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"abstract": "BACKGROUND\nThe management of metastatic progressive radioiodine-resistant differentiated thyroid cancer remains challenging for clinicians. The availability of tyrosine kinase inhibitors (TKIs), sorafenib and lenvatinib, within the last decade has expanded treatment options; however, these lead to significant adverse effects, which may curtail their use.\n\n\nMETHODS\nWe report the case of a 47-year-old female with Hurthle cell thyroid cancer who underwent total thyroidectomy followed by radioiodine ablation. During follow-up, she developed noniodine-avid renal and pulmonary metastases. With respect to her pre-existing diabetes, hypertension, and polycystic kidney disease, the tumor board decided against performing renal metastasectomy because of the risk of future renal decline requiring dialysis. Metastases were treated using sorafenib, which provided stability followed by progression within a year. We switched to lenvatinib, which led to disease regression. However, the patient experienced severe adverse effects, including cardiomyopathy, bicytopenia, renal impairment, and the rarely reported nephrotic syndrome. Renal metastasis is a rare manifes-tation of Hurthle cell thyroid cancer with only two reported cases in literature. We report the experience of our first case of renal metastasis and its treatment with TKIs. This case serves as a reminder of the adverse drug reactions associated with TKI use.\n\n\nCONCLUSIONS\nWe advocate close monitoring of patients' hematological and renal profiles as well as their cardiac status using an echocardiogram.",
"affiliations": "Department of Medicine, King Faisal Specialist Hospital, Research Centre, Al Faisal University, Riyadh 12713, Saudi Arabia. mimran74@hotmail.com.;Department of Medicine, King Faisal Specialist Hospital, Research Centre, Al Faisal University, Riyadh 12713, Saudi Arabia.;Department of Medicine, King Faisal Specialist Hospital, Research Centre, Al Faisal University, Riyadh 12713, Saudi Arabia.",
"authors": "Butt|Muhammad Imran|MI|;Khalid Bakhsh|Abdulmohsen Mohammed|AM|;Nadri|Quaid Johar|QJ|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.5306/wjco.v12.i4.272",
"fulltext": "\n==== Front\nWorld J Clin Oncol\nWJCO\nWorld Journal of Clinical Oncology\n2218-4333\nBaishideng Publishing Group Inc\n\njWJCO.v12.i4.pg272\n10.5306/wjco.v12.i4.272\nCase Report\nLenvatinib-induced multiorgan adverse events in Hurthle cell thyroid cancer: A case report\nButt MI et al. Lenvatinib-induced AEs in thyroid cancer\nButt Muhammad Imran Department of Medicine, King Faisal Specialist Hospital, Research Centre, Al Faisal University, Riyadh 12713, Saudi Arabia. mimran74@hotmail.com\n\nKhalid Bakhsh Abdulmohsen Mohammed Department of Medicine, King Faisal Specialist Hospital, Research Centre, Al Faisal University, Riyadh 12713, Saudi Arabia\n\nNadri Quaid Johar Department of Medicine, King Faisal Specialist Hospital, Research Centre, Al Faisal University, Riyadh 12713, Saudi Arabia\n\nAuthor contributions: Butt MI is the primary endocrinology physician involved in the care of the patient, and he reviewed the literature and drafted the manuscript; Bakhsh MK is the endocrinology fellow who took informed written consent from the patient and collated and prepared the laboratory data for the manuscript; Nadri QJ offered nephrology consultation and care for the management of renal adverse events; all authors reviewed and approved the final version of the manuscript.\n\nCorresponding author: Muhammad Imran Butt, FRCP, MD, MRCP, Doctor, Department of Medicine, King Faisal Specialist Hospital, Research Centre, Al Faisal University, Zahrawi St, Al Maather, Al Maazer, Riyadh 12713, Saudi Arabia. mimran74@hotmail.com\n\n24 4 2021\n24 4 2021\n12 4 272281\n22 12 2020\n30 1 2021\n7 3 2021\n©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.\n2020\nhttps://creativecommons.org/licenses/by-nc/4.0/ This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial.\nBACKGROUND\n\nThe management of metastatic progressive radioiodine-resistant differentiated thyroid cancer remains challenging for clinicians. The availability of tyrosine kinase inhibitors (TKIs), sorafenib and lenvatinib, within the last decade has expanded treatment options; however, these lead to significant adverse effects, which may curtail their use.\n\nCASE SUMMARY\n\nWe report the case of a 47-year-old female with Hurthle cell thyroid cancer who underwent total thyroidectomy followed by radioiodine ablation. During follow-up, she developed noniodine-avid renal and pulmonary metastases. With respect to her pre-existing diabetes, hypertension, and polycystic kidney disease, the tumor board decided against performing renal metastasectomy because of the risk of future renal decline requiring dialysis. Metastases were treated using sorafenib, which provided stability followed by progression within a year. We switched to lenvatinib, which led to disease regression. However, the patient experienced severe adverse effects, including cardiomyopathy, bicytopenia, renal impairment, and the rarely reported nephrotic syndrome. Renal metastasis is a rare manifes-tation of Hurthle cell thyroid cancer with only two reported cases in literature. We report the experience of our first case of renal metastasis and its treatment with TKIs. This case serves as a reminder of the adverse drug reactions associated with TKI use.\n\nCONCLUSION\n\nWe advocate close monitoring of patients’ hematological and renal profiles as well as their cardiac status using an echocardiogram.\n\nHurthle cell thyroid cancer\nLenvatinib\nNephrotic syndrome\nVascular endothelial growth factor\nProtein kinase inhibitors\nKidney neoplasms/secondary neoplasm\nCase report\n==== Body\nCore Tip: The present case study provides a unique learning and case management experience. Our patient had widespread metastasis from a histopathologically low-risk thyroid cancer coupled with two decades of survival despite noniodine-avid metastasis, treatment of renal metastasis with tyrosine kinase inhibitors, and the development of multisystem adverse events, including rare nephrotic syndrome.\n\nINTRODUCTION\n\nThe worldwide annual incidence of thyroid cancer is increasing, and it is the most common cancer that involves the endocrine organs[1]. This increase is thanks to the improved availability and sophistication of imaging technologies, such as high-resolution ultrasonography of the neck. This has led to early detection of small tumors. According to the Surveillance, Epidemiology, and End Results database, the mortality rate of thyroid cancer is exceptionally low at 0.5 per 100000 individuals per year. Moreover, the 5-year survival rate of thyroid cancer is 98.3% because of early detection as well as a predominantly localized disease[2]. In Saudi Arabia, the incidence of thyroid cancer subtypes show a pattern similar to the rest of the world, with papillary thyroid cancer at 85%, follicular thyroid cancer at 5.7%, and medullary thyroid cancer at 3.1%. However, the incidence of thyroid cancer among Saudi citizens in 2015 was 8.5% of all newly diagnosed cancers[3]. This contrasts with a much lower annual rate of 2.9% in the United States[2]. The exact reason for this is unknown. However, possi-bilities include iodine deficiency in the region, exposure to depleted uranium in the previous Gulf war, and increasing prevalence of obesity in the area.\n\nThe prognosis for patients with radioactive iodine (RAI)-avid metastatic disease remains good, with a 56% 10-year survival in avid metastasis vs 10% 10-year survival in noniodine-avid metastasis[4]. Over time, nearly two-thirds of these distant metastases progress to RAI-nonavid disease, similar to our case. Such cases present a treatment challenge. Within the last decade, the US Food and Drug Administration (FDA) approved tyrosine kinase inhibitors (TKIs), sorafenib and lenvatinib, for treating RAI-resistant progressive metastatic differentiated thyroid cancers (DTC). Patients treated with multi-targeted TKIs have shown progression-free survival in the DECISION[5] and SELECT[6] phase 3 clinical trials, albeit the overall survival benefit was not reached in these trials. However, these treatment options have undesirable side effects, which were experienced by > 95% of patients in both trials. We describe a unique case who presented with a confluence of adverse events (AEs) associated with the use of lenvatinib, including nephrotic syndrome, renal impairment, cardiomyopathy, and bicytopenia.\n\nCASE PRESENTATION\n\nChief complaints\n\nA 47-year-old female patient presented to our clinic in January 2001 with a swelling on the left side of her neck.\n\nHistory of present illness\n\nThe patient noticed that the swelling gradually increased over the preceding six months without any pain or pressure symptoms.\n\nHistory of past illness\n\nShe had a history of hypertension (HTN) and type 2 diabetes (T2DM) that were being treated with oral agents.\n\nPhysical examination\n\nPhysical examination revealed a non-tender swelling on the left side of her neck. It moved during the swallowing, was firm in consistency, and had no tethering of overlying skin. In addition, no palpable cervical lymph nodes were detected.\n\nLaboratory examinations\n\nHer complete blood count parameters as well as renal and thyroid function tests were normal.\n\nImaging examinations\n\nAn ultrasound scan of the neck revealed a large solid hypoechoic lesion with ill-defined margins measuring a maximum of 2.8 cm in the left lobe of the thyroid gland.\n\nFurther diagnostic work-up\n\nFine needle aspiration cytology showed follicular cells (many of which demonstrated a Hurthle cell change), raising the suspicion of Hurthle cell neoplasm.\n\nFINAL DIAGNOSIS\n\nShe underwent total thyroidectomy in January 2001, and the procedure was uneventful. Histopathology showed Hurthle cell thyroid cancer (HCTC) with maximum tumor size of 2.5 cm. There was one focus of capsular and two foci of small vessel invasion, and the tumor extended to the perithyroidal soft tissue. One focus of micropapillary thyroid cancer, measuring 0.5 cm, was present in the left lobe without any invasion.\n\nTREATMENT\n\nShe underwent diagnostic iodine 123 whole-body scan (WBS), which showed a tracer uptake of 1% in the thyroid bed. There was no uptake outside the neck. The stimulated thyroglobulin (TG) level upon thyroxine withdrawal was 723 mcg/L (reference 0-55 mcg/L) with thyrotropin stimulating hormone level of 59 mU/L (reference 0.35-5.5 mU/L) and free thyroid hormone (FT4) level of < 2 pmol/L (reference 11-23 pmol/L). Anti-TG antibodies were absent. She was administered a dose of 147 millicuries (mCi) radioiodine (RAI) ablation. Her post-therapy scans four days later did not show any new lesions.\n\nIn 2002, she had a recurrence in the neck, which was treated with bilateral neck dissection. Fourteen dissected lymph nodes were free of metastases. However, the pre-tracheal tissue deposit showed HCTC with prominent vascular invasion. This was followed by 60 Grays (Gy) of external beam radiotherapy to the neck delivered in two phases.\n\nShe continued to have an exceedingly high TG level, for which we performed diagnostic iodine 123 WBS that did not show any persistent or recurrent disease. In addition, 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) scan in 2003 showed no evidence of metastatic disease. In 2004, she underwent computed tomography (CT) scan of the chest, abdomen, and pelvis. CT revealed a solitary nodule (7 mm in size) in the middle lobe of the right lung, which remained stable on follow-up monitoring. Moreover, CT showed hepatic and bilateral renal cysts with radiological appearance consistent with polycystic kidney disease (PCKD). We administered another dose of 200 mCi RAI as empirical therapy in 2006 because of persistently elevated TG, although diagnostic iodine 123 WBS was negative. Her post-therapy scan did not show any radiotracer uptake.\n\nOUTCOME AND FOLLOW-UP\n\nShe was continuously monitored, and in 2011, FDG PET scan showed FDG-avid right renal mass measuring 4 cm in size and multiple micronodules in both the lung parenchyma (Figure 1). Iodine 123 WBS did not show any iodine-avid metastases (Figure 2). CT-guided biopsy of the renal mass revealed a renal oncocytoma. Given the benign nature of this renal tumor, she was monitored by urologists with no intervention. Lung nodules continued to increase in number and size, with some increasing to > 1.5-2.0 cm in size. Given this progression, in 2015, we suggested sorafenib. She reported that she felt healthy and elected not to pursue this option and was lost to follow-up. She revisited the clinic toward the end of 2017 when CT of the trunk showed significant progression of the pulmonary metastasis with some nodules > 2.5 cm in size (Figure 3). The renal mass also progressed in size, reaching 6 cm with evidence of invasion to the right renal vein. This etiology was inconsistent with a benign tumor; therefore, we reviewed the original biopsy from the renal mass. Immunohistochemistry was positive for thyroid transcription factor 1, paired box 8, and TG, which confirmed metastases from HCTC to the kidney.\n\nFigure 1 Positron emission tomography/computed tomography scan shows pulmonary metastases and new development of right renal metastasis.\n\nFigure 2 Diagnostic iodine-123 whole-body scan showing no tracer uptake in pulmonary and renal metastases. WBS: Whole-body scan.\n\nFigure 3 Chest computed tomography shows pulmonary metastases progression from Hurthle cell thyroid cancer.\n\nThe urology tumor board decided against performing a right nephrectomy because it would have left the patient with a solitary kidney with large cysts. Because of existing T2DM and HTN, there was a significant risk of future renal decline requiring renal replacement therapy; hence, no intervention was offered.\n\nShe was prescribed sorafenib 400 mg twice a day in March 2018 and she tolerated it well with a transient mouth ulcer. The dose was briefly reduced to 200 mg twice a day until the ulcer subsided. Surveillance radiological imaging at 3 mo and 6 mo showed disease stability without a reduction in TG levels. At 12 mo, PET showed progression in the number and size of pulmonary metastases (Figure 4). In August 2019, we discontinued sorafenib because of disease progression and initiated lenvatinib 24 mg daily, which has been shown to improve progression-free survival even in patients who have previously progressed with another TKI[6]. She tolerated the medication well with occasional diarrhea. Radiological monitoring at 3 mo and 6 mo showed stability with some reduction in the size of pulmonary metastases. TG levels declined in tandem with radiological stability (Figures 5 and 6A).\n\nFigure 4 Positron emission tomography/computed tomography scan shows pulmonary metastases progression one year after treatment with sorafenib. PET: Positron emission tomography.\n\nFigure 5 Positron emission tomography/computed tomography scan shows regression of pulmonary and renal metastases with lenvatinib.\n\nFigure 6 Blood test trends during tyrosine kinase inhibitor treatment. A: Thyroglobulin; B: Hemoglobin; C: Platelet counts; D: Renal profile; E: Serum albumin levels during tyrosine kinase inhibitor therapy.\n\nThe patient experienced asymptomatic bicytopenia with a decline in red blood cells and platelets 10 wk after initiating lenvatinib. Hematological markers, including Coombs test, haptoglobin, reticulocyte count, lactate dehydrogenase, and peripheral blood morphology, did not indicate hemolysis. We managed the condition as an AE of lenvatinib and reduced the dose to 14 mg, which led to an improvement in indices (Figure 6B and C).\n\nFurther monitoring showed increasing proteinuria and a new impairment in renal function; hence, treatment was discontinued for two weeks and restarted with a 10 mg daily dose in March 2020. In May 2020, she presented with a 3-d history of diarrhea and acute kidney injury. She was administered intravenous fluid replacement and symptomatic care during hospitalization. Her proteinuria progressed to the nephrotic range, reaching 6 g per 24 h, coupled with a decline in estimated glomerular filtration rate (eGFR) to < 30 mL/min per 1.73 m2 (reference eGFR > 90 mL/min per 1.73 m2). At this stage, we discontinued lenvatinib. Five months later, we noticed a trend toward improvement with proteinuria reducing to 2.4 g per 24 h, plasma albumin rising to normal levels of 32 g/dL (reference 28-46 g/L) , and serum creatinine decreasing from 258 μmol/L to 160 μmol/L (reference 64-115 μmol/L) (Figure 6D and E). We have maintained regular telephone and clinic follow-up, and the patient continues to show improvement in the hematological and renal parameters, although the lung metastasis has shown a slight increase in size. She desires to restart TKI once her metabolic derangements normalize.\n\nDISCUSSION\n\nOur patient had a long history of T2DM, HTN, and PCKD, all of which can cause varying degrees of compromise to renal function as well as lead to proteinuria. However, she had normal baseline serum urea, creatinine, and eGFR levels. She had microalbuminuria before the initiation of lenvatinib. Renal indices worsened upon the initiation of lenvatinib but improved upon discontinuation, thus providing a clue toward a causal relationship of lenvatinib with respect to renal parameters in our patient.\n\nOur patient had multiple large bilateral renal cysts. Moreover, the right kidney had a large metastatic tumor deposit from the thyroid cancer. In this context, performing a renal biopsy to determine the cause of nephrotic syndrome risked further compromise to an already impaired renal function. It was therefore deemed unsafe and not performed.\n\nRenal impairment is a well-recognized side effect associated with TKI use. Both sorafenib and lenvatinib are FDA-approved TKIs for use in patients with progressive metastatic RAI-resistant thyroid cancer. The DECISION trial did not report on sorafenib-associated renal adverse effects[5]. However, the incidence of sorafenib-associated proteinuria of any grade was 11.6%, whereas the incidence of grade ≥ 3 was 0.9% in a recent meta-analysis[7].\n\nIn the SELECT trial involving lenvatinib, nearly one-third of all patients experienced some degree of proteinuria and 10% developed grade ≥ 3 proteinuria[6]. Some degree of renal impairment developed in 14% patients, while 1.9% developed grade ≥ 3 renal impairment. In a subgroup analysis of the Japanese population in the SELECT trial, the incidence of renal adverse effects was higher with any grade proteinuria of 63% and grade 3 proteinuria of 20%, even after adjusting the dose with weight[8].\n\nThe real-world experience of using lenvatinib and sorafenib in the Japanese population showed a much higher incidence of proteinuria (all grades) of 60.8% and 27.8%, respectively[9]. The mean change in eGFR was a decrease of 6.75% with lenvatinib vs an increase of 5.9% with sorafenib[9]. The median duration of treatment was 14.9 mo with lenvatinib and 4.6 mo with sorafenib in this retrospective study, which accounts for a higher incidence of proteinuria with lenvatinib. The authors reported five patients who developed nephrotic range proteinuria based on semiquantitative analysis using urine dipstick measurement, unlike our patient who had 24-h urine collection for estimating proteinuria.\n\nAn Italian real-life observational study that included 94 patients with DTC treated with lenvatinib reported reduced AE rates with grade ≥ 3 HTN of 4.7% and proteinuria of 1.7%[10]. These results are better than those observed in the SELECT trial[6]. The likely explanation for these superior results could be increased awareness, monitoring, and treatment of HTN and proteinuria by clinicians or gradual increase in the dose. A higher rate of AE observed in Japanese studies[8,9] and a lower rate of AE observed due to lenvatinib in the Italian study[10] suggest that different populations are distinctively predisposed toward AE risks with the same drug. Therefore, it is prudent to conduct an observational study in the Middle Eastern community to quantify the risk to our population.\n\nA recent meta-analysis reported 18.7% of all grade and 2.4% of high-grade proteinuria with a nearly three-fold higher risk using anti-vascular endothelial growth factor (VEGF) TKI therapy[7]. The risk remained the same regardless of the renal or nonrenal site of the underlying cancer. Moreover, the risk varied depending on the use of different TKIs. However, the meta-analysis did not include any studies with lenvatinib. By contrast, Boursiquot et al[11] studied the use of anti-VEGF TKI therapy in patients with renal cell carcinoma. They found that it did not negatively impact the renal function of patients in the long term, even when used in patients with a pre-existing renal impairment or new development of HTN. They did not assess proteinuria pretreatment; however, only 7% of the patients had clinically relevant proteinuria during treatment.\n\nUnderstanding the structure and normal function of glomeruli provides insight into the mechanism of TKI-induced renal injury. The fenestrated endothelium, the glomerular basement membrane, and the podocytes in the Bowman capsule form a physical barrier against the filtration of macromolecules in the glomeruli. The podocytes produce nephrin, podocin, and VEGF proteins that are essential for the development, maintenance, and function of the vascular endothelium within the glomeruli[12,13]. Anti-VEGF TKI therapies suppress the production of these proteins, which impair the normal morphology and function of glomeruli, causing glomerular injury that leads to renal impairment and proteinuria.\n\nTreatment with anti-VEGF TKI therapies can lead to a new development or worsening of established HTN. Our patient had pre-existing HTN, and we optimized her medications as per requirement. There is some evidence that glomerular injury precedes the new development of HTN; therefore, HTN cannot be the sole trigger for proteinuria[12]. Moreover, some patients remain normotensive, yet they develop proteinuria. By contrast, some patients develop HTN without any accompanying proteinuria. This observation suggests that other factors may contribute to HTN development. Horowitz et al[14] demonstrated that anti-VEGF therapies could block the VEGF-mediated vasodilation via the activation of nitric oxide (NO) synthase within the endothelial cells. Therefore, HTN may be observed in patients on anti-VEGF TKI therapy. A more recent study evaluated lenvatinib-treated patients with DTC, all of whom developed new HTN. They reported a drop in serum NO levels coupled with an increase in VEGF levels 6 d after treatment, suggesting that HTN may be caused by a reduction in NO levels at the level of vascular endothelium due to anti-VEGF therapy[15]. HTN development is considered as a surrogate marker of the therapeutic effect of anti-VEGF therapy, and those who develop new or worsening HTN show a trend toward survival benefit[11].\n\nThese targeted TKIs are well known to cause cardiovascular toxicity[16]. This study also carried out a meta-analysis, which included only sorafenib among the FDA-approved therapies for thyroid cancer, showed that it increased the risk of myocardial infarction, HTN, and left ventricular systolic dysfunction[16]. Moreover, both the DECISION[5] and SELECT trials[6] reported cardiac dysfunction presenting as the prolongation of corrected QT as well as impairment of cardiac function. Our patient had a normal echocardiogram during sorafenib treatment. However, she developed mild to moderate left ventricular systolic and diastolic dysfunction and ejection fraction reduction to 40%-45% during lenvatinib treatment. The 12-lead electro-cardiograph did not show any abnormality.\n\nJensen et al[17] demonstrated that sorafenib-treated mice experienced deleterious effects in the myocardial metabolic pathways leading to systolic cardiac dysfunction, as shown on their echocardiograms after just two weeks of exposure. They noted a significant reduction in the levels of various metabolites that are involved in the taurine and hypotaurine metabolism pathways in the myocardium. Taurine, an amino acid, is available in abundance within the myocardium that functions in reducing injury caused due to oxidants[18]. Moreover, Ramila et al[19] found that taurine-deficient hearts had reduced sarcoplasmic reticulum calcium ATPase activity that affected the calcium sensitivity of myofibril proteins. They concluded that this could be responsible for deleterious effects on myocardial contractility.\n\nHematological derangements are not uncommon with TKI use. Our patient developed transient anemia and thrombocytopenia. Thrombocytopenia was the most common grade ≥ 3 AE observed in 25% of the patients in the meta-analysis of lenvatinib trials[20]. This observation was in sharp contrast with the 1.5% rate of grade ≥ 3 thrombocytopenia observed in the SELECT trial[6]. These variations could be due to different populations, inclusion/exclusion criteria, durations of exposure, pre-existing comorbidities, and concomitant use of other drugs that could predispose patients to these AEs.\n\nVEGF receptor is present on most hematopoietic cells and peripheral cells, including the platelets and monocytes. The inhibitory effect of these anti-VEGF TKIs on hematopoiesis and myelopoiesis probably causes cytopenia. In addition, these multikinases block the platelet-derived growth factor receptor present on the hematopoietic stem cells and megakaryocytes. This hampers the function of platelet-derived growth factor, which promotes the production of platelets by direct effects on the bone marrow[21]. There is some evidence that thrombocytopenia could be caused by drug-induced immune-mediated response, as shown by the presence of antiplatelet antibodies during TKI treatment[22].\n\nKidneys are an exceedingly rare metastatic site from HCTC with only two reported cases in literature[23,24]. Both patients had iodine-avid metastasis; one patient underwent nephrectomy and RAI ablation cleared metastases in the other patient. Neither of these cases required treatment with TKIs. Our patient’s cancer was noniodine avid and surgically unresectable, and she had PCKD. She required TKIs but experienced significant multiorgan AEs, all of which added more knowledge to the existing information regarding the treatment of such patients. Another unusual aspect of our patient was a progressive and metastatic tumor with a relatively low-risk pathology that otherwise carried a low risk of recurrence and metastasis[25].\n\nCONCLUSION\n\nIn conclusion, the present case was unique and provided a unique learning and case management experience. The patient had widespread metastases despite a low-risk pathology, prolonged overall survival approaching two decades despite noniodine-avid distant metastases, and a confluence of multiorgan AEs with the use of lenvatinib.\n\nACKNOWLEDGEMENTS\n\nWe thank Al-Hindi HN, Alsuhaibani H, Almsaadi S, and the Department of Endocrinology for providing invaluable support required for patient care.\n\nInformed consent statement: The patient provided a written informed consent. We conducted the study in accordance with the guidelines outlined in the declaration of Helsinki. This study was approved by the Institutional Ethics Committee of King Faisal Specialist Hospital and Research Centre (approval No. RAC 2200330).\n\nConflict-of-interest statement: The authors declare that they have no conflict of interest.\n\nCARE Checklist (2016) statement: The authors have read the CARE Checklist (2016), and the manuscript was prepared and revised according to the CARE Checklist (2016).\n\nManuscript source: Unsolicited manuscript\n\nCorresponding Author's Membership in Professional Societies: Fellow of Royal College of Physicians Glasgow UK, No. 89279; and Fellow of American Association of Clinical Endocrinology, No. 12768.\n\nPeer-review started: December 22, 2020\n\nFirst decision: January 11, 2021\n\nArticle in press: March 7, 2021\n\nSpecialty type: Oncology\n\nCountry/Territory of origin: Saudi Arabia\n\nPeer-review report’s scientific quality 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: Zhang J S-Editor: Gao CC L-Editor: A P-Editor: Yuan YY\n==== Refs\n1 Pellegriti G Frasca F Regalbuto C Squatrito S Vigneri R Worldwide increasing incidence of thyroid cancer: update on epidemiology and risk factors J Cancer Epidemiol 2013 2013 965212 23737785\n2 National Cancer Institute Surveillance, Epidemiology, and End Results Program. [cited November 28, 2020]. Available from: https://seer.cancer.gov/\n3 Saudi Health Council Cancer incidence report Saudi Arabia, 2016. [cited July 25, 2020]. Available from: https://nhic.gov.sa/en/eServices/Documents/2016.pdf\n4 Durante C Haddy N Baudin E Leboulleux S Hartl D Travagli JP Caillou B Ricard M Lumbroso JD De Vathaire F Schlumberger M Long-term outcome of 444 patients with distant metastases from papillary and follicular thyroid carcinoma: benefits and limits of radioiodine therapy J Clin Endocrinol Metab 2006 91 2892 2899 16684830\n5 Brose MS Nutting CM Jarzab B Elisei R Siena S Bastholt L de la Fouchardiere C Pacini F Paschke R Shong YK Sherman SI Smit JW Chung J Kappeler C Peña C Molnár I Schlumberger MJ DECISION investigators Sorafenib in radioactive iodine-refractory, locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 3 trial Lancet 2014 384 319 328 24768112\n6 Schlumberger M Tahara M Wirth LJ Robinson B Brose MS Elisei R Habra MA Newbold K Shah MH Hoff AO Gianoukakis AG Kiyota N Taylor MH Kim SB Krzyzanowska MK Dutcus CE de las Heras B Zhu J Sherman SI Lenvatinib versus placebo in radioiodine-refractory thyroid cancer N Engl J Med 2015 372 621 630 25671254\n7 Zhang ZF Wang T Liu LH Guo HQ Risks of proteinuria associated with vascular endothelial growth factor receptor tyrosine kinase inhibitors in cancer patients: a systematic review and meta-analysis PLoS One 2014 9 e90135 24621598\n8 Kiyota N Schlumberger M Muro K Ando Y Takahashi S Kawai Y Wirth L Robinson B Sherman S Suzuki T Fujino K Gupta A Hayato S Tahara M Subgroup analysis of Japanese patients in a phase 3 study of lenvatinib in radioiodine-refractory differentiated thyroid cancer Cancer Sci 2015 106 1714 1721 26426092\n9 Iwasaki H Yamazaki H Takasaki H Suganuma N Sakai R Nakayama H Toda S Masudo K Renal dysfunction in patients with radioactive iodine-refractory thyroid cancer treated with tyrosine kinase inhibitors: A retrospective study Medicine (Baltimore) 2019 98 e17588 31626129\n10 Locati LD Piovesan A Durante C Bregni M Castagna MG Zovato S Giusti M Ibrahim T Puxeddu E Fedele G Pellegriti G Rinaldi G Giuffrida D Verderame F Bertolini F Bergamini C Nervo A Grani G Rizzati S Morelli S Puliafito I Elisei R Real-world efficacy and safety of lenvatinib: data from a compassionate use in the treatment of radioactive iodine-refractory differentiated thyroid cancer patients in Italy Eur J Cancer 2019 118 35 40 31299580\n11 Boursiquot BC Zabor EC Glezerman IG Jaimes EA Hypertension and VEGF (Vascular Endothelial Growth Factor) Receptor Tyrosine Kinase Inhibition: Effects on Renal Function Hypertension 2017\n12 Eremina V Jefferson JA Kowalewska J Hochster H Haas M Weisstuch J Richardson C Kopp JB Kabir MG Backx PH Gerber HP Ferrara N Barisoni L Alpers CE Quaggin SE VEGF inhibition and renal thrombotic microangiopathy N Engl J Med 2008 358 1129 1136 18337603\n13 Tryggvason K Patrakka J Wartiovaara J Hereditary proteinuria syndromes and mechanisms of proteinuria N Engl J Med 2006 354 1387 1401 16571882\n14 Horowitz JR Rivard A van der Zee R Hariawala M Sheriff DD Esakof DD Chaudhry GM Symes JF Isner JM Vascular endothelial growth factor/vascular permeability factor produces nitric oxide-dependent hypotension. Evidence for a maintenance role in quiescent adult endothelium Arterioscler Thromb Vasc Biol 1997 17 2793 2800 9409257\n15 Sueta D Suyama K Sueta A Tabata N Yamashita T Tomiguchi M Takeshita T Yamamoto-Ibusuki M Yamamoto E Izumiya Y Kaikita K Yamamoto Y Hokimoto S Iwase H Tsujita K Lenvatinib, an oral multi-kinases inhibitor, -associated hypertension: Potential role of vascular endothelial dysfunction Atherosclerosis 2017 260 116 120 28390289\n16 Escalante CP Chang YC Liao K Rouleau T Halm J Bossi P Bhadriraju S Brito-Dellan N Sahai S Yusuf SW Zalpour A Elting LS Epidemiology Section of the Mucositis Study Group of the Multinational Association of Supportive Care in Cancer 2013 Meta-analysis of cardiovascular toxicity risks in cancer patients on selected targeted agents Support Care Cancer 2016 24 4057 4074 27344327\n17 Jensen BC Parry TL Huang W Beak JY Ilaiwy A Bain JR Newgard CB Muehlbauer MJ Patterson C Johnson GL Willis MS Effects of the kinase inhibitor sorafenib on heart, muscle, liver and plasma metabolism in vivo using non-targeted metabolomics analysis Br J Pharmacol 2017 174 4797 4811 28977680\n18 Schuller-Levis GB Park E Taurine: new implications for an old amino acid FEMS Microbiol Lett 2003 226 195 202 14553911\n19 Ramila KC Jong CJ Pastukh V Ito T Azuma J Schaffer SW Role of protein phosphorylation in excitation-contraction coupling in taurine deficient hearts Am J Physiol Heart Circ Physiol 2015 308 H232 H239 25437920\n20 Zhu C Ma X Hu Y Guo L Chen B Shen K Xiao Y Safety and efficacy profile of lenvatinib in cancer therapy: a systematic review and meta-analysis Oncotarget 2016 7 44545 44557 27329593\n21 Ye JY Chan GC Qiao L Lian Q Meng FY Luo XQ Khachigian LM Ma M Deng R Chen JL Chong BH Yang M Platelet-derived growth factor enhances platelet recovery in a murine model of radiation-induced thrombocytopenia and reduces apoptosis in megakaryocytes via its receptors and the PI3-k/Akt pathway Haematologica 2010 95 1745 1753 20562316\n22 Barak AF Bonstein L Lauterbach R Naparstek E Tavor S Tyrosine kinase inhibitors induced immune thrombocytopenia in chronic myeloid leukemia? Hematol Rep 2011 3 e29 22593820\n23 Madani A Jozaghi Y Tabah R How J Mitmaker E Rare metastases of well-differentiated thyroid cancers: a systematic review Ann Surg Oncol 2015 22 460 466 25192681\n24 Claimon A Suh M Cheon GJ Lee DS Kim EE Chung JK Bilateral Renal Metastasis of Hürthle Cell Thyroid Cancer with Discordant Uptake Between I-131 Sodium Iodide and F-18 FDG Nucl Med Mol Imaging 2017 51 256 260 28878853\n25 Ghossein RA Hiltzik DH Carlson DL Patel S Shaha A Shah JP Tuttle RM Singh B Prognostic factors of recurrence in encapsulated Hurthle cell carcinoma of the thyroid gland: a clinicopathologic study of 50 cases Cancer 2006 106 1669 1676 16534796\n\n",
