable. An autoimmune screen revealed positive antinuclear antibody consistent with CREST, antimitochondrial antibody and other liver autoantibodies negative. Immunoglobulin levels including immunoglobulin G4 (IgG4) were normal. Tumor markers including cancer antigen 19–9 (CA 19–9) and carcinoembryonic antigen (CEA) were similarly normal. She proceeded to magnetic resonance cholangiopancreatography (MRCP) which demonstrated a prominent common bile duct and prominent irregular central hepatic ducts with areas of beading and narrowing in both lobes favoring stricturing and PSC (Fig. 1).\n\nA liver biopsy was not pursued given her age and comorbidities, in particular her pulmonary hypertension. While this may have provided useful additional information particularly in the exclusion of other differential diagnoses, findings can be nonspecific [7]. In addition, a biopsy is generally not required for the diagnosis of PSC where cholestatic biochemical abnormalities and characteristic changes on cholangiography are present.\n\nDiscussion\nPSC is a complex heterogeneous probably immune-mediated disease with an unpredictable clinical presentation and course. Diagnosis is made in patients with a cholestatic biochemical profile and characteristic bile duct changes on cholangiography (MRCP or endoscopic retrograde cholangiopancreatography, ERCP) where secondary causes of sclerosing cholangitis have been excluded [1]. Typical symptoms include right upper quadrant abdominal pain, fatigue, pruritus and weight loss. Autoantibodies have no role in the routine diagnosis of PSC but antimitochondrial antibody is usually negative whereas it is positive in PBC [1]. Abdominal ultrasound and CT findings are usually nonspecific and ERCP has been regarded as the gold standard for diagnosis. However, MRCP has comparable diagnostic accuracy and is noninvasive without the potential for pancreatitis and bacterial cholangitis [1]. In a meta-analysis of six studies, the sensitivity and specificity of MRCP for diagnosing PSC were 86 and 94 % respectively [8]. In the presence of an abnormal cholangiogram, a liver biopsy is not required to establish a diagnosis of PSC. No drug therapy has been conclusively proven to alter the natural history of this disorder and liver transplantation is the treatment of choice for advanced liver disease [1].\n\nPSC should be differentiated from secondary causes of sclerosing cholangitis and IgG4-associated cholangitis. Another potential differential diagnosis for this case was antimitochondrial antibody negative PBC as antimitochondrial antibody may be negative in less than 10 % of cases [9]. However, patients with PBC should have a normal biliary tree on cholangiography [9]. Secondary causes of PSC were ruled out on the basis of our patient’s history, physical examination and imaging studies. Of importance, there was no dominant stricture on MRCP. IgG4-associated cholangitis is more difficult to differentiate and it is possible that IgG4-associated cholangitis, autoimmune pancreatitis and PSC are different manifestations of the same disease [10]. This is, however, an important distinction as IgG4-associated cholangitis may be glucocorticoid responsive [10], while no effective medical therapy is available for PSC. This diagnosis was thought less likely in our patient’s case as IgG4-associated cholangitis rarely occurs in the absence of pancreatitis, for which there was no evidence, and her IgG4 level was normal [10].\n\nConclusions\nBoth scleroderma and PSC are fibrotic diseases with widespread connective tissue disturbance occurring in CREST and abnormal collagen deposition in the bile duct epithelium. While PSC has been reported to occur in diffuse cutaneous systemic sclerosis, this is the first case report of PSC occurring with limited cutaneous systemic sclerosis.\n\nConsent\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\nAbbreviations\nBSEPbile salt export pump\n\nCRESTcalcinosis cutis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly and telangiectasia\n\nCTcomputed tomography\n\nERCPendoscopic retrograde cholangiopancreatography\n\nIgG4immunoglobulin G4\n\nLFTliver function tests\n\nMRCPmagnetic resonance cholangiopancreatography\n\nPBCprimary biliary cirrhosis\n\nPSCprimary sclerosing cholangitis\n\nCompeting interests\n\nThe authors declare that they have no competing interests.\n\nAuthors’ contributions\n\nAP was the medical registrar as part of the medical team caring for this patient and clinically assessed her as well as organizing and reviewing relevant investigations. She did a literature review and wrote the case report. JM was the consultant rheumatologist attending this patient as both an in-patient and out-patient. He read this case report and made several amendments and suggestions. Both authors read and approved the final manuscript.\n\nAcknowledgements\nWe thank Professor Ian Roberts-Thomson, gastroenterologist, for his review of this case report.\n==== Refs\nReferences\n1. Chapman R Fevery J Kalloo A Nagorney DM Boberg KM Shneider B Primary sclerosing cholangitis Hepatology 2010 51 660 78 10.1002/hep.23294 20101749 \n2. Fraile G Rodriguez-Garcia JL Moreno A Primary sclerosing cholangitis associated with systemic sclerosis Postgrad Med J 1991 67 189 92 10.1136/pgmj.67.784.189 2041852 \n3. Abraham S Begum S Isenberg D Hepatic manifestations of autoimmune rheumatic diseases Ann Rheum Dis 2004 63 123 9 10.1136/ard.2002.001826 14722198 \n4. Murray-Lyon IM Thompson RPH Ansell ID Williams R Scleroderma and primary biliary cirrhosis BMJ 1970 3 258 9 10.1136/bmj.3.5717.258 5448799 \n5. Fattinger K Funk C Pantze M Weber C Reichen J Stieger B The endothelin antagonist bosentan inhibits the canalicular bile salt export pump: A potential mechanism for hepatic adverse reactions Clin Pharmacol Ther 2001 69 223 31 10.1067/mcp.2001.114667 11309550 \n6. Treiber A Aanismaa P de Kanter R Delahaye S Treher M Hess P Macitentan does not interfere with hepatic bile salt transport J Pharmacol Exp Ther 2014 350 130 143 10.1124/jpet.114.214106 24769543 \n7. Yimam KK Bowlus CL Diagnosis and classification of primary sclerosing cholangitis Autoimmun Rev 2014 13 445 50 10.1016/j.autrev.2014.01.040 24424180 \n8. Dave M Elmunzer BJ Dwamena BA Higgins PD Primary sclerosing cholangitis: a meta-analysis of diagnostic performance of MR cholangiopancreatography Radiology 2010 256 387 10.1148/radiol.10091953 20656832 \n9. Kumagi T Heathcote EJ Primary biliary cirrhosis Orphanet J Rare Dis 2008 3 1 17 10.1186/1750-1172-3-1 18215315 \n10. Chapman R Fevery J Kalloo A Nagorney DM Boberg KM Shneider B Diagnosis and management of primary sclerosing cholangitis Hepatology 2010 51 660 78 10.1002/hep.23294 20101749\n\n",
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"mesh_terms": "D015746:Abdominal Pain; D000369:Aged, 80 and over; D002114:Calcinosis; D049448:Cholangiopancreatography, Magnetic Resonance; D015209:Cholangitis, Sclerosing; D015154:Esophageal Motility Disorders; D005221:Fatigue; D005260:Female; D006801:Humans; D011928:Raynaud Disease; D012017:Referral and Consultation; D013684:Telangiectasis",
"nlm_unique_id": "101293382",
"other_id": null,
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"pubdate": "2015-11-25",
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"title": "Primary sclerosing cholangitis associated with CREST (calcinosis, Raynaud phenomenon, oesophageal dysmotility, sclerodactyly and telangiectasia) in an elderly woman: a case report.",
"title_normalized": "primary sclerosing cholangitis associated with crest calcinosis raynaud phenomenon oesophageal dysmotility sclerodactyly and telangiectasia in an elderly woman a case report"
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"abstract": "Bloodstream infection (BSI) is a common complication after living-donor liver transplantation (LDLT). Some patients develop recurrent BSIs. We evaluated the impacts of early recurrent BSIs (ER-BSIs) on outcomes in LDLT recipients. LDLT cases between 2008 and 2016 were included. Early BSI (E-BSI) was defined as a BSI event that occurred within 2 months after LDLT. ER-BSIs were defined as new-onset BSIs within 2 months due to another pathogen at a ≥ 48-h interval or a relapse of BSIs by the same pathogen at a ≥ 1-week interval, with negative cultures in between. The primary objective was evaluating the all-cause mortality of each group of LDLT recipients (90 days and 1 year). The secondary objectives were analyzing associated factors of each all-cause mortality and risk factors for early single BSI and ER-BSI. Among 727 LDLT recipients, 108 patients experienced 149 events of E-BSI with 170 isolated pathogens. Twenty-eight patients (25.9%, 28/108) experienced ER-BSI. The 1-year survival rates of patients without BSI, with early single BSI event, and with ER-BSIs were 92.4%, 81.3%, and 28.6%, respectively. ER-BSI was the most significant risk factor for 1-year mortality (adjusted HR = 5.31; 95% CI = 2.27-12.40). Intra-abdominal and/or biliary complications and early allograft dysfunction were risk factors for both early single BSI and ER-BSI. Interestingly, longer cold ischemic time and recipient operative time were associated with ER-BSI. LDLT recipients with ER-BSI showed very low survival rates accompanied by intra-abdominal complications. Clinicians should prevent BSI recurrence by being aware of intra-abdominal complications.",
"affiliations": "Division of Infectious Diseases, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon, South Korea.;Division of Infectious Diseases, Department of Internal Medicine, Inje University College of Medicine, Inje University Busan Paik Hospital, Busan, South Korea.;Division of Infectious Diseases, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.;Division of Infectious Diseases, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.;Division of Infectious Diseases, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.;Division of Infectious Diseases, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.;Division of Infectious Diseases, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.;Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.;Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.;Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.;Division of Infectious Diseases, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea. krpeck@skku.edu.",
"authors": "Kim|Si-Ho|SH|;Mun|Seok Jun|SJ|;Ko|Jae-Hoon|JH|;Huh|Kyungmin|K|;Cho|Sun Young|SY|;Kang|Cheol-In|CI|;Chung|Doo Ryeon|DR|;Choi|Gyu-Seong|GS|;Kim|Jong Man|JM|;Joh|Jae-Won|JW|;Peck|Kyong Ran|KR|http://orcid.org/0000-0002-7464-9780",
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"keywords": "Bacteremia; Fungemia; Living-donor liver transplantation; Mortality; Recurrence",
"medline_ta": "Eur J Clin Microbiol Infect Dis",
"mesh_terms": "D000900:Anti-Bacterial Agents; D016470:Bacteremia; D001419:Bacteria; D001424:Bacterial Infections; D024901:Drug Resistance, Multiple, Bacterial; D006801:Humans; D007166:Immunosuppressive Agents; D016031:Liver Transplantation; D019520:Living Donors; D012008:Recurrence; D016559:Tacrolimus; D016896:Treatment Outcome",
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"title": "Poor outcomes of early recurrent post-transplant bloodstream infection in living-donor liver transplant recipients.",
"title_normalized": "poor outcomes of early recurrent post transplant bloodstream infection in living donor liver transplant recipients"
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"abstract": "Canagliflozin (Invokana) is a selective sodium glucose cotransporter-2 (SGLT-2) inhibitor that was first introduced in 2013 for the treatment of type 2 diabetes mellitus (DM). Though not FDA approved yet, its use in type 1 DM has been justified by the fact that its mechanism of action is independent of insulin secretion or action. However, some serious side effects, including severe anion gap metabolic acidosis and euglycemic diabetic ketoacidosis (DKA), have been reported. Prompt identification of the causal association and initiation of appropriate therapy should be instituted for this life threatening condition.",
"affiliations": "Section of Pulmonary and Critical Care Medicine, Providence Hospital and Medical Center, 16001 W 9 Mile Road, Southfield, MI 48075, USA.;Department of Internal Medicine, Providence Hospital and Medical Center, 16001 W 9 Mile Road, Southfield, MI 48075, USA.;Department of Internal Medicine, Providence Hospital and Medical Center, 16001 W 9 Mile Road, Southfield, MI 48075, USA.;Section of Pulmonary and Critical Care Medicine, Providence Hospital and Medical Center, 16001 W 9 Mile Road, Southfield, MI 48075, USA.;Section of Pulmonary and Critical Care Medicine, Providence Hospital and Medical Center, 16001 W 9 Mile Road, Southfield, MI 48075, USA.",
"authors": "Gelaye|Alehegn|A|;Haidar|Abdallah|A|;Kassab|Christina|C|;Kazmi|Syed|S|;Sinha|Prabhat|P|",
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"fulltext": "\n==== Front\nCase Rep Crit CareCase Rep Crit CareCRICCCase Reports in Critical Care2090-64202090-6439Hindawi Publishing Corporation 10.1155/2016/1656182Case ReportSevere Ketoacidosis Associated with Canagliflozin (Invokana): A Safety Concern Gelaye Alehegn \n1\n\n*\nHaidar Abdallah \n2\nKassab Christina \n2\nKazmi Syed \n1\nSinha Prabhat \n1\n1Section of Pulmonary and Critical Care Medicine, Providence Hospital and Medical Center, 16001 W 9 Mile Road, Southfield, MI 48075, USA2Department of Internal Medicine, Providence Hospital and Medical Center, 16001 W 9 Mile Road, Southfield, MI 48075, USA*Alehegn Gelaye: alehegn.gelaye@gmail.comAcademic Editor: Kurt Lenz\n\n2016 21 3 2016 2016 165618219 1 2016 9 3 2016 Copyright © 2016 Alehegn Gelaye et al.2016This 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.Canagliflozin (Invokana) is a selective sodium glucose cotransporter-2 (SGLT-2) inhibitor that was first introduced in 2013 for the treatment of type 2 diabetes mellitus (DM). Though not FDA approved yet, its use in type 1 DM has been justified by the fact that its mechanism of action is independent of insulin secretion or action. However, some serious side effects, including severe anion gap metabolic acidosis and euglycemic diabetic ketoacidosis (DKA), have been reported. Prompt identification of the causal association and initiation of appropriate therapy should be instituted for this life threatening condition.\n==== Body\n1. Introduction\nMore than 5 million patients are admitted annually to intensive care units (ICUs) in the United States. A number of life threatening medical conditions, including diabetic ketoacidosis, can be associated with metabolic acidosis. Metabolic acidosis may also arise from several drugs and toxins through a variety of mechanisms. Since approval of the first-in-class drug in 2013, data have emerged suggesting that Sodium Glucose Transporter-2 (SGLT-2) inhibitors, including canagliflozin, may lead to diabetic ketoacidosis [1]. We present the case of a 54-year-old male patient who was admitted to the ICU with severe anion gap metabolic acidosis and ketoacidosis with normal glucose levels. All the findings were consistent with canagliflozin (Invokana) induced ketoacidosis.\n\n2. Case Description\nA 54-year-old Middle-Eastern male with type 1 diabetes mellitus who had laparoscopic appendectomy for acute gangrenous appendicitis with localized peritonitis 2 days prior to his emergency department visit presented with vague chest discomfort, mild abdominal pain, generalized fatigue, and confusion for one day. He denies vomiting, fever, or diarrhea. He had poor appetite and stated not eating and drinking much. He was not paying attention to his carbohydrate count. He denies alcohol or nonprescription drug intake. The patient continued to take his home medication regimen which includes canagliflozin and glargine insulin 60 units at night time. He has been taking canagliflozin 300 mg daily for three years. On presentation, he had a blood glucose level of 142 mg/dL (normal 70–140), normal kidney function (eGFR 103), severe metabolic acidosis with PH of 7.058 (normal 7.35–7.45), anion gap of 37 (normal 8–16) and serum bicarb of 9 mg/dL (normal 22–28), normal lactate level, and β-hydroxybutyrate level of 12.4 mmol/L. In the setting of recent abdominal surgery, sepsis with possible diabetes ketoacidosis (DKA) was considered and he was started on intravenous (IV) fluids, IV antibiotics, and insulin infusion along with dextrose 5% in 0.45% NS. However, within few hours of his ICU admission, the patient became more encephalopathic and subsequently intubated. Repeat laboratory test revealed profound anion gap metabolic acidosis with bicarb dropped to 3 mg/dL, elevated serum osmolality of 33 mOsm/kg (normal 275–295), and osmolar gap of 36 (normal 10–15). At this time, he was started on bicarbonate infusion and testing for toxic alcohols, including methanol, ethylene glycol, and diethylene glycol, was performed. Despite the above treatment, he remained acidotic associated with significant electrolyte abnormalities. After nephrology consultation, he was started on fomepizole and to proceed with hemodialysis. Testing for toxic alcohols only showed high levels of acetone (93 mg/dL) and propylene glycol (8.3 mg/dL). Based on the above results, euglycemic ketoacidosis associated with canagliflozin was considered and insulin treatment was intensified until the ketones were cleared while maintaining the serum glucose levels. He required insulin infusion (up to 10 units/hr) along with dextrose to prevent hypoglycemia for 72 hours to normalize the anion gap and clear the ketones. Eventually the patient's symptoms and laboratory data improved leading to successful extubation, toleration of oral diet, and transition to subcutaneous insulin administration with subsequent stable discharge to home.\n\n3. Discussion\nSodium Glucose Transporter-2 (SGLT-2) inhibitors, including canagliflozin, dapagliflozin, and empagliflozin, are a newer class of antidiabetic medications that are US Food and Drug Administration (FDA) approved for use with diet and exercise to lower blood sugar in adults with type 2 diabetes. They lower plasma glucose levels by reducing the renal threshold for glucose and increasing urinary glucose excretion. On March 29, 2013, FDA approved canagliflozin (Invokana, Janssen Pharmaceuticals, Inc.), a once-daily tablet indicated as an adjunct to diet and exercise, to improve glycemic control in adults with type 2 diabetes mellitus [2, 3]. Though not FDA approved yet, increasing off-label use of SGLT-2 inhibitors has been observed, most likely due to the favorable insulin-independent glucose-lowering and weight-loss effects.\n\nResults from the preclinical and clinical studies led canagliflozin to be the first-in-class SGLT-2 inhibitor approved in the United States and support canagliflozin as a safe and effective therapeutic option across a broad range of patients with type 2 diabetes mellitus [4]. The comprehensive results of a large phase III clinical development program demonstrate that canagliflozin 100 mg and canagliflozin 300 mg provide substantial and sustained reductions in HbA1c, with additional potentially valuable clinical benefits on BP and body weight [5].\n\nCanagliflozin was generally well tolerated [6]. The most common adverse reactions associated with canagliflozin were genital mycotic infections, urinary tract infections, osmotic diuresis, and reduced intravascular volume. However, rare case reports of diabetic ketoacidosis (DKA) and related events associated with canagliflozin started to occur during the course of treatment. Erondu et al. [7] stated that DKA occurs at a low frequency in 12 patients with type 2 diabetes treated with canagliflozin. Peters et al. [8] also analyzed 13 episodes of SGLT-2 inhibitor-associated euglycemic DKA or ketosis in 9 individuals, seven with type 1 diabetes and two with type 2 diabetes. SGLT-2 inhibitors seem to be associated with euglycemic DKA and ketosis, perhaps as a consequence of their noninsulin-dependent glucose clearance, hyperglucagonemia, and volume depletion. The above findings prompt FDA to investigate the drug. Search of the FDA Adverse Event Reporting System (FAERS) database identified 20 cases of acidosis reported as diabetic ketoacidosis (DKA), ketoacidosis, or ketosis in patients treated with SGLT-2 inhibitors from March 2013 to June 6, 2014. Most of the DKA cases were reported in patients with type 2 diabetes. In most cases, a high anion gap metabolic acidosis accompanied by elevated blood or urine ketones and normal glucose levels was reported. The glucose levels were only mildly elevated at less than 200 mg/dL in some reports. These findings are not typical of diabetic ketoacidosis [1]. The European Medicines Agency had also reported a total of 101 cases of DKA in patients treated with SGLT-2 inhibitors for type 2 worldwide as of 19 May 2015 [9]. According to several studies, the overall frequency of reported events suggestive of DKA is less than 0.1% [7].