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"issue": "12(4)",
"journal": "World journal of clinical oncology",
"keywords": "Case report; Hurthle cell thyroid cancer; Kidney neoplasms/secondary neoplasm; Lenvatinib; Nephrotic syndrome; Protein kinase inhibitors; Vascular endothelial growth factor",
"medline_ta": "World J Clin Oncol",
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"title": "Lenvatinib-induced multiorgan adverse events in Hurthle cell thyroid cancer: A case report.",
"title_normalized": "lenvatinib induced multiorgan adverse events in hurthle cell thyroid cancer a case report"
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"abstract": "The present study reports a rare case of radiation recall pneumonitis attributed to ifosfamide that was used as a single antitumor agent for a recurrent malignant soft tissue tumor, arising from the chest wall. A 74-year-old man, who had a mass in his right upper chest wall, underwent surgical excision under the diagnosis of chronic expanding hematoma. He was referred to the present hospital with a recurrent tumor as the excised tumor was diagnosed as undifferentiated high-grade sarcoma. The extension of the tumor following previous surgery was aggressive and the tumor margins were unclear on magnetic resonance imaging. Wide excision was done with adequate margins for the new recurrent tumor as it was difficult to set sufficient tumor margins following the previous surgery. Radiotherapy (60 Gy) on his right subclavicular area and chemotherapy with ifosfamide (3.5 g × 4 days/cycle) was started 1 month following surgery to control the growth of residual tumors and to prevent metastases. The third cycle of chemotherapy with ifosfamide (3 g × 4 days) was started 80 days following the final surgery and 15 days following termination of radiotherapy. Following administration, he felt short of breath and dyspnea gradually increased. This condition was diagnosed as interstitial pneumonitis induced by ifosfamide following radiotherapy. Although corticosteroid pulse therapy was performed, he died due to respiratory failure. To the best of the author's knowledge, this is the first case report of radiation recall pneumonitis induced by ifosfamide used as a single anti-tumor agent. Caution is needed when ifosfamide is planned for patients who have undergone previous radiotherapy to the chest.",
"affiliations": "Department Orthopaedics, Matsushita Memorial Hospital, Moriguchi, Osaka 570-8540, Japan.;Department Orthopaedics, Matsushita Memorial Hospital, Moriguchi, Osaka 570-8540, Japan.;Department Orthopaedics, Matsushita Memorial Hospital, Moriguchi, Osaka 570-8540, Japan.;Department Orthopaedics, Matsushita Memorial Hospital, Moriguchi, Osaka 570-8540, Japan.",
"authors": "Murata|Hiroaki|H|;Koyama|Kenzou|K|;Takezawa|Yasunobu|Y|;Nishigaki|Yasunori|Y|",
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"country": "England",
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"issue": "8(4)",
"journal": "Molecular and clinical oncology",
"keywords": "chest wall; ifosfamide; malignant soft tissue tumor; radiation recall pneumonitis; radiotherapy",
"medline_ta": "Mol Clin Oncol",
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"pubdate": "2018-04",
"publication_types": "D016428:Journal Article",
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"title": "Radiation recall pneumonitis induced by ifosfamide for malignant soft tissue tumor arising from the chest wall: A case report.",
"title_normalized": "radiation recall pneumonitis induced by ifosfamide for malignant soft tissue tumor arising from the chest wall a case report"
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"abstract": "The histologic appearance of Kayexalate, an ion-exchange resin, in bronchioles and alveolar spaces is described. Aspiration of this material occurred as a terminal event in an infant who suffered neonatal asphyxia and meconium aspiration. A solution of Kayexalate prepared for comparison appears to be identical to that found in the lung sections.",
"affiliations": null,
"authors": "Oi|R H|RH|",
"chemical_list": "D007475:Ion Exchange Resins",
"country": "England",
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"doi": "10.1093/ajcp/69.1.359",
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"journal": "American journal of clinical pathology",
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"mesh_terms": "D001238:Asphyxia Neonatorum; D001980:Bronchi; D005260:Female; D005547:Foreign Bodies; D006801:Humans; D007231:Infant, Newborn; D001239:Inhalation; D007475:Ion Exchange Resins; D011650:Pulmonary Alveoli",
"nlm_unique_id": "0370470",
"other_id": null,
"pages": "359-61",
"pmc": null,
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"pubdate": "1978-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "The microscopic appearance of a sodium-potassium exchange resin in histologic sections.",
"title_normalized": "the microscopic appearance of a sodium potassium exchange resin in histologic sections"
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"companynumb": "US-CONCORDIA PHARMACEUTICALS INC.-GSH201706-003712",
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"abstract": "OBJECTIVE\nInfliximab is currently used for the treatment of active Crohn's disease (CD). We aimed to assess the efficacy and safety of infliximab therapy and to determine the predictors of response in Korean patients with CD.\n\n\nMETHODS\nA total of 317 patients who received at least one infliximab infusion for active luminal CD (n=198) and fistulizing CD (n=86) or both (n=33) were reviewed retrospectively in 29 Korean referral centers. Clinical outcomes of induction and maintenance therapy with infliximab, predictors of response, and adverse events were evaluated.\n\n\nRESULTS\nIn patients with luminal CD, the rates of clinical response and remission at week 14 were 89.2% and 60.0%, respectively. Male gender and isolated colonic disease were associated with higher remission rates at week 14. In week-14 responders, the probabilities of sustained response and remission were 96.2% and 93.3% at week 30 and 88.0% and 77.0% at week 54, respectively. In patients with fistulizing CD, clinical response and remission were observed in 85.0% and 56.2% of patients, respectively, at week 14. In week-14 responders, the probabilities of sustained response and remission were 94.0% and 97.1%, respectively, at both week 30 and week 54. Thirty-nine patients (12.3%) experienced adverse events related to infliximab. Serious adverse events developed in 19 (6.0%) patients including seven cases of active pulmonary tuberculosis.\n\n\nCONCLUSIONS\nInfliximab induction and maintenance therapy are effective and well tolerable in Korean patients with luminal and fistulizing CD. However, clinicians must be aware of the risk of rare yet critical adverse events.",
"affiliations": "Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul, Korea.;Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul, Korea.;Department of Internal Medicine, Sungkyunkwan University School of Medicine, Seoul, Korea.;Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea.;Department of Internal Medicine, Inje University College of Medicine, Busan, Korea.;Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.;Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.;Department of Internal Medicine, Kyungpook National University Graduate School of Medicine, Daegu, Korea.;Department of Internal Medicine, Dongguk University College of Medicine, Goyang, Korea.;Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.;Department of Internal Medicine, Inje University College of Medicine, Busan, Korea.;Department of Internal Medicine, Chonnam National University Medical School, Gwangju, Korea.;Department of Internal Medicine, Kyung Hee University College of Medicine, Seoul, Korea.;Department of Internal Medicine, Eulji University College of Medicine, Seoul, Korea.;Department of Internal Medicine, Sungkyunkwan University School of Medicine, Seoul, Korea.;Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.;Department of Internal Medicine, Jeju National University School of Medicine, Jeju, Korea.;Department of Gastroenterology, Ajou University School of Medicine, Suwon, Korea.;Department of Gastroenterology, University of Ulsan College of Medicine, Seoul, Korea.;Department of Gastroenterology, University of Ulsan College of Medicine, Seoul, Korea.;Department of Internal Medicine, The Catholic University of Korea College of Medicine, Seoul, Korea.;Department of Internal Medicine, The Catholic University of Korea College of Medicine, Seoul, Korea.;Department of Internal Medicine, Konkuk University College of Medicine, Seoul, Korea.;Department of Internal Medicine, Kyung Hee University College of Medicine, Seoul, Korea.;Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.;Department of Internal Medicine, Yeungnam University College of Medicine, Daegu, Korea.;Department of Internal Medicine, Inje University College of Medicine, Busan, Korea.;Department of Internal Medicine, The Catholic University of Korea College of Medicine, Seoul, Korea.;Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul, Korea.;Department of Internal Medicine, Soonchunhyang University College of Medicine, Seoul, Korea.;Department of Internal Medicine, Ewha Womans University School of Medicine, Seoul, Korea.;Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea.;Department of Internal Medicine, Kyung Hee University College of Medicine, Seoul, Korea.;Department of Internal Medicine, Hanyang University College of Medicine, Guri, Korea.;Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea. kimwonho@yuhs.ac.",
"authors": "Choi|Chang Hwan|CH|;Song|In Do|ID|;Kim|Young Ho|YH|;Koo|Ja Seol|JS|;Kim|You Sun|YS|;Kim|Joo Sung|JS|;Kim|Nayoung|N|;Kim|Eun Soo|ES|;Kim|Jae Hak|JH|;Kim|Ji Won|JW|;Kim|Tae Oh|TO|;Kim|Hyun Soo|HS|;Kim|Hyo Jong|HJ|;Park|Young Sook|YS|;Park|Dong Il|DI|;Park|Soo Jung|SJ|;Song|Hyun Joo|HJ|;Shin|Sung Jae|SJ|;Yang|Suk Kyun|SK|;Ye|Byong Duk|BD|;Lee|Kang Moon|KM|;Lee|Bo In|BI|;Lee|Sun Young|SY|;Lee|Chang Kyun|CK|;Im|Jong Pil|JP|;Jang|Byung Ik|BI|;Jeon|Tae Joo|TJ|;Cho|Yu Kyung|YK|;Chang|Sae Kyung|SK|;Jeon|Seong Ran|SR|;Jung|Sung Ae|SA|;Jeen|Yoon Tae|YT|;Cha|Jae Myung|JM|;Han|Dong Soo|DS|;Kim|Won Ho|WH|;|||",
"chemical_list": "D000893:Anti-Inflammatory Agents; D000911:Antibodies, Monoclonal; D005765:Gastrointestinal Agents; D000069285:Infliximab; D011241:Prednisone",
"country": "Korea (South)",
"delete": false,
"doi": "10.3349/ymj.2016.57.6.1376",
"fulltext": "\n==== Front\nYonsei Med JYonsei Med. JYMJYonsei Medical Journal0513-57961976-2437Yonsei University College of Medicine 10.3349/ymj.2016.57.6.1376Original ArticleGastroenterology & HepatologyEfficacy and Safety of Infliximab Therapy and Predictors of Response in Korean Patients with Crohn's Disease: A Nationwide, Multicenter Study Choi Chang Hwan 1*Song In Do 1*Kim Young-Ho 2Koo Ja Seol 3Kim You Sun 4Kim Joo Sung 5Kim Nayoung 5Kim Eun Soo 6Kim Jae Hak 7Kim Ji Won 5Kim Tae Oh 4Kim Hyun Soo 8Kim Hyo Jong 9Park Young Sook 10Park Dong Il 2Park Soo Jung 11Song Hyun Joo 12Shin Sung Jae 13Yang Suk-Kyun 14Ye Byong Duk 14Lee Kang-Moon 15Lee Bo In 15Lee Sun-Young 16Lee Chang Kyun 9Im Jong Pil 5Jang Byung Ik 17Jeon Tae Joo 4Cho Yu Kyung 15Chang Sae Kyung 1Jeon Seong Ran 18Jung Sung-Ae 19Jeen Yoon Tae 3Cha Jae Myung 9Han Dong Soo 20Kim Won Ho 11IBD Study Group of the Korean Association for the Study of the Intestinal Diseases 1 Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul, Korea.2 Department of Internal Medicine, Sungkyunkwan University School of Medicine, Seoul, Korea.3 Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea.4 Department of Internal Medicine, Inje University College of Medicine, Busan, Korea.5 Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.6 Department of Internal Medicine, Kyungpook National University Graduate School of Medicine, Daegu, Korea.7 Department of Internal Medicine, Dongguk University College of Medicine, Goyang, Korea.8 Department of Internal Medicine, Chonnam National University Medical School, Gwangju, Korea.9 Department of Internal Medicine, Kyung Hee University College of Medicine, Seoul, Korea.10 Department of Internal Medicine, Eulji University College of Medicine, Seoul, Korea.11 Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.12 Department of Internal Medicine, Jeju National University School of Medicine, Jeju, Korea.13 Department of Gastroenterology, Ajou University School of Medicine, Suwon, Korea.14 Department of Gastroenterology, University of Ulsan College of Medicine, Seoul, Korea.15 Department of Internal Medicine, The Catholic University of Korea College of Medicine, Seoul, Korea.16 Department of Internal Medicine, Konkuk University College of Medicine, Seoul, Korea.17 Department of Internal Medicine, Yeungnam University College of Medicine, Daegu, Korea.18 Department of Internal Medicine, Soonchunhyang University College of Medicine, Seoul, Korea.19 Department of Internal Medicine, Ewha Womans University School of Medicine, Seoul, Korea.20 Department of Internal Medicine, Hanyang University College of Medicine, Guri, Korea.Corresponding author: Dr. Won Ho Kim, Department of Internal Medicine, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, Korea. Tel: 82-2-2228-1950, Fax: 82-2-393-6884, kimwonho@yuhs.ac*Chang Hwan Choi and In Do Song contributed equally to this work.\n\n01 11 2016 30 8 2016 57 6 1376 1385 11 8 2015 05 3 2016 12 4 2016 © Copyright: Yonsei University College of Medicine 20162016This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Purpose\nInfliximab is currently used for the treatment of active Crohn's disease (CD). We aimed to assess the efficacy and safety of infliximab therapy and to determine the predictors of response in Korean patients with CD.\n\nMaterials and Methods\nA total of 317 patients who received at least one infliximab infusion for active luminal CD (n=198) and fistulizing CD (n=86) or both (n=33) were reviewed retrospectively in 29 Korean referral centers. Clinical outcomes of induction and maintenance therapy with infliximab, predictors of response, and adverse events were evaluated.\n\nResults\nIn patients with luminal CD, the rates of clinical response and remission at week 14 were 89.2% and 60.0%, respectively. Male gender and isolated colonic disease were associated with higher remission rates at week 14. In week-14 responders, the probabilities of sustained response and remission were 96.2% and 93.3% at week 30 and 88.0% and 77.0% at week 54, respectively. In patients with fistulizing CD, clinical response and remission were observed in 85.0% and 56.2% of patients, respectively, at week 14. In week-14 responders, the probabilities of sustained response and remission were 94.0% and 97.1%, respectively, at both week 30 and week 54. Thirty-nine patients (12.3%) experienced adverse events related to infliximab. Serious adverse events developed in 19 (6.0%) patients including seven cases of active pulmonary tuberculosis.\n\nConclusion\nInfliximab induction and maintenance therapy are effective and well tolerable in Korean patients with luminal and fistulizing CD. However, clinicians must be aware of the risk of rare yet critical adverse events.\n\nCrohn's diseaseinfliximabtuberculosis\n==== Body\nINTRODUCTION\nCrohn's disease (CD) is a chronic disorder that causes inflammation in any location of the gastrointestinal (GI) tract, although it is most commonly in the end of the small bowel and proximal large bowel.12 Patients with CD suffer from GI symptoms, such as abdominal pain and diarrhea, as well as disease-related complications, including stricture and fistula.12 Fistulas are common manifestations in CD due to its transmural nature. A variety of proteases and matrix metalloproteinases are released by immune activation, and these enzymes provoke tissue destruction, sinus tract formation, and ultimately penetration into adjacent tissues.3\n\nConventional medical therapies, such as 5-aminosalicylates, corticosteroids, and immunomodulators (IMMs) are effective in patients with CD; however, many patients continue to suffer from disabling conditions due to insufficient responses or side effects of these drugs.456 The introduction of infliximab, an antibody against tumor necrosis factor (TNF)-α, has greatly improved treatment efficacy in patients with CD. Infliximab is a chimeric immunoglobulin G 1 monoclonal antibody that neutralizes the biologic activity of TNF-α, which plays a central role in the pathogenesis of CD.78 In many studies, infliximab was effective in the induction and maintenance therapy of moderate to severely active CD in patients who had not responded to treatments with a corticosteroid or IMMs. In addition, infliximab has been demonstrated to effectively induce and maintain a clinical response in patients with fistulizing CD and to induce mucosal healing in patients with active luminal CD.1910 Treatment with infliximab is generally well tolerated. However, infliximab infusions can be associated with several adverse events, such as acute and delayed hypersensitivity (serum sickness-like reactions), infusion reactions, infectious complications, and hepatosplenic T-cell lymphomas.1112\n\nTo date, most studies that have evaluated the efficacy and safety of infliximab have been conducted in patients in Western countries who have different genetic, ethnic, and environmental backgrounds from Asian patients.13 There are limited data regarding the efficacy and safety of infliximab for Asian CD patients. Moreover, many of the Western studies were randomized controlled trials (RCTs) that might not have properly investigated CD patients encountered during routine clinical practice. In fact, many patients with CD evaluated in an outpatient clinic may not qualify for enrollment in an RCT of biological reagents.14 Use of infliximab is rapidly increasing with the accompanying increasing incidence of CD in Korea, and there is a specific concern about reactivation of tuberculosis (TB), as the prevalence of latent and active TB remains high.1516 Therefore, we aimed to investigate the efficacy and safety of infliximab therapy in Korean patients with luminal and/or fistulizing CD and to identify clinical predictors of response to the therapy.\n\nMATERIALS AND METHODS\nPatients\nThis nationwide multicenter study was carried out at 29 referral hospitals in South Korea. We retrospectively reviewed the medical records of CD patients with refractory luminal and/or fistulizing disease who received at least one infliximab (Remicade®) infusion from 2002 to 2011. At each site, one member of the Korean Association for the Study of Intestinal Diseases was responsible for data collection.\n\nDiagnosis of CD was based on standard clinical, radiologic, endoscopic, and histopathologic criteria which in turn were based on the Lennard-Jones criteria.17 Infliximab therapy was indicated for the treatment of moderate-to-severe luminal and/or fistulizing CD in patients who had not responded to aminosalicylates, corticosteroids, or IMMs.19 All patients received 5 mg/kg infliximab intravenously at weeks 0, 2, and 6 for induction therapy and then every 8 weeks for maintenance therapy if the patients' symptoms improved with induction therapy. If the response to maintenance therapy using infliximab had been inadequate, the dose was increased to 10 mg/kg.\n\nFor all eligible patients, we collected demographic data, baseline characteristics, previous and concomitant treatments, indication for infliximab, dose and number of infusions, clinical outcomes, and adverse events of infliximab treatment, particularly those associated with TB. We used the definitions of steroid dependency, steroid refractoriness, and immunomodulator refractoriness described by the European Crohn's and Colitis Organization consensus.2 The study protocol was approved by the Institutional Review Boards at all participating sites.\n\nOutcome measures\nFor the evaluation of disease activity and the response to infliximab therapy, Crohn's Disease Activity Index (CDAI) values were collected at 0, 2, 6, 14, 30, and 54 weeks and at the last follow-up visit after the first infusion of infliximab for luminal CD, and the status of fistula was determined at 0, 14, 30, and 54 weeks and at the last follow-up visit for fistulizing CD.\n\nDefinitions of clinical response and remission were adopted from the ACCENT-I and II trials.1819 In luminal CD, clinical response to treatment was defined as a decrease in CDAI score of 70 points or more from the baseline value and at least a 25% reduction in the total CDAI score, and complete response (remission) was defined as a CDAI score of less than 150. In fistulizing CD, clinical response to treatment was defined as a decrease of 50% or more in the number of fistulas and draining discharge, and complete response (remission) was defined as a complete closure of fistulas on physical examination and/or imaging studies. An external fistula was considered to be closed if no discharge was drained despite gentle finger compression. Patients with partial response were defined as those who had clinical response but did not achieve remission. Initial response and remission rates were evaluated at 2, 6, and 14 weeks for luminal CD and at 14 weeks for fistulizing CD. The estimated rates of sustained clinical response and remission were determined at weeks 30 and 54 among patients who had clinical response or remission at week 14. Loss of response or remission was defined by a CDAI score or fistula status that did not meet the response or remission criteria at weeks 30 and 54.\n\nFactors that might affect clinical remission at week 14 and sustained clinical remission at weeks 30 and 54 were evaluated as follows: sex, age at diagnosis, age at first infusion of infliximab, time from diagnosis to first infusion, body mass index, smoking, disease location, concomitant medications, and laboratory and colonoscopic findings.\n\nMucosal healing was defined as the absence of mucosal ulceration in all segments examined via ileocolonoscopy. Serious adverse events were defined as those that were life threatening, required hospitalization, or led to significant disability or incapacity.20\n\nStatistical analysis\nAll continuous data are expressed as mean±standard deviation. We used Student's t-test for continuous variables and the chis-quare test for discrete variables. Univariate and multivariate logistic regression analyses were used to identify predictors of complete response at week 14. A Kaplan-Meier analysis was used to estimate sustained response and remission rates at weeks 30 and 54, and a log-rank test was used to identify predictors associated with sustained clinical remission. Patients with sustained clinical response or remission were censored at the last clinical visit. All p values were two-tailed, and p values of <0.05 were considered to be statistically significant. Statistical analyses were performed using SPSS version 18.0 for Windows (SPSS, Inc., Chicago, IL, USA).\n\nRESULTS\nBaseline characteristics\nA total of 317 CD patients were included in this study, and data were collected from September 2009 through September 2011. All of the patients received at least one infliximab infusion for the treatment of CD between 2002 and 2011, with a mean follow-up of 23.2±18.8 months from the first infusion. Mean ages at diagnosis and at first treatment with infliximab for CD were 25.9±10.2 (range 12–79) and 29.5±10.8 (range 14–79) years, respectively. Regarding past medical history, 17 patients had a history of active TB. A tuberculosis skin test (TST), interferon gamma releasing assay (IGRA), or both tests were performed in 183 (57.7%), 100 (31.5%), and 56 (17.7%) patients, respectively, for latent TB infection (LTBI), and positive findings of TST, IGRA, and both tests were observed in 18 (9.8%), 11 (11%), and one (1.8%) patient, respectively. A simple chest X-ray was performed in all patients before infliximab infusion, and five patients had TB scar changes. Patients who had at least one positive finding among TB scars on chest X-ray, TST, and IGRA were considered to have LTBI (n=33). Among these 33 patients, 18 patients had received TB prophylaxis. Six patients had a family history of inflammatory bowel disease (CD: 5; ulcerative colitis: 1). In colonoscopic findings, ileocolonic ulcers (excluding aphthous ulcers) were observed in 79.7% (192 of 241), and a cobblestone appearance was observed in 37.3% (90 of 241). The baseline characteristics of the patients are summarized in Table 1.\n\nInfliximab therapy\nThe indication of infliximab therapy was as follows: 198 patients (62.5%) were treated for active luminal CD, 86 patients (27.1%) for fistulizing CD, and 33 patients (10.4%) for both active luminal and fistulizing CD. Among the patients with active luminal CD, 56 (28.3%) had steroid dependency, 30 (15.2%) had steroid refractoriness, and 98 (49.5%) had IMM refractoriness. Among 119 patients with fistulas, 99 (83.2%) had external fistulas, and 28 (23.5%) had internal fistulas. The median number of infliximab infusions was eight, ranging from one to 31. The standard dose of 5 mg/kg infliximab was administered and maintained in most cases. During infliximab therapy, a dose increase was applied in eight patients (2.5%) and an interval decrease in two (0.6%). One hundred thirty-three (42%) patients discontinued therapy due to primary non-response (n=26), loss of response (n=23), intolerable adverse events (n=12), follow-up loss (n=16), economic difficulties (n=12), disease remission (n=27), or other reasons (n=17). A flow chart of the study population for each analysis is presented in Fig. 1.\n\nEfficacy of infliximab in active luminal CD\nAfter the first infusion of infliximab, treatment efficacy was assessed in 227 patients at week 2, 206 patients at week 6, and 185 patients at week 14 among the 231 patients who were diagnosed with luminal CD or both luminal and fistulizing CD. Clinical response and remission were observed in 163 (71.8%) and 89 (39.2%) patients at week 2, in 177 (85.9%) and 110 (53.4%) at week 6, and in 165 (89.2%) and 111 (60.0%) at week 14, respectively (Fig. 2). CDAI scores at weeks 2, 6, and 14 decreased from the baseline value of 295.0±82.9 to 150.3±72.0, 132.1±70.2, and 134.1±84.1 at each time point, respectively. An analysis to identify factors related to clinical remission at week 2 showed a significantly higher likelihood of remission in patients whose first infusion of infliximab was less than 3 years from diagnosis than in those whose first infusion was greater than 3 years (47.1% vs. 30.6%, p=0.011); however, no other factors were associated with the remission rate. There was no factor associated with the remission rate at week 6. On analysis of the factors related to clinical remission at week 14, male gender and isolated colonic disease were associated with a high remission rate (Table 2). On multivariate logistic regression analysis, male gender [odds ratio (OR)=1.99, 95% confidence interval (CI): 1.06–3.73, p=0.032] and isolated colonic disease (OR=4.96 vs. small bowel disease, 95% CI: 1.68–14.67, p=0.004) were significantly associated with the remission rate. The other factors were not associated with the remission rate at week 14.\n\nAmong 165 patients who had a partial or complete response at week 14, the estimated rates of sustained clinical response were 96.2% at week 30 and 88.0% at week 54, respectively, on Kaplan-Meier analysis. In 111 patients with complete response (remission) at week 14, the estimated rates of sustained clinical remission were 93.3% at week 30 and 77.0% at week 54, respectively (Fig. 3). Log-rank test results showed that no clinical factors were associated with the remission rate at week 30 as well as at week 54, including sex, time from diagnosis to first infusion of infliximab, and concomitant IMM use.\n\nOf 231 patients, 170 received ileocolonoscopy before infliximab therapy. Active ulcerations and a cobblestone appearance were found in 141 (82.9%) and 65 (38.2%) patients, respectively. Among 54 patients who underwent follow-up ileocolonoscopy, mucosal healing was present in 32 (59.3%). The mean interval between the initial and follow-up ileocolonoscopies was 33.7±28.9 (range 2–121 months). There were no clinical factors associated with the mucosal healing rate.\n\nTo evaluate the long-term efficacy, we performed a subanalysis in the 185 patients who were followed-up for 6 months or more. The mean follow-up period was 28.3±18.4 months (range 6–103 months). At the time of the last follow-up, the mean CDAI score was 122.3±84.4 (range 10.6–475). Of the 185 patients, 111 (60.0%) were in remission, 54 (29.2%) had mild disease, and 20 (10.8%) had moderate or severe disease based on CDAI scores. The remission rate was higher in patients with mucosal healing than in those without mucosal healing on the follow-up ileocolonoscopies (78.1% vs. 50.0%, p=0.031).\n\nEfficacy of infliximab in fistulizing CD\nAmong the 119 patients who were diagnosed with fistulizing CD or both luminal and fistulizing CD, the efficacy of induction therapy was assessed at week 14 in 73 patients who received three doses of infliximab. Clinical response and remission were observed in 62 (85.0%) and 41 patients (56.2%), respectively (Fig. 4). The clinical response and remission rates tended to be higher in patients with external fistulas than in those with internal fistulas (87.3% and 58.2% for external fistulas vs. 69.2% and 46.2% for internal fistulas, respectively), and among the patients with external fistulas, these rates tended to be higher in patients with perianal fistulas than in those with enterocutaneous fistulas (89.6% and 56.3% for perianal fistulas vs. 77.8% and 66.7% for enterocutaneous fistulas, respectively) without statistical significance. No other clinical factors were associated with the remission rate at week 14 (Table 3).\n\nAmong the 62 patients who had a partial or complete response at week 14, three failed to maintain sustained clinical response at weeks 30 and 54. In 41 patients with complete response (remission) at week 14, one did not maintain sustained clinical remission at weeks 30 and 54. The estimated rates of sustained clinical response and remission were 94.0% and 97.1%, respectively, at both weeks 30 and 54. The predictive factors for the sustained remission were not analyzed, as only one patient failed to sustain remission at weeks 30 and 54.\n\nTo evaluate the long-term efficacy, we performed a subanalysis in the 104 patients who were followed-up for 6 months or more. The mean follow-up period was 30.3±19.0 months (range 6–103 months). At the time of the last follow-up, the clinical response and remission rates were 78.8% (82 of 104) and 54.8% (57 of 104), respectively.\n\nAdverse events\nDuring the follow-up period, 34 patients (10.7%) had new CD-related complications as follows: 27 strictures, three perianal fistulas, three intra-abdominal abscesses accompanying internal fistulas, and one case of intractable GI bleeding. Twenty-seven patients (8.5%) underwent operations as follows: seven anal fistulectomies (or fistulotomies), four seton operations, 15 segmental bowel resections, and one total proctocolectomy and ileostomy.\n\nOverall, 39 patients (12.3%) experienced an adverse event during infliximab therapy (Table 4). All of the adverse events could be directly attributed to infliximab. Two of the eight patients who had chronic hepatitis B or were hepatitis B virus carriers experienced mild elevation of alanine aminotransferase, although these responses spontaneously improved. Eighteen patients (5.7%) discontinued infliximab due to serious adverse events: seven cases of severe infusion reactions, two cases of serum sickness, two cases of intra-abdominal abscess, and seven cases of active tuberculosis. There were no mortalities in this study.\n\nIn terms of tuberculosis, seven cases of active pulmonary TB developed during infliximab therapy. Two of these patients had negative results in both latent TB screening tests (TST and IGRA), and three did not undergo either latent TB test. One patient had a past history of pulmonary TB and scar change on her chest X-ray and received anti-TB prophylaxis for 9 months with isoniazid (INH), with initiation of infliximab after 3 weeks of INH medication. In all seven patients, pulmonary TB was cured with anti-TB medications; however, infliximab treatment was restarted in only one patient who continued infliximab therapy for 28 months without TB reactivation. Detailed information on patients with active TB is provided in Table 5.\n\nDISCUSSION\nThis report presents a relatively large-scale Asian study on the efficacy and safety of infliximab therapy for CD. In patients with active luminal CD, clinical response and remission rates were 89.2% and 60.0%, respectively, at week 14. The estimated rates of sustained clinical response and remission were 96.2% and 93.3% at week 30 and 88.0% and 77.0% at week 54, respectively, among the week-14 responders. For fistulizing CD, clinical response and remission rates were 85.0% and 56.2%, respectively, at week 14, and the clinical responses were maintained in most of the week-14 responders at both weeks 30 and 54. The initial responses of infliximab on fistulizing CD tended to be more effective in patients with external fistulas, more so in those with perianal fistulas than in those with internal fistulas.\n\nThe results for the response to induction therapy in our study are comparable to those of previous studies that used infliximab, which reported early response rates of 58–96% and remission rates of 40–73%.2122232425 However, the sustained response and remission rates in patients with luminal CD were slightly higher than those of previous randomized, controlled trials (RCTs) such as the ACCENT-I study, in which the clinical response and remission rates were 50% and 39% at week 30 and 39% and 30% at week 54, respectively.18 Additionally, the estimated response rates of maintenance treatments in patients with fistulizing CD in our study were higher than those in the ACCENT-II study in which the proportions of patients with response and remission were 46% and 36% at week 54, respectively.19 This disparity in response rates may be explained by differences in the characteristics of the patients (ethnicity, indications for infliximab, disease severity, and extension) or in the study design (RCT or not).\n\nCurrent treatment goals for CD are changing from the induction of symptomatic remission to the achievement of mucosal healing, as the latter leads to improved long-term clinical outcomes.2627 Mounting evidence suggests that achieving mucosal healing may change the natural course of the disease by decreasing the need for surgery and reducing hospitalization rates of CD patients.28 Mucosal healing is now recognized as a new therapeutic goal in CD, at least in clinical trials.29 Consistent with this approach, mucosal healing was associated with a higher long-term remission rate in our study. However, this result must be validated in a future prospective study.\n\nIn the analysis of the factors related to clinical remission at week 2 for luminal CD, patients whose first infusion of infliximab was less than 3 years from diagnosis had higher remission rates than those whose first infusion occurred more than 3 years after diagnosis. This is compatible with previous reports that have convincingly shown that anti-TNF therapy is more effective in patients with a short disease history.3031 However, the disease duration from diagnosis to first infusion of infliximab was not associated with clinical remission at weeks 6 and 14. In the analysis to identify factors affecting the remission rate at week 14, sex and disease location were significantly associated with the remission rate. However, the disease location was not associated with response rates at weeks 2 and 6. Thus, we cannot confidently suggest the predictive factors for initial response to infliximab due to the inconsistency of the results. A future prospective study may confirm the possibility of sex, disease location, and duration as predictive factors for initial response to infliximab in luminal CD.\n\nNo factors were associated with the efficacy of maintenance therapy in luminal CD, including sex, disease location, and duration. The SONIC trial demonstrated that the combination of infliximab and azathioprine (AZA) was superior to either infliximab or AZA alone in patients with active luminal CD naive to IMMs and biologics.32 A large portion of the patients in our study (76.7%) had experienced IMMs before infliximab therapy; therefore, the response rates did not appear to be different between the combination therapy of infliximab plus AZA and infliximab alone. In addition, patients with high baseline C-reactive protein, those with isolated colonic disease and no previous abdominal surgery, young patients, and nonsmokers have all been suggested to be more likely to respond to anti-TNF therapy.9 However, these factors were not related to the maintenance effect of infliximab therapy in our study. Only isolated colonic disease was associated with initial response. These discrepancies might also originate from differences in the characteristics and ethnicity of the study population or the study design (prospective or retrospective). Factors related to the efficacy of maintenance therapy using infliximab also need to be investigated more in a prospective study.\n\nInduction and maintenance therapy with infliximab was well tolerated in Korean patients with CD. Overall, 39 patients (12.3%) experienced an adverse event during infliximab therapy. As this study was conducted retrospectively, the overall incidence of adverse events, including infusion reactions and infections (not serious) might have been lower than in the ACCENT-I and II trials. However, the reported incidence of serious adverse events was similar to those in previous studies.1819 In this study, 19 patients (6.0%) had serious adverse events, including seven cases of active pulmonary tuberculosis. Fortunately, there were no mortalities, and all cases of active TB were safely cured with anti-TB medications.\n\nTB is significantly more common in South Korea than in other developed countries. In the USA, the incidence rate of TB was 3.2 per 100000 person-years in 2012 and is currently in decline, 33 whereas the incidence of TB in the general Korean population is 92 per 100000 person-years.34 Moreover, anti-TNF therapy was shown to be associated with a 2.5- to 18-fold increase in the incidence of TB infection compared to healthy controls, although the actual incidence was not particularly high.343536373839 Thus, screening tests to confirm active TB and LTBI prior to starting anti-TNF therapy are essential. According to the Korean guidelines for TB, patients who are to be treated with anti-TNF agents should first be checked regarding their past TB history, contact history with patients with TB, and present suspected symptoms of TB and should have a chest X-ray examination and TB infection tests.3440 The TB infection tests should be performed by using an IGRA alone or both an IGRA and a TST. A TST alone is not recommended for testing TB infection in patients with inflammatory bowel disease, as the use of immunosuppressive agents may lead to a false negative TST result due to anergy.3440 In our study, the incidence of active TB was relatively high; moreover, two patients had negative results in TB infection tests (TST and IGRA) and normal chest X-ray results, and another patient received anti-TB prophylaxis (INH, 9 months) due to LTBI among the seven patients in whom active TB developed. Thus, a screening test for TB infection using both a TST and an IGRA at one time before starting infliximab may not be sufficient to prevent active TB development, particularly in countries with a high prevalence of TB. Physicians should thoroughly review patient histories, TST and IGRA results, and chest X-ray findings before commencing anti-TNF therapy for CD, and they should also pay attention to the risk of TB development even if the patients do not have LTBI or have taken treatment for LTBI. In addition, a substantial portion of TB cases (71%, 5 of 7) occurred within 3 months after infliximab initiation. Thus, more attention to TB development may be needed during the early period of infliximab therapy.\n\nA limitation of our study was its retrospective design. Moreover, we did not evaluate trough levels and antibodies to infliximab. Nonetheless, this was a relatively large-scale, nationwide, multicenter study to evaluate the efficacy and safety in Korean patients with CD, and it provided baseline data for subsequent well-designed prospective studies.\n\nIn conclusion, we have demonstrated the efficacy of infliximab in induction and maintenance treatments in Korean patients with luminal and fistulizing CD. Infliximab treatment was safe and well tolerated. However, physicians should always be cautious about the possible adverse effects of infliximab, particularly for TB. Further prospective studies are needed to evaluate the long-term efficacy and safety of infliximab therapy and to determine the predictors of response in patients with CD.\n\nThe authors have no financial conflicts of interest.\n\nFig. 1 Flow chart of study population. CD, Crohn's disease.\nFig. 2 Clinical response (complete and partial response) and remission (complete response) at weeks 2, 6, and 14 in patients with active luminal Crohn's disease.\nFig. 3 (A) Cumulative probabilities of sustained clinical response for week 14 responders and (B) cumulative probabilities of sustained clinical remission for patients in remission at week 14 among patients with active luminal Crohn's disease.\nFig. 4 Clinical response (complete and partial response) and remission (complete response) at week 14 in patients with fistulizing Crohn's disease.\nTable 1 Baseline Characteristics of the Patients\nCharacteristics\tn=317 (%)\t\nSex, male:female\t206 (65.0%):111 (35.0%)\t\nAge, mean±SD\t\t\n Age at diagnosis\t25.9±10.2\t\n Age at 1st infliximab treatment\t29.5±10.8\t\nBody mass index (kg/m2)\t19.1±3.2\t\nFamily history of IBD\t6 (1.9%)\t\nDisease duration prior to infliximab (yrs), mean±SD\t4.1±4.2\t\nDisease type\t\t\n Active luminal disease\t198 (62.5%)\t\n Fistulizing disease\t86 (27.1%)\t\n Both\t33 (10.4%)\t\nFistula location in fistulizing CD\t\t\n Perianal\t81 (68.1%)\t\n Enterocutaneous\t35 (29.4%)\t\n Entero-enteric\t8 (6.7%)\t\n Enterovesical\t5 (4.2%)\t\n Rectovaginal\t6 (5.0%)\t\nDisease location\t\t\n Small bowel\t50 (15.8%)\t\n Colon\t60 (19.0%)\t\n Both\t207 (65.3%)\t\nCDAI, mean±SD\t279.3±92.0\t\nLaboratory findings\t\t\n Hemoglobin (g/dL), mean±SD\t11.3±1.9\t\n C-reactive protein (mg/dL), mean±SD\t6.9±19.5\t\n Albumin (g/dL), mean±SD\t3.6±1.6\t\nPrevious medication\t\t\n 5-ASA\t280 (88.3%)\t\n Antibiotics\t185 (58.4%)\t\n Corticosteroid\t217 (68.5%)\t\n AZA or 6-MP\t243 (76.7%)\t\n Methotrexate\t6 (1.9%)\t\nConcomitant medication\t\t\n 5-ASA\t247 (77.9%)\t\n Antibiotics\t100 (31.5%)\t\n Corticosteroid\t94 (29.7%)\t\n AZA or 6-MP\t185 (58.4%)\t\n Methotrexate\t0 (0%)\t\nPrevious segmental resection\t166 (52.4%)\t\nSmoking habit\t\t\n Nonsmokers\t257 (81.1%)\t\n Former smokers\t25 (7.9%)\t\n Current smokers\t18 (5.7%)\t\n Unknown\t17 (5.4%)\t\nTuberculosis history\t17 (5.4%)\t\nChronic hepatitis\t\t\n CHB/HBV carrier\t8 (2.5%)\t\n CHC\t2 (0.6%)\t\nIBD, inflammatory bowel disease; CD, Crohn's disease; CDAI, Crohn's disease activity index; CRP, C-reactive protein; 5-ASA, 5-aminosalicylates; AZA, azathioprine; 6-MP, 6-mercaptopurine; CHB, chronic hepatitis B; HBV, hepatitis B virus; CHC, chronic hepatitis C.\n\nTable 2 Predictive Factors Related to Clinical Remission at Week 14 in Luminal Crohn's Disease\n\tRemission at week 14\tp value\t\nSex\t\t0.025\t\n Male\t78/118 (66.1%)\t\t\n Female\t33/67 (49.3%)\t\t\nAge at diagnosis (yr)\t\t0.760\t\n ≤25\t65/110 (59.1%)\t\t\n >25\t46/75 (61.3%)\t\t\nAge at 1st infliximab treatment (yr)\t\t0.114\t\n ≤25\t52/78 (66.7%)\t\t\n >25\t59/107 (55.1%)\t\t\nTime from diagnosis to first infusion (yr)\t\t0.401\t\n ≤3 years\t58/92 (63%)\t\t\n >3 years\t53/93 (57%)\t\t\nBody mass index (kg/m2)\t\t0.640\t\n ≤20\t70/118 (59.3%)\t\t\n >20\t39/62 (62.9%)\t\t\nSmoking\t\t0.544\t\n Non-smoker\t88/149 (59.2%)\t\t\n Smoker\t17/26 (65.4%)\t\t\nConcomitant use of steroid\t\t0.845\t\n No\t78/129 (60.5%)\t\t\n Yes\t33/56 (58.9%)\t\t\nConcomitant use of AZA/6-MP\t\t0.201\t\n No\t42/77 (54.5%)\t\t\n Yes\t69/108 (63.9%)\t\t\nHemoglobin (g/dL)\t\t0.391\t\n ≤10\t35/54 (64.8%)\t\t\n >10\t76/131 (58%)\t\t\nC-reactive protein (mg/dL)\t\t0.175\t\n ≤2\t46/82 (56.1%)\t\t\n >2\t50/75 (66.7%)\t\t\nDisease location\t\t0.009\t\n Small bowel\t15/33 (45.5%)\t\t\n Colon\t29/36 (80.6%)\t\t\n Both\t67/116 (57.8%)\t\t\nUlcers in ileocolonoscopy at diagnosis\t\t0.129\t\n No\t10/20 (50%)\t\t\n Yes\t79/117 (67.5%)\t\t\nAZA, azathioprine; 6-MP, 6-mercaptopurine.\n\nTable 3 Predictive Factors Related to Clinical Remission at Week 14 in Fistulizing Crohn's Disease\n\tRemission at week 14\tp value\t\nSex\t\t0.370\t\n Male\t24/46 (52.2%)\t\t\n Female\t17/27 (63.0%)\t\t\nAge at diagnosis (yr)\t\t0.679\t\n ≤25\t30/52 (57.7%)\t\t\n >25\t11/21 (52.4%)\t\t\nAge at 1st infliximab treatment (yr)\t\t0.918\t\n ≤25\t21/37 (56.8%)\t\t\n >25\t20/36 (55.6%)\t\t\nTime from diagnosis to first infusion (month)\t\t0.448\t\n ≤3\t22/42 (52.4%)\t\t\n >3\t19/31 (61.3%)\t\t\nBody mass index (kg/m2)\t\t0.736\t\n ≤20\t28/48 (58.3%)\t\t\n >20\t13/24 (54.2%)\t\t\nSmoking\t\t0.918\t\n Non-smoker\t35/61 (57.4%)\t\t\n Smoker\t5/9 (55.6%)\t\t\nConcomitant use of steroid\t\t0.226\t\n No\t31/51 (60.8%)\t\t\n Yes\t10/22 (45.5%)\t\t\nConcomitant use of AZA/6-MP\t\t0.238\t\n No\t17/26 (65.4%)\t\t\n Yes\t24/47 (51.1%)\t\t\nConcomitant use of antibiotics\t\t0.526\t\n No\t21/35 (60.0%)\t\t\n Yes\t20/38 (52.6%)\t\t\nHemoglobin (g/dL)\t\t0.891\t\n ≤10\t10/18 (55.6%)\t\t\n >10\t31/54 (57.4%)\t\t\nC-reactive protein (mg/dL)\t\t0.980\t\n ≤2\t21/39 (56.1%)\t\t\n >2\t13/24 (66.7%)\t\t\nType of fistula\t\t0.984\t\n Perianal fistula only\t27/48 (56.3%)\t\t\n Others\t14/25 (56.0%)\t\t\nAZA, azathioprine; 6-MP, 6-mercaptopurine.\n\nTable 4 Adverse Events during Infliximab Therapy\n\tn=317 (%)\t\nTotal adverse events, n (%)\t39 (12.3)\t\n Infusion reaction\t17 (5.4)\t\n Serum sickness\t9 (2.8)\t\n Infection disease\t11 (3.5)\t\n Chronic hepatitis B aggravation\t2/8 (25.0)\t\n Chronic hepatitis C aggravation\t0/2 (0)\t\nSerious adverse events, n (%)\t19 (6.0)\t\n Severe infusion reactions\t7 (2.2)\t\n Serum sickness-like reactions\t2 (0.6)\t\n Serious infections\t10 (3.2)\t\nTable 5 Details of Tuberculosis Infection\nNo.\tPatient (age/sex)\tTB history\tTST*\tIGRA\tChest PA (X-ray)\tProphylaxis\tIMMs\tSteroid\tInterval to active TB (months)\t\n1\t26/M\tNo\t(−)\t(−)\tNL\tND\tYes\tYes\t30\t\n2\t43/M\tNo\tND\tND\tNL\tND\tNo\tYes\t3\t\n3\t62/M\tNo\tND\tND\tNL\tND\tNo\tYes\t2\t\n4\t33/M\tNo\t(−)\t(−)\tNL\tND\tYes\tNo\t12\t\n5\t43/M\tNo\tND\t(−)\tNL\tND\tNo\tNo\t2\t\n6\t32/M\tNo\tND\tND\tNL\tND\tYes\tNo\t2\t\n7\t46/F\tYes/lung\t(−)\tND\tTB scar\tINH/9 months\tYes\tNo\t2\t\nTB, tuberculosis; TST, tuberculosis skin test; IGRA, interferon gamma releasing assay; IMM, immunomodulator; NL, normal; ND, not done; INH, isoniazid.\n\n*A purified protein derivative reaction measuring less than 10 mm was considered negative in TST.\n==== Refs\n1 Lichtenstein GR Hanauer SB Sandborn WJ Practice Parameters Committee of American College of Gastroenterology Management of Crohn's disease in adults Am J Gastroenterol 2009 104 465 483 19174807 \n2 Van Assche G Dignass A Panes J Beaugerie L Karagiannis J Allez M The second European evidence-based consensus on the diagnosis and management of Crohn's disease: definitions and diagnosis J Crohns Colitis 2010 4 7 27 21122488 \n3 Tozer PJ Whelan K Phillips RK Hart AL Etiology of perianal Crohn's disease: role of genetic, microbiological, and immunological factors Inflamm Bowel Dis 2009 15 1591 1598 19637358 \n4 Ford AC Kane SV Khan KJ Achkar JP Talley NJ Marshall JK Efficacy of 5-aminosalicylates in Crohn's disease: systematic review and meta-analysis Am J Gastroenterol 2011 106 617 629 21407190 \n5 Khan KJ Dubinsky MC Ford AC Ullman TA Talley NJ Moayyedi P Efficacy of immunosuppressive therapy for inflammatory bowel disease: a systematic review and meta-analysis Am J Gastroenterol 2011 106 630 642 21407186 \n6 Turner D Walsh CM Steinhart AH Griffiths AM Response to corticosteroids in severe ulcerative colitis: a systematic review of the literature and a meta-regression Clin Gastroenterol Hepatol 2007 5 103 110 17142106 \n7 Knight DM Trinh H Le J Siegel S Shealy D McDonough M Construction and initial characterization of a mouse-human chimeric anti-TNF antibody Mol Immunol 1993 30 1443 1453 8232330 \n8 Plevy SE Landers CJ Prehn J Carramanzana NM Deem RL Shealy D A role for TNF-alpha and mucosal T helper-1 cytokines in the pathogenesis of Crohn's disease J Immunol 1997 159 6276 6282 9550432 \n9 D'Haens GR Panaccione R Higgins PD Vermeire S Gassull M Chowers Y The London Position Statement of the World Congress of Gastroenterology on Biological Therapy for IBD with the European Crohn's and Colitis Organization: when to start, when to stop, which drug to choose, and how to predict response? Am J Gastroenterol 2011 106 199 212 21045814 \n10 Dignass A Van Assche G Lindsay JO Lémann M Söderholm J Colombel JF The second European evidence-based consensus on the diagnosis and management of Crohn's disease: current management J Crohns Colitis 2010 4 28 62 21122489 \n11 Hamzaoglu H Cooper J Alsahli M Falchuk KR Peppercorn MA Farrell RJ Safety of infliximab in Crohn's disease: a large single-center experience Inflamm Bowel Dis 2010 16 2109 2116 20848473 \n12 Park SK Ye BD Lee C Im JP Kim YH Kim SO Risk and clinical characteristics of lymphoma in Korean patients with inflammatory bowel diseases: a multicenter study J Clin Gastroenterol 2015 49 e11 e16 24705089 \n13 Ng SC Tsoi KK Kamm MA Xia B Wu J Chan FK Genetics of inflammatory bowel disease in Asia: systematic review and meta-analysis Inflamm Bowel Dis 2012 18 1164 1176 21887729 \n14 Ha C Ullman TA Siegel CA Kornbluth A Patients enrolled in randomized controlled trials do not represent the inflammatory bowel disease patient population Clin Gastroenterol Hepatol 2012 10 1002 1007 22343692 \n15 Jo KW Hong Y Park JS Bae IG Eom JS Lee SR Prevalence of latent tuberculosis infection among health care workers in South Korea: a multicenter study Tuberc Respir Dis (Seoul) 2013 75 18 24 23946754 \n16 Lee CH Jeong YJ Heo EY Park JS Lee JS Lee BJ Active pulmonary tuberculosis and latent tuberculosis infection among homeless people in Seoul, South Korea: a cross-sectional study BMC Public Health 2013 13 720 23914947 \n17 Lennard-Jones JE Classification of inflammatory bowel disease Scand J Gastroenterol Suppl 1989 170 2 6 2617184 \n18 Hanauer SB Feagan BG Lichtenstein GR Mayer LF Schreiber S Colombel JF Maintenance infliximab for Crohn's disease: the ACCENT I randomised trial Lancet 2002 359 1541 1549 12047962 \n19 Sands BE Anderson FH Bernstein CN Chey WY Feagan BG Fedorak RN Infliximab maintenance therapy for fistulizing Crohn's disease N Engl J Med 2004 350 876 885 14985485 \n20 Maini RN Breedveld FC Kalden JR Smolen JS Furst D Weisman MH Sustained improvement over two years in physical function, structural damage, and signs and symptoms among patients with rheumatoid arthritis treated with infliximab and methotrexate Arthritis Rheum 2004 50 1051 1065 15077287 \n21 Ardizzone S Colombo E Maconi G Bollani S Manzionna G Petrone MC Infliximab in treatment of Crohn's disease: the Milan experience Dig Liver Dis 2002 34 411 418 12132788 \n22 Kim YJ Kim JW Lee CK Park HJ Shim JJ Jang JY Clinical outcome of treatment with infliximab in Crohn's disease: a single-center experience Korean J Gastroenterol 2013 61 270 278 23756669 \n23 Orlando A Colombo E Kohn A Biancone L Rizzello F Viscido A Infliximab in the treatment of Crohn's disease: predictors of response in an Italian multicentric open study Dig Liver Dis 2005 37 577 583 15886081 \n24 Present DH Rutgeerts P Targan S Hanauer SB Mayer L van Hogezand RA Infliximab for the treatment of fistulas in patients with Crohn's disease N Engl J Med 1999 340 1398 1405 10228190 \n25 Targan SR Hanauer SB van Deventer SJ Mayer L Present DH Braakman T A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor alpha for Crohn's disease Crohn's Disease cA2 Study Group N Engl J Med 1997 337 1029 1035 9321530 \n26 Bouguen G Levesque BG Feagan BG Kavanaugh A Peyrin-Biroulet L Colombel JF Treat to target: a proposed new paradigm for the management of Crohn's disease Clin Gastroenterol Hepatol 2015 13 1042 1050.e2 24036054 \n27 D'Haens GR Sartor RB Silverberg MS Petersson J Rutgeerts P Future directions in inflammatory bowel disease management J Crohns Colitis 2014 8 726 734 24742736 \n28 Peyrin-Biroulet L Ferrante M Magro F Campbell S Franchimont D Fidder H Results from the 2nd Scientific Workshop of the ECCO I: Impact of mucosal healing on the course of inflammatory bowel disease J Crohns Colitis 2011 5 477 483 21939925 \n29 Rutgeerts P Van Assche G Sandborn WJ Wolf DC Geboes K Colombel JF Adalimumab induces and maintains mucosal healing in patients with Crohn's disease: data from the EXTEND trial Gastroenterology 2012 142 1102 1111.e2 22326435 \n30 Colombel JF Sandborn WJ Rutgeerts P Enns R Hanauer SB Panaccione R Adalimumab for maintenance of clinical response and remission in patients with Crohn's disease: the CHARM trial Gastroenterology 2007 132 52 65 17241859 \n31 D'Haens G Baert F van Assche G Caenepeel P Vergauwe P Tuynman H Early combined immunosuppression or conventional management in patients with newly diagnosed Crohn's disease: an open randomised trial Lancet 2008 371 660 667 18295023 \n32 Colombel JF Sandborn WJ Reinisch W Mantzaris GJ Kornbluth A Rachmilewitz D Infliximab, azathioprine, or combination therapy for Crohn's disease N Engl J Med 2010 362 1383 1395 20393175 \n33 Centers for Disease Control and Prevention (CDC) Trends in tuberculosis--United States, 2012 MMWR Morb Mortal Wkly Rep 2013 62 201 205 23515056 \n34 Shim TS Diagnosis and treatment of latent tuberculosis infection in patients with inflammatory bowel diseases due to initiation of anti-tumor necrosis factor therapy Intest Res 2014 12 12 19 25349559 \n35 Dixon WG Hyrich KL Watson KD Lunt M Galloway J Ustianowski A Drug-specific risk of tuberculosis in patients with rheumatoid arthritis treated with anti-TNF therapy: results from the British Society for Rheumatology Biologics Register (BSRBR) Ann Rheum Dis 2010 69 522 528 19854715 \n36 Lee SK Kim SY Kim EY Jung JY Park MS Kim YS Mycobacterial infections in patients treated with tumor necrosis factor antagonists in South Korea Lung 2013 191 565 571 23728990 \n37 Marehbian J Arrighi HM Hass S Tian H Sandborn WJ Adverse events associated with common therapy regimens for moderateto-severe Crohn's disease Am J Gastroenterol 2009 104 2524 2533 19532125 \n38 Tubach F Salmon D Ravaud P Allanore Y Goupille P Bréban M Risk of tuberculosis is higher with anti-tumor necrosis factor monoclonal antibody therapy than with soluble tumor necrosis factor receptor therapy: the three-year prospective French Research Axed on Tolerance of Biotherapies registry Arthritis Rheum 2009 60 1884 1894 19565495 \n39 Yoo IK Choung RS Hyun JJ Kim SY Jung SW Koo JS Incidences of serious infections and tuberculosis among patients receiving anti-tumor necrosis factor-α therapy Yonsei Med J 2014 55 442 448 24532516 \n40 Joint Committee for the Revision of Korean Guidelines for Tuberculosis Korea Centers for Disease Control and Prevention Korean guidelines for tuberculosis 2nd ed Cheongju Korea Centers for Disease Control and Prevention 2014\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "0513-5796",
"issue": "57(6)",
"journal": "Yonsei medical journal",
"keywords": "Crohn's disease; infliximab; tuberculosis",
"medline_ta": "Yonsei Med J",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000893:Anti-Inflammatory Agents; D000911:Antibodies, Monoclonal; D003424:Crohn Disease; D004334:Drug Administration Schedule; D005260:Female; D005765:Gastrointestinal Agents; D006801:Humans; D000069285:Infliximab; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D011241:Prednisone; D012044:Regression Analysis; D012074:Remission Induction; D012189:Retrospective Studies; D016896:Treatment Outcome",
"nlm_unique_id": "0414003",
"other_id": null,
"pages": "1376-85",
"pmc": null,
"pmid": "27593865",
"pubdate": "2016-11",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": "12047962;21122489;9550432;21407190;20848473;12132788;25349559;2617184;17241859;22343692;23914947;23728990;9321530;24742736;20393175;19174807;19637358;23946754;15886081;24036054;17142106;24705089;21887729;19532125;21122488;15077287;10228190;21407186;19854715;21045814;21939925;23515056;19565495;8232330;24532516;22326435;18295023;14985485;23756669",
"title": "Efficacy and Safety of Infliximab Therapy and Predictors of Response in Korean Patients with Crohn's Disease: A Nationwide, Multicenter Study.",
"title_normalized": "efficacy and safety of infliximab therapy and predictors of response in korean patients with crohn s disease a nationwide multicenter study"
} | [
{
"companynumb": "KR-JNJFOC-20121016606",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
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{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "INFLIXIMAB"
},
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"... |
{
"abstract": "BACKGROUND\nHyperbaric oxygen therapy (HBOT) has been utilized as adjunctive treatment of CNS tumors and for radiation necrosis (RN) with reported success. The safety and efficacy in pediatric patients is less understood.\n\n\nMETHODS\nSeven patients (ages 10-23 years, six females) were treated with HBOT (3-60 sessions) for either RN (n = 5) or tumor-associated edema (n = 2). Tumor diagnosis included low-grade glioma (n = 4, two with neurofibromatosis type 1), meningioma (n = 1), medulloblastoma (n = 1) and secondary high grade glioma (n = 1). Prior therapies included: surgery (n = 4), chemotherapy (n = 4) and radiation (N = 5: four focal, one craniospinal). Three underwent biopsy: one confirming RN, one high-grade glioma, and one low-grade glioma. Patients were assessed for clinical and radiographic changes post HBOT.\n\n\nRESULTS\nMedian time to clinical and radiographic presentation was 8.5 months (range 6 months-11 years) in those who had prior radiation. Clinical improvement after HBOT (median: 40 sessions) was observed in four of seven patients. Symptoms were stable in two and worsened in one patient. Radiographic improvement was seen in four patients; three had radiographic disease progression. In the subgroup treated for presumed and biopsy-confirmed RN (n = 5), four of five (80%) had clinical and radiographic improvement. There were no long-term adverse events due to HBOT.\n\n\nCONCLUSIONS\nHBOT is safe and well-tolerated in pediatric and young adult patients with CNS tumors. Clinical and radiographic improvements were observed in over half of patients. Clinical trials are needed to establish safety and efficacy of HBOT as adjunct therapy in pediatric CNS tumors.",
"affiliations": "University of California San Diego School of Medicine, La Jolla, CA, USA.;Division of Hyperbaric Medicine and Wound Care, Department of Emergency Medicine, University of California San Diego Medical System, San Diego, CA, USA.;Department of Neurosciences, University of California San Diego, La Jolla, CA, USA.;Rady Children's Hospital, San Diego, CA, USA.;Department of Neurosciences, University of California San Diego, La Jolla, CA, USA. jrcrawford@ucsd.edu.",
"authors": "Aghajan|Yasmin|Y|;Grover|Ian|I|;Gorsi|Hamza|H|;Tumblin|Mark|M|;Crawford|John Ross|JR|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1007/s11060-018-03021-x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0167-594X",
"issue": "141(1)",
"journal": "Journal of neuro-oncology",
"keywords": "Cerebral radiation necrosis; Effects of radiation; Hyperbaric oxygen; Pediatric brain tumors",
"medline_ta": "J Neurooncol",
"mesh_terms": "D000293:Adolescent; D001929:Brain Edema; D001932:Brain Neoplasms; D002648:Child; D003131:Combined Modality Therapy; D005260:Female; D006801:Humans; D006931:Hyperbaric Oxygenation; D008297:Male; D011832:Radiation Injuries; D012189:Retrospective Studies; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "8309335",
"other_id": null,
"pages": "151-158",
"pmc": null,
"pmid": "30426388",
"pubdate": "2019-01",
"publication_types": "D016428:Journal Article",
"references": "10390002;10685584;17476357;18786715;19465788;19526835;20399573;21287528;21420247;22768993;23054400;23647507;23957206;25279957;26279024;27438082;27485098;29117289;6572704;7569022;8898978;9366305;9670434",
"title": "Use of hyperbaric oxygen therapy in pediatric neuro-oncology: a single institutional experience.",
"title_normalized": "use of hyperbaric oxygen therapy in pediatric neuro oncology a single institutional experience"
} | [
{
"companynumb": "US-BAYER-2019-091957",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "SORAFENIB"
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"drugadditional": null,
"... |
{