\n\nFactors identified in some reports as having potentially triggered the ketoacidosis included major illnesses, infections, trauma, reduced food and fluid intake, and reduced insulin dose [1]. Given his reduced oral intake and recent bowel surgery, starvation might have played a role in activating the ketosis pathway in our patient. In addition to high anion gap metabolic acidosis and severe ketoacidosis with low levels of glucose, our patient had an elevated serum osmolal gap, findings generally characteristic of intoxication with one of the toxic alcohols (methanol, ethylene glycol, diethylene glycol, or propylene glycol) [10–12]. However, toxicology study of our patient showed only high levels of acetone and propylene glycol, which was attributed to midazolam infusion.\n\nUnlike in our case, a temporal association with SGLT-2 inhibitor initiation was noted in all cases. The median time to onset of symptoms following initiation of drug therapy was 2 weeks (range 1 to 175 days) [1]. This alerts clinicians to monitor their patients while being on SGLT-2 inhibitors. The potential complications related to SGLT-2 inhibition are predictable, detectable, and preventable so that the balance of benefits and risks favors the use of SGLT-2 inhibitors. Rosenstock and Ferrannini [13] advise that, in any event, type 1 diabetic patients who choose to take this medication off-label should sign an informed consent that makes them fully aware of the potential for euglycemic DKA, the precipitating factors, the warning symptoms and signs, and the preventative measures to adopt.\n\n4. Conclusion\nOur case clearly illustrates the rare association of severe anion gap metabolic acidosis with ketoacidosis and normal glucose levels with SGLT-2 inhibitors. Even though these patients are euglycemic, they should be treated as if they have diabetic ketoacidosis. Prompt identification of the causal association and initiation of appropriate therapy should be instituted for this life threatening condition. This case also points out that SGLT-2 inhibitors should preferably be avoided in circumstances where poor oral intake is much anticipated.\n\nAdditional Points\nFuture research should be directed toward identifying which patients are at greatest risk for this side effect. A possible association of SGLT-2 inhibitors and high osmolar gap metabolic acidosis needs to be further investigated.\n\nDisclosure\nThe corresponding author is the guarantor of submission.\n\nCompeting Interests\nThe authors declare that they have no competing interests.\n\nAuthors' Contributions\nAlehegn Gelaye was responsible for conception and design, acquisition of data, analysis and interpretation of data, drafting the paper, critical revision of the paper, and final approval of the version to be published. Abdallah Haidar, Christina Kassab, Syed Kazmi, and Prabhat Sinha were responsible for conception and design, acquisition of data, analysis and interpretations of data, critical revision of the paper, and final approval of the version to be published.\n==== Refs\n1 US Food and Drug Administration FDA Drug Safety Communication: FDA Warns That SGLT2 Inhibitors for Diabetes May Result in a Serious Condition of Too Much Acid in the Blood 2015 Bethesda, Md, USA US Food and Drug Administration \n2 Sobieraj D. M. FDA Approves First SGLT2 Inhibitor for T2DM 2013 \n3 Fala L. Invokana (Canagliflozin): first-in-class SGLT2 inhibitor approved for the treatment of type 2 diabetes American Health & Drug Benefits 2014 7 \n4 Scheen A. J. Pharmacodynamics, efficacy and safety of sodium-glucose co-transporter type 2 (SGLT2) inhibitors for the treatment of type 2 diabetes mellitus Drugs 2015 75 1 33 59 10.1007/s40265-014-0337-y 2-s2.0-84923791994 25488697 \n5 Rosenthal N. Meininger G. Ways K. Canagliflozin: a sodium glucose co-transporter 2 inhibitor for the treatment of type 2 diabetes mellitus Annals of the New York Academy of Sciences 2015 10.1111/nyas.12852 2-s2.0-84940535692 \n6 Triplitt C. Cornell S. Canagliflozin treatment in patients with type 2 diabetes mellitus Clinical Medicine Insights: Endocrinology and Diabetes 2015 8 73 81 10.4137/cmed.s31526 2-s2.0-84945958760 26523120 \n7 Erondu N. Desai M. Ways K. Meininger G. Diabetic ketoacidosis and related events in the canagliflozin type 2 diabetes clinical program Diabetes Care 2015 38 9 1680 1686 10.2337/dc15-1251 26203064 \n8 Peters A. L. Buschur E. O. Buse J. B. Cohan P. Diner J. C. Hirsch I. B. Euglycemic diabetic ketoacidosis: a potential complication of treatment with sodium-glucose cotransporter 2 inhibition Diabetes Care 2015 38 9 1687 1693 10.2337/dc15-0843 26078479 \n9 European Medicines Agency Review of diabetes medicines called SGLT2 inhibitors started: risk of diabetic ketoacidosis to be examined June 2015, http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/SGLT2_inhibitors__20/Procedure_started/WC500187926.pdf \n10 Hovda K. E. Hunderi O. H. Rudberg N. Froyshov S. Jacobsen D. Anion and osmolal gaps in the diagnosis of methanol poisoning: clinical study in 28 patients Intensive Care Medicine 2004 30 9 1842 1846 10.1007/s00134-004-2373-7 2-s2.0-4644317255 15241587 \n11 Kraut J. A. Kurtz I. Toxic alcohol ingestions: clinical features, Diagnosis, and management Clinical Journal of the American Society of Nephrology 2008 3 1 208 225 10.2215/cjn.03220807 2-s2.0-38749100254 18045860 \n12 Abramson S. Singh A. K. Treatment of the alcohol intoxications: ethylene glycol, methanol and isopropanol Current Opinion in Nephrology and Hypertension 2000 9 6 695 701 10.1097/00041552-200011000-00017 2-s2.0-0033693494 11128434 \n13 Rosenstock J. Ferrannini E. Euglycemic diabetic ketoacidosis: a predictable, detectable, and preventable safety concern with SGLT2 inhibitors Diabetes Care 2015 38 9 1638 1642 10.2337/dc15-1380 26294774\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2090-6420",
"issue": "2016()",
"journal": "Case reports in critical care",
"keywords": null,
"medline_ta": "Case Rep Crit Care",
"mesh_terms": null,
"nlm_unique_id": "101598416",
"other_id": null,
"pages": "1656182",
"pmc": null,
"pmid": "27088018",
"pubdate": "2016",
"publication_types": "D016428:Journal Article",
"references": "11128434;15241587;18045860;26523120;26203064;25488697;26305874;26078479;26294774;26629269",
"title": "Severe Ketoacidosis Associated with Canagliflozin (Invokana): A Safety Concern.",
"title_normalized": "severe ketoacidosis associated with canagliflozin invokana a safety concern"
} | [
{
"companynumb": "US-JNJFOC-20160425052",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "CANAGLIFLOZIN"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nReducing or eliminating falls is a focus of patient safety programs as well as health policy. Falls are tied to hospital reimbursement. However, little is known about the risk of falls among hospitalized patients with cirrhosis or factors that affect risk of falling.\n\n\nMETHODS\nWe conducted a retrospective cohort study of inpatients with cirrhosis from 2010 to 2013 at a liver transplant center. Our primary aim was to determine the clinical factors associated with falls and fall-related injuries for patients with cirrhosis. Our secondary aim was to describe the rate ratio of falls and fall-related injuries among patients with cirrhosis compared with general medical inpatients.\n\n\nRESULTS\nDuring the study period, there were 1749 admissions to the liver service; 55 (3.1%) resulted in falls. Patients who fell were more likely to have received benzodiazepines (50.9% vs 16.7%, P < .0001) and antipsychotic agents (30.9% vs 7.3%, P < .0001). After adjusting for hepatic encephalopathy, the respective odds of a fall after benzodiazepine or antipsychotic exposure were 6.59 (95% confidence interval [CI], 3.76-11.59) and 3.72 (95% CI, 1.90-7.06). The adjusted risk of a fall-related injury was also significantly associated with benzodiazepine and antipsychotic agents, with respective odds ratios of 3.45 (95% CI, 1.39-8.23) and 3.42 (95% CI, 1.09-8.99). Fall-related injuries occurred at a rate of 1.70/1000 patient-days for patients with cirrhosis vs 0.5/1000 patient-days for patients in the general medical service. Accordingly, the rate ratio for a fall-related injury among patients with cirrhosis was 3.37 (95% CI, 1.99-5.72; P < .0001).\n\n\nCONCLUSIONS\nPsychoactive medications are associated with an increased adjusted risk of falls and fall-related injuries in hospitalized patients with cirrhosis.",
"affiliations": "Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts. Electronic address: etapper@bidmc.harvard.edu.;Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts.;Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts.",
"authors": "Tapper|Elliot B|EB|;Risech-Neyman|Yesenia|Y|;Sengupta|Neil|N|",
"chemical_list": "D011619:Psychotropic Drugs; D001569:Benzodiazepines",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1542-3565",
"issue": "13(9)",
"journal": "Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association",
"keywords": "Antipsychotics; Benzodiazepines; Hepatic Encephalopathy; Model for End-Stage Liver Disease",
"medline_ta": "Clin Gastroenterol Hepatol",
"mesh_terms": "D000058:Accidental Falls; D000368:Aged; D001569:Benzodiazepines; D005260:Female; D006801:Humans; D007297:Inpatients; D008103:Liver Cirrhosis; D008297:Male; D008875:Middle Aged; D011619:Psychotropic Drugs; D012189:Retrospective Studies; D018570:Risk Assessment; D014947:Wounds and Injuries",
"nlm_unique_id": "101160775",
"other_id": null,
"pages": "1670-5",
"pmc": null,
"pmid": "25818078",
"pubdate": "2015-09",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Psychoactive Medications Increase the Risk of Falls and Fall-related Injuries in Hospitalized Patients With Cirrhosis.",
"title_normalized": "psychoactive medications increase the risk of falls and fall related injuries in hospitalized patients with cirrhosis"
} | [
{
"companynumb": "US-JNJFOC-20161117192",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RISPERIDONE"
},
"drugadditional": "3",
... |
{
"abstract": "Highly active antiretroviral therapy has led to greater life expectancy for human immun-deficiency virus (HIV)-positive patients. This was a report of 11 years of follow-up of an HIV-seropositive patient who underwent heart transplantation in 2006, with emphasis on the management challenges of complex drug interactions over time.",
"affiliations": "Department of Cardiology, Institut Universitaire De Cardiologie Et De Pneumologie De Québec, Laval University, Québec, Canada.;Department of Pharmacy, Institut Universitaire De Cardiologie Et De Pneumologie De Québec, Laval University, Québec, Canada.;Department of Infectious Disease, Institut Universitaire De Cardiologie Et De Pneumologie De Québec, Laval University, Québec, Canada.;Department of Cardiac Surgery, Institut Universitaire De Cardiologie Et De Pneumologie De Québec, Laval University, Québec, Canada.;Research Center, Institut Universitaire De Cardiologie Et De Pneumologie De Québec, Laval University, Québec, Canada.;Department of Cardiology, Institut Universitaire De Cardiologie Et De Pneumologie De Québec, Laval University, Québec, Canada.",
"authors": "Sénéchal|Isabelle|I|;Châteauvert|Nathalie|N|;Gervais|Philippe|P|;Voisine|Pierre|P|;Dubois|Michelle|M|;Sénéchal|Mario|M|",
"chemical_list": "D007166:Immunosuppressive Agents",
"country": "Turkey",
"delete": false,
"doi": "10.5543/tkda.2019.63479",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1016-5169",
"issue": "48(2)",
"journal": "Turk Kardiyoloji Dernegi arsivi : Turk Kardiyoloji Derneginin yayin organidir",
"keywords": null,
"medline_ta": "Turk Kardiyol Dern Ars",
"mesh_terms": "D023241:Antiretroviral Therapy, Highly Active; D004347:Drug Interactions; D015658:HIV Infections; D016027:Heart Transplantation; D006801:Humans; D007166:Immunosuppressive Agents; D008297:Male; D008875:Middle Aged",
"nlm_unique_id": "9426239",
"other_id": null,
"pages": "180-184",
"pmc": null,
"pmid": "32147653",
"pubdate": "2020-03",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Complex drug interactions in an HIV-seropositive heart transplant recipient.",
"title_normalized": "complex drug interactions in an hiv seropositive heart transplant recipient"
} | [
{
"companynumb": "CA-JNJFOC-20200415254",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ABACAVIR"
},
"drugadditional": "3",
"dr... |
{
"abstract": "OBJECTIVE\nThe aim of the present study was to compare treated lymphoma-associated Epstein-Barr virus (EBV)-positive mucocutaneous ulcer (EBVMCU) and methotrexate (MTX)-associated EBVMCU.\n\n\nRESULTS\nOf a series of 15 Japanese patients (11 women, four men; median age 74 years, range 35-84 years), seven received MTX for the treatment of autoimmune disease and eight developed EBVMCU after treatment of malignant lymphoma [diffuse large B-cell lymphoma (n = 4) without EBV association, adult T-cell leukaemia/lymphoma (n = 2), angioimmunoblastic T-cell lymphoma (n = 1), and follicular lymphoma (n = 1)]. Ulcers were observed in the oral cavity (n = 11), gastrointestinal tract (n = 2), and skin (n = 2). All were histologically characterised by a mixture of EBV-positive large B-cell proliferation and Hodgkin/Reed-Sternberg-like cells on a polymorphous background. A total of 46% (6/13) had monoclonal immunoglobulin heavy chain gene rearrangement, but none had clonal T-cell receptor gene rearrangement. Spontaneous regression occurred in 13 of 15 cases (87%); the other two cases (13%) achieved complete remission after treatment. Of two patients in the treated lymphoma-associated subgroup, one developed multiple new ulcerative lesions on previously unaffected skin, and the other had a relapse of EBVMCU in the oral cavity. No significant clinicopathological differences were found between the subgroups. Notably, none of the patients died from EBVMCU. However, the treated lymphoma-associated subgroup had lower overall survival (P = 0.004) and a shorter follow-up period (P = 0.003) than the MTX-associated subgroup, owing to death from non-associated causes.\n\n\nCONCLUSIONS\nTreated lymphoma-associated EBVMCU, which is an indolent and self-limited condition, must be recognised to avoid misdiagnosing it as a relapse of malignant lymphoma during treatment.",
"affiliations": "Department of Pathology and Laboratory Medicine, Nagoya University Hospital, Nagoya, Japan.;Department of Pathology and Laboratory Medicine, Nagoya University Hospital, Nagoya, Japan.;Department of Pathology and Laboratory Medicine, Nagoya University Hospital, Nagoya, Japan.;Department of Surgical Pathology, Aichi Medical University Hospital, Nagakate, Japan.;Department of Pathology and Laboratory Medicine, Nagoya University Hospital, Nagoya, Japan.;Department of Pathology and Division of Dermatology, Uwajima City Hospital, Uwajima, Japan.;Department of Pathology and Division of Dermatology, Uwajima City Hospital, Uwajima, Japan.;Department of Pathology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.;Department of Pathology and Laboratory Medicine, Nagoya University Hospital, Nagoya, Japan.;Department of Clinical Laboratory, Nagano Prefectural Suzaka Hospital, Nagano, Japan.;Department of Pathology and Molecular Diagnostics, Aichi Cancer Centre Hospital, Aichi, Japan.",
"authors": "Daroontum|Teerada|T|http://orcid.org/0000-0001-5968-218X;Kohno|Kei|K|;Eladl|Ahmed E|AE|;Satou|Akira|A|http://orcid.org/0000-0002-7921-6087;Sakakibara|Ayako|A|;Matsukage|Shoichi|S|;Yakushiji|Naoki|N|;Ya-In|Charin|C|;Nakamura|Shigeo|S|;Asano|Naoko|N|http://orcid.org/0000-0001-7536-6179;Kato|Seiichi|S|http://orcid.org/0000-0001-9713-3691",
"chemical_list": "D007166:Immunosuppressive Agents; D008727:Methotrexate",
"country": "England",
"delete": false,
"doi": "10.1111/his.13464",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0309-0167",
"issue": "72(7)",
"journal": "Histopathology",
"keywords": "EBV-positive mucocutaneous ulcer; methotrexate-associated EBVMCU; treated lymphoma-associated EBVMCU",
"medline_ta": "Histopathology",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001327:Autoimmune Diseases; D020031:Epstein-Barr Virus Infections; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D007564:Japan; D008223:Lymphoma; D008297:Male; D008727:Methotrexate; D008875:Middle Aged; D014456:Ulcer",
"nlm_unique_id": "7704136",
"other_id": null,
"pages": "1115-1127",
"pmc": null,
"pmid": "29314151",
"pubdate": "2018-06",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Comparison of Epstein-Barr virus-positive mucocutaneous ulcer associated with treated lymphoma or methotrexate in Japan.",
"title_normalized": "comparison of epstein barr virus positive mucocutaneous ulcer associated with treated lymphoma or methotrexate in japan"
} | [
{
"companynumb": "PHHY2018JP013392",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "METHOTREXATE"
},
"drugadditional": null,
"dr... |
{
"abstract": "Pazopanib, a multityrosine kinase inhibitor used for treating malignant soft tissue tumors, rarely causes adverse events associated with the respiratory system. We report a case of a 73-year-old male with leiomyosarcoma treated with pazopanib. Four months after treatment initiation, chest computed tomography showed bilateral patchy consolidation and ground-glass opacities. Bronchoscopy revealed increased lymphocytes in the bronchoalveolar lavage fluid. Histological analysis of lung tissue demonstrated intraluminal fibrotic changes in alveolar spaces. According to these findings, we diagnosed the patient with pazopanib-induced organizing pneumonia. To best of our knowledge, this is the first report of such a case.",
"affiliations": "Division of Infectious Diseases and Respiratory Medicine, Department of Internal Medicine, National Defense Medical College, 3-2, Namiki, Tokorozawa-shi, Saitama, Japan.;Division of Infectious Diseases and Respiratory Medicine, Department of Internal Medicine, National Defense Medical College, 3-2, Namiki, Tokorozawa-shi, Saitama, Japan.;Division of Infectious Diseases and Respiratory Medicine, Department of Internal Medicine, National Defense Medical College, 3-2, Namiki, Tokorozawa-shi, Saitama, Japan.;Division of Infectious Diseases and Respiratory Medicine, Department of Internal Medicine, National Defense Medical College, 3-2, Namiki, Tokorozawa-shi, Saitama, Japan.;Division of Infectious Diseases and Respiratory Medicine, Department of Internal Medicine, National Defense Medical College, 3-2, Namiki, Tokorozawa-shi, Saitama, Japan.;Division of Infectious Diseases and Respiratory Medicine, Department of Internal Medicine, National Defense Medical College, 3-2, Namiki, Tokorozawa-shi, Saitama, Japan.;Division of Infectious Diseases and Respiratory Medicine, Department of Internal Medicine, National Defense Medical College, 3-2, Namiki, Tokorozawa-shi, Saitama, Japan.;Division of Infectious Diseases and Respiratory Medicine, Department of Internal Medicine, National Defense Medical College, 3-2, Namiki, Tokorozawa-shi, Saitama, Japan.;Division of Infectious Diseases and Respiratory Medicine, Department of Internal Medicine, National Defense Medical College, 3-2, Namiki, Tokorozawa-shi, Saitama, Japan.;Division of Infectious Diseases and Respiratory Medicine, Department of Internal Medicine, National Defense Medical College, 3-2, Namiki, Tokorozawa-shi, Saitama, Japan.;Division of Infectious Diseases and Respiratory Medicine, Department of Internal Medicine, National Defense Medical College, 3-2, Namiki, Tokorozawa-shi, Saitama, Japan.;Department of Urology, National Defense Medical College, 3-2, Namiki, Tokorozawa-shi, Saitama, Japan.;Division of Infectious Diseases and Respiratory Medicine, Department of Internal Medicine, National Defense Medical College, 3-2, Namiki, Tokorozawa-shi, Saitama, Japan.",
"authors": "Watanabe|Chie|C|;Miyata|Jun|J|;Esaki|Kotoba|K|;Suematsu|Ryohei|R|;Sano|Tomoya|T|;Yamamoto|Takayuki|T|;Sasaki|Hisashi|H|;Maki|Yohei|Y|;Tagami|Yoichi|Y|;Kimizuka|Yoshifumi|Y|;Fujikura|Yuji|Y|;Ito|Keiichi|K|;Kawana|Akihiko|A|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1016/j.rmcr.2020.101112",