"abstract": "This case report describes 2 siblings with myoclonic epilepsy who had novel mutations in the glutamine synthetase (GLUL) gene: c.316C>T, p.(Arg106*) and c.42G>C, p.(Lys14Asn). Valproic acid improved seizure control, but was associated with hyperammonemic encephalopathy. Addition of carglumic acid reduced ammonia levels but drug coverage was declined. We therefore designed a protocol to measure the reduction in plasma ammonia in response to carglumic acid therapy. After the first dose of carglumic acid, Patient 1 showed a reduction in plasma ammonia levels within 3 hours, from 114 umol/L to 68 umol/L (reference 12-47 umol/L), and Patient 2 from 108 umol/L to 80 umol/L, which was sustained over a 2 week period. Overall, there was a strong negative correlation between plasma ammonia levels and carglumic acid levels (r = -0.86, p = 0.0013), and recurrence of hyperammonemic encephalopathy was not observed while the patients were taking carglumic acid.",
"affiliations": "Department of Medical Genetics and Pediatrics, Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.;Department of Medical Genetics and Pediatrics, Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.;Department of Medical Genetics and Pediatrics, Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.;Department of Medical Genetics and Pediatrics, Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.;Department of Medical Genetics and Pediatrics, Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.",
"authors": "Bennett|Jennifer|J|https://orcid.org/0000-0003-0701-4002;Gilkes|Christy|C|;Klassen|Karin|K|;Kerr|Marina|M|;Khan|Aneal|A|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1177/2329048X20967880",
"fulltext": "\n==== Front\nChild Neurol Open\nChild Neurol Open\nCNO\nspcno\nChild Neurology Open\n2329-048X SAGE Publications Sage CA: Los Angeles, CA \n\n10.1177/2329048X20967880\n10.1177_2329048X20967880\nCase Report\nTwo Siblings With Valproate-Related Hyperammonemia and Novel Mutations in Glutamine Synthetase (GLUL) Treated With Carglumic Acid\nhttps://orcid.org/0000-0003-0701-4002Bennett Jennifer BA1 Gilkes Christy BSP, RPh1 Klassen Karin RN1 Kerr Marina BHSc, BHSc (Hon)1 Khan Aneal MSc, MD, FRCPC, FCCMG1 \n1 Department of Medical Genetics and Pediatrics, 157744Alberta Children’s Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada\nAneal Khan, Alberta Children’s Hospital, 28 Oki Drive NW, Calgary, Alberta, Canada T3B 6A8. Email: khaa@ucalgary.ca\n22 10 2020 \nJan-Dec 2020 \n7 2329048X20967880© The Author(s) 20202020SAGE PublicationsThis 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).This case report describes 2 siblings with myoclonic epilepsy who had novel mutations in the glutamine synthetase (GLUL) gene: c.316C>T, p.(Arg106*) and c.42G>C, p.(Lys14Asn). Valproic acid improved seizure control, but was associated with hyperammonemic encephalopathy. Addition of carglumic acid reduced ammonia levels but drug coverage was declined. We therefore designed a protocol to measure the reduction in plasma ammonia in response to carglumic acid therapy. After the first dose of carglumic acid, Patient 1 showed a reduction in plasma ammonia levels within 3 hours, from 114 umol/L to 68 umol/L (reference 12-47 umol/L), and Patient 2 from 108 umol/L to 80 umol/L, which was sustained over a 2 week period. Overall, there was a strong negative correlation between plasma ammonia levels and carglumic acid levels (r = −0.86, p = 0.0013), and recurrence of hyperammonemic encephalopathy was not observed while the patients were taking carglumic acid.\n\nglutamine synthetaseGLULhyperammonemiacarglumic acidvalproic acidepilepsycover-dateJanuary-December 2020typesetterts3\n==== Body\nIntroduction\nAmmonia is produced from the breakdown of proteins (whether endogenous or ingested) through deamination of amino acids, and by microorganisms in the gastrointestinal tract.1,2 Hyperammonemia typically occurs when plasma ammonia levels are above 50 umol/L; the exposure of the central nervous system to such an environment can lead to encephalopathy at levels double that.3 Changes in neuronal pH, neuronal membrane potentials, astrocytic swelling, altered neurotransmitter response, and changes in cerebral energy metabolism and reduced ATP are considered some of the mechanisms of ammonia neurotoxicity.4,5 Hyperammonemic disorders can be due to liver dysfunction, side-effects from certain medications (valproic acid, topiramate, carbamazepine, thiazides, isoniazid, or chemotherapies), impaired circulation where portal vein flow to the liver is reduced (because of obstruction or surgical bypass), or inborn errors of metabolism.6,7 Due to its neurotoxicity, mechanisms have evolved to remove ammonia before it reaches systemic circulation—approximately 90% of ammonia is converted to urea via the urea cycle in periportal hepatocytes.8 The other 10% is removed by glutamine synthetase (GS) as part of the synthesis of glutamine in perivenous hepatocytes, astrocytes, the kidneys, and skeletal muscles.\n\nGS is an enzyme that synthesizes the amino acid glutamine from a condensation reaction between glutamate and ammonia.9 Glutamate itself contains ammonia, so producing one molecule of glutamine in effect removes 2 molecules of ammonia.10 Pathogenic mutations in the GLUL gene, which encodes GS, results in a rare genetic disorder that is characterized by global development delay and epilepsy, in which the anti-convulsant valproic acid (VPA) has demonstrated efficacy.11 However, adverse reactions related to VPA can also inhibit the urea cycle and induce hyperammonemia. Although the mechanism underlying VPA inhibition of the urea cycle has not been fully elucidated,12 VPA’s reactive metabolite, valproyl-CoA is considered to inhibit N-acetylglutamate synthase (NAGS)—an activator of the urea cycle. The activator NAGS synthesizes N-acetylglutamate (NAG), which activates carbamyl phosphatase synthetase I (CPS-I); CPS-I catalyzes the important first step of ammonia detoxification (Figure 1), which is the rate-limiting step in the urea cycle in individuals who do not have a urea cycle disease. Therefore, valproyl-CoA’s inhibition of urea cycle initiation has the potential to result in hyperammonemia in patients who have no urea cycle disease. Chicharro, de Marinis, and Kanner (2007) conducted a meta-analysis that suggested 16%-100% of patients receiving VPA have hyperammonemia as an adverse effect.13 However, many of these patients are described as asymptomatic (not showing signs of ammonia toxicity).\n\nFigure 1. Ammonia removal pathways and the mechanism of action of carglumic acid. Metabolites of VPA inhibit the initiation of the urea cycle. Carglumic acid circumvents this inhibition by directly stimulating CPS-I. Due to the inefficiency of GS in our patients, they need an active urea cycle to effectively remove a sufficient amount of ammonia to prevent encephalopathy.\n\nCarnitine supplementation has demonstrated efficacy in treating some patients with VPA-induced hyperammonemia. These patients have decreased carnitine levels due to valproylcarnitine formation and VPA inhibition of cellular carnitine uptake.14 Mitochondrial beta-oxidation requires carnitine as a co-factor; when carnitine’s levels are reduced, omega-oxidation becomes dominant.15 This can lead to the increased production of toxic metabolites, including propionic acid, which inhibits CPS-I. Therefore, by supplementing patients with carnitine, and conjugation and removal of the toxic inhibitory substances, the inhibition of CPS-I can be relieved (Figure 2).15 However, treatment with carnitine does not always reduce ammonia levels; factors other than accumulation of valprolylcarnitine may cause inhibition of ammonia detoxification. Further, the dose of carnitine required to remove the toxic metabolite may not be tolerable to patients, especially when taken orally, because it can lead to gastrointestinal symptoms. In patients where the discontinuation of VPA is not a favorable option, and carnitine treatment is not successful, an alternate method to reduce ammonia levels is required.\n\nFigure 2. Carnitine mechanism of action. VPA decreases cellular carnitine through the formation of valproylcarnitine and through the inhibition of cellular carnitine uptake. Decreased carnitine levels leads to increased beta-oxidation, which leads to the increased production of the toxic metabolite, propionic acid. Propionic acid inhibits CPS-I. Carnitine supplementation increases cellular carnitine levels, allowing for beta-oxidation, which does not lead to propionic acid production.\n\nCarglumic acid supplementation is typically used to treat NAGS deficiency. Carglumic acid is a synthetic structural analog of NAG, and thus, also has the ability to activate CPS-I. In VPA-induced hyperammonemia, carglumic acid can be used to reduce the inhibition of NAGS and stimulate CPS-I directly (Figure 1). For example, a case of VPA-induced hyperammonemia, with failed carnitine but successful carglumic acid treatment, is described by Sattar et al. (2018).16\n\n\nPatients and Methods\nTwo sisters of Filipino ancestry were referred to our clinic with a seizure disorder. The presentation of both affected siblings followed a similar clinical course, with developmental delay and onset of myoclonic epilepsy as early as 9 months of age; they were 21 and 12 years of age, respectively, when the carglumic acid treatment was started. Brain neuroimaging showed no specific abnormal findings. Patient 2 was initially referred to the Metabolic Clinic at Alberta Children’s Hospital with suspicion of an underlying metabolic disease. She underwent a muscle biopsy through our standard mitochondrial protocol with negative results for a mitochondrial disease, and no diagnostic findings on blood and urine metabolite analysis (plasma amino acids, plasma acyl-carnitine profile, urine organic acids, and urine orotic acid). She was also enrolled in our whole exome sequencing study called MITO-FIND (Mitochondrial Functional and Integrative Next Generation Diagnostics), which identified 2 heterozygous variants in GLUL using techniques that have been previously described.17 Based on this initial result, clinical verification was performed through family testing (both sisters and both parents), through Blueprint Genetics (Finland), confirmed 2 heterozygous variants in GLUL, signifying a compound heterozygous genotype: a c.316C>T, p.(Arg106*) non-sense variant leading to a premature stop codon, and a missense variant c.42G>C, p.(Lys14Asn). Both siblings had the same variants and they were bi-parentally inherited consistent with the clinical features of glutamine synthetase deficiency.\n\nThere were several anticonvulsant medications that were implemented to improve seizure control prior to exome sequencing which included lamotrigine, levetiracetam, clonazepam, and topiramate, but the best response (reduced severity and frequency of seizures) was achieved with VPA. Unfortunately, both patients had to discontinue VPA several times due to VPA-induced symptomatic encephalopathy, with the ammonia threshold for symptoms determined to be greater than 100 umol/L (peak levels were 128 umol/L in Patient 1, and 156 umol/L in Patient 2). Hyperammonemic symptoms included tremors, fatigue, behavioral outbursts, disorientation, and the inability to walk. Levocarnitine was tried, with one patient responding to a high dose (200 mg/kg per dose; patient weight: 21.3 kg) of intravenous levocarnitine; however, this was not sustainable as an outpatient. Neither patient would tolerate even 50 mg/kg/day of levocarnitine due vomiting and gastrointestinal discomfort, and subsequently, ammonia levels would rebound. On one admission with Patient 2, once the initial bolus of 200 mg/kg/dose of levocarnitine intravenous infusion was completed and plasma ammonia levels rebounded, the patient subsequently was treated with carglumic acid (Tables 1 and 2). This led to a reduction of plasma ammonia levels, but a supply for outpatient use of carglumic acid was declined because the patient did not meet the criteria of a primary urea cycle disorder. The only other choice was to discontinue VPA, but this led to an increase in seizure frequency, decreased responsiveness during the day, and reduced appetite and weight loss in both patients. Several months following VPA discontinuation, Patient 1 presented to the hospital with status epilepticus and VPA was restarted. This resulted in improved seizure control, but ammonia levels increased again. Shortly thereafter, Patient 2 was also restarted on VPA, which improved seizure control, but resulted in a rise in ammonia as well.\n\nTable 1. The First Patient’s Ammonia Levels as a Product of Her Treatment Regimen.a\n\n\nCarnitine\tValproic acid\tCarglumic acid\tAmmonia levels (umol/L)\t\n-\t-\t-\t39\t\n-\t+\t-\t103, 128b\n\t\n+\t+\t-\t103, 99\t\n-\t+\t+\t80\t\n\na When she was not on carnitine, valproic acid, or carglumic acid, her ammonia level was 39umol/L, but seizures were not controlled. When her ammonia levels increased as a result of valproic acid treatment (103umol/L), she was treated with one dose of carnitine 100mg/kg/dose (weight: 46.5 kg). This was ineffective as ammonia levels remained around 103umol/L, with a low of 99umol/L. During the carglumic acid trial, her ammonia levels decreased to 80umol/L.\n\n\nb Peak ammonia level patient experienced.\n\nTable 2. The Second Patient’s Ammonia Levels as a Product of Her Treatment Regimen.a\n\n\nCarnitine\tValproic acid\tCarglumic acid\tAmmonia levels (umol/L)\t\n-\t-\t-\t47\t\n-\t+\t-\t130, 156b\n\t\n+\t+\t-\t61, 100\t\n-\t+\t+\t76\t\n\na When she not on carnitine, valproic acid, or carglumic acid, her ammonia level was 47umol/L, but seizures were not controlled. When ammonia levels increased as a result of valproic acid treatment (130umol/L), she was treated with 200mg/kg IV carnitine (weight: 21.3 kg), then was put on 700 mg IV Q8 H. Ammonia levels decreased to 61umol/L, but then rebounded to 100umol/L when measured 17 hours later, on a maintenance dose. During the carglumic acid trial, her ammonia decreased to 76 umol/L.\n\n\nb Peak ammonia level patient experienced.\n\nBecause of Patient 2’s success using carglumic acid to reduce ammonia levels while on valproic acid, we made an application for compassionate use of carglumic acid through Health Canada’s special access program. Using this data, medication reimbursement could be provided for long-term use if there was demonstrated efficacy directly related to the use of carglumic acid.\n\nWithin these regulatory requirements, we designed a protocol to treat both patients with carglumic acid over 14 days to try to reduce plasma ammonia levels without discontinuing valproic acid. The objective was to determine the degree of ammonia reduction, whether this could be sustained on an outpatient basis, and if the drug could be tolerated. The carglumic acid was dosed at target of 250 mg/kg per day, in 2 divided doses over the day. Patient 1 (46 kg) was given 29 tablets (29 x 200 mg = 5800 mg; 252 mg/kg/day) and Patient 2 (36 kg) was given 22 tablets (22 x 200 mg = 4400 mg; 244 mg/kg/day) of carglumic acid per day. Blood levels of ammonia and carglumic acid were collected as follows: Day 0, 9:00 am (fasting) followed by first carglumic acid dose and repeat bloodwork at 12:30 pm (3 hours post first dose carglumic acid and after the first morning meal), Day 3: 9:00 am (before feeds and carglumic acid morning dose), Day 7: 9:00 am (before feeds and carglumic acid morning dose) and Day 14: 9:00 am (before feeds and carglumic acid morning dose). Only a 2 week supply of carglumic acid was available and repeat laboratory tests were drawn 4 weeks after carglumic acid was stopped. Testing of carglumic acid levels was performed by Biopharma Services Inc., Toronto, Ontario using standard protocols. Ammonia levels were tested at Alberta Precision Laboratories using standardized protocols in clinical care.18 The patients were not on a protein-restricted diet (because previous attempts to try this were not successful and they lost weight) and we advised the family to continue with the usual diet, and they informed us that no changes in diet were required over the duration of this protocol.\n\nResults\nFasting ammonia levels were measured before carglumic acid treatment was initiated, and 4 times throughout the 14 day trial. The carglumic acid was stopped after day 14, in order to check rebound ammonia levels 28 days after stopping carglumic acid (day 42) (Figure 3A and B). After the first dose of carglumic acid, the first patient showed a reduction in plasma ammonia levels within 3 hours, from 114 umol/L to 68 umol/L (reference 12-47 umol/L), and the second patient from 108 umol/L to 80 umol/L, following with a rise in carglumic acid levels. Patient 1 continued to have a sustained reduction in ammonia levels with a strong negative correlation (r = −0.86; p = 0.0013) over the course of the trial (Figure 4). Similarly, in Patient 2, there was a strong negative correlation (r = −0.86; p = 0.0013), suggesting a linear dose-dependent association between the carglumic acid level and plasma ammonia level. This implies that higher carglumic acid levels are associated with decreased ammonia levels. Both patients tolerated the dosing of carglumic acid well without gastrointestinal upset. Patient 1 had a rebound hyperammonemia of 103 umol/L at the 4 week post-carglumic acid follow-up, and Patient 2’s levels rebounded to 133 umol/L over the same time period. We compared the association between ammonia and carglumic acid levels in both patients. One of the patients took longer to consume their diet on the first day, so the immediate post-drug levels on the first day were therefore excluded for both patients; only first morning blood levels for both compounds, prior to any food intake or the morning carglumic acid doses, were compared for linear regression. The linear regression showed a strong inverse association between blood carglumic acid levels and ammonia levels (Figure 4) that was statistically significant, showing that the reduction in ammonia levels was commensurate with rising blood carglumic acid levels following first order kinetics.\n\nFigure 3. A, The first patient’s ammonia levels over the 42 day trial. (A) Baseline ammonia and carglumic acid levels before treatment initiation. (B) First blood draw following carglumic acid initiation. Ammonia levels stabilized near 80 umol/L. (C) Carglumic acid treatment was stopped. (D) Ammonia and carglumic acid levels returned near baseline, 28 days after treatment ceased. B, The second patient’s ammonia levels over the 42 day trial. (A) Baseline ammonia and carglumic acid levels before treatment initiation. (B) First blood draw following carglumic acid initiation. Ammonia levels were reduced to 88 umol/L at this point, despite the fact she vomited. Ammonia levels continued to decrease to 76 umol/L on day seven. (C) Carglumic acid treatment was stopped. (D) Ammonia levels rebounded above baseline to 133 umol/L 28 days after treatment ceased.\n\nFigure 4. The linear relationship between ammonia levels and carglumic acid levels in both patients. This shows a strong negative correlation (r = −0.86, p = 0.0013).\n\nDiscussion\nThe literature describes 3 previous cases of GS deficiency, of which all the patients are deceased.12,19 The first patient was a boy in Turkey born to consanguineous parents, who was resuscitated at birth. He had epileptic encephalopathy and multiple organ failure, resulting in his death at 2 days of age.19 This patient was homozygous for the c.970C>T, p.(Arg324Cys) mutation in the GLUL gene. The second patient was a girl in Turkey, born to consanguineous parents, who experienced convulsions and respiratory failure on the first day of life.12 She was diagnosed with epileptic encephalopathy, characterized by multifocal seizures, and developed a blistering erythematous rash after 2 weeks. At 28 days of life she passed away as a result of multiple organ failure. She was found to be homozygous for the c.1021C>T, p.(Arg341Cys) mutation in GLUL. The third patient was a Sudanese boy born to consanguineous parents. He presented slightly differently than the first 2 patients; he survived until 6 years of age, at which point he died of acute respiratory decompensation.12 At 13 days of age, he developed tonic-clonic seizures, and had repeated hospitalizations for uncontrolled seizures, apnea, upper and lower airway infections, and necrolytic erythema. He was found to be homozygous for the mutation c.970C>A, p.(Arg324Ser) in GLUL, which affects the same codon as the first patient, but demonstrated a different clinical course.\n\nFrieg et al. (2016) conducted molecular dynamics simulations comparing the enzymatic activity of Arg324Cys, Arg341Cys, and Arg324Ser.20 Residual enzyme activity was seen in the Arg324Ser variant, which corresponds to the milder phenotype observed in that patient. However, the variants Arg324Cys and Arg341Cys result in structurally defective proteins leading to a complete loss of enzyme activity.\n\nThere are several differences and similarities between these 3 patients and our patients. Our patients’ mutation is compound heterozygous, with a non-sense variant and a missense variant, which may have produced a non-lethal phenotype. Therefore, our patients’ may have higher level of residual activity in GS in the liver compared to the other 3 variants. The patients reported by Häberle et al. (2005, 2011) all had low levels of glutamine and high levels of ammonia, but our patients had high ammonia despite normal glutamine levels.12,19 Brain MRIs on those patients were similar, including cerebral and cerebellar atrophy, agyria, immature white matter, hypomyelination, paraventricular cysts, subependymal cysts, and enlarged lateral ventricles.21 Our patients have significant developmental delay and difficult to control seizures, but without major structural abnormalities on brain neuroimaging. This suggests that whole exome sequencing, and not biochemical screening, may be more effective in detecting more cases.\n\nThe use of VPA was associated with improved seizure control, but symptomatic hyperammonemia in our patients with GLUL deficiency. The VPA levels stayed in the therapeutic range during our period of monitoring (819 umol/L in Patient 1, 602 umol/L in Patient 2; reference 350-700 umol/L). One limitation of this trial was our inability to monitor valproic acid metabolites to see if any changes occurred with carglumic acid therapy.22 We were unable to find laboratories that could test VPA metabolites, and therefore, we do not know if using carglumic acid reduces metabolites of VPA, or whether it increases the detoxification of ammonia using the urea cycle. With stable and therapeutic blood valproic acid levels, and normal urea cycle function (no mutations were identified in the urea cycle enzymes), we hypothesize that carglumic acid likely removes the inhibition of valproic acid on residual glutamine synthetase activity or on carbamoyl phosphate synthetase 1. In an experimental animal model of glutamine synthetase, protein restriction was not helpful,23 and when we tried protein restriction in our 2 patients, they both lost weight and were actually less interactive. The optimal clinical solution in our patients was unrestricted protein, valproic acid to treat the seizures, and carglumic acid to control ammonia levels. It is not clear whether other patients who have valproate-induced hyperammonemia may have mutations in GLUL or may benefit from carglumic acid, but only a wider study in a larger number of patients would be able to provide further insight on this.\n\nAcknowledgments\nWe would like to thank Igor Grahovac at Biopharma Services Inc. (Toronto, Ontario) for performing the carglumic acid level analysis.\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) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: We did not receive any direct funding for the work in this study but compassionate use of carglumic acid medication and blood level measurements were provided in kind by Recordati Rare Diseases Canada Inc., Toronto, Ontario.\n\nORCID iD: Jennifer Bennett, BA \nhttps://orcid.org/0000-0003-0701-4002\n==== Refs\nReferences\n1 \nWalker V \nAmmonia metabolism and hyperammonemic disorders\n. Adv Clin Chem . 2014 ;67 :73 –150\n.25735860 \n2 \nPatra AK Aschenbach JR \nUreases in the gastrointestinal tracts of ruminant and monogastric animals and their implication in urea-N/ammonia metabolism: a review\n. J Adv Res . 2018 ;13 :39 –50\n.30094081 \n3 \nGriffin JWD Bradshaw PC \nEffects of a high protein diet and liver disease in an in silico model of human ammonia metabolism\n. Theor Biol Med Model . 2019 ;16 (1 ):11 .31366360 \n4 \nLiu J Lkhagva E Chung HJ Kim HJ Hong ST \nThe pharmabiotic approach to treat hyperammonemia\n. Nutrients . 2018 ;10 (2 ):140 .\n5 \nOzanne B Nelson J Cousineau J , et al.\nThreshold for toxicity from hyperammonemia in critically ill children\n. J Hepatol . 2012 ;56 (1 ):123 –128\n.21703182 \n6 \nHaberle J Boddaert N Burlina A , et al.\nSuggested guidelines for the diagnosis and management of urea cycle disorders\n. Orphanet J Rare Dis . 2012 ;7 :32 .22642880 \n7 \nLazier J Lupichuk SM Sosova I Khan AA \nHyperammonemic encephalopathy in an adenocarcinoma patient managed with carglumic acid\n. Curr Oncol . 2014 ;21 (5 ):e736 –e739\n.25302046 \n8 \nSavy N Brossier D Brunel-Guitton C Ducharme-Crevier L Du Pont-Thibodeau G Jouvet P \nAcute pediatric hyperammonemia: current diagnosis and management strategies\n. Hepat Med . 2018 ;10 :105 –115\n.30254497 \n9 \nSuarez I Bodega G Fernandez B \nGlutamine synthetase in brain: effect of ammonia\n. Neurochem Int . 2002 ;41 (2-3 ):123 –142\n.12020613 \n10 \nHakvoort TB He Y Kulik W , et al.\nPivotal role of glutamine synthetase in ammonia detoxification\n. Hepatology . 2017 ;65 (1 ):281 –293\n.27641632 \n11 \nInoue K Takahashi T Yamamoto Y , et al.\nInfluence of glutamine synthetase gene polymorphisms on the development of hyperammonemia during valproic acid-based therapy\n. Seizure . 2015 ;33 :76 –80\n.26599579 \n12 \nHaberle J Shahbeck N Ibrahim K Hoffmann GF Ben-Omran T \nNatural course of glutamine synthetase deficiency in a 3 year old patient\n. Mol Genet Metab . 2011 ;103 (1 ):89 –91\n.21353613 \n13 \nChicharro AV de Marinis AJ Kanner AM \nThe measurement of ammonia blood levels in patients taking valproic acid: looking for problems where they do not exist?\n\nEpilepsy Behav . 2007 ;11 (3 ):361 –366\n.17845866 \n14 \nBohles H Sewell AC Wenzel D \nThe effect of carnitine supplementation in valproate-induced hyperammonaemia\n. Acta Paediatr . 1996 ;85 (4 ):446 –449\n.8740302 \n15 \nMock CM Schwetschenau KH \nLevocarnitine for valproic-acid-induced hyperammonemic encephalopathy\n. Am J Health Syst Pharm . 2012 ;69 (1 ):35 –39\n.22180549 \n16 \nSattar Y Wasiq S Yasin W , et al.\nCarglumic acid treatment of a patient with recurrent valproic acid-induced hyperammonemia: a rare case report\n. Cureus . 2018 ;10 (9 ):e3292 .30443462 \n17 \nKhan A Bennett J Scantlebury MH Wei XC Kerr M \nAIMP1 mutation long-term follow-up, with decreased brain N-acetylaspartic acid and secondary mitochondrial abnormalities\n. Child Neurol Open . 2019 ;6 :2329048X19829520 .\n18 \nOrton DJ Gifford JL Seiden-Long I Khan A de Koning L \nCritically high plasma ammonia in an adolescent girl\n. Clin Chem . 2016 ;62 (12 ):1565 –1568\n.27899453 \n19 \nHaberle J Gorg B Rutsch F , et al.\nCongenital glutamine deficiency with glutamine synthetase mutations\n. N Engl J Med . 2005 ;353 (18 ):1926 –1933\n.16267323 \n20 \nFrieg B Gorg B Homeyer N Keitel V Haussinger D Gohlke H \nMolecular mechanisms of glutamine synthetase mutations that lead to clinically relevant pathologies\n. PLoS Comput Biol . 2016 ;12 (2 ):e1004693 .26836257 \n21 \nSpodenkiewicz M Diez-Fernandez C Rufenacht V Gemperle-Britschgi C Haberle J \nMinireview on glutamine synthetase deficiency, an ultra-rare inborn error of amino acid biosynthesis\n. Biology (Basel) . 2016 ;5 (4 ):40 .\n22 \nGopaul S Farrell K Abbott F \nEffects of age and polytherapy, risk factors of valproic acid (VPA) hepatotoxicity, on the excretion of thiol conjugates of (E)-2,4-diene VPA in people with epilepsy taking VPA\n. Epilepsia . 2003 ;44 (3 ):322 –328\n.12614387 \n23 \nWu C. \nGlutamine synthetase IV. Its formation in rat liver following partial hepatectomy and during repletion\n. Arch Biochem Biophys . 1964 ;106 :402 –409\n.14217187\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2329-048X",
"issue": "7()",
"journal": "Child neurology open",
"keywords": "GLUL; carglumic acid; epilepsy; glutamine synthetase; hyperammonemia; valproic acid",
"medline_ta": "Child Neurol Open",
"mesh_terms": null,
"nlm_unique_id": "101691975",
"other_id": null,
"pages": "2329048X20967880",
"pmc": null,
"pmid": "33150193",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "12020613;25735860;22180549;27641632;29382084;25302046;8740302;30443462;30828585;26836257;30094081;31366360;12614387;21353613;14217187;16267323;27899453;30254497;27775558;21703182;26599579;22642880;17845866",
"title": "Two Siblings With Valproate-Related Hyperammonemia and Novel Mutations in Glutamine Synthetase (GLUL) Treated With Carglumic Acid.",
"title_normalized": "two siblings with valproate related hyperammonemia and novel mutations in glutamine synthetase glul treated with carglumic acid"
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"abstract": "Ibrutinib increases the risk of atrial fibrillation (AF), but the associated risk factors are not clearly defined. We performed retrospective review of ibrutinib-treated patients in a large academic practice to identify risk factors for new-onset AF. Variables with p-values <.05 in logrank analysis were included as pairs in two-variable Cox regression. Of the 168 patients treated with ibrutinib, 60.7% had chronic lymphocytic leukemia/small lymphocytic lymphoma and 39.3% other histologies. The incidence of AF was 11.9% after a median 154-day ibrutinib exposure. Only heart failure (hazard ratio, 95% confidence interval; 14.1, 5.3-37.2) and left atrial abnormality on electrocardiogram (5.4, 1.9-15.4) were independently significant in paired Cox regression. Eighty-seven percent of patients with HF satisfied Framingham clinical criteria. As structural heart disease is a strong risk factor for incident AF, we emphasize the importance of baseline electrocardiogram, recommend baseline clinical screening for HF and, in specific instances, a baseline echocardiogram.",
"affiliations": "a Department of Internal Medicine, Division of General Internal Medicine , Northwestern University Feinberg School of Medicine , Chicago , IL , USA.;a Department of Internal Medicine, Division of General Internal Medicine , Northwestern University Feinberg School of Medicine , Chicago , IL , USA.;b Department of Internal Medicine, Division of Hematology and Oncology , Northwestern University Feinberg School of Medicine , Chicago , IL , USA.;c Department of Internal Medicine, Division of Cardiology , Northwestern University Feinberg School of Medicine , Chicago , IL , USA.",
"authors": "Lentz|Robert|R|;Feinglass|Joseph|J|;Ma|Shuo|S|;Akhter|Nausheen|N|",
"chemical_list": "D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; C551803:ibrutinib; D000225:Adenine",
"country": "United States",
"delete": false,
"doi": "10.1080/10428194.2018.1533129",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1026-8022",
"issue": "60(6)",
"journal": "Leukemia & lymphoma",
"keywords": "Atrial fibrillation; Bruton’s tyrosine kinase inhibitor; cardio-oncology; heart failure; ibrutinib; left atrial abnormality",
"medline_ta": "Leuk Lymphoma",
"mesh_terms": "D000225:Adenine; D000368:Aged; D001281:Atrial Fibrillation; D015897:Comorbidity; D004562:Electrocardiography; D005260:Female; D006333:Heart Failure; D006801:Humans; D015994:Incidence; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009369:Neoplasms; D063868:Patient Outcome Assessment; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D012189:Retrospective Studies; D012307:Risk Factors",
"nlm_unique_id": "9007422",
"other_id": null,
"pages": "1447-1453",
"pmc": null,
"pmid": "30730240",
"pubdate": "2019-06",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural",
"references": null,
"title": "Risk factors for the development of atrial fibrillation on ibrutinib treatment.",
"title_normalized": "risk factors for the development of atrial fibrillation on ibrutinib treatment"
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"companynumb": "US-ABBVIE-18K-163-3121470-00",
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"abstract": "Odontogenic bacteremia, most commonly involving gram-positive oral flora, can result from daily self-care practices or professional dental procedures. Though usually transient and quickly cleared by the immune system, the presence of periodontal disease increases the frequency of exposure and risk of persistence of oral-systemic infections. Comorbidities such as asplenia, alcoholism, and immunocompromise increase the risk of complications of hematogenous spread and severe systemic illness. Capnocytophaga is a genus of anaerobic fastidious gram-negative bacilli, which is a common member of human oral flora, and its density is proportional to mass of dental plaques and periodontal diseases. Capnocytophaga spp that colonize humans are less virulent and are uncommon causes of bacteremia when compared with the Capnocytophaga typical of canines. C gingivalis has been rarely reported as a cause of disease in immunocompromised or immunocompetent hosts. In this article, we present a case of an immunocompromised 70-year-old man with poor oral hygiene, on methotrexate and prednisone for rheumatoid arthritis and sarcoidosis, who was admitted for chronic obstructive pulmonary disease exacerbation and developed C gingivalis bacteremia and septic shock after an episode of upper gastrointestinal bleeding. Poor oral hygiene in our patient is believed to have increased his risk as an immunocompromised patient to developing C gingivalis bacteremia. This case highlights the importance of oral care in immunocompromised patients especially while hospitalized, and those about to receive transplant, chemotherapy, or on immune modulators.",
"affiliations": "Augusta University, Augusta, GA, USA.;Augusta University, Augusta, GA, USA.",
"authors": "Lawal|Folake J|FJ|0000-0003-2312-2054;Baer|Stephanie L|SL|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1177/23247096211020672",
"fulltext": "\n==== Front\nJ Investig Med High Impact Case Rep\nJ Investig Med High Impact Case Rep\nHIC\nsphic\nJournal of Investigative Medicine High Impact Case Reports\n2324-7096\nSAGE Publications Sage CA: Los Angeles, CA\n\n34041953\n10.1177/23247096211020672\n10.1177_23247096211020672\nCase Report\nCapnocytophaga gingivalis Bacteremia After Upper Gastrointestinal Bleeding in Immunocompromised Patient\nhttps://orcid.org/0000-0003-2312-2054\nLawal Folake J. MD, MPH 12\nBaer Stephanie L. MD 12\n1 Augusta University, Augusta, GA, USA\n2 Charlie Norwood Veteran Affairs Medical Center, Augusta, GA, USA\nStephanie L. Baer, MD, Charlie Norwood Veteran Affairs Medical Center, 1 Freedom Way (235), Augusta, GA 30904, USA. Email: stephanie.baer@va.gov\n27 5 2021\nJan-Dec 2021\n9 232470962110206725 4 2021\n1 5 2021\n4 5 2021\n© 2021 American Federation for Medical Research\n2021\nAmerican Federation for Medical Research\nhttps://creativecommons.org/licenses/by-nc/4.0/ 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 page (https://us.sagepub.com/en-us/nam/open-access-at-sage).\nOdontogenic bacteremia, most commonly involving gram-positive oral flora, can result from daily self-care practices or professional dental procedures. Though usually transient and quickly cleared by the immune system, the presence of periodontal disease increases the frequency of exposure and risk of persistence of oral-systemic infections. Comorbidities such as asplenia, alcoholism, and immunocompromise increase the risk of complications of hematogenous spread and severe systemic illness. Capnocytophaga is a genus of anaerobic fastidious gram-negative bacilli, which is a common member of human oral flora, and its density is proportional to mass of dental plaques and periodontal diseases. Capnocytophaga spp that colonize humans are less virulent and are uncommon causes of bacteremia when compared with the Capnocytophaga typical of canines. C gingivalis has been rarely reported as a cause of disease in immunocompromised or immunocompetent hosts. In this article, we present a case of an immunocompromised 70-year-old man with poor oral hygiene, on methotrexate and prednisone for rheumatoid arthritis and sarcoidosis, who was admitted for chronic obstructive pulmonary disease exacerbation and developed C gingivalis bacteremia and septic shock after an episode of upper gastrointestinal bleeding. Poor oral hygiene in our patient is believed to have increased his risk as an immunocompromised patient to developing C gingivalis bacteremia. This case highlights the importance of oral care in immunocompromised patients especially while hospitalized, and those about to receive transplant, chemotherapy, or on immune modulators.\n\nsepsis\nCapnocytophaga gingivalis\nimmunocompromised\noral flora\ngastrointestinal bleeding\ncover-dateJanuary-December 2021\ntypesetterts1\n==== Body\nIntroduction\n\nBacteria of the genus Capnocytophaga are anaerobic or microaerophilic, fastidious, and fusiform gram-negative bacillus that are part of oral flora of humans, dogs, and cats.\n\nCapnocytophaga gingivalis is one of 6 identified human colonist species found in adults and children. So far C canimorsus and C cynodegmi are the 2 species identified as part of animal oral flora.1-3\n\nCapnocytophaga spp have a worldwide distribution across all ages as normal flora of the oral cavity. Pathologically, they can cause nonfulminant diseases such as periodontitis, caries, and plaque across all ages.4 Comorbidities such as diabetes and malignancies in children increase the oral bacterial burden of Capnocytophaga spp isolated.5,6 The Capnocytophaga animal microbiota may be transmitted through bites, scratches, or nontraumatic contact with dog or cat saliva.2 C canimorsus and C cynodegmi are more virulent than species found as human flora, and fulminant infections can be seen in immunocompetent patients, though they are more prevalent in immunocompromised patients with comorbidities including alcoholism, asplenia, or malignancies. The infections cause can range from localized cellulitis to fulminant life-threatening illnesses.7-9 C canimorsus, however, is the most frequently isolated species in fulminant life-threatening disease.\n\nIn contrast, C gingivalis has rarely been reported as an invasive pathogen in humans, which could be a result of only genus-level identification with previous microbiologic technologies. In this case, we present an elderly immunocompromised man with severe C gingivalis infection.\n\nCase Presentation\n\nA 70-year-old man presented with 3 days of loose watery stool, worsening generalized weakness, 1 day of confusion, and inability to walk. He had a history of chronic medical problems including asthma/chronic obstructive pulmonary disease (COPD) requiring 4 L of home oxygen therapy, rheumatoid arthritis, sarcoidosis, and chronic kidney disease. He was on long-term 17.5 mg methotrexate weekly and 10 mg prednisone daily.\n\nVital signs recorded on admission included normal temperature with normal heart rate and blood pressure. On initial physical examination, he was noted to be awake but lethargic and had poor oral hygiene with multiple dental caries. On auscultation, there was reduced air entry into his lungs, and bilateral wheezing, and his abdomen was tender to palpation. He was noted to have extensive bruising over his left hand and bilateral pitting pedal edema. He was admitted and managed for COPD exacerbation and dehydration due to diarrhea.\n\nOn admission, he was started on intravenous methylprednisolone and bronchodilator treatments; on day 2, his mental status became more altered. He was later intubated urgently after failure of bilevel positive airway pressure (BiPAP) trial for acute on chronic hypercapnic respiratory failure. He was also started on diuretics initially and later hemodialysis for acute kidney injury. After 3 days of intubation, his mental and respiratory status had improved remarkably, and he was successfully extubated on day 5 of admission.\n\nOn day 9 of admission, he developed fever of 38.7 °C. Blood and urine cultures were collected, and he was promptly started on empiric vancomycin, cefepime, and metronidazole.\n\nBy day 10, his mental status declined, and he was again in hypercapnic respiratory failure. He failed BiPAP trial again and had to be re-intubated. At time of intubation, a pool of blood was noted in mouth and hypopharynx and 2.5 L of bloody fluid suctioned from his stomach. He was placed on pantoprazole infusion for suspected gastrointestinal (GI) bleeding and aspiration was strongly suspected. Broad antibiotics that had been started the prior day were continued. A few hours later, norepinephrine infusion and stress-dose hydrocortisone were started due to persistent hypotension. Esophagogastroduodenoscopy revealed esophageal erosion, gastric, and duodenal ulcers.\n\nOn day 11, he still required high doses of norepinephrine despite resolution of fever. Urine culture obtained on day 9 had >100 000 colony forming units/mL of Escherichia coli. Vancomycin and metronidazole were stopped to target urinary tract infection with E coli. Computed tomography scan of abdomen showed bilateral lower lobe consolidations suspicious for pneumonia.\n\nBlood cultures obtained on day 9 became positive on the fourth day of culture, with Gram-negative bacilli in one anaerobic bottle of 4 culture bottles, his antibiotic was switched to piperacillin-tazobactam and tobramycin. The isolate was identified 2 days later, on hospital day 14, as Capnocytophaga spp. The infectious disease (ID) team was consulted, piperacillin-tazobactam and tobramycin was discontinued in favor of renally dosed ampicillin-sulbactam. During a discussion with his wife by the ID team on day 15 of admission, she reported having a dog that was not usually in contact with her husband, and she reported that the patient chews tobacco, stores, and then re-chews tobacco that he stored at room temperature for varying lengths of time. Patient’s right upper extremity remained edematous and a venous duplex confirmed suspicion of a deep vein thrombosis in the right internal jugular and right brachiocephalic veins, which was associated with the central venous catheter.\n\nThe patient was taken off vasopressors on hospital day 16 and extubated on day 17. The patient was treated for 4 weeks with renally dosed intravenous ampicillin-sulbactam for endovascular infection due to the occlusive thrombosis detected while patient had bacteremia.\n\nUsing 16s rRNA gene sequencing, Capnocytophaga spp isolated was reported to be C gingivalis by Quest Diagnostics, Nichols Institute, Chantilly, Virginia. He was counseled and advised to keep up his dental appointments and stop re-chewing his tobacco.\n\nDiscussion\n\nBacteremia resulting from a break in mucosal barrier is common: from the oral cavity, routine activities such as brushing and flossing regularly cause transient bacteremia with oral flora. Odontogenic diseases pose an increased risk of persistent bacteremia due to undrained foci of infection. Bioburden, such as in extensive dental plaques, or mucosal disruption in gingivitis, oral ulcers, gastritis, colitis, peptic ulcer disease, and inflammatory bowel diseases can also increase the risk of microbial gut translocation.10-12 Our patient had been on methotrexate and prednisone for rheumatoid arthritis causing him to be immunocompromised. Prolonged use of glucocorticoids and methotrexate have individually been shown to lower the integrity of the gut mucosa leading to ulcerations, perforations, and increased risk of bleeding.13-15\n\nOnly one case of bacteremia due to Capnocytophaga has been previously reported in a patient with rheumatoid arthritis on methotrexate. This individual subsequently died of disseminated intravascular coagulation, and acute respiratory distress syndrome from C canimorsus infection following dog bite.16 Our patient notably had poor dentition with dense plaques, multiple dental caries, and a habit of re-chewing saved tobacco, stored at room temperature, which may have contributed to increased oral bacterial colonization. The mechanism of his bacteremia in this patient was thought to be translocation of oral flora colonized with C gingivalis through compromised gastric mucosa due to the upper GI bleeding. The Capnocytophaga isolated was finally reported to be C gingivalis using 16s rRNA sequencing sensitive to ampicillin-sulbactam, meropenem, and metronidazole, resistant to clindamycin and penicillin (Table 1).\n\nTable 1. Microbiology Susceptibility Report for Isolated Capnocytophaga gingivalis.\n\nOrganism isolated: Capnocytophaga gingivalis (sequence ID)\t\nMIC report\tMIC\t\t\nAntibiotic\t(µg/mL)\tInterpretation\t\nAmpicillin/sulbactam\t0.094\tSusceptible\t\nClindamycin\t>256\tResistant\t\nMeropenem\t0.032\tSusceptible\t\nMetronidazole\t8.0\tSusceptible\t\nPenicillin\t2.0\tResistant\t\n\nA detailed literature search was conducted using the search words “Capnocytophaga gingivalis” in PubMed. Ninety-three abstracts were found for Capnocytophaga gingivalis as shown in flow diagram in Figure 1. Capnocytophaga gingivalis + Filters: Humans yielded 71 abstracts. Addition of filter case reports yielded 7 abstracts. This contained 4 human case reports of C gingivalis systemic infections, 1 Japanese abstract, 2 periodontal diseases abstracts, and 1 molecular immunology abstract. This initial search erroneously eliminated a previously found case report, prompting a manual review after alternate search parameters were used. Finally, search using Capnocytophaga gingivalis [Title] Filters: Abstract yielded 14 abstracts that included all 5 case reports for C gingivalis systemic infection in humans, which is reflected in Figure 1.\n\nFigure 1. Case reports search flow diagram.\n\nPolymicrobial and primary oral/periodontal abstracts were excluded from this review. Five case reports of human non-oral C gingivalis infections were found and included in this case review. Three of the cases were related to lung infections, 2 cases were in immunocompromised hosts, 1 joint infection, and 1 related to oral infection. The cases included bacteremia in a 6-year-old with acute lymphocytic leukemia and gingivitis,8 pneumonia, and bacteremia in 30-year-old man post autologous stem cell transplant,17 lung abscess in a normal host,18 insidious joint infection in a normal 3-year-old,19 and an acute COPD exacerbation20 (Table 2).\n\nTable 2. Capnocytophaga gingivalis Case Report Summary.\n\nCase\tPatient demography\tComorbidity\tImmune status\tManifestation\tManagement\tDrug resistance\tOutcome\t\nElodie, 2006\t78 years, male\tChronic respiratory failure\tAbnormal\tCOPD exacerbation/respiratory infection\tAmoxicillin-clavulanate\n14 days\tFluoroquinolone, macrolide, lincosamide and streptogramin, and β-lactamase\tResolution\t\nFukuoka, 2000\t48 years, male\tNone\tNormal\tLung abscess\tCeftizoxime and clindamycin\n28 days (4 weeks)\tTobramycin, fosfomycin\tResolution\t\nGeisler, 2001\t30 years, male\tAutologous stem cell transplant\tAbnormal\tPneumonia, bacteremia\tLinezolid and metronidazole\tGentamicin, fluoroquinolones\tResolution\t\nMantadakis, 2003\t6 years, female\tB cell ALL, and gingivitis\tAbnormal\tBacteremia\tCeftazidime and amikacin\n10 days\tBactrim\tResolution\t\nRodgers, 2001\t3 years, male\tNone\tNormal\tSeptic arthritis\tAmpicillin-sulbactam\n21 days (3 weeks)\tNone\tResolution\t\nAbbreviation: COPD, chronic obstructive pulmonary device.\n\nAntimicrobial susceptibilities in the identified cases followed no specific pattern as 4 of the 5 cases had class resistance reported, with only one multi-drug resistant case resistant to 4 classes of antibiotics. As in our case, many of the C gingivalis strains appear to remain susceptible to cephalosporins and β-lactam/β-lactamase inhibitor combinations.\n\nIn conclusion, in this case, poor dental hygiene with periodontitis posed an increased risk of infection with human oral strains of genus Capnocytophaga in immunocompromised patients. Optimal oral care while inpatient can reduce the oral bacterial burden in the event of aspiration and is an important part of the ventilator acquired pneumonia bundle. This case highlights the importance of oral care in immunocompromised patients and the risk of bacterial translocation with GI bleeding or aspiration.\n\nAuthors’ Note: The contents of this article do not represent the views of the Department of Veterans Affairs or the US government. This work was previously presented at the Southern Regional Meeting, New Orleans, Louisiana, 2019.\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) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The material is the result of work supported with resources and the use of facilities at the Charlie Norwood VA Medical Center. The funding organizations had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. The contents of this publication are solely the responsibility of the authors and do not represent do not necessarily reflect the views, opinions or policies of The Department of Veterans Affairs, or the the U.S. Government. Mention of trade names, commercial products, or organizations does not imply endorsement by the U.S. Government.\n\nEthics Approval: Our institution does not require ethical approval for reporting individual cases or case series.\n\nInformed Consent: Verbal informed consent was obtained from the patient for their anonymized information to be published article.\n\nORCID iD: Folake J. Lawal https://orcid.org/0000-0003-2312-2054\n==== Refs\nReferences\n\n1 Socransky SS Holt SC Leadbetter ER Tanner ACR Savitt E Hammond BF. Capnocytophaga: new genus of Gram-negative gliding bacteria. III. Physiological characterization. Arch Microbiol. 1979;122 :29-33. doi:10.1007/BF00408042 518236\n2 Mashima I Theodorea CF Thaweboon B Thaweboon S Scannapieco FA Nakazawa F. Exploring the salivary microbiome of children stratified by the oral hygiene index. PLoS One. 2017;12 :e0185274. doi:10.1371/journal.pone.0185274\n3 Chen WP Chang SH Tang CY Liou ML Tsai SJJ Lin YL. Composition analysis and feature selection of the oral microbiota associated with periodontal disease. Biomed Res Int. 2018;2018 :3130607. doi:10.1155/2018/3130607 30581850\n4 Heller D Silva-Boghossian CMI do Souto RM Colombo APV . Subgingival microbial profiles of generalized aggressive and chronic periodontal diseases. Arch Oral Biol. 2012;57 :973-980. doi:10.1016/j.archoralbio.2012.02.003 22377404\n5 Campbell JR Edwards MS. Capnocytophaga species infections in children. Pediatr Infect Dis J. 1991;10 :944-948. doi:10.1097/00006454-199112000-00013 1766712\n6 Graves DT Corrêa JD Silva TA. The oral microbiota is modified by systemic diseases. J Dent Res. 2019;98 :148-156. doi:10.1177/0022034518805739 30359170\n7 Brichacek M Blake P Kao R. Capnocytophaga canimorsus infection presenting with complete splenic infarction and thrombotic thrombocytopenic purpura: a case report. BMC Res Notes. 2012;5 :695. doi:10.1186/1756-0500-5-695 23267527\n8 Mantadakis E Danilatou V Christidou A Stiakaki E Kalmanti M. Capnocytophaga gingivalis bacteremia detected only on quantitative blood cultures in a child with leukemia. Pediatr Infect Dis J. 2003;22 :202-204. doi:10.1097/00006454-200302000-00025 12613461\n9 Lion C Escande F Burdin JC. Capnocytophaga canimorsus infections in human: review of the literature and cases report. Eur J Epidemiol. 1996;12 :521-533. doi:10.1007/bf00144007 8905316\n10 Parahitiyawa NB Jin LJ Leung WK Yam WC Samaranayake LP. Microbiology of odontogenic bacteremia: beyond endocarditis. Clin Microbiol Rev. 2009;22 :46-64. doi:10.1128/CMR.00028-08 19136433\n11 Forner L Larsen T Kilian M Holmstrup P. Incidence of bacteremia after chewing, tooth brushing and scaling in individuals with periodontal inflammation. J Clin Periodontol. 2006;33 :401-407. doi:10.1111/j.1600-051X.2006.00924.x 16677328\n12 Vaishnavi C. Translocation of gut flora and its role in sepsis. Indian J Med Microbiol. 2013;31 :334-342. doi:10.4103/0255-0857.118870 24064638\n13 Curtis JR Xie F Chen L , et al . The incidence of gastrointestinal perforations among rheumatoid arthritis patients. Arthritis Rheum. 2011;63 :346-351. doi:10.1002/art.30107 20967860\n14 Tsukada T Nakano T Miyata T Sasaki S. Life-threatening gastrointestinal mucosal necrosis during methotrexate treatment for rheumatoid arthritis. Case Rep Gastroenterol. 2013;7 :470-475. doi:10.1159/000356817 24348319\n15 Fadul CE Lemann W Thaler HT Posner JB. Perforation of the gastrointestinal tract in patients receiving steroids for neurologic disease. Neurology. 1988;38 :348-352. doi:10.1212/wnl.38.3.348 3258062\n16 Tamura S Koyama A Yamashita Y , et al . Capnocytophaga canimorsus sepsis in a methotrexate-treated patient with rheumatoid arthritis. IDCases. 2017;10 :18-21. doi:10.1016/j.idcr.2017.08.002 28831382\n17 Geisler WM Malhotra U Stamm WE. Pneumonia and sepsis due to fluoroquinolone-resistant Capnocytophaga gingivalis after autologous stem cell transplantation. Bone Marrow Transplant. 2001;28 :1171-1173. doi:10.1038/sj.bmt.1703288 11803363\n18 Fukuoka K Mochizuki Y Nakahara Y Kawamura T Watanab S Sasaki S. A case report of lung abscess caused by Capnocytophaga gingivalis infection [in Japanese]. J Jpn Assoc Infect Dis. 2000;74 :594-597. doi:10.11150/kansenshogakuzasshi1970.74.594\n19 Rodgers GL Mortensen JE Goldsmith DP. Pyogenic arthritis caused by Capnocytophaga gingivalis in an immunocompetent three-year-old male. J Clin Rheumatol. 2001;7 :265-267. doi:10.1097/00124743-200108000-00016 17039147\n20 Ehrmann E Jolivet-Gougeon A Bonnaure-Mallet M Fosse T. Multidrug-resistant oral Capnocytophaga gingivalis responsible for an acute exacerbation of chronic obstructive pulmonary disease: case report and literature review. Anaerobe. 2016;42 :50-54. doi:10.1016/j.anaerobe.2016.08.003 27531625\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2324-7096",
"issue": "9()",
"journal": "Journal of investigative medicine high impact case reports",
"keywords": "Capnocytophaga gingivalis; gastrointestinal bleeding; immunocompromised; oral flora; sepsis",
"medline_ta": "J Investig Med High Impact Case Rep",
"mesh_terms": "D000368:Aged; D016470:Bacteremia; D002206:Capnocytophaga; D006471:Gastrointestinal Hemorrhage; D016905:Gram-Negative Bacterial Infections; D006801:Humans; D016867:Immunocompromised Host; D008297:Male",
"nlm_unique_id": "101624758",
"other_id": null,
"pages": "23247096211020672",
"pmc": null,
"pmid": "34041953",
"pubdate": "2021",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013486:Research Support, U.S. Gov't, Non-P.H.S.",
"references": "28934367;10965664;28831382;1766712;518236;30581850;22377404;8905316;16677328;30359170;19136433;11803363;3258062;20967860;23267527;24064638;17039147;12613461;24348319;27531625",
"title": "Capnocytophaga gingivalis Bacteremia After Upper Gastrointestinal Bleeding in Immunocompromised Patient.",
"title_normalized": "capnocytophaga gingivalis bacteremia after upper gastrointestinal bleeding in immunocompromised patient"
} | [
{
"companynumb": "US-ACCORD-227896",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": "3",
"druga... |
{
"abstract": "OBJECTIVE\nThe microRNA miR-27a was recently shown to directly regulate dihydropyrimidine dehydrogenase (DPD), the key enzyme in fluoropyrimidine catabolism. A common polymorphism (rs895819A>G) in the miR-27a genomic region (MIR27A) was associated with reduced DPD activity in healthy volunteers, but the clinical relevance of this effect is still unknown. Here, we assessed the association of MIR27A germline variants with early-onset fluoropyrimidine toxicity.\n\n\nMETHODS\nMIR27A was sequenced in 514 patients with cancer receiving fluoropyrimidine-based chemotherapy. Associations of MIR27A polymorphisms with early-onset (cycles 1-2) fluoropyrimidine toxicity were assessed in the context of known risk variants in the DPD gene (DPYD) and additional covariates associated with toxicity.\n\n\nRESULTS\nThe association of rs895819A>G with early-onset fluoropyrimidine toxicity was strongly dependent on DPYD risk variant carrier status (Pinteraction = 0.0025). In patients carrying DPYD risk variants, rs895819G was associated with a strongly increased toxicity risk [OR, 7.6; 95% confidence interval (CI), 1.7-34.7; P = 0.0085]. Overall, 71% (12/17) of patients who carried both rs895819G and a DPYD risk variant experienced severe toxicity. In patients without DPYD risk variants, rs895819G was associated with a modest decrease in toxicity risk (OR, 0.62; 95% CI, 0.43-0.9; P = 0.012).\n\n\nCONCLUSIONS\nThese results indicate that miR-27a and rs895819A>G may be clinically relevant for further toxicity risk stratification in carriers of DPYD risk variants. Our data suggest that direct suppression of DPD by miR-27a is primarily relevant in the context of fluoropyrimidine toxicity in patients with reduced DPD activity. However, miR-27a regulation of additional targets may outweigh its effect on DPD in patients without DPYD risk variants.",
"affiliations": "University Institute of Clinical Chemistry, Inselspital, Bern University Hospital, and University of Bern, Bern, Switzerland.;Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic Cancer Center, Rochester, Minnesota.;University Institute of Clinical Chemistry, Inselspital, Bern University Hospital, and University of Bern, Bern, Switzerland.;Department of Medical Oncology, Cantonal Hospital St. Gallen, St. Gallen, Switzerland.;Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic Cancer Center, Rochester, Minnesota.;University Institute of Clinical Chemistry, Inselspital, Bern University Hospital, and University of Bern, Bern, Switzerland. carlo.largiader@insel.ch.",
"authors": "Amstutz|Ursula|U|;Offer|Steven M|SM|;Sistonen|Johanna|J|;Joerger|Markus|M|;Diasio|Robert B|RB|;Largiadèr|Carlo R|CR|",
"chemical_list": "D000970:Antineoplastic Agents; C531388:MIRN27 microRNA, human; D035683:MicroRNAs; D042943:Dihydrouracil Dehydrogenase (NADP); D005472:Fluorouracil",
"country": "United States",
"delete": false,
"doi": "10.1158/1078-0432.CCR-14-2817",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1078-0432",
"issue": "21(9)",
"journal": "Clinical cancer research : an official journal of the American Association for Cancer Research",
"keywords": null,
"medline_ta": "Clin Cancer Res",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents; D042943:Dihydrouracil Dehydrogenase (NADP); D005260:Female; D005472:Fluorouracil; D006801:Humans; D008297:Male; D035683:MicroRNAs; D008875:Middle Aged; D009369:Neoplasms; D020641:Polymorphism, Single Nucleotide; D020133:Reverse Transcriptase Polymerase Chain Reaction; D055815:Young Adult",
"nlm_unique_id": "9502500",
"other_id": null,
"pages": "2038-44",
"pmc": null,
"pmid": "25655103",
"pubdate": "2015-05-01",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Polymorphisms in MIR27A Associated with Early-Onset Toxicity in Fluoropyrimidine-Based Chemotherapy.",
"title_normalized": "polymorphisms in mir27a associated with early onset toxicity in fluoropyrimidine based chemotherapy"
} | [
{
"companynumb": "CH-ROCHE-1642526",
"fulfillexpeditecriteria": "1",
"occurcountry": "CH",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FLUOROURACIL"
},
"drugadditional": null,
"dr... |
{
"abstract": "Neuroendocrine neoplasms (NENs) comprise a heterogeneous group of tumours, which can be classified into neuroendocrine tumours (NETs), neuroendocrine carcinomas (NECs) and mixed neuroendocrine non-neuroendocrine neoplasms (MiNENs). To date, there is no consensus regarding the optimal therapy, which usually depends on the primary location and classification, according to morphological features of differentiation and proliferation rates. Nevertheless, multidisciplinary strategies combining medical treatments and locoregional strategies have yielded better efficacy results. Here, we report the case of a patient diagnosed with a nonfunctional rectal NECs with metastatic widespread to pelvic lymph nodes and bilateral lung metastases. The patient received three cycles of platinum-etoposide, concomitantly with palliative radiotherapy. Although CT scan after three cycles showed a significant partial response, there was an early fatal progression only 3 months after having stopped systemic therapy. As formerly described in the literature, this case highlights the aggressive behaviour of NECs, rare tumours that often present in advanced stages at diagnosis. Lately, new insights into the molecular biology of NECs have unveiled the possibility of using novel drugs, such as targeted agents or immunotherapy, in molecularly selected subgroups of patients. In this review, we discuss the current management of this rare entity and provide an overview of the most relevant molecular findings, whilst illustrating the potential value that prescreening panels can offer, searching for actionable targets (MSI/dMMR, PD-L1, BRAFv600E) to guide therapy with promising agents that could fill a void in this disease.",
"affiliations": "Radiation Oncology Department, Catalan Institute of Oncology (ICO)-Badalona; Germans Trias i Pujol University Hospital (HUGTiP), Badalona, Barcelona, Spain.;Medical Oncology Department, Catalan Institute of Oncology (ICO)-Badalona; Badalona-Applied Research Group in Oncology (B-ARGO)-Germans Trias i Pujol Institute (IGTP); Germans Trias i Pujol University Hospital (HUGTiP), Badalona, Barcelona, Spain.;Pathology Department, Germans Trias i Pujol University Hospital (HUGTiP), Badalona, Barcelona, Spain.;Radiation Oncology Department, Catalan Institute of Oncology (ICO)-Badalona; Germans Trias i Pujol University Hospital (HUGTiP), Badalona, Barcelona, Spain.;Medical Oncology Department, Catalan Institute of Oncology (ICO)-Badalona; Badalona-Applied Research Group in Oncology (B-ARGO)-Germans Trias i Pujol Institute (IGTP); Germans Trias i Pujol University Hospital (HUGTiP), Badalona, Barcelona, Spain.;Medical Oncology Department, Catalan Institute of Oncology (ICO)-Badalona; Badalona-Applied Research Group in Oncology (B-ARGO)-Germans Trias i Pujol Institute (IGTP); Germans Trias i Pujol University Hospital (HUGTiP), Badalona, Barcelona, Spain.;Medical Oncology Department, Catalan Institute of Oncology (ICO)-Badalona; Badalona-Applied Research Group in Oncology (B-ARGO)-Germans Trias i Pujol Institute (IGTP); Germans Trias i Pujol University Hospital (HUGTiP), Badalona, Barcelona, Spain.;Radiation Oncology Department, Catalan Institute of Oncology (ICO)-Badalona; Germans Trias i Pujol University Hospital (HUGTiP), Badalona, Barcelona, Spain.;Medical Oncology Department, Catalan Institute of Oncology (ICO)-Badalona; Badalona-Applied Research Group in Oncology (B-ARGO)-Germans Trias i Pujol Institute (IGTP); Germans Trias i Pujol University Hospital (HUGTiP), Badalona, Barcelona, Spain.",
"authors": "Antelo|Gabriela|G|;Hierro|Cinta|C|;Fernández|Juan Pablo|JP|;Baena|Eduardo|E|;Bugés|Cristina|C|;Layos|Laura|L|;Manzano|José Luis|JL|;Caro|Mónica|M|;Mesia|Ricard|R|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.7573/dic.2020-2-4",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1740-4398",
"issue": "9()",
"journal": "Drugs in context",
"keywords": "chemotherapy; epigenetic; gastro-entero-pancreatic neuroendocrine neoplasms; immunotherapy; molecular alterations; neuroendocrine carcinomas; radiotherapy; targeted agents",
"medline_ta": "Drugs Context",
"mesh_terms": null,
"nlm_unique_id": "101262187",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "32477420",