"fulltext": "\n==== Front\nRespir Med Case Rep\nRespir Med Case Rep\nRespiratory Medicine Case Reports\n2213-0071 Elsevier \n\nS2213-0071(20)30187-8\n10.1016/j.rmcr.2020.101112\n101112\nCase Report\nPazopanib-induced organizing pneumonia in a patient with leiomyosarcoma: A case report\nWatanabe Chie chwatanabe@ndmc.ac.jpa Miyata Jun junmiyata@ndmc.ac.jpa∗ Esaki Kotoba kookaberra615@gmail.coma Suematsu Ryohei ryouhei.0724@gmail.coma Sano Tomoya t_sano3527@ndmc.ac.jpa Yamamoto Takayuki yamataka0219@gmail.coma Sasaki Hisashi tak_inaba_sasaki@yahoo.co.jpa Maki Yohei goriking24@yahoo.co.jpa Tagami Yoichi y.tagami8@gmail.coma Kimizuka Yoshifumi ykimizuka@ndmc.ac.jpa Fujikura Yuji fujikura@ndmc.ac.jpa Ito Keiichi itok@ndmc.ac.jpb Kawana Akihiko kawana59@ndmc.ac.jpa a Division of Infectious Diseases and Respiratory Medicine, Department of Internal Medicine, National Defense Medical College, 3-2, Namiki, Tokorozawa-shi, Saitama, Japan\nb Department of Urology, National Defense Medical College, 3-2, Namiki, Tokorozawa-shi, Saitama, Japan\n∗ Corresponding author. Division of Infectious Diseases and Respiratory Medicine, Department of Internal Medicine, National Defense Medical College, 3-2, Namiki, Tokorozawa-shi, Saitama, 359-8513, Japan. junmiyata@ndmc.ac.jp\n31 5 2020 \n2020 \n31 5 2020 \n30 10111225 4 2020 26 5 2020 28 5 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/).Pazopanib, a multityrosine kinase inhibitor used for treating malignant soft tissue tumors, rarely causes adverse events associated with the respiratory system. We report a case of a 73-year-old male with leiomyosarcoma treated with pazopanib. Four months after treatment initiation, chest computed tomography showed bilateral patchy consolidation and ground-glass opacities. Bronchoscopy revealed increased lymphocytes in the bronchoalveolar lavage fluid. Histological analysis of lung tissue demonstrated intraluminal fibrotic changes in alveolar spaces. According to these findings, we diagnosed the patient with pazopanib-induced organizing pneumonia. To best of our knowledge, this is the first report of such a case.\n\nHighlights\n• Pazopanib is a multityrosine kinase inhibitor used for treating soft tissue tumors.\n\n• Pazopanib rarely causes adverse events associated with the respiratory system.\n\n• This is the first report of a patient with pazopanib-induced organizing pneumonia.\n\n\n\nKeywords\nPazopanibMultityrosine kinase inhibitorOrganizing pneumoniaeLeiomyosarcomaDrug-induced lung injuryAdverse event\n==== Body\n1 Background\nPazopanib is a multiple tyrosine kinase inhibitor-targeting fibroblast growth factor, platelet-derived growth factor, and vascular endothelial growth factor. It is used for renal cell carcinoma and malignant soft tissue tumor [[1], [2], [3]]. Recently, clinical trials have examined its therapeutic effects on solid cancers of the breast, thyroid, lung, and head and neck [[4], [5], [6], [7], [8], [9], [10], [11]].\n\nThe most common adverse events of multiple tyrosine kinase inhibitors are fatigue, diarrhea, nausea, weight loss, and hypertension [12]. Pneumothorax is the most frequently reported respiratory system-related adverse event [[13], [14], [15], [16], [17]]. A case of pazopanib-induced lung injury presenting with a usual interstitial pneumonia pattern has already been reported; however, the patient had poor prognosis [18]. There is no known report of pathologically diagnosed pazopanib-induced organizing pneumonia.\n\n2 Case presentation\nA 73-year-old man presented with bloody urine. Imaging examination showed a tumor around the superior and inferior venae cavae, which was surgically resected. In accordance with the histological findings, the patient was diagnosed with leiomyosarcoma. A year and 5 months later, magnetic resonance imaging demonstrated local recurrence of the tumor, for which resection was performed. However, 1 year after the second surgery, computed tomography showed multiple lung metastases with local recurrence of the tumor surrounding the inferior vena cava. Because of the distant metastasis, systemic treatment using pazopanib (800 mg/day) was initiated. Most of the metastatic lung tumors were unchanged, and progression of the primary tumor and enlargement of metastatic lesions were not observed.\n\nChest X-ray showed bilateral peripheral consolidations, which were lower-lung-field dominant 4 months after the start of this treatment (Fig. 1). Chest computed tomography revealed non-segmental infiltration with bronchial transillumination surrounded by ground-glass opacities. Fine crackles were heard posteriorly over the lower portion of the lung on auscultation. Laboratory examinations showed elevated levels of KL-6, surfactant protein-A, and surfactant protein-D, which were indicative of interstitial pneumonia (Table 1). No elevation in the proportion of eosinophils in peripheral blood leukocytes was observed. Specific markers, including angiotensin converting enzyme, soluble interleukin-2 receptor, and anti-nuclear antibody, were within normal levels, which excluded the possibilities of collagen diseases and sarcoidosis. On the basis of these findings, pazopanib-induced lung injury was suspected.Fig. 1 Chest radiography and computed tomography findings before and after pazopanib treatment.\n\nFig. 1Table 1 Laboratory findings of patients at the first visit.\n\nTable 1Hematological parameters\t\tSerological and biochemical parameters\t\t\t\t\nWhite blood cells\t4500\t/uL\tT-Bil\t0.48\tmg/dL\tCRP\t<0.3\tmg/dL\t\nNeutrophil\t53.6\t%\tAST\t36.0\tIU/L\tProcalcitonin\t0.02\tng/mL\t\nLymphocyte\t34.4\t%\tALT\t15.0\tIU/L\tACE\t11.8\tIU/L\t\nBasophil\t0.4\t%\tLDH\t209\tIU/L\tBNP\t6.9\tpg/mL\t\nEosinophil\t4.6\t%\tTP\t6.6\tg/dL\tsIL-2R\t953\tU/mL\t\nMonocyte\t7\t%\tAlb\t3.6\tg/dL\t1-3- β-D glucan\t17.0\tpg/mL\t\nRed blood cells\t425\t×104/μL\tBUN\t10.0\tmg/dL\tRheumatoid Factor\t<3.0\tU/mL\t\nHemoglobin\t14.1\tg/dL\tCr\t0.88\tmg/dL\tMPO ANCA\t<1.0\tU/mL\t\nHematocrit\t41.7\t%\tKL‐6\t1686\tU/mL\tPR-3 ANCA\t<1.0\tU/mL\t\nPlatelets\t21.9\t×104/μL\tSP-A\t79.4\tng/mL\tT-SPOT. TB\t(-)\t\t\n\t\t\tSP-D\t361\tng/mL\t\t\t\t\nAbbreviation: KL-6, Krebs von den Lungen‐6; SP-A, surfactant protein-A; SP-D, surfactant protein-D.\n\nACE, angiotensin converting enzyme; BNP, brain natriuretic peptide; sIL-2R, soluble interleukin-2 receptor.\n\nMPO, myeloperoxidase; PR-3, proteinase-3; ANCA, anti-neutrophil cytoplasmic antibody.\n\n\n\nChest radiography indicates baseline image (A) and bilateral areas of consolidation mainly involving the lower lung zones after therapy (B). Computed tomography shows several pulmonary nodules before using pazopanib (C) and bilateral areas of consolidation predominantly involving the peripheral regions on the 128th day of retreatment (D).\n\nBronchoscopy was performed for further investigation. The percentage of lymphocytes in bronchoalveolar lavage fluid had increased. A specimen obtained by transbronchial lung biopsy was histologically analyzed using hematoxylin and eosin and elastic-van Gieson staining, which showed intraluminal fibrosis alveolar spaces consistent with the findings of organizing pneumonia (Fig. 2). Thus, the diagnosis of pazopanib-induced organizing pneumonia was confirmed.Fig. 2 Pathological analysis of transbronchial lung biopsy specimen.\n\nFig. 2\n\nAlveolar spaces containing Masson bodies and plugs of cellular fibrotic tissue (arrows) are evident (A: Hematoxylin and eosin staining, magnification, 200×; B: Elastica van Gieson staining, magnification, 200×).\n\nImaging results showed no change even after discontinuation of pazopanib. Thus, systemic treatment with an oral corticosteroid (prednisolone, 0.5 mg/kg/day) was started, resulting in gradual improvement of organizing pneumonia accompanied by a reduction in KL-6 (183 U/L). When the prednisolone dose was reduced to 12.5 mg, trabectedin [a transcription inhibitor] was initiated for the treatment of leiomyosarcoma. The patient showed no signs of remission of organizing pneumonia after discontinuing prednisolone.\n\n3 Discussion\nOrganizing pneumonia is of two types: idiopathic and secondary. The latter is caused by various factors, such as drugs, infections, collagen diseases, hematological disorders, and malignancies. Typical imaging findings of sporadic infiltrative shadows in the lung are similar to those of eosinophilic pneumonia, and suggestive histological findings of alveolar organizing components are similar to the findings that indicate hypersensitivity pneumonitis. Therefore, combined examinations are needed to diagnose organizing pneumonia accurately.\n\nHistological findings of organizing pneumonia, a specific type of interstitial lung disease, mainly comprise intraluminal organizing fibrosis and buds of granulation tissue consisting of fibroblast-myofibroblasts in distal airspaces [19]. An increased number of infiltrative lymphocytes in the alveolar spaces is also characteristic of this disease, which is indicative of an underlying immunological mechanism.\n\nTo date, there has been no report of organizing pneumonia caused by pazopanib. Moreover, interstitial lung disease is rare; however, there has been a case of a usual pattern of interstitial pneumonia with pazopanib treatment [18]. In this case, the patient required treatment with both a corticosteroid and an immunosuppressant and was re-treated with pazopanib to confirm the causal relationship. However, as the patient in our case was histologically diagnosed with organizing pneumonia, only corticosteroid was prescribed, which was effective. This indicated that pathological diagnosis is useful in establishing a prognosis and choosing the optimal therapy for pazopanib-induced interstitial pneumonia.\n\nCorticosteroids are mostly efficacious when used as an initial treatment of organizing pneumonia [19]. Steroid pulse therapy and/or immunosuppressive drug therapy is used in limited refractory cases [20]. Some cases show spontaneous remission. In this case, steroid treatment was started because no improvement was observed after pazopanib withdrawal. A previous report of a case with life-threatening, pazopanib-induced lung injury increased the necessity of steroid treatment [18]. Steroid tapering frequently induces disease relapse, though suspected drug discontinuation might have enabled cessation of steroid therapy in the presented case.\n\nPrevious studies have reported cases of organizing pneumonia induced by tyrosine kinase inhibitors, including epidermal growth factor receptor tyrosine kinase inhibitor and EML4-ALK fusion tyrosine kinase inhibitor, although the frequency is low [21,22]. However, as only a small number of these cases are reported, inhibition of tyrosine kinases may not necessarily cause organizing pneumonia. Further investigation is needed to identify the mechanism.\n\nThe relationship between organizing pneumonia and multiple pulmonary metastases remains unknown. A previous study reported a case of organizing pneumonia with multiple pulmonary metastases of melanoma, indicative of a possible trigger of organizing pneumonia [23]. Additionally, atypical lung metastatic lesions might resemble organizing pneumonia, suggesting the importance of histological analysis [24].\n\n4 Conclusion\nThis case report describes a rare case of drug-induced lung injury caused by pazopanib used to treat leiomyosarcoma with lung metastasis. To our knowledge, this is the first confirmed diagnosis of organizing pneumonia caused by pazopanib. As demonstrated in this report, histological analysis may be useful in establishing a diagnosis of this disease and distinguishing it from lung metastasis. Clinicians should recognize the importance of prompt diagnostic and therapeutic approaches for improving the outcome of pazopanib-related lung injury.\n\nFunding\nThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\n\nCRediT authorship contribution statement\nChie Watanabe: Conceptualization, Investigation, Data curation, Writing - original draft, Visualization. Jun Miyata: Writing - review & editing, Supervision. Kotoba Esaki: Resources, Writing - review & editing. Ryohei Suematsu: Resources, Writing - review & editing. Tomoya Sano: Resources, Writing - review & editing. Takayuki Yamamoto: Resources, Writing - review & editing. Hisashi Sasaki: Resources, Writing - review & editing. Yohei Maki: Resources, Writing - review & editing. Yoichi Tagami: Resources, Writing - review & editing. Yoshifumi Kimizuka: Resources, Writing - review & editing. Yuji Fujikura: Resources, Writing - review & editing. Keiichi Ito: Resources, Writing - review & editing. Akihiko Kawana: Resources, Writing - review & editing, Project administration.\n\nDeclaration of competing interest\nNone.\n\nAppendix A Supplementary data\nThe following is the Supplementary data to this article:Multimedia component 1\nMultimedia component 1 \n\nAcknowledgements\nWe are grateful to the patient for kindly contributing to this report. In addition, we would like to thank Yuki Komatsu for her assistance with our clinical practice.\n\nAppendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.rmcr.2020.101112.\n==== Refs\nReferences\n1 Schutz F.A. Choueiri T.K. Sternberg C.N. Pazopanib: clinical development of a potent anti-angiogenic drug Crit. Rev. Oncol. Hematol. 77 2011 163 171 20456972 \n2 van der Graaf W.T. Blay J.Y. Chawla S.P. Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial Lancet 379 2012 1879 1886 22595799 \n3 Altorki N. Lane M.E. Bauer T. Phase II proof-of-concept study of pazopanib monotherapy in treatment-naive patients with stage I/II resectable non-small-cell lung cancer J. Clin. Oncol. 28 2010 3131 3137 20516450 \n4 Besse B. Mazieres J. Ribassin-Majed L. Pazopanib or placebo in completely resected stage I NSCLC patients: results of the phase II IFCT-0703 trial Ann. Oncol. 28 2017 1078 1083 28327934 \n5 Koinis F. Agelaki S. Karavassilis V. Second-line pazopanib in patients with relapsed and refractory small-cell lung cancer: a multicentre phase II study of the Hellenic Oncology Research Group Br. J. Canc. 117 8–14 2017 \n6 Messaritakis I. Politaki E. Koinis F. Dynamic changes of phenotypically different circulating tumor cells sub-populations in patients with recurrent/refractory small cell lung cancer treated with pazopanib Sci. Rep. 8 2018 2238 29396560 \n7 O'Brien M.E. Gaafar R. Hasan B. Maintenance pazopanib versus placebo in Non-Small Cell Lung Cancer patients non-progressive after first line chemotherapy: a double blind randomised phase III study of the lung cancer group, EORTC 08092 [EudraCT: 2010-018566-23. NCT01208064] Eur. J. Canc. 51 2015 1511 1528 \n8 Spigel D.R. Burris H.A. 3rd Greco F.A. Erlotinib plus either pazopanib or placebo in patients with previously treated advanced non-small cell lung cancer: a randomized, placebo-controlled phase 2 trial with correlated serum proteomic signatures Cancer 124 2018 2355 2364 29645086 \n9 Sun J.M. Lee K.H. Kim B.S. Pazopanib maintenance after first-line etoposide and platinum chemotherapy in patients with extensive disease small-cell lung cancer: a multicentre, randomised, placebo-controlled Phase II study (KCSG-LU12-07) Br. J. Canc. 118 2018 648 653 \n10 Weiss J.M. Villaruz L.C. Socinski M.A. A single-arm phase II trial of pazopanib in patients with advanced non-small cell lung cancer with non-squamous histology with disease progression on bevacizumab containing therapy Lung Canc. 86 2014 288 290 \n11 Zhao H. Yang F. Shen W. Pazopanib diminishes non-small cell lung cancer [NSCLC] growth and metastases in vivo Thorac Cancer 6 2015 133 140 26273349 \n12 Tan Q. Wang W. Long Y. Chen G. Therapeutic effects and associated adverse events of multikinase inhibitors in metastatic renal cell carcinoma: a meta-analysis Exp Ther Med 9 2015 2275 2280 26136973 \n13 Çelik B. Sürücü Z.P. Yılmaz V. Çelik H.K. A case report of secondary simultaneous bilateral pneumothorax due to pazopanib treatment Turk Thorac J 19 2018 49 51 29404187 \n14 Leuzzi G. Alessandrini G. Ferraresi V. Ferretti G. Forcella D. Facciolo F. Bilateral spontaneous pneumothorax and massive pneumomediastinum under Pazopanib therapy Thorac Cancer 6 2015 110 111 26273345 \n15 Nakahara Y. Fukui T. Katono K. Pneumothorax during pazopanib treatment in patients with soft-tissue sarcoma: two case reports and a review of the literature Case Rep Oncol 10 2017 333 338 28559816 \n16 Nakano K. Motoi N. Tomomatsu J. Risk factors for pneumothorax in advanced and/or metastatic soft tissue sarcoma patients during pazopanib treatment: a single-institute analysis BMC Canc. 16 2016 750 \n17 Sabath B. Muhammad H.A. Balagani A. Secondary spontaneous pneumothorax in patients with sarcoma treated with Pazopanib, a case control study BMC Canc. 18 2018 937 \n18 Ide S. Sakamoto N. Hara S. Interstitial lung disease induced by pazopanib treatment Intern. Med. 56 2017 79 83 28050004 \n19 Cordier J.F. Cryptogenic organising pneumonia Eur. Respir. J. 28 2006 422 446 16880372 \n20 Purcell I.F. Bourke S.J. Marshall S.M. Cyclophosphamide in severe steroid-resistant bronchiolitis obliterans organizing pneumonia Respir. Med. 91 1997 175 177 9135858 \n21 Asai N. Yokoi T. Yamaguchi E. Kubo A. Successful crizotinib rechallenge after crizotinib-induced organizing pneumonia in anaplastic lymphoma kinase-rearranged non-small cell lung cancer Case Rep Oncol 7 2014 681 684 25408663 \n22 Lee H. Lee H.Y. Sun J.M. Transient asymptomatic pulmonary opacities during osimertinib treatment and its clinical implication J. Thorac. Oncol. 13 2018 1106 1112 29775809 \n23 Sano T. Uhara H. Mikoshiba Y. Nivolumab-induced organizing pneumonia in a melanoma patient Jpn. J. Clin. Oncol. 46 2016 270 272 26759348 \n24 Lacerda C. Lages J. Rolo R. Secondary organizing pneumonia mimicking pulmonary metastasis of a diffuse large cell lymphoma Arch. Bronconeumol. 54 2017 386\n\n",
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"keywords": "Adverse event; Drug-induced lung injury; Leiomyosarcoma; Multityrosine kinase inhibitor; Organizing pneumoniae; Pazopanib",
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"title": "Pazopanib-induced organizing pneumonia in a patient with leiomyosarcoma: A case report.",
"title_normalized": "pazopanib induced organizing pneumonia in a patient with leiomyosarcoma a case report"
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"abstract": "The use of synthetic cannabinoids (SCBs) is associated with many severe adverse effects that are not observed with marijuana use. We report a unique case of a patient who developed rhabdomyolysis and acute kidney injury (AKI) requiring dialysis after use of SCBs combined with quetiapine. Causes for the different adverse effects profile between SCBs and marijuana are not defined yet. Cases reported in literature with SCBs use have been associated with reversible AKI characterized by acute tubular necrosis and interstitial nephritis. Recent studies have showed the involvement of cytochromes P450s (CYPs) in biotransformation of SCBs. The use of quetiapine which is a substrate of the CYP3A4 and is excreted (73%) as urine metabolites may worsen the side effect profiles of both quetiapine and K2. SCBs use should be included in the differential diagnosis of AKI and serum Creatinine Phosphokinase (CPK) level should be monitored. Further research is needed to identify the mechanism of SCBs nephrotoxicity.",
"affiliations": "State University of New York Downstate Medical Center, 450 Clarkson Avenue, Brooklyn, NY 11203, USA.;State University of New York Downstate Medical Center, 450 Clarkson Avenue, Brooklyn, NY 11203, USA.;State University of New York Downstate Medical Center, 450 Clarkson Avenue, Brooklyn, NY 11203, USA.;State University of New York Downstate Medical Center, 450 Clarkson Avenue, Brooklyn, NY 11203, USA.;State University of New York Downstate Medical Center, 450 Clarkson Avenue, Brooklyn, NY 11203, USA.",
"authors": "Zhao|Aiyu|A|;Tan|Maybel|M|;Maung|Aung|A|;Salifu|Moro|M|;Mallappallil|Mary|M|",
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"doi": "10.1155/2015/235982",