"pubdate": "2020",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": "21306237;21306238;29431699;22701038;12068308;16971718;26486986;16051944;15496622;30892987;31433515;26703889;20234360;24975505;25902707;26731483;22967994;30580091;22940375;19194127;18534701;30338051;1712661;26943788;21252315;30670489;28456055;26958083;27226359;30181415;22973169;31279236;28448665;24445147;24715269;23008301;24213223;26237193;27142424;31963850;21327441;16751073;23872332;26743120;31896137;25465415;31167197;30219817;28190018;31720931;31660035;28384065;21456005;20139156;31143376;31857137;31672771;10604732;23591432;26643092;29684743;21498724;31794158;26731334;27482646;11571721;23529007;11547717;23430217;27048246;16110023;26854147;30212595;25265492;25157273;18974627;27401895;30482824;21615243;16630755",
"title": "Rectal neuroendocrine carcinoma: case report of a rare entity and perspective review of promising agents.",
"title_normalized": "rectal neuroendocrine carcinoma case report of a rare entity and perspective review of promising agents"
} | [
{
"companynumb": "ES-ACCORD-197405",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ETOPOSIDE"
},
"drugadditional": "1",
"drugad... |
{
"abstract": "Hypoparathyroidism with sensorineural deafness and renal dysplasia (HDR) syndrome is an autosomal dominant condition caused by mutations of the gene encoding the dual zinc-finger transcription factor, GATA3. A previous study identified some patients with GATA3 gene variants and breast cancer, suggesting that GATA3 variants may contribute to tumorigenesis in estrogen receptor 1-positive breast tumors; however, these patients did not have HDR syndrome. A 32-year-old nonsmoking Japanese woman was histologically diagnosed with lung squamous cell carcinoma associated with HDR syndrome and a c.C952T>C (p.C318R) germline mutation in GATA3. This is the first report describing cancer in a patient with HDR syndrome. Our data indicates that GATA3 mutations may be a potential therapeutic target for lung cancer.",
"affiliations": "Division of Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan.;Division of Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan.;Division of Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan.;Department of Diagnostic Pathology, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan.;Division of Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan.;Division of Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan.;Division of Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan.;Division of Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan.;Division of Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan.;Department of Medical Genetics, Shizuoka General Hospital, Shizuoka City, Shizuoka, Japan.;Division of Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan.",
"authors": "Kojima|Mariko|M|;Nagano|Tatsuya|T|;Nakata|Kyosuke|K|;Hara|Shigeo|S|;Katsurada|Naoko|N|;Yamamoto|Masatsugu|M|;Tachihara|Motoko|M|;Kamiryo|Hiroshi|H|;Kobayashi|Kazuyuki|K|;Usui|Takeshi|T|;Nishimura|Yoshihiro|Y|",
"chemical_list": null,
"country": "New Zealand",
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"doi": "10.2147/OTT.S161420",
"fulltext": "\n==== Front\nOnco Targets TherOnco Targets TherOncoTargets and TherapyOncoTargets and therapy1178-6930Dove Medical Press 10.2147/OTT.S161420ott-11-1595Case ReportLung squamous cell carcinoma associated with hypoparathyroidism with sensorineural deafness and renal dysplasia syndrome: a case report Kojima Mariko 1Nagano Tatsuya 1Nakata Kyosuke 1Hara Shigeo 2Katsurada Naoko 1Yamamoto Masatsugu 1Tachihara Motoko 1Kamiryo Hiroshi 1Kobayashi Kazuyuki 1Usui Takeshi 3Nishimura Yoshihiro 1\n1 Division of Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan\n2 Department of Diagnostic Pathology, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan\n3 Department of Medical Genetics, Shizuoka General Hospital, Shizuoka City, Shizuoka, JapanCorrespondence: Tatsuya Nagano, Division of Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, Hyogo 650-0017, Japan, Tel +81 78 382 5660, Fax +81 78 382 5661, Email tnagano@med.kobe-u.ac.jp2018 20 3 2018 11 1595 1599 © 2018 Kojima et al. This work is published and licensed by Dove Medical Press Limited2018The 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.Hypoparathyroidism with sensorineural deafness and renal dysplasia (HDR) syndrome is an autosomal dominant condition caused by mutations of the gene encoding the dual zinc-finger transcription factor, GATA3. A previous study identified some patients with GATA3 gene variants and breast cancer, suggesting that GATA3 variants may contribute to tumorigenesis in estrogen receptor 1-positive breast tumors; however, these patients did not have HDR syndrome. A 32-year-old nonsmoking Japanese woman was histologically diagnosed with lung squamous cell carcinoma associated with HDR syndrome and a c.C952T>C (p.C318R) germline mutation in GATA3. This is the first report describing cancer in a patient with HDR syndrome. Our data indicates that GATA3 mutations may be a potential therapeutic target for lung cancer.\n\nKeywords\nlung cancerGATA3missense varianthypoparathyroidismsensorineural deafnessrenal dysplasia\n==== Body\nIntroduction\nHypoparathyroidism with sensorineural deafness and renal dysplasia (HDR) syndrome (OMIM: 146255) is an autosomal dominant condition characterized by incomplete penetrance and clinical heterogneity,1 and is caused by mutations of GATA3 (OMIM: 131320).2\nGATA3 consists of 6 exons which encode a dual zinc-finger transcription factor.3 The C-terminal zinc finger of GATA3 is encoded by exon 5 and has a crucial role in DNA binding, whereas the N-terminal zinc finger is encoded by exon 4 and functions in stabilizing DNA binding and interactions with multitype zinc-finger proteins.4 Many types of GATA3 mutations can cause HDR syndrome, including intragenic deletions, along with nonsense, acceptor splice site, and missense mutations.3 The missense variants p.C318R and p.N320K are predicted to disrupt the C-terminal zinc finger of GATA3.3 The detailed structure of GATA3 has been described previously.3\n\nLung squamous cell carcinoma is a major histological subtype of non-small-cell lung cancer and is typically induced by cigarette smoking.5,6 Recently, potentially oncogenic mutations have been recognized in approximately 60% of lung adenocarcinoma, and molecular targeting therapies have been shown to improve the clinical outcomes of patients with these mutations. Nevertheless, oncogenic mutations are rare in lung squamous cell carcinoma, and the majority of patients are treated with conventional chemotherapy.5 Herein, we report a case of a young, nonsmoking woman with HDR syndrome who developed lung squamous cell carcinoma.\n\nCase report\nA 32-year-old nonsmoking Japanese woman was admitted to Kobe University Hospital in February 2017 to receive chemotherapy under hemodialysis.\n\nThe patient was congenitally disabled, with hearing difficulties. She underwent hemodialysis in 2012 because of congenital right renal deficiency and left renal hypoplasia. At that time, she had low levels of parathyroid hormone, due to hypoparathyroidism. After obtaining informed consent, she was diagnosed with HDR syndrome by analysis of a whole blood sample via polymerase chain reaction amplification of all GATA3 coding exons and exon–intron boundaries, followed by bidirectional Sanger sequencing. The results indicated that she carried the missense variant, c.C952T>C (p.C318R), in exon 5 of GATA3 (Figure 1). According to the standards and guidelines for the interpretation of sequence variants, this variant is classified as “likely pathogenic.”7 Intriguingly, she was born to healthy parents and had no family history of a similar disorder (Figure 2).\n\nIn November 2016, she attended the hospital complaining of pain in the left back, and chest X-ray revealed left pleural effusion. She underwent a diagnostic bronchoscopy. Histopathological examination of tumor samples revealed dysplasia with coarse chromatin, and specimens stained positive for cytokeratin 5/6, and p63 (markers for squamous cell carcinoma), weakly positive for thyroid transcription factor-1, and negative for Napsin (markers for adenocarcinoma). Consequently, she was histologically diagnosed with lung squamous cell carcinoma (Figure 3). Her clinical stage of cancer progression was cT2aN0M1c, stage IVB, according to the TNM classification of the Union for International Cancer Control. Sequencing analysis of the tumor sample revealed no mutations of EGFR or EML4-ALK. Positron emission tomography–computed tomography revealed multiple bone metastases, including to the cervical, thoracic, and lumbar areas, along with the pelvis, humerus, and right ribs. Intriguingly, this is the only case of a young nonsmoking woman developing lung squamous cell carcinoma that has presented at Kobe University Hospital in the period 2011–2017 (Figure 4).\n\nUpon hospitalization in February 2017, her Eastern Cooperative Oncology Group Performance Status was 2. A physical examination identified anemic palpebral conjunctiva and decreased left breath sounds. Chest X-ray revealed left pleural effusion, pleural thickening, and scoliosis (Figure 5). Chest computed tomography revealed mass-like opacity combined with atelectasis at the left apex, left pleural thickening, and left pleural effusion.\n\nShe consented to a combination chemotherapy regimen to treat her non-small-cell lung cancer. On day 1 (non-hemodialysis day), she began treatment with carboplatin (area under the curve 5, estimated glomerular filtration rate 0, 120 mg/body) and paclitaxel (200 mg/m2, 310 mg/body). On day 2, her serum AST and ALT levels transiently increased to 364 and 233 U/L, respectively, before falling to Grade 3, according to the Common Terminology Criteria for Adverse Events version 4.0 (US National Cancer Institute, Rockville, MD, USA). From day 7, she experienced appetite loss (Grade 2) and nausea (Grade 2). On day 9, she experienced febrile neutropenia and was treated with 1 g/d (hemodialysis day) or 2 g/d (non-hemodialysis day) cefepime and 75 µg of granulocyte colony-stimulating factor. Fortunately, she recovered from these toxicities and left Kobe University Hospital on day 17; however, the pain in her right upper arm and lower back were exacerbated (Numerical Rating Scale 5/10) from this point.\n\nShe was rehospitalized for chemotherapy in March 2017; however, her Eastern Cooperative Oncology Group Performance Status deteriorated to 3 because of pain induced by pathological fractures at sites of bone metastases (Th9, Th11, L2, and L4). Therefore, she was treated with vertebroplasty twice for the vertebral body metastases and radiation therapy for the bone metastases, rather than chemotherapy. Although her pain was improved to Numerical Rating Scale 3/10, she decided to terminate the chemotherapy and left Kobe University Hospital in March 2017.\n\nDiscussion\nGATA3 is a member of a family of zinc-finger transcription factors present in vertebrate organisms and involved in the differentiation of breast epithelia, urothelia, and a subset of T lymphocytes.8 A previous study identified 5 patients with GATA3 gene mutations among 111 individuals with breast cancer; however, none of them had HDR syndrome.9 To our knowledge, there have been no reports describing patients with lung squamous cell carcinoma associated with HDR syndrome, although it has previously been suggested that disruption of GATA3 is associated with cancer.\n\nPatients with HDR syndrome express various clinical phenotypes. Ferraris et al10 reported that of 77 patients, 48 (62.3%) exhibited the complete clinical triad (ie, hypoparathyroidism, deafness, and renal dysplasia), 22 (28.6%) lacked the renal disorder, 2 (2.6%) did not exhibit hypoparathyroidism, and 5 (6.5%) were not deaf. Although the pedigree of this patient indicates that no family members had symptoms associated with HDR syndrome, it is possible that some family members may have been partially or unknowingly affected. In addition, we were unable to determine the genetic status of other family members; therefore, we cannot conclude that the patient developed a de novo GATA3 p.C318R mutation. However, in this case, it is unlikely that there was undisclosed adoption, mistaken identity at the birthing facility, or marital infidelity. Indeed, Esch et al11 reported patients with a de novo 49 bp frameshift deletion mutation in family 26/99, and Ferraris et al also reported a de novo heterozygous deletion of the nucleotides GG in codons 36 and 37 of GATA3.10\n\nLung adenocarcinoma accounts for the greatest proportion of lung cancers in women worldwide (ranging from 38% in the United States to 69% in Japan);12 however, lung squamous cell carcinoma accounts for only 11% of all lung cancers among women.12 Furthermore, in Japan, only 2.1% of lung cancer cases were diagnosed among women aged 0–34 years.13\n\nThe most significant risk factor for the development of lung cancer is tobacco smoking; smokers have a 15- to 30-fold higher risk of developing lung cancer than nonsmokers.14 Furthermore, exposure to indoor radon is considered to be the second-most significant environmental risk factor for lung cancer in the United States.15 Other risk factors for lung cancer include exposure to second-hand smoke; family history of lung cancer; air pollution; preexisting disease of the lungs, such as tuberculosis or pneumonia; exposure to a high dose of radiation; and exposure to industrial or chemical carcinogens, such as asbestos, silica, and arsenic.16–19 However, these risk factors were not applicable to this patient.\n\nGiven the above, we feel comfortable concluding that nonsmoking women in their thirties rarely develop cancer, except in response to genetic abnormalities. Indeed, recent studies have reported several genetic abnormalities that cause lung squamous cell carcinoma, including mutations in FGFR, PIL3CA, PTEN, AKT, DDR2, BRAF, PDGFRA, SOX2, EphA2, and IGF-1R.20–22 However, these genetic abnormalities are relatively rare, and their precise frequencies are unknown.\n\nGATA3 can regulate cell survival or terminal cell differentiation in many nontransformed tissues and also influence tumor differentiation and suppresses tumor dissemination in a luminal breast cancer model.23 In addition, GATA3 interacts with and stabilizes HIF-1α, which is important in the pathogenesis of various human cancers, and can enhance cancer cell invasiveness.24 These data support the hypothesis that the GATA3 mutation identified in the present case is associated with her development of lung squamous cell carcinoma.\n\nNakamura et al1 described another GATA3 missense variant in the same position (p.C318S; this patient carries p.C318R) without clinical history of cancer. Further investigations are needed to clarify the different effects of these changes on oncogenesis.\n\nWe analyzed a whole blood sample from the patient using polymerase chain reaction-direct sequencing and found that she was carrying the missense variant, p.C318R, in exon 5; however, we were unable to perform further analyses of genetic abnormalities, including of GATA3 in the lung tumor, because the patient refused to give consent.\n\nConclusion\nThis is the first report describing the co-occurrence of cancer in a patient with HDR syndrome. Our study may provide valuable information regarding the pathogenesis of lung squamous cell carcinoma and indicate that GATA3 mutations may be a potential therapeutic target for lung cancer.\n\nAcknowledgments\nWe wish to thank the patient and family involved in this study for providing written informed consent for publication of this detailed case report. We also thank The Charlesworth Group for English language editing services.\n\nAuthor contributions\n\nMK, TN, and MT drafted the manuscript. KN, NK, and HK were involved in the clinical care of the patient. MY, KK, and YN interpreted clinical and laboratory data. SH provided histopathology results. TU coordinated genetic diagnosis, interpreted data, and critically revised the manuscript. All authors contributed toward data analysis, drafting and critically revising the paper and agree to be accountable for all aspects of the work. All authors read and approved the final manuscript.\n\nDisclosure\n\nThe authors report no conflicts of interest in this work.\n\nFigure 1 Polymerase chain reaction-direct sequencing.\n\nNotes: Chromatogram showing the germline mutation in the case included in the present study. Arrow indicates the missense variant c.C952T>C (p.C318R) in exon 5 of GATA3.\n\nFigure 2 Pedigree.\n\nNotes: Arrow indicates the proband. Males are represented by squares and females by circles. The filled circle indicates the affected female. A diagonal line through a square or circle indicates a deceased person.\n\nFigure 3 Images of bronchoscopic specimens stained for H&E and the indicated markers.\n\nNotes: Dysplasia with a coarse chromatin was observed in fibrous tissue. The tumor was positive for CK 5/6 and p63, weakly positive for TTF-1, and negative for Napsin. Magnification is ×400.\n\nAbbreviations: CK 5/6, cytokerTIN 5/6; H&E, hematoxylin and eosin; TTF-1, thyroid transcription factor-1.\n\nFigure 4 Age of nonsmoking patients diagnosed with lung squamous cell carcinoma at Kobe University Hospital from 2011 to 2017.\n\nNote: Of 263 patients diagnosed with lung squamous cell carcinoma at Kobe University Hospital, 16 were nonsmokers.\n\nFigure 5 Chest X-ray.\n\nNote: Left pleural effusion, pleural thickening, and scoliosis were detected.\n\nAbbreviations: R, right; P-A, posteroanterior.\n==== Refs\nReferences\n1 Nakamura A Fujiwara F Hasegawa Y Molecular analysis of the GATA3 gene in five Japanese patients with HDR syndrome Endocr J 2011 58 2 123 130 21157112 \n2 Bilous RW Murty G Parkinson DB Brief report: autosomal dominant familial hypoparathyroidism, sensorineural deafness, and renal dysplasia N Engl J Med 1992 327 15 1069 1074 1522843 \n3 Nesbit MA Bowl MR Harding B Characterization of GATA3 mutations in the hypoparathyroidism, deafness, and renal dysplasia (HDR) syndrome J Biol Chem 2004 279 21 22624 22634 14985365 \n4 Tsang AP Visvader JE Turner CA FOG, a multitype zinc finger protein, acts as a cofactor for transcription factor GATA-1 in erythroid and megakaryocytic differentiation Cell 1997 90 1 109 119 9230307 \n5 Tiseo M Gelsomino F Alfieri R FGFR as potential target in the treatment of squamous non small cell lung cancer Cancer Treat Rev 2015 41 6 527 539 25959741 \n6 Sobue T Yamamoto S Hara M Sasazuki S Sasaki S Tsugane S JPHC Study Group Japanese Public Health Center Cigarette smoking and subsequent risk of lung cancer by histologic type in middle-aged Japanese men and women: the JPHC study Int J Cancer 2002 99 2 245 251 11979440 \n7 Richards S Aziz N Bale S Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology Genet Med 2015 17 5 405 424 25741868 \n8 Pandolfi PP Roth ME Karis A Targeted disruption of the GATA3 gene causes severe abnormalities in the nervous system and in fetal liver haematopoiesis Nat Genet 1995 11 1 40 44 7550312 \n9 Usary J Llaca V Karaca G Mutation of GATA3 in human breast tumors Oncogene 2004 23 46 7669 7678 15361840 \n10 Ferraris S Del Monaco AG Garelli E HDR syndrome: a novel “de novo” mutation in GATA3 gene Am J Med Genet A 2009 149A 4 770 775 19248180 \n11 Van Esch H Groenen P Nesbit MA GATA3 haplo-insufficiency causes human HDR syndrome Nature 2000 406 6794 419 422 10935639 \n12 Youlden DR Cramb SM Baade PD The international epidemiology of lung cancer: geographical distribution and secular trends J Thorac Oncol 2008 3 8 819 831 18670299 \n13 GLOBOCAN 2002 Cancer incidence, mortality and prevalence worldwide IARC CancerBase No. 5 (version 20) Lyon, France IARC Press 2004 Available from: http://www-dep.iarc.fr/ Accessed June 29, 2017 \n14 Sasco AJ Secretan MB Straif K Tobacco smoking and cancer: a brief review of recent epidemiological evidence Lung Cancer 2004 45 Suppl 2 S3 S9 \n15 Alberg AJ Ford JG Samet JM American College of Chest Physicians Epidemiology of lung cancer: ACCP evidence-based clinical practice guidelines (2nd edition) Chest 2007 132 Suppl 3 29S 55S 17873159 \n16 Alberg AJ Samet JM Epidemiology of lung cancer Chest 2003 123 Suppl 1 21S 49S 12527563 \n17 Wakelee HA Chang ET Gomez SL Lung cancer incidence in never smokers J Clin Oncol 2007 25 5 472 478 17290054 \n18 Bilello KS Murin S Matthay RA Epidemiology, etiology, and prevention of lung cancer Clin Chest Med 2002 23 1 1 25 11901905 \n19 Subramanian J Govindan R Lung cancer in never smokers: a review J Clin Oncol 2007 25 5 561 570 17290066 \n20 Heist RS Sequist LV Engelman JA Genetic changes in squamous cell lung cancer: a review J Thorac Oncol 2012 7 5 924 933 22722794 \n21 Kim Y Hammerman PS Kim J Integrative and comparative genomic analysis of lung squamous cell carcinomas in East Asian patients J Clin Oncol 2014 32 2 121 128 24323028 \n22 Bai Y Kim JY Watters JM Adaptive responses to dasatinib-treated lung squamous cell cancer cells harboring DDR2 mutations Cancer Res 2014 74 24 7217 7228 25348954 \n23 Kouros-Mehr H Bechis SK Slorach EM GATA-3 links tumor differentiation and dissemination in a luminal breast cancer model Cancer Cell 2008 13 2 141 152 18242514 \n24 Lin MC Lin JJ Hsu CL Juan HF Lou PJ Huang MC GATA3 interacts with and stabilizes HIF-1α to enhance cancer cell invasiveness Oncogene 2017 36 30 4243 4252 28263977\n\n",
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"title": "Lung squamous cell carcinoma associated with hypoparathyroidism with sensorineural deafness and renal dysplasia syndrome: a case report.",
"title_normalized": "lung squamous cell carcinoma associated with hypoparathyroidism with sensorineural deafness and renal dysplasia syndrome a case report"
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"abstract": "Standard induction therapy for lupus nephritis (LN) with mycophenolate mofetil (MMF) or cyclophosphamide (CYC) is often ineffective. Evidence on rescue induction regimens is scarce. We analyzed efficacy and tolerability of multitarget immunosuppression with MMF and cyclosporine A (CsA) as induction treatment for LN (class III/IV/V) refractory to CYC and/or MMF. We included all six refractory LN patients (class IV = 3, class V = 2, class III = 1) from our 400-patient tertiary Lupus Clinic observed between 2012 and 2015. Four patients had previously received pulse CYC. All six received MMF as first or second induction therapy and CsA was added once failure to reach remission was established. Daily dose of MMF was 2-3 g and CsA was dosed up to 2.6-3.7 mg/kg/day. Mean proteinuria was reduced from 2407 mg/24 hours at the start of the MMF+CsA regimen to 544 mg/day after six months. The mean prednisolone dose was reduced from 17.5 to 6 mg/day after six months of MMF+CsA. Four patients achieved a complete renal response, one patient had a partial renal response and one failed to respond. None of the patients presented with adverse events. These data suggest that adding CsA to MMF can induce complete remission of refractory LN and is well tolerated.",
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"abstract": "Leishmaniasis is important as a cause of hemophagocytic lymphohistiocytosis (HLH) and must be considered and excluded in patients with HLH because it can cause severe or even fatal complications. When HLH is present, there is a deficient downregulation of the immune response, leading to an uncontrolled inflammation. We report a case of visceral leishmaniasis-HLH where the therapy with tocilizumab, targeting interleukin 6, help to regulate the immune response for the infection of Leishmania.",
"affiliations": "1Autoimmune Systemic Diseases Unit, Hospital Clínico San Cecilio, C/Dr Olóriz sn, Granada, Spain; and 2Department of Cellular Biology and Immunology, Instituto de Parasitología y Biomedicina López-Neyra, IPBLN-CSIC, P. T. Ciencias de la Salud, Granada, Spain.",
"authors": "Rios-Fernández|Raquel|R|;Callejas-Rubio|Jose-Luis|JL|;García-Rodríguez|Sonia|S|;Sancho|Jaime|J|;Zubiaur|Mercedes|M|;Ortego-Centeno|Norberto|N|",
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"title": "Tocilizumab as an Adjuvant Therapy for Hemophagocytic Lymphohistiocytosis Associated With Visceral Leishmaniasis.",
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"abstract": "A 20-year-old woman was diagnosed with stage 4 lung adenocarcinoma with an epidermal growth factor receptor (EGFR) exon 20 insertion gene mutation. Although the patient underwent chemotherapy, her lesions progressed. Liquid biopsy for EGFR T790M mutation showed negative results. After administering osimertinib, reduction of the lesions at the primary site was observed, and the patient's respiratory condition improved. Previous reports showing successful treatment of EGFR exon 20 insertion-positive lung adenocarcinoma with the standard osimertinib dose of 80 mg are limited. The present case demonstrated that osimertinib could be a possible treatment option for EGFR exon 20 insertion-positive lung adenocarcinoma.",
"affiliations": "Postgraduate Clinical Training Center, Yamagata University Hospital, Yamagata, Japan.;Department of Cardiology, Pulmonology, and Nephrology, Yamagata University Faculty of Medicine, Yamagata, Japan.;Department of Cardiology, Pulmonology, and Nephrology, Yamagata University Faculty of Medicine, Yamagata, Japan.;Department of Cardiology, Pulmonology, and Nephrology, Yamagata University Faculty of Medicine, Yamagata, Japan.;Department of Cardiology, Pulmonology, and Nephrology, Yamagata University Faculty of Medicine, Yamagata, Japan.",
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"fulltext": "\n==== Front\nEXCLI JEXCLI JEXCLI JEXCLI Journal1611-2156Leibniz Research Centre for Working Environment and Human Factors 2019-178610.17179/excli2019-1786Doc893Case ReportOsimertinib as treatment for EGFR exon 20 insertion-positive lung adenocarcinoma Murano Chihiro 1Igarashi Akira 2Yamauchi Keiko 2Inoue Sumito *2Watanabe Masafumi 2\n1 Postgraduate Clinical Training Center, Yamagata University Hospital, Yamagata, Japan\n2 Department of Cardiology, Pulmonology, and Nephrology, Yamagata University Faculty of Medicine, Yamagata, Japan*To whom correspondence should be addressed: Sumito Inoue, Department of Cardiology, Pulmonology, and Nephrology, Yamagata University Faculty of Medicine, 2-2-2 Iida-Nishi, Yamagata 990-9585, Japan; Tel: +81-23-628-5302, Fax: +81-23-628-5305, E-mail: sinoue@med.id.yamagata-u.ac.jp07 10 2019 2019 18 893 898 03 9 2019 25 9 2019 Copyright © 2019 Murano et al.2019This is an Open Access article distributed under the terms of the Creative Commons Attribution Licence (http://creativecommons.org/licenses/by/4.0/) You are free to copy, distribute and transmit the work, provided the original author and source are credited.This article is available from https://www.excli.de/vol18/Inoue_07102019_proof.pdfA 20-year-old woman was diagnosed with stage 4 lung adenocarcinoma with an epidermal growth factor receptor (EGFR) exon 20 insertion gene mutation. Although the patient underwent chemotherapy, her lesions progressed. Liquid biopsy for EGFR T790M mutation showed negative results. After administering osimertinib, reduction of the lesions at the primary site was observed, and the patient's respiratory condition improved. Previous reports showing successful treatment of EGFR exon 20 insertion-positive lung adenocarcinoma with the standard osimertinib dose of 80 mg are limited. The present case demonstrated that osimertinib could be a possible treatment option for EGFR exon 20 insertion-positive lung adenocarcinoma.\n\nlung canceradenocarcinomaEGFR exon 20 insertion gene mutationosimertinib\n==== Body\nIntroduction\nThe frequency of exon 20 insertions in the epidermal growth factor receptor (EGFR) gene has been reported to account for 2.0-5.8 % of the total EGFR mutations. According to previous reports, non-small cell lung cancers with EGFR exon 20 insertions are resistant to EGFR-tyrosine kinase inhibitor (TKI) treatment. Only a small number of cases have been reported in which osimertinib was administered to patients with lung cancer who were positive for EGFR exon 20 insertions (Jänne et al., 2015[3], Piotrowska et al., 2018[6], Riess et al., 2017[7], Veggel et al., 2018[8]). There is currently limited research on the effect of EGFR-TKI on exon 20 insertion positive non-small cell lung cancer. Osimertinib may be an effective treatment for non-small cell lung cancer with exon 20 insertions.\n\nCase report\nA woman in her 20s with no previous history of smoking was diagnosed with stage 4 lung adenocarcinoma (cT2aN3M1b) with associated liver metastasis, multiple bone metastasis, and multiple brain metastasis. Her staging was based on the classification of lung cancer as per The Japan Lung Cancer Society, 7th edition. Gene analysis revealed positive results for an EGFR exon 20 insertion mutation and negative results for an echinoderm microtubule-associated protein-like 4 anaplastic lymphoma kinase (EML4-ALK) gene fusion. PD-L1 expression in the lung biopsy tissue was 80-90 %.\n\nShe received cisplatin and pemetrexed sodium hydrate (PEM) chemotherapy. Following single-agent PEM chemotherapy administration, we observed tumor progression and an increasing number of cysts in the lung. Thoracoscopic lung biopsy revealed multiple metastatic lesions in the lung field and cystic lesions associated with the check valve mechanism containing cancer cells, but no evidence of interstitial pneumonia or vasculitis was noted. There were no findings in the laboratory data suggesting any collagenous diseases. In September X+1 year, she was administered 30 mg of afatinib orally, but administration was discontinued after 30 days due to hepatic dysfunction. After her hepatic function improved, she received 20 mg of afatinib; however, a liver function disorder was observed 5 days after the afatinib administration. Due to hepatic dysfunction and disease progression, afatinib was discontinued. In November X+1 year, she received docetaxel hydrate (DTX) without ramucirumab, because of the high risk of bleeding from the bronchus. Even though the treatment effects of DTX were obtained, her treatment was changed to pembrolizumab because it was commercially available. However, tumor progression was observed even though three courses of pembrolizumab treatment were administered. DTX was administered again from June to August X year, and tumor growth was still observed despite the total eight courses of treatment. In September, the patient received one course of amrubicin, but it was ineffective. Because of an eating disorder, malaise, and breathing difficulty, the patient was readmitted to the hospital in October (2 years from the diagnosis). Blood biochemical examination findings at this time revealed the following: leukocyte increased to 16400/μl (neutrophils, 91.0 %; lymphocytes, 4.1 %; monocytes, 4.4 %; eosinophils, 0.10 %; and basophils, 0.40 %), hemoglobin level reduced to 10.5 g/dl, C-reactive protein level increased to 16.93 mg/dl, and CYFRA level increased to 17.94 ng/dl. The results of the EGFR mutation plasma test were negative for the T790M mutation and positive for the exon 20 insertion. Histological examination to assess the EGFR mutation could not be performed due to her poor general condition. A chest X-ray (Figure 1(Fig. 1)) revealed a tumor shadow in the right hilar area, an invasive shadow in the left middle and lower lung fields, and pleural effusion on both sides. \n\nComputed tomography (CT) (Figure 2(Fig. 2)) revealed tumors in the right middle and lower lobes, multiple cystic lesions in the lung field, mild pneumothorax of the right lung (Figure 2a(Fig. 2)), and pleural effusion on both sides (Figure 2b(Fig. 2)).\n\nAfter hospitalization, deterioration of her respiratory condition and performance status (PS) was observed due to disease progression (PS=3). A standard dose (80 mg) of osimertinib was administered after explaining the effects and side effects of the treatment to the patient and her family. Respiratory state improved, and PS improved from 3 to 1, approximately 1 week from the introduction of osimertinib; cavitation and decrease in size of the primary lesion were observed via CT after 43 (Figure 3a(Fig. 3)) and 81 days (Figure 3b(Fig. 3)), respectively. The maximum effect was judged as a partial response (PR). CYFRA level decreased to 6.02 ng/dl, and CRP level decreased to 0.43 mg/dl at 16 days from the administration of osimertinib. Approximately 4 months after initiating osimertinib treatment, her respiratory condition deteriorated due to hemoptysis, and the patient died approximately 2 years and 5 months after the initial diagnosis of lung cancer.\n\nDiscussion\nTo the best of our knowledge, there is only a small number of case reports that demonstrate successful treatment of EGFR exon 20 insertion-positive lung adenocarcinoma with a standard osimertinib dose of 80 mg (Jänne et al., 2015[3], Piotrowska et al., 2018[6], Riess et al., 2017[7], Veggel et al., 2018[8]). Exon 19 deletion mutations and exon 21 L858R mutations constitute approximately 90 % of EGFR mutations (Beau-Faller et al., 2014[1]). Other gene mutations, generally known as uncommon mutations such as E709X, G719X, S768I, P848L, L861Q, and exon 20 insertions, are located in exons 18-21. Exon 20 insertions have been reported in 2.0-5.8 % of EGFR mutation cases; such cases are considered to be resistant to EGFR-TKI (Kobayashi and Mitsudomi, 2016[4]; Yasuda et al., 2012[9]). In previous reports, one patient with exon 20 insertions received 40 mg osimertinib in the AURA test (Phase I), but disease progression was observed (Jänne et al., 2015[3]). Two other reports showed partial responses with 160 mg osimertinib used for treating patients with exon 20 positive insertions (Piotrowska et al., 2018[6]; Riess et al., 2017[7]). However, interstitial pneumonia was observed, and therefore, administration was discontinued (Riess et al., 2017[7]). In 2018, Veggel et al. reported the standard dose effect of osimertinib for patients with EGFR exon 20 insertion-positive non-small-cell lung cancer (Veggel et al., 2018[8]). They observed only one patient with partial response. The objective response rate was reported to be 6 %.\n\nSeveral genetic variants have been reported in EGFR exon 20 insertion mutations (Kobayashi and Mitsudomi, 2016[4]; Oxnard et al., 2013[5]; Yasuda et al., 2012[9], 2013[10]). Genetic variants sensitive to first-generation EGFR-TKIs have also been observed (Kobayashi and Mitsudomi, 2016[4]). Although the gene mutation type of exon 20 insertions in this case is unknown, we believe that it is not a type of mutation that demonstrates the effects of first-generation EGFR-TKIs. Hirano et al. examined the effect of EGFR-TKI on culture cell lines transfected with exon 20 insertion mutations. The IC50 value of osimertinib was lower than that of other EGFR-TKIs in any cell lines. For exon 20 insertions, it is suggested that osimertinib may be more effective than other EGFR-TKIs (Hirano et al., 2015[2]). In this case, afatinib was administered only for 1 month due to liver dysfunction; owing to a short period of afatinib administration, the effect was not observed. The T790M mutation was not detected via the plasma test before the administration of osimertinib. Although tissue specimens could not be studied immediately before administering osimertinib, we believe that a possible T790M mutation being induced by afatinib is very low.\n\nAlthough exon 20 insertions are known to be resistant to EGFR-TKIs, osimertinib may be effective. Clinical trials are currently underway to examine the effects of several EGFR-TKIs on non-small cell lung cancer positivity for exon 20 insertion mutations (UMIN000031929, ClinicalTrials.gov Identifier: NCT03066206, ClinicalTrials.gov Identifier: NCT03414814). We hope that these results will establish evidence that osimertinib and other EGFR-TKIs are effective for non-small cell lung cancer positivity for exon 20 insertion mutations.\n\nAcknowledgement\nWe would like to thank Editage (www.editage.jp) for English language editing.\n\nConflict of interest\nWe have no financial relationship with the organization that sponsored the research.\n\nFigure 1 Chest X-ray scan revealed a tumor shadow in the right hilar area, an invasive shadow in the left middle and lower lung fields, and pleural effusion on both sides.\nFigure 2 Computed tomography (CT) scan before administration of osimertinib. Primary lesions in the right middle and lower lobes, multiple cystic lesions in the lung field, and mild pneumothorax were observed in the right lung (a). Pleural effusion on both sides was observed (b).\nFigure 3 CT images after administration of osimertinib. Cavitation and decrease in size of the primary lesion were observed after 43 (a) and 81 days (b).\n==== Refs\n1 Beau-Faller M Prim N Ruppert AM Nanni-Metéllus I Lacave R Lacroix L Rare EGFR exon 18 and exon 20 mutations in non-small-cell lung cancer on 10 117 patients: a multicentre observational study by the French ERMETIC-IFCT network Ann Oncol 2014 25 126 131 24285021 \n2 Hirano T Yasuda H Tani T Hamamoto J Oashi A Ishioka K In vitro modeling to determine mutation specificity of EGFR tyrosine kinase inhibitors against clinically relevant EGFR mutants in non-small-cell lung cancer Oncotarget 2015 6 38789 38803 26515464 \n3 Jänne PA Yang JC Kim DW Planchard D Ohe Y Ramalingam SS AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer N Engl J Med 2015 372 1689 1699 25923549 \n4 Kobayashi Y Mitsudomi T Not all epidermal growth factor receptor mutations in lung cancer are created equal: Perspectives for individualized treatment strategy Cancer Sci 2016 107 1179 1186 27323238 \n5 Oxnard GR Lo PC Nishino M Dahlberg SE Lindeman NI Butaney M Natural history and molecular characteristics of lung cancers harboring EGFR exon 20 insertions J Thorac Oncol 2013 8 179 184 23328547 \n6 Piotrowska Z Fintelmann FJ Sequist LV Jahagirdar B Response to osimertinib in an EGFR exon 20 insertion-positive lung adenocarcinoma J Thorac Oncol 2018 13 e204 e206 30244855 \n7 Riess J Floch N Martin M Orme J Staniszewska A Menard L Antitumor activity of osimertinib in NSCLC harboring EGFR exon 20 insertions J Clin Oncol 2017 35 Suppl 9030 \n8 Veggel B Wekken A Hashemi S Cornelissen R Monkhorst K Heideman D Osimertinib treatment for patients with EGFR exon 20 insertion positive non-small-cell lung cancer Ann Oncol 2018 29 Suppl 8 viii493 viii547 \n9 Yasuda H Kobayashi S Costa DB EGFR exon 20 insertion mutations in non-small-cell lung cancer: preclinical data and clinical implications Lancet Oncol 2012 13 e23 e31 21764376 \n10 Yasuda H Park E Yun CH Sng NJ Lucena-Araujo AR Yeo WL Structural, biochemical, and clinical characterization of epidermal growth factor receptor (EGFR) exon 20 insertion mutations in lung cancer Sci Transl Med 2013 5 216ra177\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1611-2156",
"issue": "18()",
"journal": "EXCLI journal",
"keywords": "EGFR exon 20 insertion gene mutation; adenocarcinoma; lung cancer; osimertinib",
"medline_ta": "EXCLI J",
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"nlm_unique_id": "101299402",
"other_id": null,
"pages": "893-898",
"pmc": null,
"pmid": "31645848",
"pubdate": "2019",
"publication_types": "D002363:Case Reports",
"references": "30244855;26515464;24285021;24353160;25923549;27323238;21764376;23328547",
"title": "Osimertinib as treatment for EGFR exon 20 insertion-positive lung adenocarcinoma.",
"title_normalized": "osimertinib as treatment for egfr exon 20 insertion positive lung adenocarcinoma"
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"abstract": "BACKGROUND\nMetformin-associated lactic acidosis is a rare but serious complication of taking metformin. Making the diagnosis in the emergency department requires vigilance because the presentation can mimic other diseases.\n\n\nMETHODS\nWe present a case of a patient with diabetes who presented moribund with symptoms and signs consistent with mesenteric ischemia. This diagnosis was seemingly confirmed through computed tomography, and as a result the patient was brought to surgery for emergent exploratory laparotomy. Our patient made a remarkable recovery upon initiation of hemodialysis, demonstrating the need to initiate this life-saving procedure early. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Metformin levels are rarely available in the setting of the emergency department. Clinicians must remain alert, recognize that imaging studies may be misleading, and consider hemodialysis early in addition to surgical interventions.",
"affiliations": "Department of Emergency Medicine, University Medical Center, LSU Emergency Medicine Residency, New Orleans, Louisiana.;Department of Emergency Medicine, University Medical Center, LSU Emergency Medicine Residency, New Orleans, Louisiana.;Department of Emergency Medicine, University Medical Center, LSU Emergency Medicine Residency, New Orleans, Louisiana.;Department of Emergency Medicine, University Medical Center, LSU Emergency Medicine Residency, New Orleans, Louisiana.",
"authors": "Zhang|Qi Charles|QC|;Hastings|Casey|C|;Johnson|Kelly|K|;Slaven|Ellen|E|",
"chemical_list": "D007004:Hypoglycemic Agents; D019344:Lactic Acid; D008687:Metformin; D003404:Creatinine",
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"issue": "57(5)",
"journal": "The Journal of emergency medicine",
"keywords": "lactic acidosis; mesenteric ischemia; metformin; metformin-associated lactic acidosis",
"medline_ta": "J Emerg Med",
"mesh_terms": "D000140:Acidosis, Lactic; D003404:Creatinine; D003924:Diabetes Mellitus, Type 2; D004636:Emergency Service, Hospital; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents; D019344:Lactic Acid; D007813:Laparotomy; D065666:Mesenteric Ischemia; D008687:Metformin; D008875:Middle Aged",
"nlm_unique_id": "8412174",
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"pmc": null,
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"pubdate": "2019-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Metformin-Associated Lactic Acidosis Presenting Like Acute Mesenteric Ischemia.",
"title_normalized": "metformin associated lactic acidosis presenting like acute mesenteric ischemia"
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"abstract": "Drug-induced liver injury (DILI) that progresses to acute liver failure (ALF) has a high mortality rate, and therapeutic options are limited. Acetylcysteine has a labeled indication for use as an antidote for acetaminophen toxicity and has also been used with limited success in treatment of non-acetaminophen-induced liver injury, with small clinical trials indicating an increase in transplant-free survival. Recommendations for management of non-acetaminophen-induced DILI include withdrawal of the offending agent and supportive care. Treatment guidelines generally discourage a rechallenge with an offending medication, except in cases where there are no other therapeutic options for management of a serious disease, such as active tuberculosis (TB).\n\n\n\nThis case report describes the reversal of ALF due to DILI in a patient receiving antitubercular agents for active TB. After withdrawal of initially prescribed antitubercular agents, the patient was switched to a less hepatotoxic anti-TB regimen and intravenous acetylcysteine pending results of antimicrobial susceptibility testing. After stabilization of the patient's liver enzyme levels, intravenous acetylcysteine was discontinued and oral acetylcysteine was continued for 5 days without an increase in hepatic enzyme levels or clinical deterioration. After 5 days, oral acetylcysteine was discontinued due to patient-reported nausea and vomiting.\n\n\n\nGiven the limited number of therapeutic interventions shown to be beneficial in ALF and data suggesting a protective effect against DILI with initiation of acetylcysteine at the start of treatment with anti-TB medications, acetylcysteine can be considered for patients with anti-TB - associated DILI.",
"affiliations": "Department of Pharmacy, University of New Mexico Hospitals, Albuquerque, NM.;Total Dose Community Pharmacy, Oklahoma City, OK.;Department of Hematology/Oncology, Stevenson Cancer Center, Oklahoma City, OK.;Department of Pharmacy: Clinical and Administrative Sciences, University of Oklahoma College of Pharmacy, Oklahoma City, OK.",
"authors": "Fox|Ashley N|AN|;Nation|Brooke E|BE|;Autry|Marcus Tad|MT|;Johnson|Peter N|PN|",
"chemical_list": "D000931:Antidotes; D000995:Antitubercular Agents; D000111:Acetylcysteine",
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"issue": "77(18)",
"journal": "American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists",
"keywords": "\n N-acetylcystine; RIPE liver injury; acetylcysteine; drug-induced liver injury; nonacetaminophen acute liver failure",
"medline_ta": "Am J Health Syst Pharm",
"mesh_terms": "D000111:Acetylcysteine; D000284:Administration, Oral; D000328:Adult; D000931:Antidotes; D000995:Antitubercular Agents; D056486:Chemical and Drug Induced Liver Injury; D005260:Female; D006801:Humans; D017114:Liver Failure, Acute; D014376:Tuberculosis",
"nlm_unique_id": "9503023",
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"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Possible role for acetylcysteine as a treatment for acute liver failure secondary to antitubercular medication use.",
"title_normalized": "possible role for acetylcysteine as a treatment for acute liver failure secondary to antitubercular medication use"
} | [
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"companynumb": "US-HIKMA PHARMACEUTICALS USA INC.-US-H14001-21-01749",
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"abstract": "Here we report a case of a 10-year-old female with unclassified epileptic encephalopathy who showed forced normalization after administration of levetiracetam (LEV). She initially presented with intractable tonic and myoclonic seizures that were observed about 10 times a day along with frequent multifocal sharp and slow wave complexes on electroencephalography (EEG). We were forced to decrease the topiramate dose because of the appearance of nystagmus, and her myoclonic seizures became worse. We added LEV (250 mg/day) and her tonic and myoclonic seizures disappeared one day after initiation of LEV administration. However, she showed hyporesponsiveness and akinesia. The disappearance of paroxysmal discharges on EEG confirmed the diagnosis of forced normalization. Despite continuous administration of LEV, tonic and myoclonic seizures relapsed within a month but her psychotic symptoms resolved simultaneously. To the best of our knowledge, this is the first reported case of forced normalization after LEV administration. It should be noted that LEV may cause forced normalization although it can be started at an adequate dosage.",
"affiliations": "Department of Pediatrics, Faculty of Medicine, Yamagata University, Yamagata. kikuchi-ygt@umin.ac.jp",
"authors": "Kikuchi|Takahiro|T|;Kato|Mitsuhiro|M|;Takahashi|Nobuya|N|;Nakamura|Kazuyuki|K|;Hayasaka|Kiyoshi|K|",
"chemical_list": "D000927:Anticonvulsants; D000077287:Levetiracetam; D010889:Piracetam",
"country": "Japan",
"delete": false,
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"issn_linking": "0029-0831",
"issue": "45(5)",
"journal": "No to hattatsu = Brain and development",
"keywords": null,
"medline_ta": "No To Hattatsu",
"mesh_terms": "D000927:Anticonvulsants; D058256:Brain Waves; D002648:Child; D004569:Electroencephalography; D004827:Epilepsy; D005260:Female; D006801:Humans; D000077287:Levetiracetam; D010889:Piracetam; D016896:Treatment Outcome",
"nlm_unique_id": "0215224",
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"pages": "375-8",
"pmc": null,
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"pubdate": "2013-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Epileptic encephalopathy associated with forced normalization after administration of levetiracetam.",
"title_normalized": "epileptic encephalopathy associated with forced normalization after administration of levetiracetam"
} | [
{
"companynumb": "PHHY2013JP113180",
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"activesubstancename": "TOPIRAMATE"
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{
"abstract": "Continuous electroencephalography (CEEG) is chiefly performed at The Medical University of South Carolina (MUSC) for identifying seizures, including its refined use within the epilepsy monitoring unit (EMU) as a differentiator between epileptic and psychogenic etiologies. CEEG also provides critical data that carry implications outside the bounds of both epilepsy and psychogenic events, such as the characterization of unorthodox clinical phenomena that are of physiological (though nonepileptic) origins. Although nonepileptic events (NEEs) are primarily linked with psychogenic phenomena (conversion disorder, malingering) that can mimic epileptic activity, they, like seizures, have diverse semiologies and etiologies. Although it is reasonable for seasoned neurodiagnostics professionals to develop an expectation that NEEs are of psychogenic origin, it is essential to acknowledge that they include etiologies that lay beyond those of psychiatric influence. Such a case is presented in which a 74-year-old female patient who, though initially suspected of having either psychogenic or epileptic seizures, was found to be having frequent episodes of the life-threatening cardiac convulsive syncope torsades de pointes (TdP). The patient had several known risk factors for TdP, including a prolonged QT complex, female gender, advancing age, active medications known to provoke TdP, and electrolyte imbalances (low magnesium and potassium) (Trinkley et al. 2013). TdP was first suspected through the CEEG by a combination of remarkable EEG background changes, recorded video evidence of clinical features, and accompanying single-lead electrocardiogram (ECG) data captured during the events. Upon proper diagnosis, the patient was urgently treated with restorative measures, including electrolyte replenishment, pacemaker implantation, and cessation of provocative medications.",
"affiliations": "a Department of Clinical Neurophysiology , Medical University of South Carolina , Charleston , South Carolina.;a Department of Clinical Neurophysiology , Medical University of South Carolina , Charleston , South Carolina.;a Department of Clinical Neurophysiology , Medical University of South Carolina , Charleston , South Carolina.",
"authors": "Ham|Andrew Todd|AT|http://orcid.org/0000-0002-6003-6924;Mackey|Jill|J|;Semb|Gary|G|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1080/21646821.2018.1456292",
"fulltext": null,
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"issn_linking": "2164-6821",
"issue": "58(2)",
"journal": "The Neurodiagnostic journal",
"keywords": "Cardiac convulsive syncope; cerebral hypoperfusion; electroencephalograph (EEG); nonepileptic event (NEE); torsades de pointes (TdP)",
"medline_ta": "Neurodiagn J",
"mesh_terms": null,
"nlm_unique_id": "101573167",
"other_id": null,
"pages": "91-106",
"pmc": null,
"pmid": "29923812",
"pubdate": "2018",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "The Identification of Torsades de Pointes via CEEG: A Case Report on a Patient with Physiologically Provoked Nonepileptic Events.",
"title_normalized": "the identification of torsades de pointes via ceeg a case report on a patient with physiologically provoked nonepileptic events"
} | [
{
"companynumb": "US-CIPLA LTD.-STD201201-000064",
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"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ALBUTEROL"
},
"drugadditional": null,
... |
{
"abstract": "Common adverse effects of serotonin-norepinephrine reuptake inhibitors are nausea, dry mouth, dizziness and headache. We describe the case of a patient with dysosmia and subsequent dysgeusia associated with duloxetine. A 68-year-old Japanese woman with a history of type 1 diabetes mellitus, hypertension, insomnia and reflux esophagitis presented to a local hospital with bilateral leg pain; she was treated with duloxetine. However, after 4 weeks, she sensed rotten egg smell, experienced nausea and vomiting and was admitted to our hospital. We diagnosed dysosmia using the T&T olfactometer threshold test and dysgeusia using filter paper disk method. Taste was assessed using electrogustometry. We suspected that dysosmia and dysgeusia were adverse effects of duloxetine. After stopping duloxetine, her symptoms gradually subsided and the above test results improved, despite continuing the other ongoing medication. To the best of our knowledge, this is the first case report of dysosmia and dysgeusia associated with duloxetine.",
"affiliations": "Division of General Medicine, Department of Comprehensive Medicine 1, Saitama Medical Center, Jichi Medical University, Saitama, Saitama, Japan.;Division of General Medicine, Department of Comprehensive Medicine 1, Saitama Medical Center, Jichi Medical University, Saitama, Saitama, Japan.;Division of General Medicine, Department of Comprehensive Medicine 1, Saitama Medical Center, Jichi Medical University, Saitama, Saitama, Japan.",
"authors": "Yoshida|Katsuyuki|K|;Fukuchi|Takahiko|T|;Sugawara|Hitoshi|H|",
"chemical_list": "D000068760:Serotonin and Noradrenaline Reuptake Inhibitors; D000068736:Duloxetine Hydrochloride",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2017-222470",
"fulltext": "\n==== Front\nBMJ Case RepBMJ Case RepcasereportsbmjcasereportsBMJ Case Reports1757-790XBMJ Publishing Group BMA House, Tavistock Square, London, WC1H 9JR bcr-2017-22247010.1136/bcr-2017-222470Case Report1506382Dysosmia and dysgeusia associated with duloxetine Yoshida Katsuyuki 1Fukuchi Takahiko 2Sugawara Hitoshi 31 Division of General Medicine, Department of Comprehensive Medicine 1, Saitama Medical Center, Jichi Medical University, Saitama, Saitama, Japan2 Division of General Medicine, Department of Comprehensive Medicine 1, Saitama Medical Center, Jichi Medical University, Saitama, Saitama, Japan3 Division of General Medicine, Department of Comprehensive Medicine 1, Saitama Medical Center, Jichi Medical University, Saitama, Saitama, JapanCorrespondence to Dr Katsuyuki Yoshida, d06sm098@yahoo.co.jp2017 23 11 2017 23 11 2017 2017 bcr20172224706 11 2017 © BMJ Publishing Group Ltd (unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.2017This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/Common adverse effects of serotonin–norepinephrine reuptake inhibitors are nausea, dry mouth, dizziness and headache. We describe the case of a patient with dysosmia and subsequent dysgeusia associated with duloxetine. A 68-year-old Japanese woman with a history of type 1 diabetes mellitus, hypertension, insomnia and reflux esophagitis presented to a local hospital with bilateral leg pain; she was treated with duloxetine. However, after 4 weeks, she sensed rotten egg smell, experienced nausea and vomiting and was admitted to our hospital. We diagnosed dysosmia using the T&T olfactometer threshold test and dysgeusia using filter paper disk method. Taste was assessed using electrogustometry. We suspected that dysosmia and dysgeusia were adverse effects of duloxetine. After stopping duloxetine, her symptoms gradually subsided and the above test results improved, despite continuing the other ongoing medication. To the best of our knowledge, this is the first case report of dysosmia and dysgeusia associated with duloxetine.\n\nPharmacology And TherapeuticsUnwanted Effects / Adverse Reactionsspecial-featureunlocked\n==== Body\nBackground\nSerotonin–norepinephrine reuptake inhibitors (SNRI) are used to treat depressive disorders and certain types of chronic pain.1 The most common adverse effects of SNRIs are nausea, dry mouth, dizziness and headache.2 It remains unknown which drug is likely to cause drug-related concomitant taste and smell dysfunction.3–5 Here we describe distortion of taste (dysosmia) and smell (dysgeusia) as new adverse effects of duloxetine.\n\nCase presentation\nA 68-year-old Japanese woman with medical histories of type 1 diabetes mellitus, hypertension, insomnia and reflux esophagitis presented to a local hospital with bilateral leg pain due to diabetic neuropathy and was treated with duloxetine. After 4 weeks, she vomited blood and was admitted to our hospital for further investigation. Prior to hospitalisation, she reported a 4-day history of a rotten egg smell, vomiting and an inability to eat. She described that she experienced the smell for the first time when she visited a coffee shop. She had no history of smoking, head trauma, allergic rhinitis or upper respiratory tract infection before the onset of symptoms and also showed no symptoms of chronic or acute recurrent rhinosinusitis or rhinitis.\n\nHer medication included long-acting insulin analogue (glargine) 14 units at bed time, rapid-acting insulin analogue (aspart) 8 units each before meals, amlodipine (5 mg/day), lansoprazole (15 mg/day), brotizolam (0.25 mg/day) and duloxetine (20 mg/day).\n\nPhysical examination revealed a body mass index of 20.5 kg/m2, temperature of 37.3°C, pulse of 127 beats/min, blood pressure of 184/100 mm Hg, respiratory rate of 20 breaths/min and oxygen saturation of 96% in room air. She was alert and oriented, with no evidence of dementia. Her mouth was dry, but her capillary refill time was <2 s. There was no sinus or abdominal tenderness. Neurological findings were normal, with no evidence of tremor at rest, rigidity and postural instability.\n\nInvestigations\nThe laboratory data were as follows: white cell count, 10.28x109/L; haemoglobin, 15 g/dL; platelets, 25.9×104/μL; haemoglobin A1c, 5.9%; casual plasma glucose level, 244 mg/dL; blood urea nitrogen, 34 mg/dL; creatinine, 0.49 mg/dL; potassium, 2.9 mmol/L; zinc, 49 µg/dL (65–110); and copper, 128 µg/dL (76–141). Upper gastrointestinal endoscopy showed an oesophageal erosive lesion but no bleeding or obstruction. Head MRI showed fluid intensity in the maxillary sinus but no atrophy of the hippocampus or diffuse changes in the temporal and frontal lobes.\n\nOlfactory acuity tests were performed using the T&T olfactometer threshold test (figure 1), which showed that olfactory detection thresholds were <2, except those for the rotten egg smell, and all olfactory recognition thresholds were <3. The filter paper disk method was used for taste assessment, which indicated that recognition levels for sweet, salt, sour and bitter tastes were <4 (table 1). Electrogustometry (table 2) of the areas of the chorda tympani and glossopharyngeal and major petrosus nerves showed that taste recognition levels were all bilaterally >10 dB.\n\nTable 1 Filter paper disk method for taste assessment on admission day (HD 1) and 7 days after discontinuing duloxetine (HD 7)\n\nNerve\tTaste\t\nSweet\tSalt\tSour\tBitter\t\nHD 1\tHD 7\tHD 1\tHD 7\tHD 1\tHD 7\tHD 1\tHD 7\t\nChorda tympani\tRight\tVI\tII\tV\tIII\tVI\tI\tV\tIII\t\nLeft\tV\tIV\tVI\tIII\tV\tII\tVI\tIV\t\nGlossopharyngeal\tRight\tVI\tIII\tVI\tIII\tV\tV\tV\tII\t\nLeft\tV\tV\tV\tII\tV\tIII\tVI\tVI\t\nMajor petrosus\tRight\tVI\tVI\tVI\tVI\tVI\tVI\tVI\tVI\t\nLeft\tVI\tVI\tVI\tVI\tVI\tVI\tVI\tV\t\nRoman numbers indicate taste concentration (ranges I–V); lower number indicates lighter. VI means no recognition of the taste.\n\nHD, hospital day.\n\nFigure 1 T&T olfactometer threshold test on admission day (left) and 7 days after discontinuing duloxetine (right). Alphabets represent specific odours: A, rose; B, caramel; C, rotten egg; D, sweet; and E, faeces. Range: −2 to 5, lower number indicates better smell threshold. Circle indicates the smell detection threshold. Saltire indicates the smell recognition.\n\nTable 2 Electrogustometry on admission day (HD 1) and 7 days after discontinuing duloxetine (HD 7)\n\nNerve\tDecibel\t\nHD 1\tHD 7\t\nChorda tympani\tRight\t10\t−6\t\nLeft\t20\t−4\t\nGlossopharyngeal\tRight\t20\t8\t\nLeft\t20\t6\t\nMajor petrosus\tRight\t>34\t34\t\nLeft\t>34\t30\t\nValues indicate taste detection threshold. Lower value indicates better detection threshold.\n\nHD, hospital day.\n\nDifferential diagnosis\nThe patient showed both smell and taste disorders. Using the history of the patient and laboratory, physiological and imaging findings, the differential diagnosis for the taste disorder included adverse drug effects of duloxetine started before the onset of dysgeusia or the other ongoing medication, zinc deficiency, sinusitis and diabetic neuropathy, and that for the smell disorder included adverse drug effects of duloxetine started before the onset of dysosmia or the other ongoing medication, sinusitis and diabetic neuropathy.\n\nTreatment\nSoon after stopping duloxetine, both smell and taste disorders improved (figure 1 and tables 1 and 2), despite continuing the other ongoing medication.\n\nOutcome and follow-up\nSeven days after discontinuing duloxetine (hospital day 7), olfactory acuity tests showed improved recognition levels of rose, rotten egg and faeces smells of >3. Taste assessment using the filter paper disk method showed that the recognition level was partially improved by >3 and that using electrogustometry showed that the detection level was improved by >10 dB in the areas of the chorda tympani and glossopharyngeal nerve. If the other differential diagnosis was correct, then the symptom would not have improved only by stopping duloxetine.\n\nAfter discharging from our hospital, her olfactory and taste disorders have not recurred so far.\n\nDiscussion\nThis report indicates that duloxetine caused dysosmia and subsequent dysgeusia because both smell and taste disorders reversibly recovered 7 days after discontinuing duloxetine, despite continuing the other ongoing medication. This clinical course between the discontinuation of duloxetine and improvement of taste and smell sensation provides objective evidence to support duloxetine as the cause of these adverse effects. Two important clinical issues arise from the clinical course of the present study patient. The first is whether these disorders have already been reported as adverse effects of duloxetine, and the second concerns the mechanism by which duloxetine or by which drug interactions with duloxetine cause these disorders.\n\nThe primary causes of olfactory dysfunction are allergic and viral rhinitis, influenza, head trauma, dementia of the Alzheimer type, Parkinson’s disease, diabetes mellitus and malnutrition.3 Although this patient had several years’ history of type 1 diabetes mellitus, hypertension, insomnia, reflux esophagitis, and chronic bilateral maxillary sinusitis and low serum zinc levels, which were found at this admission, there had been no problem with her sense of smell before taking duloxetine, and her sense of smell recovered soon after discontinuing duloxetine, despite continuing the other ongoing medication. This clinical course proved that duloxetine was the major cause of dysosmia and subsequent dysgeusia in this patient.\n\nAlthough the incidence of drug-induced taste and smell disorders is quite high, there are few reports available in the literature regarding their true incidence.3–5 Thus, the true incidence of drug-induced taste and smell disorder may possibly be underestimated. Available evidence from two reviews3 4 and a report of an Italian database5 indicates that calcium channel blockers (amlodipine, nifedipine, diltiazem), doxazosin, ACE inhibitors (enalapril, ramipril), enalapril maleate-felodipine, enalapril maleate-hydrochlorothiazide, tocainide, amiodarone, statins (lovastatin, atorvastatin), fluoroquinolones (moxifloxacin, levofloxacin), macrolides (clarithromycin, azithromycin, roxithromycin), amoxicillin/clavulanate, terbinafine, beclomethasone and methotrexate impair the sense of both smell and taste. We specifically searched the PubMed database for literature published in English and Japanese until July 2017 to identify eligible articles that simultaneously met the Medical Subject Headings terms ‘duloxetine hydrochloride’ and ‘olfaction disorders’ or ‘taste disorders’, but we could not find any article. To the best of our knowledge, this is the first case report of duloxetine causing dysosmia and subsequent dysgeusia.\n\nThe specific mechanisms of drug-induced taste and smell disorders elicited by duloxetine and by the other drugs remain unknown. Moreover, the possible drug interactions with duloxetine related to concomitant taste and/or smell dysfunction, particularly ongoing amlodipine6 and lansoprazole5 which were prescribed before and after admission for this patient and, which have been associated with the above side effects, could not be excluded. Two possible hypotheses were proposed by Tuccori et al5 as a mechanism of drug-induced taste and/or smell alternations. The primary mechanisms resulted from a direct action of the drug; drug–receptor interaction, disturbance of action potential propagation in cell membranes, alteration of the neurotransmitter function and changes in connections between neural networks in brain regions associated with sensory coding and modulation. The secondary mechanisms include limiting the access of chemicals to sensing receptors, and changing the chemical or ionic milieu in the environment of sensing receptors.\n\nBy comparing olfactory acuity tests before and after discontinuing duloxetine (figure 1), it was observed that duloxetine impaired all olfactory detection thresholds to <2 levels, except for those of the rotten egg smell. This explains why the patient could smell rotten eggs at the coffee shop. In this patient, duloxetine decreased olfactory recognition thresholds, particularly of rose and rotten egg smells.\n\nConclusions\nThis is the first report of duloxetine causing dysosmia and subsequent dysgeusia. Because duloxetine may impair olfactory cognitive function rather than olfactory detection threshold, close attention must be paid to the decreased sense of smell when duloxetine is prescribed.\n\nLearning points\nThis is the first report of duloxetine causing dysosmia and subsequent dysgeusia.\n\nThis adverse effect was reversible because both dysosmia and dysgeusia were improved when duloxetine was discontinued.\n\nClose attention must be paid to the decreased sense of smell and/or taste when duloxetine is prescribed.\n\nContributors: All the authors examined the patient clinically. KY drafted the manuscript. HS and TF edited and revised the final version. All authors agreed and authorised the final document for submission.\n\nCompeting interests: None declared.\n\nPatient consent: Obtained.\n\nProvenance and peer review: Not commissioned; externally peer reviewed.\n==== Refs\nReferences\n1 Khouzam HR \nPsychopharmacology of chronic pain: a focus on antidepressants and atypical antipsychotics . Postgrad Med \n2016 ;128 :323 –30 . 10.1080/00325481.2016.1147925 26821680 \n2 Hudson JI , Wohlreich MM , Kajdasz DK , et al \nSafety and tolerability of duloxetine in the treatment of major depressive disorder: analysis of pooled data from eight placebo-controlled clinical trials . Hum Psychopharmacol \n2005 ;20 :327 –41 . 10.1002/hup.696 15912562 \n3 Ackerman BH , Kasbekar N \nDisturbances of taste and smell induced by drugs . Pharmacotherapy \n1997 ;17 :482 –96 .9165552 \n4 Doty RL , Bromley SM \nEffects of drugs on olfaction and taste . Otolaryngol Clin North Am \n2004 ;37 :1229 –54 . 10.1016/j.otc.2004.05.002 15563912 \n5 Tuccori M , Lapi F , Testi A , et al \nDrug-induced taste and smell alterations . Drug Saf \n2011 ;34 :849 –59 . 10.2165/11593120-000000000-00000 21879779 \n6 Sadasivam B , Jhaj R \nDysgeusia with amlodipine–a case report . Br J Clin Pharmacol \n2007 ;63 :253 \n10.1111/j.1365-2125.2006.02727.x 17274793\n\n",