"fulltext": "\n==== Front\nCase Rep NephrolCase Rep NephrolCRINCase Reports in Nephrology2090-66412090-665XHindawi Publishing Corporation 10.1155/2015/235982Case ReportRhabdomyolysis and Acute Kidney Injury Requiring Dialysis as a Result of Concomitant Use of Atypical Neuroleptics and Synthetic Cannabinoids Zhao Aiyu \n*\nTan Maybel Maung Aung Salifu Moro http://orcid.org/0000-0002-3693-8362Mallappallil Mary State University of New York Downstate Medical Center, 450 Clarkson Avenue, Brooklyn, NY 11203, USA*Aiyu Zhao: aiyuzhao@gmail.comAcademic Editor: Neil Boudville\n\n2015 13 10 2015 2015 2359828 6 2015 21 9 2015 29 9 2015 Copyright © 2015 Aiyu Zhao 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.The use of synthetic cannabinoids (SCBs) is associated with many severe adverse effects that are not observed with marijuana use. We report a unique case of a patient who developed rhabdomyolysis and acute kidney injury (AKI) requiring dialysis after use of SCBs combined with quetiapine. Causes for the different adverse effects profile between SCBs and marijuana are not defined yet. Cases reported in literature with SCBs use have been associated with reversible AKI characterized by acute tubular necrosis and interstitial nephritis. Recent studies have showed the involvement of cytochromes P450s (CYPs) in biotransformation of SCBs. The use of quetiapine which is a substrate of the CYP3A4 and is excreted (73%) as urine metabolites may worsen the side effect profiles of both quetiapine and K2. SCBs use should be included in the differential diagnosis of AKI and serum Creatinine Phosphokinase (CPK) level should be monitored. Further research is needed to identify the mechanism of SCBs nephrotoxicity.\n==== Body\n1. Introduction\nAKI is the abrupt loss of kidney function, resulting in the retention of urea and other nitrogenous waste products and in the dysregulation of volume and electrolytes [1]. Rhabdomyolysis is characterized by muscle necrosis and the leakage of muscle-cell contents like electrolytes, myoglobin, and sarcoplasmic proteins (CPK, aldolase, lactate dehydrogenase, alanine aminotransferase, and aspartate aminotransferase) into the circulation [2]. AKI is a complication of severe rhabdomyolysis and is seen in about 7–10% of all cases of AKI in the United States. The causes of rhabdomyolysis may be classified as traumatic, nontraumatic exertional, and nontraumatic nonexertional causes [2, 3].\n\nCannabis is the most commonly used illegal substance in the world [4]. It contains over 400 compounds, including more than 60 cannabinoids. The primary psychoactive cannabinoid is delta-9-tetrahydrocannabinol (THC) [5].\n\nSCBs have multiple brand names most commonly “Spice” or “K2” and many street names such as “Fake Pot” [5]. They are a heterogeneous group of compounds developed to probe the endogenous cannabinoid system (ECS) [4, 5]. SCBs can be divided into 7 major structural groups: naphthoylindoles (JWH-018 and JWH-073), naphthylmethylindoles, naphthoylpyrroles, naphthylmethylindenes, phenylacetylindoles (JWH-250), cyclohexylphenols (CP-47,497), and classical cannabinoids (HU-210). There are no structural similarities in SCBs with THC [5, 6].\n\nRecreational use of SCBs was noticed initially in the early 2000s in Europe. After European and Russian authorities banned SCBs in 2010, the K2 epidemic emerged in the United States [5]. Previously they were referred to as “legal highs” or “herbal highs”; these compounds are now classified as Class I controlled substances by the United States Drug Enforcement Administration [7]. Illicit use remains significant and reports of illness are increasing. In March 2012, 16 cases of AKI after SCBs use were reported in six states [8]. Four cases of oliguric AKI associated with use of SCBs were reported in 2013 [9]. However, rhabdomyolysis was not reported in the above cases. To our knowledge, there is only case report of rhabdomyolysis associated with SCB use in the USA [10].\n\nWe are reporting a unique case of a patient with history of Cannabis dependence and paranoid schizophrenia who developed severe rhabdomyolysis and AKI requiring dialysis after use of K2 combined with quetiapine.\n\n2. Case Presentation\nA 39-year-old African American man from a supervised living facility, with history of paranoid schizophrenia and Cannabis dependence, presented with generalized bodyache, back pain, and weakness. He had been smoking one joint of K2 daily purchased from the street for several years, with increased use in the one week prior to admission. The day prior to admission he took 10 tablets of quetiapine from his roommate with the intention of suicide. Subsequently he felt nauseated and vomited. He noticed that his urine “was darker.” He had a history of paranoid schizophrenia with many failed antipsychotic regimens. In the last 2 years, he had been receiving monthly intramuscular haloperidol decanoate 250 mg and the last injection was 3 weeks prior to admission. He denied history of trauma or injury and denied chest pain, shortness of breath or dizziness or other medications, and supplement or other illicit drugs' use. There was no similar episode in the past.\n\nOn examination, he was afebrile, initial blood pressure was 136/87 mmHg with pulse of 111 per minute, and respiratory rate was 18 per minute. There was no orthostatic hypotension. Oxygenation saturation was 100% in room air. He was lethargic but oriented to person, place, and date. His pupils were equal and reactive to light and measured about 3 mm in size. His lungs were clear to auscultation; heart rate was regular with no murmurs; abdomen was soft and there is no tenderness or organomegaly. There was 2+ pitting edema in bilateral lower extremities up to the knees; there was diffuse tenderness upon palpation. Foley catheter was inserted with 50 milliliters of tea color urine returned.\n\n\nTable 1 shows the daily laboratory values. His creatinine was 1 mg/dL (88.4 μmol/L) in November 2013. Urine microscopy showed muddy brown casts of acute tubular necrosis. Urine myoglobin was strongly positive. FeNa (the fractional excretion of sodium) was 1.8%. Urine toxicity screen for barbiturate, benzodiazepines, cocaine, methadone, and opiates was negative. Urine for cannabinoid was negative as expected with SCBs use. Alcohol and salicylate level was undetectable. HIV (the human immunodeficiency virus), HBV (hepatitis B virus), HCV (hepatitis C virus), EBV (Epstein-Barr virus), anti-DNase B, ANA (antinuclear antibody), P-ANCA (Perinuclear Anti-Neutrophil Cytoplasmic Antibodies), C-ANCA (Cytoplasmic Anti-Neutrophil Cytoplasmic Antibodies), and anti-glomerular basement membrane (anti-GBM) antibody were all negative; complements were within normal limits. ABG revealed pH of 7.29, PCO2 of 30.6 mmHg, PO2 of 178 mmHg, and bicarbonate of 16 mmol/L, which was consistent with high anion gap metabolic acidosis with respiratory compensation. High anion metabolic acidosis is likely due to AKI, as there was no evidence of lactic acidosis, ketoacidosis, toxic alcohol, acetaminophen, or salicylate ingestion.\n\nElectrocardiogram showed normal sinus rhythm with no PT prolongation. There was no hydronephrosis in renal sonogram.\n\nA diagnosis of AKI secondary to rhabdomyolysis and K2 use was made. His FeNa was more than 1 which is different from typical rhabdomyolysis-induced AKI when FeNa may frequently be less than 1%. The workup for AKI has been unrevealing except for positive urine myoglobin. The additional K2 nephrotoxicity might have explained this finding [11, 12]. The etiology of rhabdomyolysis was thought to be secondary to use of K2 combined with quetiapine. Neuroleptic malignant syndrome was in the differential diagnosis, however, thought to be less likely as the patient had never been febrile with no rigidity and no tremor or signs of autonomic dysfunction.\n\nHe was started on aggressive intravenous hydration with normal saline at 200 mL/hr. After 12 hours, no increase in urine output was noticed. The IV fluid rate increased to 500 mL/hour; he remained oliguric with persistent hyperkalemia. Hemodialysis was started on Day 3 of the hospitalization. He was dialyzed for 10 sessions. Urine output started to improve on Day 13 when his 24 hours' urine output was 900 mL. His last dialysis was on Day 14 of hospitalization after which creatinine and CK continued to decrease without dialysis. After 26 days of hospitalization he was discharged back to the supervised living facility; upon discharge, his creatinine was 2.25 mg/dL and CK was 299 IU/L.\n\nWith the resolution of oliguria in AKI which is the commonest marker for improvement in renal function, we noted a decrease in serum CPK and decrease in the number of muddy brown casts on sequential urine microscopy [11].\n\n3. Discussion\nUnlike many other “traditional” drugs of abuse, SCBs appear to have variable and unknown toxicities, including many not seen with marijuana use like tachycardia, hypertension, nausea, vomiting, convulsions, agitation, hallucinations, and psychosis [4, 5]. More recently, separate reports of rhabdomyolysis and kidney failure after SCBs use have been published [4, 5, 7–10, 13]. SCBs use has also been implicated in cases of acute myocardial infarction in three otherwise healthy teenagers. Dependence and withdrawal symptoms associated with chronic use have also been reported [6].\n\nSCBs interact with cannabinoid receptors (CBRs) and elicit cannabimimetic effects similar to THC [6, 14, 15]. The endogenous cannabinoid system (ECS) is widely dispersed through the body. To date, two endogenous cannabinoid receptors, CBR1 and CBR2, are well characterized [6, 14, 15]. CBR1 and CBR2 are G protein-coupled receptors (GPCRs). CBR1 is mainly expressed in the brain and mediates the CNS effects of THC and other cannabinoids. CBR1 also is expressed peripherally in adipocytes and skeletal muscle. Recent studies have showed that ECS affects skeletal muscle oxidation [6]. CBR2 is located primarily on the T cells, B cells, and macrophages and in hematopoietic cells and is involved in regulating immune function. In general, CBR2 activation is immunosuppressive, inhibits production of proinflammatory cytokines, enhances production of anti-inflammatory cytokines, induces apoptosis of immune cells, and suppresses macrophage chemotaxis. Activation of CBR2 is thought to underlie the anti-inflammatory and immunosuppressive effects of marijuana [6, 16].\n\nCauses for the different adverse effects profile between SCBs and marijuana are not defined yet. Four possible mechanisms are postulated [6]. The first two mechanisms are potential differences in pharmacodynamics. First, these effects are probably mediated by actions of SCBs at noncannabinoid receptors. Second, as most SCBs examined to date possess higher potency and efficacy than THC at CBRs it is possible that SCBs, especially taken in the various combinations found in SCB products, achieve levels of CBR1 and CBR2 activation high enough to produce severe, clinically observable physiological and psychological disturbances.\n\nThird, the active components of marijuana and SCBs are likely metabolized differently and thus have distinct pharmacokinetic profiles. Some active metabolites of SBCs likely contribute to the effects by activating CBRs. THC is metabolized by CYP2C9 to a predominant single biologically active metabolite, 11-hydroxy-D9-THC, which then inactivated carboxylation and glucuronidated prior to excretion. In contrast, several major metabolites of SCBs exhibit greater CBR1 affinity, potency, and efficacy than THC, both in vitro and in vivo. And these metabolites also retain in vitro pharmacological activity at CBR2s with greater potency.\n\nThe fourth mechanism is that drug-drug interactions, such as synergy, may increase risk of adverse effects as multiple drug use is common with SCBs abuse.\n\nAccording to a study by Ginsburg et al. in 2012, adverse effects following consumption of SCBs are unlikely due to impurities or residue from the manufacturing process [17]. However, different content of nonpsychoactive substances in the marijuana plant versus SCB products might play a role in the adverse symptoms.\n\nNeuroleptics can cause acute rhabdomyolysis as part of a neuroleptic malignant syndrome (NMS) or via direct toxic effect on myocytes. One suggested mechanism of rhabdomyolysis in the absence of NMS is an increase of skeletal muscle-cell membrane permeability [2, 3]. It is unknown whether rhabdomyolysis is dose or duration dependent when neuroleptics are involved [13]. There has been evidence that endocannabinoid has effect on the skeletal muscle oxidation [18]. But the complete endocannabinoid action on skeletal muscle metabolism is still to be elucidated. If both SCBs and quetiapine have effect on skeletal muscle, the combination of them might have made the injury more severe.\n\nSCB causing AKI is thought to be via acute tubular necrosis which does not present with rhabdomyolysis. Cases reported in literature with K2 use and AKI have been associated with reversible acute kidney injury characterized by acute tubular necrosis and interstitial nephritis [9]. THC is initially metabolized via oxidation by CYP2C9 and CYP3A4 [19, 20]. Recent in vitro metabolism studies, using recombinant CYPs, identified CYP2C9 and CYP1A2 as the primary hepatic P450 isoforms involved in the oxidation of JWH-018 [19, 21]. Other structural groups of SCBs might have involved CYP3A4. In this case the combination with quetiapine which is a substrates of the CYP3A4 system and which is excreted mostly (73%) in the urine as metabolites may worsen the side effect profiles of both quetiapine and K2.\n\n4. Conclusion\nComplete pharmacological knowledge of synthetic cannabinoids is lacking. The confirmation of SCBs use was hindered by lack of known biomarkers. It is important for the clinician to always take a thorough history and have a complete list of medications the patients are exposed to. SCBs use should be included in the differential diagnosis of AKI and CK level should be monitored. Further research is needed to identify the mechanism of SCBs nephrotoxicity.\n\nConflict of Interests\nThe authors declare that there is no conflict of interests regarding the publication of this paper.\n\nTable 1 Daily laboratory values.\n\n \tCK (IU/L)\tPotassium (mmol/L)\tBUN (mg/dL)\tCreatinine (mg/dL)\tAST (IU/L)\tALT (IU/L)\tUrine output (mL)\tNote\t\nDay 1\t>22,000\t6.9\t68\t6.09\t3167\t964\t 10\tIVF\t\nDay 2\t148,643\t6.5\t83\t7.56\t2307\t724\t 20\tIVF\t\nDay 3\t>22,000\t6.8\t92\t9.39\t1520\t597\t 0\tHD\t\nDay 4\t81,620\t5.2\t84\t9.15\t973\t530\t 0\tHD\t\nDay 5\t>22,000\t5.6\t87\t9.69\t610\t442\t 0\tHD\t\nDay 6\t51,030\t4.8\t75\t8.36\t523\t406\t 0\tHD\t\nDay 7\t28,060\t4.9\t76\t8.77\t315\t331\t 0\tHD\t\nDay 8\t16,339\t4.4\t62\t7.79\t222\t237\t 50\tNo HD\t\nDay 9\t10,701\t5\t75\t9.7\t188\t218\t100\tHD\t\nDay 10\t6242\t4.4\t63\t8.87\t128\t200\t150\tHD\t\nDay 11\t4230\t4.8\t58\t8.75\t91\t161\t200\tHD\t\nDay 12\t2719\t4.9\t58\t8.61\t65\t123\t300\tNo HD\t\nDay 13\t2199\t4.6\t64\t9.38\t57\t112\t900\tHD\t\nDay 14\t1835\t4.4\t57\t8.69\t51\t109\t 1200\tHD\t\n CK: Creatine Kinase, BUN: Blood Urea Nitrogen, AST: Aspartate Transaminase, and ALT: Alanine Transaminase.\n==== Refs\n1 Mehta R. L. Chertow G. M. Acute renal failure definitions and classification: time for change? Journal of the American Society of Nephrology 2003 14 8 2178 2187 10.1097/01.asn.0000079042.13465.1a 2-s2.0-0042844692 12874474 \n2 Bosch X. Poch E. Grau J. M. Rhabdomyolysis and acute kidney injury The New England Journal of Medicine 2009 361 1 62 72 10.1056/nejmra0801327 2-s2.0-67649644926 19571284 \n3 Vanholder R. Sever M. S. Erek E. Lameire N. Rhabdomyolysis Journal of the American Society of Nephrology 2000 11 8 1553 1561 2-s2.0-0033928804 10906171 \n4 Leggett T. A review of the world cannabis situation Bulletin on Narcotics 2006 58 1-2 1 155 19066071 \n5 Lindsay L. White M. L. Herbal marijuana alternatives and bath salts—‘barely legal’ toxic highs Clinical Pediatric Emergency Medicine 2012 13 4 283 291 10.1016/j.cpem.2012.09.001 2-s2.0-84874480616 \n6 Brents L. K. Prather P. L. The K2/Spice phenomenon: emergence, identification, legislation and metabolic characterization of synthetic cannabinoids in herbal incense products Drug Metabolism Reviews 2014 46 1 72 85 10.3109/03602532.2013.839700 2-s2.0-84893220502 24063277 \n7 US Drug Enforcement Administration Chemicals used in ‘Spice’ and ‘K2’ type products now under federal control and regulation 2011, http://www.dea.gov/pubs/pressrel/pr030111.html \n8 Centers for Disease Control and Prevention (CDC) Acute kidney injury associated with synthetic cannabinoid use—multiple states, 2012 Morbidity and Mortality Weekly Report 2013 62 6 93 98 23407124 \n9 Bhanushali G. K. Jain G. Fatima H. Leisch L. J. Thornley-Brown D. AKI associated with synthetic cannabinoids: a case series Clinical Journal of the American Society of Nephrology 2013 8 4 523 526 10.2215/cjn.05690612 2-s2.0-84876061412 23243266 \n10 Durand D. Delgado L. L. de la Parra-Pellot D. M. Nichols-Vinueza D. Psychosis and severe rhabdomyolysis associated with synthetic cannabinoid use Clinical Schizophrenia & Related Psychoses 2015 8 4 205 208 10.3371/csrp.dude.031513 2-s2.0-84921646747 23518784 \n11 Mallappallil M. C. Mehta R. Yoshiuchi E. Briefel G. Lerma E. Salifu M. Parameters used to discontinue dialysis in acute kidney injury recovery: a survey of United States Nephrologists Nephron 2015 130 1 41 47 10.1159/000381924 25999063 \n12 Corwin H. L. Schreiber M. J. Fang L. S. T. Low fractional excretion of sodium. Occurrence with hemoglobinuric- and myoglobinuric-induced acute renal failure Archives of Internal Medicine 1984 144 5 981 982 10.1001/archinte.144.5.981 2-s2.0-0021361931 6712414 \n13 Aggarwal R. Guanci N. Marambage K. Caplan J. P. A patient with multiple episodes of rhabdomyolysis induced by different neuroleptics Psychosomatics 2014 55 4 404 408 10.1016/j.psym.2013.05.003 2-s2.0-84903730150 24016383 \n14 Castaneto M. S. Gorelick D. A. Desrosiers N. A. Hartman R. L. Pirard S. Huestis M. A. Synthetic cannabinoids: epidemiology, pharmacodynamics, and clinical implications Drug and Alcohol Dependence 2014 144 12 41 10.1016/j.drugalcdep.2014.08.005 2-s2.0-84908879029 25220897 \n15 Harris C. R. Brown A. Synthetic cannabinoid intoxication: a case series and review The Journal of Emergency Medicine 2013 44 2 360 366 10.1016/j.jemermed.2012.07.061 2-s2.0-84873157996 22989695 \n16 Steffens S. Pacher P. Targeting cannabinoid receptor CB2 in cardiovascular disorders: promises and controversies British Journal of Pharmacology 2012 167 2 313 323 10.1111/j.1476-5381.2012.02042.x 2-s2.0-84865418404 22612332 \n17 Ginsburg B. C. McMahon L. R. Sanchez J. J. Javors M. A. Purity of synthetic cannabinoids sold online for recreational use Journal of Analytical Toxicology 2012 36 1 66 68 bkr018 10.1093/jat/bkr018 2-s2.0-84862254143 22290755 \n18 Cavuoto P. McAinch A. J. Hatzinikolas G. Cameron-Smith D. Wittert G. A. Effects of cannabinoid receptors on skeletal muscle oxidative pathways Molecular and Cellular Endocrinology 2007 267 1-2 63 69 10.1016/j.mce.2006.12.038 2-s2.0-33847306530 17270342 \n19 Fantegrossi W. E. Moran J. H. Radominska-Pandya A. Prather P. L. Distinct pharmacology and metabolism of K2 synthetic cannabinoids compared to Δ9 -THC: mechanism underlying greater toxicity? Life Sciences 2014 97 1 45 54 10.1016/j.lfs.2013.09.017 2-s2.0-84894041500 24084047 \n20 Watanabe K. Yamaori S. Funahashi T. Kimura T. Yamamoto I. Cytochrome P450 enzymes involved in the metabolism of tetrahydrocannabinols and cannabinol by human hepatic microsomes Life Sciences 2007 80 15 1415 1419 10.1016/j.lfs.2006.12.032 2-s2.0-33847633815 17303175 \n21 Chimalakonda K. C. Seely K. A. Bratton S. M. Cytochrome P450-mediated oxidative metabolism of abused synthetic cannabinoids found in K2/Spice: identification of novel cannabinoid receptor ligands Drug Metabolism and Disposition 2012 40 11 2174 2184 10.1124/dmd.112.047530 2-s2.0-84867684839 22904561\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2090-665X",
"issue": "2015()",
"journal": "Case reports in nephrology",
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"medline_ta": "Case Rep Nephrol",
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"nlm_unique_id": "101598418",
"other_id": null,
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"pmid": "26550500",
"pubdate": "2015",
"publication_types": "D016428:Journal Article",
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"title": "Rhabdomyolysis and Acute Kidney Injury Requiring Dialysis as a Result of Concomitant Use of Atypical Neuroleptics and Synthetic Cannabinoids.",
"title_normalized": "rhabdomyolysis and acute kidney injury requiring dialysis as a result of concomitant use of atypical neuroleptics and synthetic cannabinoids"
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"companynumb": "US-ALKEM-001347",
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"activesubstancename": "QUETIAPINE FUMARATE"
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"abstract": "Sodium-glucose cotransporter 2 (SLGT2) inhibitors has been associated with an increased risk of genital infections secondary to increased glycosuria.\n\n\n\nWe report a case of a 41-year-old man with type 2 diabetes treated with empagliflozin and metformin who presented with scrotal swelling. He described multiple preceding episodes of genital thrush for which he self-administered over-the-counter anti-fungal treatment. On examination, he was afebrile and hemodynamically stable. Perineal examination revealed grossly swollen and indurated scrotum with bilateral inguinal lymphadenopathy. Investigations showed elevated inflammatory markers and HbA1c of 99 mmol/mol (11.2%). Computed tomography revealed features consistent with Fournier's gangrene. He underwent emergency exploration and debridement under anaesthetic with a later return to theatre for further exploration, washout and application of a vacuum dressing. He then received a split skin graft to his perineum. He required a 2-week course of intravenous antibiotics and was discharged home on oral antibiotics. Empagliflozin was ceased on admission and he was commenced on a basal bolus insulin regimen for glycaemic optimisation.\n\n\n\nThere is a wide clinical spectrum of genital infections associated with SGLT2 inhibitors with most being generally mild and easily treated. However, risk factors such as diabetes, obesity, immunosuppressed states, smoking, alcohol abuse and end-stage renal or liver failure may increase the risk of potentially more severe infections such as Fournier's gangrene. Timely cessation of SGLT2 inhibitors in individuals with multiple risk factors may help prevent progression to more severe genital infections.",
"affiliations": "Department of Diabetes and Endocrinology, Royal Melbourne Hospital, Parkville, VIC, Australia.;Department of Urology, Royal Melbourne Hospital, Parkville, VIC, Australia.;Department of Diabetes and Endocrinology, Royal Melbourne Hospital, Parkville, VIC, Australia.",
"authors": "Kumar|S|S|0000-0001-9134-3671;Costello|A J|AJ|;Colman|P G|PG|",
"chemical_list": "D001559:Benzhydryl Compounds; D005960:Glucosides; D007328:Insulin; D008687:Metformin; C570240:empagliflozin",
"country": "England",
"delete": false,
"doi": "10.1111/dme.13508",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0742-3071",
"issue": "34(11)",
"journal": "Diabetic medicine : a journal of the British Diabetic Association",
"keywords": null,
"medline_ta": "Diabet Med",
"mesh_terms": "D000328:Adult; D001559:Benzhydryl Compounds; D003924:Diabetes Mellitus, Type 2; D057915:Drug Substitution; D004359:Drug Therapy, Combination; D018934:Fournier Gangrene; D005832:Genital Diseases, Male; D005960:Glucosides; D006801:Humans; D007328:Insulin; D008297:Male; D008687:Metformin; D012611:Scrotum",
"nlm_unique_id": "8500858",
"other_id": null,
"pages": "1646-1648",
"pmc": null,
"pmid": "28887847",
"pubdate": "2017-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Fournier's gangrene in a man on empagliflozin for treatment of Type 2 diabetes.",
"title_normalized": "fournier s gangrene in a man on empagliflozin for treatment of type 2 diabetes"
} | [
{
"companynumb": "AU-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2017-BI-050284",
"fulfillexpeditecriteria": "1",
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"patient": {
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"actiondrug": null,
"activesubstance": {
"activesubstancename": "METFORMIN HYDROCHLORIDE"
... |
{
"abstract": "Ovarian hyperstimulation syndrome (OHSS) is a feared complication of controlled ovarian stimulation (COS) and can be associated with significant morbidity and mortality. Risk factors for OHSS include a history of OHSS, young age, low body mass index (BMI), polycystic ovary syndrome, elevated serum levels of anti-Müllerian hormone (AMH), large number of recruited follicles, elevated serum levels of estradiol, and higher gonadotropin doses during COS. However, OHSS may develop in patients with minimal risk factors. We present the case of a patient with minimal risk factors who developed severe late-onset OHSS in early pregnancy with liver dysfunction requiring hospitalization. After hospital discharge, her pregnancy resulted in a term live birth. We recommend that clinicians include OHSS in the differential diagnosis of elevated levels of liver enzymes in early pregnancy.",
"affiliations": "Department of Obstetrics and Gynecology, Texas A&M College of Medicine, Baylor Scott & White Health, 2401 South 31 St, Temple, TX, USA.;Division of Reproductive Endocrinology, Infertility, and Genetics, Department of Obstetrics and Gynecology, Medical College of Georgia at Augusta University, 1120 5 St, Augusta, GA, USA.;Central Georgia Fertility at Navicent Health, 777 Hemlock Street, Macon, GA, USA.;Division of Reproductive Endocrinology, Infertility, and Genetics, Department of Obstetrics and Gynecology, Medical College of Georgia at Augusta University, 1120 5 St, Augusta, GA, USA.",
"authors": "Chae-Kim|Jennifer J|JJ|;Roman|Robert|R|;Hawkins|Kristina|K|;Gavrilova-Jordan|Larisa|L|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.crwh.2021.e00332",
"fulltext": "\n==== Front\nCase Rep Womens Health\nCase Rep Womens Health\nCase Reports in Women's Health\n2214-9112\nElsevier\n\nS2214-9112(21)00050-3\n10.1016/j.crwh.2021.e00332\ne00332\nArticle\nSevere late-onset ovarian hyperstimulation syndrome presenting with liver dysfunction after in vitro fertilization: A case report\nChae-Kim Jennifer J. jennifer.chaekim@bswhealth.org\na⁎\nRoman Robert rroman@augusta.edu\nb\nHawkins Kristina c\nGavrilova-Jordan Larisa lgavrilovajordan@augusta.edu\nb\na Department of Obstetrics and Gynecology, Texas A&M College of Medicine, Baylor Scott & White Health, 2401 South 31st St, Temple, TX, USA\nb Division of Reproductive Endocrinology, Infertility, and Genetics, Department of Obstetrics and Gynecology, Medical College of Georgia at Augusta University, 1120 5th St, Augusta, GA, USA\nc Central Georgia Fertility at Navicent Health, 777 Hemlock Street, Macon, GA, USA\n⁎ Corresponding author. jennifer.chaekim@bswhealth.org\n04 6 2021\n7 2021\n04 6 2021\n31 e0033226 5 2021\n28 5 2021\n1 6 2021\n© 2021 Published by Elsevier B.V.\n2021\n\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).\nOvarian hyperstimulation syndrome (OHSS) is a feared complication of controlled ovarian stimulation (COS) and can be associated with significant morbidity and mortality. Risk factors for OHSS include a history of OHSS, young age, low body mass index (BMI), polycystic ovary syndrome, elevated serum levels of anti-Müllerian hormone (AMH), large number of recruited follicles, elevated serum levels of estradiol, and higher gonadotropin doses during COS. However, OHSS may develop in patients with minimal risk factors. We present the case of a patient with minimal risk factors who developed severe late-onset OHSS in early pregnancy with liver dysfunction requiring hospitalization. After hospital discharge, her pregnancy resulted in a term live birth. We recommend that clinicians include OHSS in the differential diagnosis of elevated levels of liver enzymes in early pregnancy.\n\nHighlights\n\n• Ovarian hyperstimulation syndrome is a feared complication of controlled ovarian stimulation.\n\n• Transaminitis can be seen in moderate to severe ovarian hyperstimulation syndrome.\n\n• Ovarian hyperstimulation syndrome should be considered in the differential diagnosis of transaminitis in early pregnancy.\n\nKeywords\n\nOvarian hyperstimulation syndrome\nTransaminitis\nLiver dysfunction\nEarly pregnancy\nCase report\n==== Body\n1 Introduction\n\nOvarian hyperstimulation syndrome (OHSS) is a complication of controlled ovarian stimulation (COS) and can be associated with significant morbidity and mortality. [1] The pathophysiology of OHSS is not fully understood, but it involves increased capillary permeability and extravasation of fluid from intravascular spaces to the third space. [2] This is thought to be mediated by multiple vasoactive substances, including vascular endothelial growth factor (VEGF), which acts on VEGFR-2 receptors – found on vasculature as well as luteinized granulosa cells – to induce capillary permeability. While OHSS is primarily mediated by VEGF, other pro-inflammatory markers have been implicated, such as interleukin-6 (IL-6), insulin-like growth factor-1 (IGF-1), and transforming growth factor-β (TGF- β). [1]\n\nOHSS is classified as mild, moderate, severe, or critical, based on the clinical presentation. Mild OHSS can present with abdominal distension, nausea, vomiting, or diarrhea. Moderate, severe, and critical OHSS can result in symptomatic ascites, hydrothorax, oliguria or anuria, renal failure, liver dysfunction with transaminitis, thromboembolism, adult respiratory distress syndrome, and sepsis.[1]–[3] OHSS can also be defined as “early” or “late,” based on the onset of symptoms after administration of human chorionic gonadotropin (hCG). Early OHSS presents 3–7 days after exogenous hCG administration, with hCG potentiating VEGF to induce OHSS. Late OHSS presents about 12–17 days after the initial hCG administration, and commonly represents the rising endogenous hCG from early pregnancy. [4]\n\nReproductive endocrinologists are vigilant and risk-stratify patients to determine which patients are at high risk of OHSS. Common risk factors for OHSS include: polycystic ovary syndrome (PCOS), serum estradiol (E2) levels above 3500 pg/mL, development of ≥25 follicles during COS, retrieval of ≥24 oocytes, anti-Müllerian hormone (AMH) > 3.4 ng/mL, history of OHSS in previous COS cycle, use of ovulatory doses of hCG, and higher doses of gonadotropins, although a specific dosage threshold has not been identified. [1,5] Young age and lower body mass index (BMI) have been associated with OHSS, although the predictive value of these characteristics is unclear. The likelihood and severity of OHSS also increase in the setting of early pregnancy, as rising hCG levels from the placenta exacerbate ovarian stimulation and VEGF production. Late-onset OHSS appears more likely with multiple gestations. [6]\n\nUnder the CARE guidelines, we present a case of severe late-onset OHSS in a patient with minimal risk factors, to highlight the importance of considering OHSS in the differential diagnosis of liver dysfunction in early pregnancy. The patient provided consent for this report.\n\n2 Case Presentation\n\nA 34-year-old nulliparous woman presented to an academic reproductive endocrinology and infertility clinic for evaluation of infertility. Her history was significant for hypothyroidism, obesity (BMI 32 kg/m2) and male factor infertility secondary to hypogonadotropic hypogonadism. Her AMH was 5.2 ng/mL. She underwent COS with GnRH antagonist protocol with ganirelix acetate (Ganirelix ®), follitropin alfa (Gondal-F ®), and menotropin (Menopur ®). Her total gonadotropin dose was 2875 IU throughout stimulation. Transvaginal ultrasound (TVUS) on cycle day 9 showed 10 antral follicles on both ovaries, with the largest follicles measuring 20 mm on the left ovary and 21 mm on the right ovary. Serum E2 and endometrial thickness were documented throughout stimulation, as shown in Table 1. Subcutaneous hCG was administered on stimulation cycle day 9 and the patient underwent transvaginal ultrasound-guided oocyte retrieval 36 h later. Fourteen oocytes were retrieved. The patient underwent fresh elective single blastocyst transfer (Gardner grade 4AA). Eight blastocysts were cryopreserved.Table 1 Summary of estradiol (E2) and endometrial thickness (ET) during COS.\n\nTable 1Stimulation day\tE2 (pg/ml)\tET (mm)\t\n5\t700\t8.1\t\n7\t1895\t10.2\t\n9\t2772\t9.5\t\n\nTen days after embryo transfer, the patient presented to the office with abdominal fullness and nausea, with ascites seen on ultrasound. Initial laboratory workup revealed β-hCG 181 mIU/mL, transaminitis with aspartate transaminase (AST) 92 U/L, alanine aminotransferase (ALT) 131 U/L, as well as moderate-severe hyponatremia. [7] Other causes of acute transaminitis, including hepatitis, were excluded. Based on her clinical presentation and laboratory findings, she was admitted for inpatient management of late-onset OHSS. Management included strict volume management with intravenous fluids and albumin. The patient's liver function tests peaked at the following levels: AST 112 U/L 14 days after embryo transfer (hospital day 5), and ALT 246 U/L 16 days after embryo transfer (hospital day 7). Serial liver function tests and sodium levels during admission are presented in Fig. 1, Fig. 2. The patient improved and was discharged on hospital day 11 after resolution of transaminitis and hyponatremia. The remainder of her pregnancy was uneventful, and resulted in a term live birth. The timeline of events is set out in Fig. 3.Fig. 3 Timeline of events.\n\nFig. 3\n\nFig. 1 AST and ALT derangements during hospital days 1–11. AST: aspartate aminotransferase; ALT: alanine aminotransferase.This description should go with Figure 1 (above)\n\nFig. 1\n\nFig. 2 Serum sodium (Na+) levels from hospital day 1–11.\n\nFig. 2\n\n3 Discussion\n\nOHSS is an uncommon but serious iatrogenic complication of COS, with moderate to severe forms of OHSS occurring in about 1–5% of COS cycles. [1] Although the pathophysiology is undefined, the fluid shifts seen in OHSS are thought to be secondary to inflammatory mediators, primarily VEGF. Research also suggests dysregulation of the renin-angiotensin system, leading to elevated levels of antidiuretic hormone (ADH) and hyponatremia, which was seen in our case. [8] Patients with OHSS develop clinical signs of ascites and hypovolemia, leading to decreased end-organ perfusion, and they can present with liver dysfunction.\n\nThe mechanism of liver dysfunction in OHSS remains unclear but may be secondary to increased vascular permeability in hepatocellular cells leading to hepatic edema, or microvascular thromboses leading to end-organ ischemia. [6] Hepatic damage from increased E2 has also been proposed, [9,10] although one report did not find a correlation between E2 levels and liver function test derangements. [11] Liver biopsies of OHSS patients have shown focal distribution of fatty change in the periphery of hepatic lobules (acinar zone 1), and structural changes suggestive of an estrogen effect. [12,13] Another study, however, reported relatively normal histology despite lab values indicating liver dysfunction. [10] The timeframe and duration for which laboratory evidence of liver dysfunction may be expected are also unclear. Serum aminotransferase levels, measured by AST and ALT, are commonly used lab measurements of liver function. However, ALT is a more specific marker for liver tissue injury. In our case, while AST and ALT were both elevated, the patient had higher elevations in ALT. Based on a review of the literature, liver enzyme derangements do tend to resolve with resolution of OHSS. [[11], [12], [13], [14]]\n\nTransaminitis in OHSS was first reported in a 1988 case report, in which the patient received hCG luteal phase support after COS. [3] More recent reports have demonstrated severe OHSS with transaminitis, among other derangements, after COS in high-risk patients. [14,15] There is evidence that certain measures can reduce the risk of OHSS, including the use of GnRH antagonists COS cycles, GnRH agonist trigger, dopamine agonist administration at the time of hCG administration, freeze-all cycle, or metformin for PCOS patients. [1] However, these measures do not prevent OHSS, so clinicians should include OHSS in the differential diagnoses of elevated LFTs in early pregnancy.\n\nDuring pregnancy, serum aminotransferases remain within normal limits. In the evaluation of a pregnant patient with transaminitis, the differential diagnosis is dependent on the gestational age. In the first trimester, the differential diagnosis includes OHSS, hyperemesis gravidarum, molar pregnancy, gallbladder/biliary tract disease, liver disease, viral or autoimmune hepatitis, drug-induced hepatitis, or thrombotic etiology. OHSS evaluation requires a detailed history and physical exam, laboratory evaluation (including complete blood count, complete metabolic panel, and possible coagulation studies), and transvaginal ultrasound to assess the severity of disease. Hyperemesis gravidarum (HG) is characterized by severe nausea/vomiting, weight loss, and/or electrolyte abnormalities in pregnancy. While not diagnostic, HG can present in the first trimester with transaminitis. Similar to OHSS, there is a higher ALT/AST ratio, and elevated transaminases often resolve with hydration and improvement of nausea/vomiting. Patients with HG do not exhibit signs of third spacing such as pulmonary edema or abdominal ascites, which can help distinguish it from OHSS in early pregnancy. A patient with molar pregnancy can present with vaginal bleeding in early pregnancy, nausea/vomiting, transaminitis, as well as hyperthyroid symptoms. On exam, uterine size may be significantly greater than gestational age, and grape-like cysts may be seen protruding from the vagina. Gallbladder disease, drug-induced, alcohol-induced, or viral hepatitis can present in any trimester. Workup may include metabolic profile, right upper quadrant abdominal ultrasound, and testing for viral hepatitis. Autoimmune hepatitis should also be considered. Venous thromboembolic events, which pregnant women are at increased risk of due to the hypercoagulable state of pregnancy, may also involve the liver, as seen in Budd-Chiari syndrome.\n\nIn the second or third trimesters, elevated liver enzymes may be seen in cholestasis of pregnancy; patients classically endorse pruritus in the absence of a rash. Evaluation should include bile acids and testing for viral hepatitis. Beyond 20 weeks of gestation, pregnancy-induced hypertensive disorders such as pre-eclampsia with severe features or HELLP syndrome must be ruled out in new-onset transaminitis. The differential diagnoses for elevated liver enzymes in pregnancy are listed in Table 2.Table 2 Differential diagnosis of elevated transaminases in pregnancy.\n\nTable 2Diagnosis\tPregnancy trimester\tPresentation\tEvaluation\tNotes\t\nOvarian hyperstimulation syndrome⁎\t1st\tAbdominal distention or bloating, nausea, vomiting, diarrhea, chest pain, orthopnea, oliguria/anuria, lower extremity swelling\tImaging: TVUS, CXR, LE dopplers\nLabs: CBC, CMP, UA, PT/INR, PTT\tSuspect in patient with history of OI (rare), COS, or IVF\t\nHyperemesis gravidarum⁎\t1st\tNausea, vomiting, weight loss, hyperthyroid symptoms\tLabs: UA, CMP, amylase, lipase, TSH, free T4, T3\tPossible complication: Wernicke's encephalopathy\t\nMolar pregnancy⁎\t1st\tVaginal bleeding, grape-like cysts on exam, nausea, vomiting, enlarged uterus (size greater than dates), hyperthyroid symptoms\tLabs: quant b-hCG, CBC, CMP, TSH, free T4, T3, PT/INR, PTT\nImaging: TVUS, CXR\tPossible complication: gestational trophoblastic neoplasia\t\nGallbladder, biliary tract, or liver disease\tAny\tRUQ abdominal pain, fever, nausea, vomiting, jaundice, dark urine, clay-colored stools\tLabs: CBC, CMP, amylase, lipase\n\nImaging: RUQ U/S, CT,§ hepatobiliary scintigraphy, MRCP/ERCP\tPossible complications: pancreatitis, peritonitis, sepsis\t\nDrug-induced hepatitis\tAny\tAbdominal pain, jaundice, fatigue\tLabs: CMP, PT/INR, PTT, blood alcohol test, drug screen, acetaminophen level\nImaging: RUQ U/S\tMay consider liver biopsy for diagnosis\t\nInfectious hepatitis (viral)†\tAny\tFever, fatigue, loss of appetite, abdominal pain, jaundice, dark urine, clay-colored stools\tHepatitis panel (most commonly hepatitis A, B, C)\tTransmission routes: hepatitis A (oral-fecal); B and C (bodily fluids)\t\nAutoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis\tAny\tFatigue, abdominal pain, jaundice, enlarged liver, loss of appetite, spider angiomas\tLabs: CMP, AMA, ANA, SMA IgG, hepatitis panel\n\nImaging: RUQ U/S, cholangiogram, MRCP/ERCP\tMay consider liver biopsy for diagnosis. If untreated, may lead to cirrhosis and liver failure\t\nThrombotic event (Budd-Chiari syndrome, portal vein thrombosis)\tAny\tRUQ abdominal pain, jaundice, enlarged liver, ascites, abdominal distention\tLabs: CMP, PT/INR, PTT\n\nImaging: RUQ U/S, CT angiography,§ MRA\tPossible complications: liver cirrhosis, hepatic encephalopathy\t\nIntrahepatic cholestasis of pregnancy⁎\t2nd, 3rd\tPruritus, absence of rash\tLabs: Bile acids, hepatitis screening\tPossible complication: intrauterine fetal demise\t\nPre-eclampsia⁎\t2nd, 3rd\tChest pain, shortness of breath, headache, visual disturbances, third spacing\tLabs: P/C ratio, 24 h UPT, CBC, CMP, LDH\n\nImaging: CXR\tMay evolve to eclampsia\t\nHELLP syndrome⁎\t2nd, 3rd\tGeneral malaise, RUQ pain, nausea, vomiting\tLabs: CBC, CMP, LDH\n\nImaging: RUQ U/S, CXR\tPossible complications: hepatic rupture\t\nAcute fatty liver of pregnancy⁎\t2nd, 3rd\tNausea, vomiting, abdominal pain, jaundice\tLabs: CBC, CMP, LDH, PT/INR, PTT\n\nImaging: RUQ U/S\tPossible complications: hepatic encephalopathy, pancreatitis\t\n⁎ Occurs only in pregnancy or assisted reproduction.\n\n† Consider parasitic and fungal infections.\n\n§ Consider CT as second-line imaging modality if diagnosis uncertain after ultrasound, and after counseling patient regarding risks of radiation exposure in pregnancy.\n\nIn conclusion, this case report highlights the importance of considering OHSS in the differential diagnosis of liver dysfunction in early pregnancy, particularly in the context of assisted reproduction. Further studies examining the long-term outcomes of patients who develop OHSS are warranted.\n\nTable 2 abbreviations (in alphabetical order): AMA: Anti-mitochondrial antibody; ANA: Anti-nuclear antibody; b-hCG: beta human chorionic gonadotropin; CBC: complete blood count; CMP: complete metabolic profile; COS: controlled ovarian stimulation; CT: computed tomography scan; CXR: chest x-ray; ERCP: endoscopic retrograde cholangiopancreatography; LDH: lactate dehydrogenase; LE dopplers: lower extremity dopplers; IgG: immunoglobulin G antibodies; IVF: in vitro fertilization; MRCP: magnetic resonance cholangiopancreatography; MRA: magnetic resonance angiography; OI: ovulation induction; P/C ratio: protein to creatinine ratio; PT/INR: prothrombin time and international normalized ratio; PTT: partial thromboplastin time; RUQ: right upper quadrant; SMA: Smooth muscle antibody; TSH: thyroid stimulating hormone; TVUS: transvaginal ultrasound; UA: urinalysis; UPT: urine protein test.\n\nContributors\n\nJennifer J. Chae-Kim, the primary author, was involved in drafting the initial manuscript, editing the manuscript, and approved the final submission.\n\nRobert Roman was involved in drafting the initial manuscript, revising the manuscript, and approved the final submission.\n\nKristina Hawkins was the attending physician involved in patient care, revised the manuscript and approved the final submission.\n\nLarisa Gavrilova-Jordan was the attending physician involved in patient care, revised the manuscript and approved the final submission.\n\nConflict of interest\n\nThe authors declare that they have no conflict of interest regarding the publication of this case report.\n\nFunding\n\nNo funding from an external source supported the publication of this case report.\n\nPatient consent\n\nObtained.\n\nProvenance and peer review\n\nThis case report was peer reviewed.\n\nAcknowledgements\n\nThe authors would like to thank the patient and healthcare team who provided care during her hospitalization.\n==== Refs\nReferences\n\n1 Pfeifer S. Prevention and treatment of moderate and severe ovarian hyperstimulation syndrome: a guideline Fertil. Steril. 106 7 2016 1634 1647 27678032\n2 Fritz M.S. Clinical Gynecologic Endocrinology and Infertility 2010\n3 Younis J. Zeevi D. Rabinowitz R. Laufer N. Schenker J. Transient liver function test abnormalities in ovarian hyperstimulation syndrome Fertil. Steril. 1988 50(1)\n4 Mathur R.S. Akande A.V. Keay S. Hunt L. Jenkins J. Distinction between early and late ovarian hyperstimulation syndrome Fertil. Steril. 73 5 2000 901 907 10785214\n5 Lee T.H. Serum anti-mullerian hormone and estradiol levels as predictors of ovarian hyperstimulation syndrome in assisted reproduction technology cycles Hum. Reprod. 23 1 2007 160 167 18000172\n6 Delvigne A. Review of clinical course and treatment of ovarian hyperstimulation syndrome (OHSS) Hum. Reprod. Update 9 1 2003 77 96 12638783\n7 Tran T.T. Ahn J. Reau N.S. ACG clinical guideline: liver disease and pregnancy Am. J. Gastroenterol. 111 2 2016 176 194 26832651\n8 Bili H. New insights of osmoregulatory system changes in ovarian hyperstimulation syndrome Fertil. Steril. 95 1 2011 304 306 20850728\n9 Balasch J. Carmona F. Llach J. Arroyo V. Jove I. Vanrell J. Acute prerenal failure and liver dysfunction in a patient with severe ovarian hyperstimulation syndrome Hum. Reprod. 5 3 1990 348 351 2112558\n10 Sueldo C.E. Price H.M. Bachenberg K. Steinleitner A. Gitlin N. Swanson J. Liver dysfunction in ovarian hyperstimulation syndrome. A case report J. Reprod. Med. 33 4 1988 387 390 3130483\n11 Wakim A.F.S. Elevated liver function tests in a case of moderate ovarian hyperstimulation syndrome Hum. Reprod. 11 3 1996 588 589 8671272\n12 Obrzut B.K. Kuczynski W. Grygoruk C. Putowski L. Kluz S. Skret A. Liver dysfunction in severe ovarian hyperstimulation syndrome Gynecol. Endocrinol. 21 1 2005 45 49 16048801\n13 Ryley N. Forman R. Barlow D. Fleming K. Trowell J. Liver abnormality in ovarian hyperstimulation syndrome Hum. Reprod. 5 8 1990 938 943 1982004\n14 Singh N. Severe early-onset ovarian hyperstimulation syndrome with liver dysfunction in an IVF segmentation cycle BMJ Case Rep. 13 1 2020 e233379\n15 Kasaven L.S. Goumenou A. Adegoke K. Multiorgan failure associated with severe ovarian hyperstimulation syndrome due to inadequate protocol optimisation: a rare but avoidable complication BMJ Case Rep. 2018 1 3 p. bcr-2017-223418\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2214-9112",
"issue": "31()",
"journal": "Case reports in women's health",
"keywords": "Case report; Early pregnancy; Liver dysfunction; Ovarian hyperstimulation syndrome; Transaminitis",
"medline_ta": "Case Rep Womens Health",
"mesh_terms": null,
"nlm_unique_id": "101682122",
"other_id": null,
"pages": "e00332",
"pmc": null,
"pmid": "34159057",
"pubdate": "2021-07",
"publication_types": "D002363:Case Reports",
"references": "27678032;18000172;26832651;3130483;3384112;31988058;10785214;8671272;1982004;29507026;2112558;16048801;20850728;12638783",
"title": "Severe late-onset ovarian hyperstimulation syndrome presenting with liver dysfunction after in vitro fertilization: A case report.",
"title_normalized": "severe late onset ovarian hyperstimulation syndrome presenting with liver dysfunction after in vitro fertilization a case report"
} | [
{
"companynumb": "US-ORGANON-O2108USA000524",
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"patient": {
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{
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"activesubstance": {
"activesubstancename": "CHORIOGONADOTROPIN ALFA"
},
"drugadditional":... |
{
"abstract": "Elderly patients with advanced-stage diffuse large-cell lymphomas (DLCLs) are either excluded from or under-represented in most clinical trials of combination chemotherapy regimens because they tolerate treatment poorly and usually have a worse outcome. We report two brief weekly chemotherapy regimens designed specifically for elderly patients. Eligible patients were aged 65 to 85 years, had advanced-stage DLCL (diffuse mixed, diffuse large-cleaved or noncleaved, immunoblastic, or diffuse large-cell not otherwise specified). Advanced stage was defined as Ann Arbor stage III or IV or stage I or II with a mass greater than 10 cm or B symptoms. Low-dose doxorubicin, cyclophosphamide, vincristine, bleomycin, and prednisone (LD-ACOP-B) accrued 40 patients between March 1983 and September 1985; 65% achieved a complete response (CR), there were two toxic deaths, the actuarial failure-free survival (FFS) is 19%, disease-specific survival (DSS) 30%, and overall survival (OS) 28%, with a maximum follow-up of 6 years. The regimen of etoposide, doxorubicin, vincristine, bleomycin, and prednisone (VABE) accrued 32 patients between July 1985 and June 1987; 63% achieved a CR, there were two toxic deaths, and the actuarial FFS is 34%, DSS 45%, and OS 36%, with a maximum follow-up of 4 years. There is no difference in FFS, DSS, or OS between these two regimens. VABE caused more myelosuppression and infectious complications, although the toxic death rates were similar. We prefer LD-ACOP-B because follow-up is longer and toxicity is less.",
"affiliations": "Division of Medical Oncology, British Columbia Cancer Agency, Vancouver, Canada.",
"authors": "O'Reilly|S E|SE|;Klimo|P|P|;Connors|J M|JM|",
"chemical_list": "D001761:Bleomycin; D014750:Vincristine; D005047:Etoposide; D004317:Doxorubicin; D003520:Cyclophosphamide; D011241:Prednisone",
"country": "United States",
"delete": false,
"doi": "10.1200/JCO.1991.9.5.741",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0732-183X",
"issue": "9(5)",
"journal": "Journal of clinical oncology : official journal of the American Society of Clinical Oncology",
"keywords": null,
"medline_ta": "J Clin Oncol",
"mesh_terms": "D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D001761:Bleomycin; D003520:Cyclophosphamide; D004317:Doxorubicin; D004334:Drug Administration Schedule; D005047:Etoposide; D005260:Female; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse; D008297:Male; D009367:Neoplasm Staging; D011241:Prednisone; D016019:Survival Analysis; D014750:Vincristine",
"nlm_unique_id": "8309333",
"other_id": null,
"pages": "741-7",
"pmc": null,
"pmid": "1707954",
"pubdate": "1991-05",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article",
"references": null,
"title": "Low-dose ACOP-B and VABE: weekly chemotherapy for elderly patients with advanced-stage diffuse large-cell lymphoma.",
"title_normalized": "low dose acop b and vabe weekly chemotherapy for elderly patients with advanced stage diffuse large cell lymphoma"
} | [
{
"companynumb": "CA-PFIZER INC-2021455468",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": "3",
... |
{
"abstract": "Neurosurgical complications from epidural injections have rarely been reported.\n\n\n\nTo define the spectrum of complications from these procedures in order to identify risk factors and strategies for prevention.\n\n\n\nA prospectively maintained database of 14 247 neurosurgical admissions over 8 yr was screened to identify patients who had suffered procedural complications associated with 1182 cervical and 4617 lumbar interlaminar epidural injection procedures performed at a single institution. Patients who developed new neurological symptoms or deficits were included. A retrospective analysis of demographic and procedural features was performed.\n\n\n\nThirteen patients experienced complications requiring neurosurgical treatment, accounting for an overall procedural complication rate of 0.22% (0.51% and 0.15% for cervical and lumbar injections, respectively), and representing 0.09% of all neurosurgical admissions over 8 yr. There were 3 categories: hemorrhage (n = 7), infection (n = 3), and inadvertent dural penetration (n = 3). There was significant association with anticoagulation use among patients with hemorrhagic vs nonhemorrhagic complications ( P < .01, Fisher's exact test). Six patients who developed epidural hematoma had been managed in accordance with current guidelines, either after prolonged cessation of anticoagulation (n = 3) or taking only aspirin (n = 3); all were decompressed promptly with good long-term outcome. All infections were associated with lumbar injection. Dural penetration resulted in diffuse pneumocephalus (n = 1), intramedullary air at the site of injection (n = 1), and acutely symptomatic colloid cyst (n = 1).\n\n\n\nA majority of neurosurgical complications from epidural injections are hemorrhagic and associated with anticoagulation, although infection and inadvertent dural penetration also occur. Prompt treatment of compressive lesions is associated with good outcome.",
"affiliations": "Department of Neurosurgery, University Hospitals Case Medical Center, Cleveland, Ohio.;Department of Neurosurgery, University Hospitals Case Medical Center, Cleveland, Ohio.;Department of Neurosurgery, University Hospitals Case Medical Center, Cleveland, Ohio.;Department of Neurosurgery, University Hospitals Case Medical Center, Cleveland, Ohio.;Division of Pain Medicine, Depart-ment of Anesthesiology, University Hospi-tals Case Medical Center, Cleveland, Ohio.;Department of Neurosurgery, University Hospitals Case Medical Center, Cleveland, Ohio.",
"authors": "Smith|Gabriel A|GA|;Pace|Jonathan|J|;Strohl|Madeleine|M|;Kaul|Anand|A|;Hayek|Salim|S|;Miller|Jonathan P|JP|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1093/ons/opw014",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2332-4252",
"issue": "13(2)",
"journal": "Operative neurosurgery (Hagerstown, Md.)",
"keywords": "Complications; Epidural steroid injection; Pain",
"medline_ta": "Oper Neurosurg (Hagerstown)",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D006801:Humans; D007268:Injections, Epidural; D008137:Longitudinal Studies; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009422:Nervous System Diseases; D019635:Neurosurgical Procedures; D011183:Postoperative Complications; D012189:Retrospective Studies; D015898:Tomography Scanners, X-Ray Computed",
"nlm_unique_id": "101635417",
"other_id": null,
"pages": "271-279",
"pmc": null,
"pmid": "28927205",
"pubdate": "2017-04-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Rare Neurosurgical Complications of Epidural Injections: An 8-Yr Single-Institution Experience.",
"title_normalized": "rare neurosurgical complications of epidural injections an 8 yr single institution experience"
} | [
{
"companynumb": "US-BAYER-2017-117908",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ASPIRIN"
},
"drugadditional": null,
"dr... |
{
"abstract": "As the population ages and cardiovascular disease becomes more prevalent, an increasing number of patients are receiving implantable cardioverter-defibrillators (ICDs). When these patients present to the emergency department, it is imperative that physicians are not only aware of the possible underlying medical issues that may have precipitated their admission but should also have a good understanding of the potential interactions that any medical intervention may have on the patient's device. We discuss a case in which a patient known to have an ICD in situ was transcutaneously paced for the management of bradycardia, leading to an unnecessary shock.",
"affiliations": null,
"authors": "Somani|Riyaz|R|;DeJong|Peggy|P|;Michael|Kevin|K|;Baranchuk|Adrian|A|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.2310/8000.2013.130948",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1481-8035",
"issue": "16(4)",
"journal": "CJEM",
"keywords": null,
"medline_ta": "CJEM",
"mesh_terms": "D000368:Aged; D002304:Cardiac Pacing, Artificial; D016757:Death, Sudden, Cardiac; D017147:Defibrillators, Implantable; D004562:Electrocardiography; D004868:Equipment Failure; D006801:Humans; D008297:Male; D017202:Myocardial Ischemia; D019564:Unnecessary Procedures",
"nlm_unique_id": "100893237",
"other_id": null,
"pages": "330-3",
"pmc": null,
"pmid": "25060089",
"pubdate": "2014-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Unnecessary shock from an implantable cardioverter-defibrillator following transcutaneous pacing.",
"title_normalized": "unnecessary shock from an implantable cardioverter defibrillator following transcutaneous pacing"
} | [
{
"companynumb": "CA-TEVA-642232USA",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AMIODARONE"
},
"drugadditional": null,
"dru... |
{
"abstract": "In about 4% of cases, amyloid light chain (AL) amyloidosis is due to an underlying lymphoplasmacytic lymphoma (LPL) or other monoclonal protein forming low-grade B-cell lymphoma, instead of a plasma cell neoplasm. We report an unusual case of a 55-year-old male with co-localization of an IgG positive LPL and AL amyloidosis in his endomyocardial biopsy (EMB). The patient was diagnosed 4 years earlier with a low grade B-cell non Hodgkin lymphoma stage IV, at the time classified as marginal zone lymphoma. He received several lines of treatment for his lymphoma, which had shown progressive disease. Four years after initial diagnosis, he developed increasing dyspnea on exertion. Echocardiography demonstrated left and right ventricular hypertrophy with classical apical sparing, suspicious for cardiac amyloidosis. Bone marrow biopsy revealed massive infiltration by his low grade B-cell lymphoma, which was now reclassified as LPL based on the demonstration of a MYD88 L265P mutation. An EMB confirmed the presence of amyloid, which was typed as AL amyloidosis by the use of immunoelectron microscopy. In addition, mild B-cell infiltrates were present in the EMB, which were shown to be part of his LPL by the demonstration of the MYD88 L265P mutation using the highly sensitive droplet digital polymerase chain reaction technique. This is a rare case of cardiac AL amyloidosis based on an IgG kappa positive LPL, in which not only the amyloid but also the lymphoma itself were present in the EMB. In addition, this case nicely illustrates the use of 2 highly sensitive techniques (immunoelectron microscopy and droplet digital polymerase chain reaction), which both can be performed on small, formalin-fixed paraffin-embedded biopsies.",
"affiliations": "Department of Pathology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands. Electronic address: R.J.Leguit-2@umcutrecht.nl.;Department of Pathology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.;Department of Cardiology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.;Department of Hematology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.;Department of Cardiology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.",
"authors": "Leguit|Roos J|RJ|;Vink|Aryan|A|;de Jonge|Nicolaas|N|;Minnema|Monique C|MC|;Oerlemans|Marish I F|MIF|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.carpath.2021.107348",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1054-8807",
"issue": "53()",
"journal": "Cardiovascular pathology : the official journal of the Society for Cardiovascular Pathology",
"keywords": null,
"medline_ta": "Cardiovasc Pathol",
"mesh_terms": null,
"nlm_unique_id": "9212060",
"other_id": null,
"pages": "107348",
"pmc": null,
"pmid": "34038803",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Endomyocardial biopsy with co-localization of a lymphoplasmacytic lymphoma and AL amyloidosis.",
"title_normalized": "endomyocardial biopsy with co localization of a lymphoplasmacytic lymphoma and al amyloidosis"
} | [
{
"companynumb": "NL-ROCHE-2941623",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BENDAMUSTINE HYDROCHLORIDE"
},
"drugadditional": "3",
... |
{
"abstract": "Cutaneous blisters and/or bullae can occur in autoimmune disorders, infections, genetic diseases, and drug hypersensitivity. We present the case of a 62-year-old man with two autoimmune conditions who was admitted for antibiotic treatment of a lower extremity infection and suddenly developed a bullous rash. His physical examination was significant for tense, bullous lesions that involved his chin, palms, and inner thighs. Narrowing the differential diagnosis for patients with blistering skin lesions is imperative for timely and appropriate management.",
"affiliations": null,
"authors": "Generoso|August J|AJ|;Goldman|Jordana A|JA|;Wolff|Alan H|AH|",
"chemical_list": "D000900:Anti-Bacterial Agents; D014640:Vancomycin",
"country": "United States",
"delete": false,
"doi": "10.2500/aap.2021.42.200055",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1088-5412",
"issue": "42(2)",
"journal": "Allergy and asthma proceedings",
"keywords": null,
"medline_ta": "Allergy Asthma Proc",
"mesh_terms": "D000900:Anti-Bacterial Agents; D003937:Diagnosis, Differential; D003875:Drug Eruptions; D006801:Humans; D008297:Male; D008875:Middle Aged; D011237:Predictive Value of Tests; D012307:Risk Factors; D012867:Skin; D012872:Skin Diseases, Vesiculobullous; D014640:Vancomycin",
"nlm_unique_id": "9603640",
"other_id": null,
"pages": "175-179",
"pmc": null,
"pmid": "33685564",
"pubdate": "2021-03-01",
"publication_types": "D002363:Case Reports",
"references": "23815152;27303171;1806226;22137225;10886170;30364778;30450358;3056993;10672401;1806227;21762507;29128161;7904616;11736908;15127983;16882196;32011724;15183590;8621822;27995619;21605811;15059226;28168063;28084616;21605812;30809685;21738885;16962027;10457136;28452830;20062563",
"title": "A 62-year-old man with new-onset bullae.",
"title_normalized": "a 62 year old man with new onset bullae"
} | [
{
"companynumb": "US-AXELLIA-003787",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FUROSEMIDE"
},
"drugadditional": "3",
"drug... |
{
"abstract": "Metformin is an oral hypoglycemic agent that is commonly used in the treatment of type 2 diabetes mellitus. Although metformin-associated gastrointestinal upset and metabolic acidosis is widely recognized side effect of this drug, metformin-induced liver injury has been rarely reported in the literature. In most cases reported, metformin-induced liver injury was associated with concomitant intake of other hepatotoxic drugs. Here, we report a case of a 70-year-old white woman who suffered metformin-induced liver injury 5 weeks after starting on this medication, and she was not on any other hepatotoxic agent. With increasing prescription of metformin, this case deserves particular attention for this rare but important side effect.",
"affiliations": "Division of Hospital Medicine, Department of Medicine, Cooper University Hospital, Cooper Medical School of Rowan University, Camden, NJ.",
"authors": "Zheng|Lin|L|",
"chemical_list": "D007004:Hypoglycemic Agents; D008687:Metformin",
"country": "United States",
"delete": false,
"doi": "10.1097/MJT.0000000000000007",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1075-2765",
"issue": "23(1)",
"journal": "American journal of therapeutics",
"keywords": null,
"medline_ta": "Am J Ther",
"mesh_terms": "D000368:Aged; D056486:Chemical and Drug Induced Liver Injury; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents; D008687:Metformin",
"nlm_unique_id": "9441347",
"other_id": null,
"pages": "e315-7",
"pmc": null,
"pmid": "24263160",
"pubdate": "2016",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Metformin as a Rare Cause of Drug-Induced Liver Injury, a Case Report and Literature Review.",
"title_normalized": "metformin as a rare cause of drug induced liver injury a case report and literature review"
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"abstract": "BACKGROUND\nThere exists an inherent risk of increased venous thromboembolism (VTE) in surgical spine patients, which is independent of their existing risk factors. Prophylaxis and treatment of VTE is an imprecise practice and may have serious complications even well after the initial surgery. Furthermore, there are no clear guidelines on how to manage postoperative spine patients with regards to the timing of anticoagulation.\n\n\nMETHODS\nHere, we present the case of a middle-aged male, status post L2/3 laminectomy and discectomy who developed bilateral below the knee deep venous thrombosis. He was started on Enoxaparin and transitioned to Warfarin and returned with axial back pain, and was found to have a postoperative hematoma almost 3 weeks later in a delayed fashion.\n\n\nCONCLUSIONS\nDelayed surgical wound hematoma with neural compression is an important complication to identify and should remain high on the differential diagnosis in patients on warfarin who present with axial spinal pain.",
"affiliations": "Department of Neurological Surgery, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, New York, USA.;Department of Neurological Surgery, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, New York, USA.;Department of Neurological Surgery, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, New York, USA.;Department of Neurological Surgery, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, New York, USA.;Department of Neurological Surgery, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, New York, USA.",
"authors": "Kinon|Merritt D|MD|;Nakhla|Jonathan|J|;Brown|Kenroy|K|;Bhashyam|Niketh|N|;Yassari|Reza|R|",
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"doi": "10.4103/2152-7806.196766",
"fulltext": "\n==== Front\nSurg Neurol IntSurg Neurol IntSNISurgical Neurology International2229-50972152-7806Medknow Publications & Media Pvt Ltd India SNI-7-108910.4103/2152-7806.196766Case ReportUltra-delayed lumbar surgical wound hematoma Kinon Merritt D. mdkinon@gmail.comNakhla Jonathan jonathan.nakhla@gmail.com*Brown Kenroy kenroy.brown@ymail.comBhashyam Niketh nbhashya@mail.einstiein.yu.eduYassari Reza ryassari@montefiore.orgDepartment of Neurological Surgery, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, New York, USA* Corresponding author\n2016 26 12 2016 7 Suppl 42 SNI: Spine, a supplement to Surgical Neurology InternationalS1089 S1091 07 10 2016 14 10 2016 Copyright: © 2016 Surgical Neurology International2016This 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.Background:\nThere exists an inherent risk of increased venous thromboembolism (VTE) in surgical spine patients, which is independent of their existing risk factors. Prophylaxis and treatment of VTE is an imprecise practice and may have serious complications even well after the initial surgery. Furthermore, there are no clear guidelines on how to manage postoperative spine patients with regards to the timing of anticoagulation.\n\nCase Description:\nHere, we present the case of a middle-aged male, status post L2/3 laminectomy and discectomy who developed bilateral below the knee deep venous thrombosis. He was started on Enoxaparin and transitioned to Warfarin and returned with axial back pain, and was found to have a postoperative hematoma almost 3 weeks later in a delayed fashion.\n\nConclusion:\nDelayed surgical wound hematoma with neural compression is an important complication to identify and should remain high on the differential diagnosis in patients on warfarin who present with axial spinal pain.\n\nAnticoagulationcomplicationspinal decompressionvenous thromboembolismwound hematoma\n==== Body\nINTRODUCTION\nThe risk of venous thromboembolism (VTE) in a post-surgical spine patient can be increased due to existing comorbidities in addition to the inherent increased risk of the spine surgery itself. The current literature suggests that, although there are no specific recommendations for VTE, prophylaxis, elastic compression stockings, low molecular weight heparin (LMWH), low dose unfractionated heparin (LDUH), early ambulation, or intermittent pneumatic compression may help in VTE prevention in these patients.[2] Furthermore, when to start prophylactic or therapeutic treatment for VTE is not well-established and possesses a myriad of complications including spinal epidural hematoma and delayed surgical wound hematoma.[210]\n\nWound hematoma is an important differential diagnosis for patients on warfarin who have a “relatively” recent history of spinal surgery and present with axial spinal pain and swelling around their surgical wound. In general, such a complication occurs within a few days to a week after starting postoperative anticoagulation therapy.[2911] Little evidence otherwise exists for wound hematoma occurring after this usual time period. However, this report demonstrates that wound hematoma can occur well after its suspected time period, and up to 3 weeks after the index operation.\n\nCASE PRESENTATION\nOur patient, a middle-aged male, status post L2-L3 laminectomy and discectomy for acute lower extremity weakness, developed bilateral below the knee deep venous thrombosis (DVT) on postoperative day 10 (POD) and was started on therapeutic Enoxaparin immediately. On POD 18, he was transitioned to Warfarin. Two days after starting Warfarin (POD 20), he developed terrible low back pain as well as worsening lower extremity weakness. At the time of arrival to our Emergency Department, his international normalized ratio (INR) was 2.8. His surgical wound was well healed, however, it was extremely tense and tender to touch. There was significant swelling that tracked from his lumbar wound out laterally to his flanks. Magnetic resonance (MR) imaging of the lumbar spine was done and showed a large, heterogeneous, multiloculated collection concerning for hematoma extending from the laminectomy defect to the overlying subcutaneous fat and dissecting out laterally to his flanks with significant epidural compression [Figure 1]. The collection measured 8.4 cm × 10 cm × 13 cm. The patient's INR was emergently corrected and he was taken to the operating room for surgical wound exploration. Intraoperatively, a large hematoma with varying stages of clot organization was encountered with extensive dissection into the adjacent soft tissues. The hematoma was evacuated and meticulous hemostasis was achieved. Anticoagulation was held after surgery and an IVC filter was placed.\n\nFigure 1 (a) Sagittal and (b) axial MRI T2-weighted images showing a large hematoma with severe compression of the thecal sac and spinal nerves. (c) Axial CT scan showing the decompression and a large hypodense collection\n\nDISCUSSION\nLittle evidence exists supporting post-surgical delayed wound hematoma in a patient over a week after starting anticoagulation therapy.[2911] Furthermore, there is little evidence documenting similar large wound hematomas occurring as late as 3 weeks post-surgery. However, this report documents an unusual and unique case of a large wound hematoma that occurred 3 weeks post-spine surgery, and over 1 week after starting anticoagulation therapy.\n\nLarge wound hematomas in a spine surgery patient can cause neural compression and also have symptoms consistent with acute spinal epidural hematomas. The symptoms of acute spinal epidural hematoma, as described in the medical literature, are sudden onset of severe pain along the spinal column lasting from a few minutes to a few hours, possibly with focal or evolving neurological symptoms such as flaccid paralysis or loss of sphincter control.[1417] Occasionally, there is transient improvement in the neurology.[8] Thus, acute spinal pain in a patient on anticoagulants should raise the suspicion of spinal epidural hematoma even before any neurological symptoms appear. The anticoagulants should be withheld immediately and coagulation abnormalities should be corrected. MRI is the investigation of choice to diagnose and to show the extent of epidural hematoma.[12] Gadolinium-enhanced MRI can localize spinal epidural hematoma preoperatively and can also show any underlying spinal vascular malformations.[5] The surgical approach is dictated by the location and extent of hematoma. The majority of epidural hematomas are located dorsally, therefore, decompressive laminectomy is the treatment of choice.[7] Ventral hematomas may require more extensive procedures.[4]\n\nCertain conditions appear to predispose individuals to VTE. The American College of Chest Physicians Consensus Conference on Antithrombotic and Thrombolytic Therapy has a scoring to predict VTE, which includes the following as major risk factors: Age, bed confinement, history of malignancy, history of DVT, obesity, and spinal cord injury with paralysis.[1] Furthermore, patients undergoing spinal surgery alone are at risk of developing VTE when combined with other risk factors should be kept in mind preoperatively. Additional risk factors are prolonged immobilization postoperatively, incision pain, postoperative paralysis, and duration of surgery. The neurosurgeon is thus left to weigh the risks of postoperative hematoma formation against the benefits of protecting against DVT.[3]\n\nAs the complexity of spinal surgery has increased, so has the incidence of DVT and pulmonary embolism (PE). In spite of the use of different prophylactic methods, VTE is still a significant complication following spinal surgery. In surgery of the lumbosacral spinal, the lowest quoted rates are 0.6% for DVT and 0.3% for PE.[15] The true incidence of VTE in spinal surgery remains unknown. Oda et al. reported evidence that the incidence of DVT after posterior spinal surgery is higher than appreciated, and that increased age and posterior lumbar surgery are risk factors.[16] Initial treatment with elastic compressive stockings, LMWH, LDUH, intermittent pneumatic compression, and early ambulation are the primary treatment measures.[2] A transition to Coumadin therapy for DVT is common, even in the postoperative period. However, there is no clear consensus in the current literature as when it is safe to start anticoagulation therapy after surgery.[2] Neurosurgical procedures, including spinal surgery procedures, carry an inherent high risk of postoperative bleeding because any compression of the neural elements can have significant morbidity.[613] Some authors recommend starting anticoagulation for thromboembolism 72 hours after surgery because the high risk of developing postoperative thromboembolism and complication associated with it are usually 3 to 5 days after surgery, whereas others recommend restarting anticoagulation after 7 days in patients who have suffered a spontaneous hemorrhage due to anticoagulation.[911] As such, no clear guidelines exist for DVT prophylaxis or postoperative treatment, and are still on a per patient basis. However, this report suggests careful postoperative follow-up and monitoring for complications, including delayed wound hematomas, in any patient who underwent spine surgery, and was subsequently started on prophylactic anticoagulant therapy is necessary even up to 3 weeks after the index surgery.\n\nCONCLUSION\nThe incidence of VTE has risen along with the rise of complexity in spinal surgery. Neurological procedures themselves have an inherent risk of VTE and there is no consensus as to when to begin anticoagulant therapy. With many unknowns and individual patient treatment needs, one should maintain high suspicion for wound hematoma even in patients 3 weeks out from surgery on anticoagulants.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n\nhttp://surgicalneurologyint.com/Ultra-delayed-lumbar-surgical-wound-hematoma/\n==== Refs\nREFERENCES\n1 Stein P Goldhaber S Gottschalk A Hull R Hyers T Leeper K Opinions regarding the diagnosis and management of venous thromboembolic disease. ACCP Consensus Committee on Pulmonary Embolism. American College of Chest Physicians Chest 1998 113 499 504 9498971 \n2 Brambilla S Ruosi C La Maida GA Caserta S Prevention of venous thromboembolism in spinal surgery Eur Spine J 2004 13 1 8 14610663 \n3 Browd SR Ragel BT Davis GE Scott AM Skalabrin EJ Couldwell WT Prophylaxis for deep venous thrombosis in neurosurgery: A review of the literature Neurosurg Focus 2004 17 E1 \n4 Carroll SG Malhotra R Eustace D Sharr M Morcos S Spontaneous spinal extradural hematoma during pregnancy J Matern Fetal Med 1997 6 218 9 9260119 \n5 Crisi G Sorgato P Colombo A Scarpa M Falasca A Angiari P Gadolinium-DTPA-enhanced MR imaging in the diagnosis of spinal epidural haematoma. Report of a case Neuroradiology 1990 32 64 6 2333136 \n6 Daniels PR Peri-procedural management of patients taking oral anticoagulants BMJ 2015 351 h2391 26174061 \n7 Dziedzic T Kunert P Krych P Marchel A Management and neurological outcome of spontaneous spinal epidural hematoma J Clin Neurosci 2015 22 726 9 25677879 \n8 Galzio RJ Zenobii M D’Ecclesia G Spontaneous spinal epidural hematoma: Report of a case with complete recovery Surg Neurol 1980 14 263 5 7434194 \n9 Hawryluk GW Furlan JC Austin JW Fehlings MG Individual characteristics and management decisions affect outcome of anticoagulated patients with intracranial hemorrhage World Neurosurg 2014 81 742 51 23336984 \n10 Janku GV Paiement GD Green HD Prevention of venous thromboembolism in orthopaedics in the United States Clin Orthop Relat Res 1996 313 21 8998892 \n11 Kunkala MR Kehl J Zielinski MD Spontaneous rectus sheath hematomas: When to restart anticoagulation? World J Surg 2013 37 2555 9 23881089 \n12 Lawton MT Porter RW Heiserman JE Jacobowitz R Sonntag VK Dickman CA Surgical management of spinal epidural hematoma: Relationship between surgical timing and neurological outcome J Neurosurg 1995 83 1 7 7782824 \n13 Liao CC Hsieh PC Lin TK Lin CL Lo YL Lee SC Surgical treatment of spontaneous spinal epidural hematoma: A 5-year experience J Neurosurg Spine 2009 11 480 6 19929346 \n14 Minato T Miyagi M Saito W Shoji S Nakazawa T Inoue G Spinal Epidural Hematoma after Thoracolumbar Posterior Fusion Surgery without Decompression for Thoracic Vertebral Fracture Case Rep Orthop 2016 2016 6295817 26989542 \n15 Nicol M Sun Y Craig N Wardlaw D Incidence of thromboembolic complications in lumbar spinal surgery in 1,111 patients Eur Spine J 2009 18 1548 52 19484271 \n16 Oda T Fuji T Kato Y Fujita S Kanemitsu N Deep venous thrombosis after posterior spinal surgery Spine 2000 25 2962 7 11074685 \n17 Rangwala SD Birk DM Tobin MK Hahn YS Nikas DC Spontaneous Resolution of Spinal Epidural Hematoma Resulting from Domestic Child Abuse: Case Report Pediatr Neurosurg 2016\n\n",
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"issn_linking": "2152-7806",
"issue": "7(Suppl 42)",
"journal": "Surgical neurology international",
"keywords": "Anticoagulation; complication; spinal decompression; venous thromboembolism; wound hematoma",
"medline_ta": "Surg Neurol Int",
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"nlm_unique_id": "101535836",
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"pages": "S1089-S1091",
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"pmid": "28144491",
"pubdate": "2016",
"publication_types": "D002363:Case Reports",
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"title": "Ultra-delayed lumbar surgical wound hematoma.",
"title_normalized": "ultra delayed lumbar surgical wound hematoma"
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"abstract": "BACKGROUND\nVascular access site management is crucial to safe, efficient, and comfortable diagnostic or interventional percutaneous procedures. The Angioseal™ vascular closure device has been shown to be safe and effective in reducing the time to hemostasis following angiographic or interventional procedures. Relatively few studies have been conducted in the UK to assess the safety and efficacy of the device in a local setting.\n\n\nMETHODS\nData were retrospectively reviewed on 147 patients who underwent either diagnostic angiography or percutaneous interventional procedures from January 2008 to October 2009, and who had the femoral access site closed by 6F VIP Angioseal. A total of 147 patients (F: 49, M: 98), including 80 right femoral punctures, 57 left femoral punctures, and 10 bilateral punctures were reviewed using radiological reports and patients' clinical data. Data on antiplatelet and anticoagulant therapy were recorded. All procedures were carried out by two interventional radiologists at a single institution, under similar operating conditions.\n\n\nRESULTS\nThere were a total of six complications (4.47%), of which one was a major complication (0.75%), i.e., retroperitoneal bleed. There were five minor complications (3.73%), which included device deployment failure (2), device malfunction (2), and a superficial hematoma (>6 cm). Total complications were 6 out of 157 (3.8%) [95% CI = 0.8-6.8%)]. Successful hemostasis was achieved in less than 5 min in over 97% of patients. Successful device deployment was seen in over 98% of cases.\n\n\nCONCLUSIONS\nWe conclude that in our experience, the Angioseal vascular closure device is a safe and efficient means of achieving hemostasis post antegrade or retrograde puncture for diagnostic and percutaneous intervention procedures.",
"affiliations": "Department of Interventional Radiology, Sandwell and West Birmingham NHS Trust, Birmingham, West Midlands, UK.",
"authors": "Modi|Sachin|S|;Gadvi|Rakesh|R|;Babu|Suresh|S|",
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"doi": "10.4103/0971-3026.116566",
"fulltext": "\n==== Front\nIndian J Radiol ImagingIndian J Radiol ImagingIJRIThe Indian Journal of Radiology & Imaging0971-30261998-3808Medknow Publications & Media Pvt Ltd India IJRI-23-13410.4103/0971-3026.116566Vascular and Interventional Radiology Mini SymposiaInitial experience with Angioseal™: Safety and efficacy of the endovascular closure device Modi Sachin Gadvi Rakesh Babu Suresh Department of Interventional Radiology, Sandwell and West Birmingham NHS Trust, Birmingham, West Midlands, UKCorrespondence: Dr. Sachin Modi, Department of Radiology, City Hospital, Dudley Road, Birmingham, B18 7QH. E-mail: sachin.modi@doctors.net.ukApr-Jun 2013 23 2 134 138 Copyright: © Indian Journal of Radiology and Imaging2013This 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.Background:\nVascular access site management is crucial to safe, efficient, and comfortable diagnostic or interventional percutaneous procedures. The Angioseal™ vascular closure device has been shown to be safe and effective in reducing the time to hemostasis following angiographic or interventional procedures. Relatively few studies have been conducted in the UK to assess the safety and efficacy of the device in a local setting.\n\nMaterials and Methods:\nData were retrospectively reviewed on 147 patients who underwent either diagnostic angiography or percutaneous interventional procedures from January 2008 to October 2009, and who had the femoral access site closed by 6F VIP Angioseal. A total of 147 patients (F: 49, M: 98), including 80 right femoral punctures, 57 left femoral punctures, and 10 bilateral punctures were reviewed using radiological reports and patients’ clinical data. Data on antiplatelet and anticoagulant therapy were recorded. All procedures were carried out by two interventional radiologists at a single institution, under similar operating conditions.\n\nResults:\nThere were a total of six complications (4.47%), of which one was a major complication (0.75%), i.e., retroperitoneal bleed. There were five minor complications (3.73%), which included device deployment failure (2), device malfunction (2), and a superficial hematoma (>6 cm). Total complications were 6 out of 157 (3.8%) [95% CI = 0.8-6.8%)]. Successful hemostasis was achieved in less than 5 min in over 97% of patients. Successful device deployment was seen in over 98% of cases.\n\nConclusion:\nWe conclude that in our experience, the Angioseal vascular closure device is a safe and efficient means of achieving hemostasis post antegrade or retrograde puncture for diagnostic and percutaneous intervention procedures.\n\nAngiographyAngioseal™endovascular interventionvascular access site closure\n==== Body\nIntroduction\nHemostasis\nHemostasis of arterial puncture sites is still a critical point of vascular interventional.[12] Vascular access site complications occur in 5% of cases.[3] Access site complications lengthen hospital stay. Patients sometimes require blood transfusions and surgical repairs.[4] Monitoring of coagulation parameters, delayed arterial sheath removal, manual compression, and supine bed rest (for at least 6-8 h after sheath pull out) are considered effective preventative measures, but increase patient discomfort and nursing time.[15]\n\nTo overcome these issues, hemostatic devices have been developed to allow immediate arterial sheath removal after the procedure, as well as early patient mobilization and hospital discharge.[4] Newly available femoral arteriotomy closure/sealing devices have received rapid acceptance from invasive cardiology and vascular radiology communities.[6]\n\nAt our institution, a femoral arteriotomy closure device is used to achieve immediate post-procedure hemostasis: Angioseal™ (St. Jude Medical, Minnetonka, MN, USA). The efficacy and safety of the Angioseal vascular closure device post retrograde and antegrade puncture are well established in the literature.[14789]\n\nCFA puncture\nVascular radiological interventional procedures are almost always performed following puncture of the common femoral artery (CFA).[1011] The standard retrograde CFA puncture is used for diagnostic lower limb angiography and aorto-iliac interventions. Antegrade puncture refers to placement of an angiographic needle in the CFA in the direction of arterial flow.\n\nThe inguinal ligament is the anatomical landmark that separates the external iliac artery from the CFA.[6] The inguinal ligament extends from the anteroiliac spine to the pubic tubercle. Fluoroscopy is helpful in guiding the arterial puncture. As the ligaments are not radiopaque, the proximal end of the CFA can be correlated with the proximal edge of the femoral head keeping in mind the imaginary line transversing from the anteroiliac spine to the pubic tubercle.[10]\n\nA high puncture (above the inguinal ligament) is associated with increased incidence of groin hematoma and retroperitoneal haemorrhage.[1011] A low puncture is associated with increased incidence of arterio-venous (AV) fistula, vessel thrombosis, and pseudoaneursym formation.[61011]\n\nPrior to the introduction of arterial closure devices, all patients who had common femoral arterial puncture required manual compression of the puncture site for up to 20 min and bed rest for up to 12 h to achieve hemostasis.[7] This was often associated with re-bleeding at the puncture site.\n\nAngioseal\nThe Angioseal vascular closure device [Figure 1A and B] closes the defect in the common femoral arterial wall by percutaneous access through a sheath. It comprises an absorbable polymer anchor (D, L-lactide co-glycolide polymer) deployed intra-arterially, a small collagen sponge plug positioned in the arteriotomy, and a self-tightening suture trimmed below the skin. Hemostasis is achieved by compressing the collagen plug between the anchor and the suture, which is supplemented by the coagulation inducing properties of the collagen [Figure 1C].[12] All the Angioseal components are absorbed within 60-90 days.[413]\n\nFigure 1 (A-C) (A) Angioseal device.[14] (B) Angioseal device components.[14] (C) Collagen plug[14]\n\nThe Angioseal device complications have been extensively evaluated and the adverse effects have been divided [Table 1].[15]\n\nTable 1 Adverse effects of Angioseal[15]\n\nThis study is a retrospective review of a patient cohort who underwent diagnostic angiography or percutaneous intervention with puncture of the CFA, in whom the 6F VIP STS Angioseal vascular closure device was used. Specifically we look at the complication rates, types of complications, and the overall efficacy.\n\nMaterials and Methods\nThe study data were collected at a busy district general hospital over two tertiary care centers, with a moderate volume of interventional vascular procedures.\n\nThe radiological reports and medical notes of 147 patients, who were referred to two interventional radiologists for diagnostic angiography or percutaneous intervention, between January 2008 and October 2009, were reviewed.\n\nInformation recorded included patient age, gender, and procedure type. With regard to the procedure itself, puncture direction, complications of Angioseal deployment, time from removal of sheath to hemostasis and whether hemostasis was successful or not were assessed.\n\nData were collected on whether patients were receiving antiplatelet or anticoagulant therapy. Information was gathered as to what therapy or combination of therapy the patients were taking at the time of the procedure.\n\nAll procedures were carried out under standard conditions by two experienced interventional radiologists, using the same 6F VIP STS Angioseal device.\n\nIn all patients, closure of the puncture site took place in the interventional radiology room immediately after the procedure. The guidewire provided with the Angioseal set was passed through the arterial sheath. Manual pressure was applied at the puncture site and the sheath was carefully removed over the wire. The 6F Angioseal sheath was then passed over the wire and placed into the artery. The anchor was set in position by deploying the device through the sheath. The anchor was then pulled back gently and the puncture sealed by pulling the self-tightening string. The string was then cut short to the skin.\n\nResults\nThere were 98 male patients and 49 female patients. The mean age of the patient group was 67 years, with a range of 36-98 years. A total of 157 CFA punctures were performed. Fifty-seven patients (38.7%) had a left-sided puncture, 80 patients (54.4%) had a right-sided puncture, and 10 patients (6.8%) had bilateral punctures [Table 2].\n\nTable 2 Patient information\n\nOut of the total 157 punctures, 122 (77.7%) were antegrade punctures and 35 (22.2%) were retrograde. There were a total of 157 procedures, 23 (14.6%) of which were diagnostic angiograms and 134 (85.3%) were interventional procedures [Table 2].\n\nOne major complication (0.75%) was a retroperitoneal hematoma in a female patient [Table 3]. The patient was an inpatient, who developed shortness of breath 4 days post angioplasty. On checking her hemoglobin level, it was found to be low, and a subsequent ultrasound scan revealed a large retroperitoneal hematoma. She was managed conservatively and was transfused 3 units of blood. She was discharged home 13 days post procedure after an uneventful recovery.\n\nTable 3 Complications\n\nOf the minor complications, one (0.75%) included a superficial hematoma in a male [Table 3]. This was evacuated in theater 12 days after the interventional procedure. The patient made an uneventful recovery.\n\nThere were 2 (1.49%) minor complications relating to device malfunction, where the puncture site continued to ooze despite satisfactory deployment of the Angioseal device. These patients had manual compression for 20 min to achieve hemostasis.\n\nIn further 2 (1.49%) patients, the Angioseal device failed to deploy [Table 3]. One of these patients was noted to have multiple previous femoral punctures leading to a large amount of scar tissue. Again in these two patients, manual compression for 20 min was used to achieve satisfactory hemostasis.\n\nFigures for time to haemostasis and successful deployment can be seen in Tables 4 and 5. In 153 (97%) patients, hemostasis was achieved in less than 5 min, and in 155 (98.7%) patients the device was successfully deployed.\n\nTable 4 Efficacy\n\nTable 5 Deployment\n\nOut of all the complications (6-4.48%), four patients were males (66.6%) and two (33.3%) were females. Four (66.6%) were antegrade punctures and two (33.3%) were retrograde punctures. All the procedures resulting in any complications were interventional procedures.\n\nOverall, out of 157 punctures, there were six total complications (3.8%) [95% CI = 0.8-6.8%]. Five out of these six patients were on Aspirin 75 mg and Clopidogrel 75 mg and the other patient was on Aspirin 75 mg and Dipyridamole 200 mg.\n\nA total of 90 (61%) patients were on antiplatelet or anticoagulant therapy, and 57 (39%) were not taking antiplatelet or anticoagulant therapy. The distribution of antiplatelet or anticoagulant therapy is seen in Table 6.\n\nTable 6 Antiplatelet and anticoagulant therapy\n\nDiscussion\nBefore the advent of vascular closure devices, manual or mechanical compression of the puncture site followed by up to 12 h bed rest was commonplace in order to obtain satisfactory hemostasis.[5]\n\nThe disadvantages of this include patient discomfort from groin pressure for prolonged periods and bed rest. In addition, many of the patients undergoing such procedures, as in our series, have multiple comorbidities (e.g., respiratory or cardiac failure), where lying flat for such a period of time is not possible. There are also the disadvantages of increased workloads for medical and nursing staff and increased hospital stay, increasing bed demands.[16]\n\nAngioseal offers many advantages, especially immediate hemostasis in less than 5 min in most cases, allowing early ambulation and hospital discharge leading to reduced requirements for hospital resources.[7] There have been studies showing Angioseal to reduce hospital stay and improve patient satisfaction.[17181920]\n\nThe disadvantages are the cost of the product, which is currently £80 for the type used at our institution. However, it is felt that this is largely offset by the reduced staff and bed requirement. There are various studies outside the UK which have reported cost benefit since the introduction of Angioseal into their practice.[221]\n\nOther disadvantages include operator training and recognition of potential device-related complications.\n\nWe showed an overall efficacy rate of over 97% in both diagnostic and interventional subgroups. We also showed a major complication rate of just 0.75%, with no incidences of major vascular injury/occlusion necessitating surgery or intervention, fistula, infection, aneurysm, or incidences of late bleeding. Our minor complication rate was also low at 3.73%. The overall complication rate for diagnostic and interventional procedures was 3.8%.\n\nThe results obtained in our study have an incidence of vascular complications similar to or lower than those with manual compression. Popma et al. reported a 5.9% rate of vascular complications with hemostasis achieved through manual compression.[22]\n\nThe complication and device success rates obtained are comparable to previous studies which have been undertaken. In a meta-analysis of randomized and non-randomized controlled trial investigating collagen plug devices, Silber reported a success rate of 97% with a complication rate of 6.7% in Angioseal patients.[23] Compared to this data, we achieved a similar rate of device success and lower incidences of vascular complications, with especially less major complications.\n\nNinety (61%) patients undergoing procedures were on some form of anticoagulation, but the 6 (100%) patients who suffered complications were all on two antiplatelet medications. Although the numbers in this study are too small to draw significant conclusions, the role of antiplatelet therapy in Angioseal complications has been previously described.\n\nOur high efficacy and low complication rate is similar if not better than those in previous studies.[157222324]\n\nThis study has important limitations in its retrospective and non-randomized nature. Criteria to select patients for Angioseal were biased by the operator, whose decision was based on clinical factors. We also do not have equivalent numbers within the diagnostic and interventional subgroups.\n\nDespite these drawbacks, we conclude that in our experience, vascular access site closure with Angioseal is safe, efficient, and uncomplicated, resulting in more favorable patient outcomes with acceptable levels of patient morbidity.\n\nSource of Support: Nil\n\nConflict of Interest: No.\n==== Refs\n1 Duffin DC Muhlestein JB Allisson SB Horne BD Fowles RE Sorensen SG Femoral arterial puncture management after percutaneous coronary procedures: A comparison of clinical outcomes and patient satisfaction between manual compression and two different vascular closure devices J Invasive Cardiol 2001 13 354 62 11385148 \n2 Resin FS Aurora N Mathieu M Reynolds MR A cost minimisation analysis of the Angioseal vascular closure device following percutaneous coronary intervention Am J Cardiol 2007 99 766 70 17350361 \n3 Heintzen MP Stauer BE Peripheral arterial complications after heart catheterisation Herz 1998 23 4 20 9541843 \n4 Kussmaul WG 3rd Buchbinder M Whitlow PL Aker UT Heuser RR King SB Rapid arterial haemostasis and decreased access site complications after cardiac catheterisation and angioplasty J Am Coll Cardiol 1995 25 1685 92 7759724 \n5 Sesana M Vaghetti M Albiero R Corvaja N Martini G Sivieri G Effectiveness and Complications of Vascular Access Closure Devices After Interventional Procedures J Invasive Cardiol 2000 12 395 9 10953101 \n6 Patel RP Jneid H Derdeyn CP Klein LW Levine GN Lookstein RA Arteriotomy closure devices for cardiovascular procedures Circulation 2010 122 1882 93 20921445 \n7 Looby S Keeling AN McErlean A Given MF Geoghegan T Lee MJ Efficacy and safety of the Angioseal vascular closure device post antegrade puncture Cardiovasc Intervent Radiol 2008 31 558 62 18253787 \n8 Yakubov SJ Kahn JK Bergman GW Mewissen MW Device reliability and safety using the Angioseal STS vascular closure device in interventional patients Am J Cardiol 2001 88 32G \n9 Eggebrecht H Haude M Woertgen U Schmermund A von Birgelen C Naber C Systematic use of a collagen-based vascular closure device immediately after cardiac catheterisation procedures in 1317 consecutive patients Catheter Cardiovasc Intervent 2002 57 486 95 \n10 Schnyder G Sawhney N Whisenant B Tsimikas S Turi ZG Common femoral artery anatomy is influenced by demographics and comorbidity: Implications for cardiac and peripheral invasive studies Catheter Cardiovasc. Intervent 2001 55 289 95 \n11 Grier D Hartnell G Percutaneous femoral artery puncture: Practice and anatomy Br J Radiol 1990 63 602 4 2400874 \n12 O’Sullivan GJ Buckenham TM Belli AM The use of the Angioseal haemostatic puncture closure device in high risk patients Clin Radiol 1998 54 51 5 9915511 \n13 Kensey KR Puncture site haemostasis J Invasive Cardiol 1994 6 273 6 10155082 \n14 St. Jude Medical, Angio-seal, Evolution are trademarks of St. Jude Medical, Inc. Or its related companies. Reprinted with permission of St. Jude Medical™, ©2013. All rights reserved \n15 Chevalier B Lancelin B Koning R Henry M Gommeaux A Pilliere R Effect of a closure device on complication rates in high-local-risk-patients: Results of a randomised multicenter trial Catheter Cardiovasc Interv 2003 58 285 91 12594688 \n16 Park Y Roh HG Choo SW Lee SH Shin SW Do YS Prospective comparison of collagen plug (Angioseal) and suture mediated (Closure S) closure devices at the femoral access sites Korean J Radiol 2005 6 248 55 16374083 \n17 Moran T Increased throughput, staff efficiencies and patient comfort with the use of the Angioseal device Cath Lab Digest 2001 16 18 Current Innovations in Vascular Sealing Supp \n18 Lowrie M Closing femoral artery punctures: A new approach Cath Lab Digest 1995 3 6 \n19 Yee KM Lazzam C Richards J Ross J Seidelin PH Same day discharge after coronary stenting: A faesability study using a haemostatic femoral puncture closure device J Interv Cardiol 2004 17 315 20 15491335 \n20 Upponi SS Ganeshan AG Warakaulle DR Phillips-Hughes J Boardman P Uberoi R Angioseal versus manual compression for haemostasis following peripheral vascular diagnostic and interventional procedures: A randomised controlled trial Eur J Radiol 2007 61 332 4 17071040 \n21 Sumter D Sivadon A Lorenz L The path of least resistance: How Angioseal helped one lab find the road to better economic performance Cath Lab Digest 2004 12 3 \n22 Popma JJ Satler LF Pichard AD Kent KM Campbell A Chuang YC Vascular complications after balloon and new device angioplasty Circulation 1993 88 1569 78 8403304 \n23 Sibler S Haemostasis success rates and local complications using collagen after femoral access for cardiac catheterisation Am J Heart 1998 135 152 6 \n24 Ratnam LA Raja J Munneke GJ Morgan RA Belli AM Prospective non randomised trial of manual compression and Angioseal Starclose arterial closure devices in common femoral punctures Cardiovasc Interv Radiol 2007 30 182 8\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0970-2016",
"issue": "23(2)",
"journal": "The Indian journal of radiology & imaging",
"keywords": "Angiography; Angioseal™; endovascular intervention; vascular access site closure",
"medline_ta": "Indian J Radiol Imaging",
"mesh_terms": null,
"nlm_unique_id": "8503873",
"other_id": null,
"pages": "134-8",
"pmc": null,
"pmid": "24082477",
"pubdate": "2013-04",
"publication_types": "D016428:Journal Article",
"references": "15491335;10155082;9453535;11385148;7759724;10953101;11458402;17200896;9915511;16374083;12455083;2400874;17071040;18253787;9541843;20921445;8403304;12594688;17350361",
"title": "Initial experience with Angioseal™: Safety and efficacy of the endovascular closure device.",
"title_normalized": "initial experience with angioseal safety and efficacy of the endovascular closure device"
} | [
{
"companynumb": "GB-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2015-BI-71753BI",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ASPIRIN"
},
"d... |
{
"abstract": "Infantile hemangiomas (IH) are neoplastic proliferations of endothelial cells which occur with an incidence of 10 to 12% within the first year of life. IH grow after birth and usually regress spontaneously, but still can lead to deformities when they are located in the facial areas of the lip, eyelid, nasal tip or the ear. We wanted to share our experience in the treatment of problematic IH with propranolol. A retrospective review of medical charts was performed for 40 consecutive children treated with propranolol because of problematic IH between 2009 and 2012. 40 patients (33 girls, 7 boys) with a median age of 4.2 months (aged 1 to 11 months) were treated because of problematic IH. Rapid improvement was reported in the first days of treatment in 38 patients. In one case we had to terminate the treatment because serious tachycardia developed within the first 48 hours after propranolol was started. In this case the patient benefited from alternative treatment with timolol maleate gel. 35 patients (87%) showed an excellent response with complete resolution of the lesion. 4 patients (10%) showed a good result with >50% reduction in the size of the hemangioma. Also a patient with residual IH after terminating oral propranolol benefited from topical treatment with timolol maleate gel. A minor side effect was poor weight gain during prolonged treatment in one patient and tachycardia in another patient in which case we had to terminate the treatment.\n\n\nCONCLUSIONS\nOur observations show that gradually increasing the dosage of propranolol up to 3 mg/kg and gradually weaning the dosage is safe and effective in treatment of problematic IH. Timolol maleate gel should be considered as a complementary treatment for residual hemangiomas after terminating propranolol treatment or as an alternative treatment in patients who do not tolerate oral propranolol well.",
"affiliations": "Pediatric Surgery Department, Medical University of Bialystok, Poland.;Pediatric Surgery Department, Medical University of Bialystok, Poland.;Pediatric Surgery Department, Medical University of Bialystok, Poland.;Pediatric Surgery Department, Medical University of Bialystok, Poland.;Pediatric Surgery Department, Medical University of Bialystok, Poland.;Pediatric Surgery Department, Medical University of Bialystok, Poland.",
"authors": "Oksiuta|Marzanna|M|;Matuszczak|Ewa|E|;Dębek|Wojciech|W|;Dzienis-Koronkiewicz|Ewa|E|;Hermanowicz|Adam|A|;Tylicka|Marzena|M|",
"chemical_list": "D000319:Adrenergic beta-Antagonists; D011433:Propranolol",
"country": "Poland",
"delete": false,
"doi": "10.5604/17322693.1120990",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0032-5449",
"issue": "68()",
"journal": "Postepy higieny i medycyny doswiadczalnej (Online)",
"keywords": null,
"medline_ta": "Postepy Hig Med Dosw (Online)",
"mesh_terms": "D000284:Administration, Oral; D000319:Adrenergic beta-Antagonists; D005260:Female; D018324:Hemangioma, Capillary; D006801:Humans; D007223:Infant; D007224:Infant Care; D007231:Infant, Newborn; D008297:Male; D009386:Neoplastic Syndromes, Hereditary; D011433:Propranolol; D012189:Retrospective Studies; D012878:Skin Neoplasms; D016896:Treatment Outcome",
"nlm_unique_id": "101206517",
"other_id": null,
"pages": "1138-44",
"pmc": null,
"pmid": "25228522",
"pubdate": "2014-09-12",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": null,
"title": "Treatment of problematic infantile hemangiomas with propranolol: a series of 40 cases and review of the literature.",
"title_normalized": "treatment of problematic infantile hemangiomas with propranolol a series of 40 cases and review of the literature"
} | [
{
"companynumb": "PHHY2015PL086839",
"fulfillexpeditecriteria": "1",
"occurcountry": "PL",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PROPRANOLOL\\PROPRANOLOL HYDROCHLORIDE"
},
"drugadditi... |
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