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"mesh_terms": "D000368:Aged; D000068736:Duloxetine Hydrochloride; D004408:Dysgeusia; D005260:Female; D006801:Humans; D000857:Olfaction Disorders; D000068760:Serotonin and Noradrenaline Reuptake Inhibitors",
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"title": "Dysosmia and dysgeusia associated with duloxetine.",
"title_normalized": "dysosmia and dysgeusia associated with duloxetine"
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"abstract": "Hyperkalaemia risk precludes optimal renin-angiotensin-aldosterone system inhibitor use in patients with heart failure (HF), particularly those with chronic kidney disease (CKD). Patiromer is a sodium-free, non-absorbed potassium (K+ )-binding polymer approved for the treatment of hyperkalaemia. In PEARL-HF, patiromer 25.2 g (fixed dose) prevented hyperkalaemia in HF patients with or without CKD initiating spironolactone. The current study evaluated the effectiveness of a lower starting dose of patiromer (16.4 g/day) followed by individualized titration in preventing hyperkalaemia and hypokalaemia when initiating spironolactone.\n\n\n\nThis open-label 8-week study enrolled 63 patients with CKD, serum K+ 4.3-5.1 mEq/L, and chronic HF, who, based on investigator opinion, should receive spironolactone. Eligible patients started spironolactone 25 mg/day and patiromer 16.8 g/day (divided into two doses), with patiromer titrated to maintain serum K+ 4.0-5.1 mEq/L. Mean (standard deviation) serum K+ was 4.78 (0.51) mEq/L at baseline; weekly values were 4.48-4.70 mEq/L during treatment. Serum K+ of 3.5-5.5 mEq/L at the end of study treatment (primary endpoint) was achieved by 57 (90.5%) patients; 53 (84.1%) had serum K+ 4.0-5.1 mEq/L. One patient (1.6%) developed hypokalaemia, and two patients (3.2%) developed hypomagnesaemia. Spironolactone was increased to 50 mg/day in all patients; 43 (68%) patients required one or more patiromer dose titration. Adverse events (AEs) occurred in 36 (57.1%) patients, with a low rate of discontinuations [four (6.3%) patients]. The most common AE was mild to moderate abdominal discomfort [four (6.3%) patients].\n\n\n\nIn this open-label study, patiromer 16.8 g/day followed by individualized titration maintained serum K+ within the target range in the majority of patients with HF and CKD, all of whom were uptitrated to spironolactone 50 mg/day, patiromer was well tolerated, with a low incidence of hyperkalaemia, hypokalaemia, and hypomagnesaemia.",
"affiliations": "Department of Medicine, Cardiovascular Center, University of Michigan, Ann Arbor, MI, USA.;Division of Nephrology, Department of Medicine, University of Rochester School of Medicine, Rochester, NY, USA.;Cardiovascular Medicine Section, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA.;Clinic of Cardiology, University Heart Centre, University Hospital, Zurich, Switzerland.;Cardiology Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health, University of Brescia, Brescia, Italy.;Heart Failure Unit, Department of Cardiology, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece.;INSERM, Centre d'Investigations Cliniques-Plurithématique 1433, UMR 1116 Université de Lorraine, CHRU de Nancy, French-Clinical Research Infrastructure Network (F-CRIN) INI-CRCT, Nancy, France.;Biometrics, Relypsa, Inc., a Vifor Pharma Group Company, Redwood City, CA, USA.;Medical Affairs, Relypsa, Inc., a Vifor Pharma Group Company, Redwood City, CA, USA.;Medical Affairs, Relypsa, Inc., a Vifor Pharma Group Company, Redwood City, CA, USA.;Department of Internal Medicine, General Hospital Murska Sobota and Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.",
"authors": "Pitt|Bertram|B|;Bushinsky|David A|DA|;Kitzman|Dalane W|DW|;Ruschitzka|Frank|F|;Metra|Marco|M|;Filippatos|Gerasimos|G|;Rossignol|Patrick|P|;Du Mond|Charles|C|;Garza|Dahlia|D|;Berman|Lance|L|;Lainscak|Mitja|M|;|||",
"chemical_list": "D015415:Biomarkers; D000451:Mineralocorticoid Receptor Antagonists; D011108:Polymers; C568789:patiromer; D013148:Spironolactone; D011188:Potassium",
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"fulltext": "\n==== Front\nESC Heart FailESC Heart Fail10.1002/(ISSN)2055-5822EHF2ESC Heart Failure2055-5822John Wiley and Sons Inc. Hoboken 10.1002/ehf2.12265EHF212265ESCHF-17-00102Original Research ArticleOriginal Research ArticlesEvaluation of an individualized dose titration regimen of patiromer to prevent hyperkalaemia in patients with heart failure and chronic kidney disease Patiromer: controlling serum K+ in patients with HF and CKDB. Pitt et al.Pitt Bertram bpitt@med.umich.edu \n1\nBushinsky David A. \n2\nKitzman Dalane W. \n3\nRuschitzka Frank \n4\nMetra Marco \n5\nFilippatos Gerasimos \n6\nRossignol Patrick \n7\nDu Mond Charles \n8\nGarza Dahlia \n9\nBerman Lance \n9\nLainscak Mitja \n10\non behalf of the Patiromer‐204 Investigators \n1 \nDepartment of Medicine, Cardiovascular Center\nUniversity of Michigan\nAnn Arbor\nMI\nUSA\n\n2 \nDivision of Nephrology, Department of Medicine\nUniversity of Rochester School of Medicine\nRochester\nNY\nUSA\n\n3 \nCardiovascular Medicine Section, Department of Internal Medicine\nWake Forest School of Medicine\nWinston‐Salem\nNC\nUSA\n\n4 \nClinic of Cardiology\nUniversity Heart Centre, University Hospital\nZurich\nSwitzerland\n\n5 \nCardiology Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health\nUniversity of Brescia\nBrescia\nItaly\n\n6 \nHeart Failure Unit, Department of Cardiology\nNational and Kapodistrian University of Athens, School of Medicine\nAthens\nGreece\n\n7 \nINSERM, Centre d'Investigations Cliniques‐Plurithématique 1433\nUMR 1116 Université de Lorraine, CHRU de Nancy, French‐Clinical Research Infrastructure Network (F‐CRIN) INI‐CRCT\nNancy\nFrance\n\n8 \nBiometrics\nRelypsa, Inc., a Vifor Pharma Group Company\nRedwood City\nCA\nUSA\n\n9 \nMedical Affairs\nRelypsa, Inc., a Vifor Pharma Group Company\nRedwood City\nCA\nUSA\n\n10 \nDepartment of Internal Medicine, General Hospital Murska Sobota and Faculty of Medicine\nUniversity of Ljubljana\nLjubljana\nSlovenia\n* \nCorrespondence to: Bertram Pitt, MD, Department of Medicine, Cardiovascular Center, University of Michigan School of Medicine, 1500 E. Medical Center Drive, Ann Arbor, MI 48109, USA. Tel: +1 734 936 5260; Fax: +1 734 936 5256.\n\nEmail: bpitt@med.umich.edu\n25 1 2018 6 2018 5 3 10.1002/ehf2.v5.3257 266 16 6 2017 04 12 2017 22 12 2017 © 2018 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.Abstract\nAims\nHyperkalaemia risk precludes optimal renin–angiotensin–aldosterone system inhibitor use in patients with heart failure (HF), particularly those with chronic kidney disease (CKD). Patiromer is a sodium‐free, non‐absorbed potassium (K+)‐binding polymer approved for the treatment of hyperkalaemia. In PEARL‐HF, patiromer 25.2 g (fixed dose) prevented hyperkalaemia in HF patients with or without CKD initiating spironolactone. The current study evaluated the effectiveness of a lower starting dose of patiromer (16.4 g/day) followed by individualized titration in preventing hyperkalaemia and hypokalaemia when initiating spironolactone.\n\nMethods and results\nThis open‐label 8‐week study enrolled 63 patients with CKD, serum K+ 4.3–5.1 mEq/L, and chronic HF, who, based on investigator opinion, should receive spironolactone. Eligible patients started spironolactone 25 mg/day and patiromer 16.8 g/day (divided into two doses), with patiromer titrated to maintain serum K+ 4.0–5.1 mEq/L. Mean (standard deviation) serum K+ was 4.78 (0.51) mEq/L at baseline; weekly values were 4.48–4.70 mEq/L during treatment. Serum K+ of 3.5–5.5 mEq/L at the end of study treatment (primary endpoint) was achieved by 57 (90.5%) patients; 53 (84.1%) had serum K+ 4.0–5.1 mEq/L. One patient (1.6%) developed hypokalaemia, and two patients (3.2%) developed hypomagnesaemia. Spironolactone was increased to 50 mg/day in all patients; 43 (68%) patients required one or more patiromer dose titration. Adverse events (AEs) occurred in 36 (57.1%) patients, with a low rate of discontinuations [four (6.3%) patients]. The most common AE was mild to moderate abdominal discomfort [four (6.3%) patients].\n\nConclusions\nIn this open‐label study, patiromer 16.8 g/day followed by individualized titration maintained serum K+ within the target range in the majority of patients with HF and CKD, all of whom were uptitrated to spironolactone 50 mg/day, patiromer was well tolerated, with a low incidence of hyperkalaemia, hypokalaemia, and hypomagnesaemia.\n\nHeart failureChronic kidney diseasePatiromerPotassium‐binding polymerMineralocorticoid receptor antagonistRelypsa, Inc., a Vifor Pharma Group Company source-schema-version-number2.0component-idehf212265cover-dateJune 2018details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:version=5.3.7.2 mode:remove_FC converted:03.05.2018\n\n\nPitt , B. \n, \nBushinsky , D. A. \n, \nKitzman , D. W. \n, \nRuschitzka , F. \n, \nMetra , M. \n, \nFilippatos , G. \n, \nRossignol , P. \n, \nDu Mond , C. \n, \nGarza , D. \n, \nBerman , L. \n, \nLainscak , M. \n, and on behalf of the Patiromer‐204 Investigators (2018 ) Evaluation of an individualized dose titration regimen of patiromer to prevent hyperkalaemia in patients with heart failure and chronic kidney disease . ESC Heart Failure , 5 : 257 –266 . doi: 10.1002/ehf2.12265.\n\n\nClinical trial registration: http://ClinicalTrials.gov registry identifier NCT01130597\n==== Body\nIntroduction\nRenin–angiotensin–aldosterone system inhibitors (RAASi) are guideline recommended with a Class 1 indication to reduce cardiovascular and total mortality in patients with heart failure (HF) and reduced left ventricular ejection fraction (EF).1, 2, 3, 4, 5, 6 In patients with HF with reduced EF (HFrEF) at highest risk of cardiovascular death, such as those with diabetes mellitus and/or chronic kidney disease (CKD), the risk of worsening renal function and hyperkalaemia often precludes or limits the use of optimal doses of RAASi, especially mineralocorticoid receptor antagonists (MRAs).7, 8, 9 Given that the risk of hyperkalaemia may change over time in patients with HF due to dose changes in RAASi, dietary changes, use of diuretics, and changes in renal function, it is desirable to have a titratable drug that can be used to manage serum potassium (K+) without resorting to discontinuation or dose reduction of evidence‐based HF and CKD treatments.\n\nPatiromer is a non‐absorbed K+‐binding polymer that uses calcium rather than sodium as the cation for exchange with K+. It is approved for the treatment of hyperkalaemia in the USA and in Europe.10, 11, 12 Patiromer has been shown to reduce serum K+ in hyperkalaemic patients with CKD with or without other co‐morbidities, such as HF, diabetes mellitus, and/or hypertension.13, 14, 15 Patiromer has also been demonstrated in a randomized, double‐blind, placebo‐controlled study to prevent hyperkalaemia in normokalaemic patients with HF with or without CKD who were initiated on spironolactone.16 This study used a relatively high fixed total daily dose of patiromer (25.2 g given as a divided dose twice daily), which was associated with approximately 7% incidence of hypokalaemia (serum K+ <3.5 mEq/L).16 The present study was designed to assess a lower starting dose of patiromer followed by individualized titration based on serum K+ levels in preventing hyperkalaemia and hypokalaemia in patients with HF and CKD who were initiated on spironolactone 25 mg/day in addition to standard therapy, including one or more of the following: an angiotensin‐converting enzyme inhibitor (ACEi) and angiotensin receptor blocker (ARB) or a beta adrenergic receptor blocker (BB).\n\nIt was hypothesized that the lower starting dose followed by individually optimized dose titration would minimize the risk of hypokalaemia and still prevent hyperkalaemia, thus allowing continued usage of RAASi in these patients. The secondary aim of the study was to assess the effects of patiromer on serum K+ and the safety and tolerability of patiromer in HF patients with CKD.\n\nMethods\nThis 8 week, open‐label study (registered at http://ClinicalTrials.gov, NCT01130597) was conducted at 13 centres in Georgia and Slovenia between May 2010 and September 2010. All participating sites received approval from their nationally or locally appointed Independent Ethics Committee, and all patients provided written informed consent. The study was performed in accordance with the Declaration of Helsinki, current local and national regulations, the International Conference on Harmonization, and Good Clinical Practice guidelines and fulfilled other applicable requirements governing the conduct of human clinical trials.\n\nPatients and assessments\nEligible patients were ≥18 years old with chronic HF who, in the opinion of the investigator, should receive spironolactone therapy. Patients also had to have CKD with a screening estimated glomerular filtration rate (eGFR) of <60 mL/min/1.73 m2 based on central laboratory creatinine measurement and calculated using the Modification of Diet in Renal Disease formula.17 Serum K+ at screening and at baseline had to be 4.3–5.1 mEq/L, and patients had to be receiving at least one of the following: ACEi, ARB, or a BB. Patients were excluded if they had a history of severe gastrointestinal (GI) disorders, major GI surgery, bowel obstruction, or swallowing disorders, or if they had severe or unstable hypertensive or cardiovascular disease or severe renal disease, including history of or anticipated need for heart or kidney transplantation or dialysis during the study. Prohibited medications during the study included polymer‐based drugs, other K+ binders or phosphate binders, other K+‐sparing diuretics (including non‐study aldosterone antagonists), and K+ supplements. Investigators were instructed to maintain a constant dose of cardiac medications during the entire study. Oral diuretics (loop and thiazide) were permitted during the study if the dose was stable for at least 21 days prior to the start of the study and was expected to remain stable during the study.\n\nPatients who completed screening and satisfied the eligibility criteria returned to the clinic for baseline assessments, which included a physical examination, weight and height, resting heart rate, supine blood pressure, a 12‐lead electrocardiogram (ECG), determination of serum K+, and clinical laboratory tests, including serum chemistry, haematology, and urinalysis. Patients who continued to satisfy all eligibility criteria were enrolled in the study and were initiated on spironolactone 25 mg once daily and patiromer 16.8 g/day on Day 1. Patiromer was supplied as a powder for oral suspension, which was to be mixed with water or a low‐K+ food and consumed with meals—8.4 g with breakfast and 8.4 g with dinner.\n\nThe patiromer and spironolactone dosing algorithm is shown in Table\n\nS1\n of the Supporting Information. Starting on Day 3, the patiromer dose could be adjusted up or down in increments of 8.4 g/day based on the patient's local laboratory serum K+ value in order to maintain serum K+ within the target range of 4.0–5.1 mEq/L. The only exception was if the serum K+ was <4.0 mEq/L on a visit when the patient was eligible for a spironolactone dose increase. In such cases, the patiromer dose was to be maintained. Patiromer doses could be titrated to a minimum of 0 g/day or to a maximum of 50.4 g/day. Starting on Day 7, the spironolactone dose was increased to 50 mg once daily provided that the patient's serum K+ concentration was ≤5.1 mEq/L; spironolactone dose reductions were not allowed. During the course of the study, the minimum spironolactone dose was 25 mg/day, and the maximum was 50 mg/day. Patiromer and spironolactone dose adjustments were not permitted on the same day. Patients were to discontinue both patiromer and spironolactone and were to be withdrawn from the study if their local laboratory serum K+ was <3.5 or >5.5 mEq/L at two consecutive visits despite titration of patiromer or spironolactone on the first of the two visits.\n\nDuring the 8 week treatment period, serum K+ was monitored at each clinic visit, scheduled on Day 3 and weekly from Weeks 1 through 8. At each visit, 12‐lead ECG was obtained, the need for patiromer dose titration was assessed (except at the Week 8 visit), and concomitant medications and adverse events (AEs) were assessed. Vital signs, body weight, and an evaluation for spironolactone uptitration were assessed weekly from Weeks 1 through 8 (except spironolactone uptitration assessment at the Week 8 visit). Serum chemistry testing was performed at Weeks 2, 4, 6, and 8, and haematology testing was performed at Weeks 4 and 8. One week after completion of the treatment period (or following premature discontinuation of patiromer and spironolactone), patients returned to the clinic for a safety follow‐up visit.\n\nClinical endpoints\nThe primary efficacy outcome was the proportion of patients with a serum K+ 3.5–5.5 mEq/L at the end of study treatment (i.e., the final visit of the treatment period while on study drug). Secondary endpoints included (1) proportion of patients with serum K+ 3.5–5.5 mEq/L, by visit and during the entire treatment period; (2) proportion of patients with serum K+ 4.0–5.1 mEq/L, by visit and during the entire treatment period; (3) proportion of patients whose spironolactone dose could be increased to 50 mg/day; (4) mean number of patiromer titrations; (5) proportion of patients requiring patiromer uptitration or downtitration; (6) mean time to the first patiromer titration; and (7) mean dose of patiromer by visit and at the end of the study.\n\nThe safety of patiromer was assessed based on (1) AEs recorded during the study and through 7 days after the last dose of study drug; (2) clinically significant changes from baseline in clinical laboratory (haematology and serum chemistry) values, vital signs, and ECG parameters and proportion of patients who discontinued the study owing to hyperkalaemia (serum K+ >5.5 mEq/L); and (3) proportion of patients discontinuing because of hypokalaemia (serum K+ <3.5 mEq/L on two consecutive visits despite patiromer or spironolactone dose titration on the first of the two visits).\n\nStatistical analysis\nA total of 63 patients were enrolled to ensure that at least 50 patients would receive patiromer and provide efficacy data for analysis. The sample size was based on the patiromer response predicted from the PEARL‐HF study.16 For the primary efficacy endpoint, the proportion of patients with serum K+ 3.5–5.5 mEq/L at the end of the study treatment was summarized along with 95% confidence intervals (CIs). The analysis population for the primary and secondary efficacy endpoints, and for assessment of safety, was the intent‐to‐treat population (i.e., all enrolled patients). Baseline values were obtained from the last available measurement prior to the start of patiromer. For categorical secondary endpoints, the proportion of patients and 95% CIs were summarized. AEs were summarized descriptively.\n\nStatistical analyses were performed using SAS Version 9.4 (SAS Institute Inc., Cary, NC, USA).\n\nResults\nBaseline characteristics and disposition\nA total of 63 patients [100% White, 39 (61.9%) men] were enrolled in the study, all of whom received at least one dose of patiromer and had at least one post‐baseline serum K+ assessment. The mean [standard deviation (SD)] age was 70.8 (8.5) years (Table\n1). All patients had a history of HF with a mean (SD) duration of 3.9 (4.1) years, which was characterized at study entry as New York Heart Association Class II (46% of patients) or Class III (54%). Patients had a mean (SD) EF of 38.6% (9.3%); 33 (52.4%) patients had an EF <40% (Table\n1). The aetiology of HF was ischaemic in 40 (63.5%) patients. Overall, 93.7% of patients had a history of hypertension, and 42.9% had diabetes. All patients had CKD; the mean (SD) eGFR was 46.2 (15.2) mL/min/1.73 m2 at baseline; 57 patients were in Stage 3a or 3b and six patients in Stage 4 or 5. The mean (SD) duration of CKD was 2.5 (3.3) years, and the most common aetiologies of CKD were hypertension only (30.2%), hypertension and diabetes (27.0%), and unknown (30.2%).\n\nTable 1 Baseline demographic and clinical characteristics\n\nParameter\tPatiromer (N = 63)\t\nDemographics\t\t\nAge (years), mean ± SD\t70.8 ± 8.5\t\nMale, n (%)\t39 (61.9)\t\nWhite, n (%)\t63 (100)\t\nBMI (kg/m2), mean ± SD\t28.6 ± 3.8\t\nCardiac history and parameters\t\t\nHF duration (years), mean ± SD\t3.9 ± 4.1\t\nHF aetiology: ischaemic, n (%)\t40 (63.5)\t\nLVEF (%), mean ± SDa\n\t38.6 ± 9.3\t\nPatients with LVEF of <40%, n (%)\t33 (52.4)\t\nPatients with LVEF of 40–50%, n (%)\t24 (38.1)\t\nPatients with LVEF of >50%, n (%)\t5 (7.9)\t\nNYHA Class, n (%) II\t29 (46.0)\t\nIII\t34 (54.0)\t\nCKD history\t\t\nCKD duration (years), mean ± SDa\n\t2.5 ± 3.3\t\nCKD aetiology, n (%)a\n\t\t\nHypertension (only)\t19 (30.2)\t\nHypertension and diabetes\t17 (27.0)\t\nDiabetes (only)\t4 (6.3)\t\nUrologic or congenital\t2 (3.2)\t\nUnknown\t19 (30.2)\t\neGFR (mL/min/1.73 m2), mean ± SD\t46.2 ± 15.2\t\nPatients with eGFR (mL/min/1.73m2), n (%)\t\t\n<15\t1 (1.6)\t\n15–<30\t5 (7.9)\t\n30–45\t26 (41.3)\t\n>45\t31 (49.2)\t\nACR (mg/g), mean ± SD [n (%)]\t\t\n<30 mg/g\t10.8 ± 5.7 [28 (44.4)]\t\n≥30 mg/g\t749.6 ± 1341.9 [35 (55.6)]\t\nVital signs\t\t\nHeart rate (b.p.m.)\t70.5 ± 12.8\t\nSystolic blood pressure (mmHg)\t133.3 ± 16.6\t\nDiastolic blood pressure (mmHg)\t82.1 ± 7.6\t\nOther co‐morbid conditions\t\t\nHistory of diabetes, n (%)\t27 (42.9)\t\nHistory of hypertension, n (%)\t59 (93.7)\t\nHF medications at baseline\t63 (100)\t\nDiuretics\t52 (82.5)\t\nLoop\t46 (73.0)\t\nThiazide\t11 (17.5)\t\nACEi\t45 (71.4)\t\nARB\t18 (28.6)\t\nBeta‐blocker\t48 (76.2)\t\nACEi only\t9 (14.3)\t\nARB only\t5 (7.9)\t\nBeta‐blocker only\t1 (1.6)\t\nACEi + ARB\t1 (1.6)\t\nACEi + beta‐blocker\t35 (55.6)\t\nARB + beta‐blocker\t12 (19.0)\t\nACEi + ARB + beta‐blocker\t0\t\nACEi, angiotensin‐converting enzyme inhibitor; ACR, albumin‐to‐creatinine ratio; ARB, angiotensin receptor blocker; BMI, body mass index; b.p.m., beats per minute; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; HF, heart failure; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association functional class; SD, standard deviation.\n\na \nn = 62.\n\nAt baseline, all patients were receiving a RAASi or a BB; 45 (71.4%) patients were on an ACEi, 18 (28.6%) were on an ARB, and 48 (76.2%) were on a BB (Table\n1). One (1.6%) patient was on dual therapy of ACEi and ARB, 35 (55.6%) were on dual therapy of ACEi and BB, 12 (19.0%) were on dual therapy of ARB and BB, and no patient was on triple therapy (ACEi, ARB, and BB) (Table\n1). Thirty‐two (51%) patients were receiving 50% or more of the maximal daily dose of an ACEi or ARB, while 26 (41%) patients were receiving 25% or less of the maximal daily dose of an ACEi or ARB. Of the 48 patients taking beta‐blockers at baseline, 11 (23%) were receiving 50% or more of the maximal daily dose, while 13 (27%) were receiving 25% or less of the maximal daily dose. In addition, 52 (82.5%) patients were on a diuretic at baseline, and the same proportion (82.5%) was receiving diuretic therapy during the study.\n\nFifty‐six (88.9%) patients completed the 8 week treatment period, and seven (11.1%) prematurely discontinued treatment; the most common reason for discontinuation was AEs (four patients; 6.3%) (see Supporting Information, Figure\n\nS1\n).\n\nEfficacy\nAt baseline, the mean (SD) serum K+ was 4.78 (0.51) mEq/L. Mean (SD) change in serum K+ from baseline to end of study treatment was −0.13 (0.69) mEq/L, range: −1.9 to 1.3 mEq/L. During the treatment period, weekly mean serum K+ values were 4.48–4.70 mEq/L. At the end of study treatment, 57 (90.5%; 95% CI: 80.4%, 96.4%) patients had serum K+ 3.5–5.5 mEq/L (primary endpoint), including five of six patients with eGFR <30 mL/min/1.73 m2 at baseline. Fifty‐three (84.1%; 95% CI: 72.7%, 92.1%) patients had serum K+ 4.0–5.1 mEq/L. Figure\n1 shows the proportions of patients with serum K+ in the ranges of 3.5–5.5 and 4.0–5.1 mEq/L at all post‐baseline visits. The proportion ranged from 91.2% to 100% for patients with serum K+ 3.5–5.5 mEq/L and from 72.6% to 90.3% for patients with serum K+ 4.0–5.1 mEq/L (Figure\n1). Serum K+ was maintained in the range of 3.5–5.5 mEq/L in 48 (76.2%; 95% CI: 63.8%, 86.0%) patients and in the range of 4.0–5.1 mEq/L in 19 (30.2%; 95% CI: 19.2%, 43.0%) patients during the entire treatment period.\n\nFigure 1 Proportion of patients with serum K+ in the range of 3.5–5.5 mEq/L and 4.0–5.1 mEq/L by study visit. ET, end of treatment; K+, potassium.\n\nThe mean (SD) number of prescribed patiromer dose titrations during the study was 1.3 (1.1): 20 (31.7%) patients did not require any titration, 21 (33.3%) had one or more uptitrations, 8 (12.7%) had one or more downtitrations, and 14 (22.2%) had both one or more uptitrations and one or more downtitrations. The median (95% CI) time to the first patiromer dose titration was 21.0 (14.0, 36.0) days.\n\nOver the course of the study, the mean (SD) duration of exposure to patiromer was 53.9 (8.6) days, and the mean (SD) dose was 18.7 (6.4) g/day. The mean (SD) dose of patiromer at the end of the study was 19.6 (10.4) g/day. In the majority of patients, the last prescribed dose was either 16.8 g/day (44.4%) or 25.2 g/day (17.5%) (see Supporting Information, \nTable S2\n). On average, serum K+ decreased by 0.34 mEq/L 1 week following an 8.4 g/day uptitration in patiromer dose and increased by 0.46 mEq/L 1 week following an 8.4 g/day downtitration of patiromer dose (Figure\n2).\n\nFigure 2 Serum K+ before and after an uptitration or downtitration. *Total number of titrations during the study. K+, potassium; SD, standard deviation.\n\nThe mean (SD) duration of exposure to spironolactone was 53.6 (8.7) days. One patient initiated treatment with spironolactone 50 mg/day (protocol deviation) and continued this dose through the completion of the study. Of the 62 patients who initiated spironolactone treatment at 25 mg/day, the MRA was successfully uptitrated to 50 mg/day in all 62 patients by Day 14 of the study. The uptitration occurred in 57 patients during the first week and in five during the second week. The median time to titration was 8 days (range: 6–16 days). The mean (SD) dose of spironolactone during the study treatment period was 45.5 (3.4) mg/day.\n\nPatients' dosing compliance with patiromer and spironolactone was measured by examination of the drug sachets and blister packs, respectively, which were returned to the clinic at each visit. The mean (SD) dosing compliance rate was 98.7% (1.9%) for patiromer and 98.5% (5.6%) for spironolactone.\n\nSafety\nA total of 36 (57.1%) patients had at least one AE, regardless of severity, seriousness, or relatedness to patiromer (Table\n2); the most common AEs (occurring in at least three patients) were worsening of renal function in eight (12.7%) patients, abdominal discomfort in four (6.3%) patients, and flatulence, headache, and hypertension, each occurring in three (4.8%) patients. In the majority of patients, the AEs were mild or moderate in intensity (83.3%) and in most patients (69.5%) were unrelated to patiromer. Mild peripheral oedema was reported in two (3.2%) patients; both cases were considered not related to patiromer by the investigator. In all eight patients with worsening of renal function, the AE was considered unrelated to patiromer by the investigator, and in three patients, the AE was considered related to spironolactone (see Supporting Information, \nTable S3\n). Eleven patients had patiromer‐related AEs, most commonly GI‐related (abdominal discomfort, three; flatulence, three; diarrhoea, two; abdominal pain, one). All GI‐related AEs were reported as either mild or moderate. Four (6.3%) patients had a total of six AEs that led to discontinuation of patiromer; in three patients, the AEs leading to discontinuation were serious (discussed below). The non‐serious AE leading to discontinuation was moderate diarrhoea.\n\nTable 2 Safety summary\n\nParameter, n (%)\t(N = 63)\t\nAny adverse event\t36 (57.1)\t\nAdverse eventsa occurring in ≥3 (~5%) patients\t\t\nWorsening of renal functiona\n\t8 (12.7)\t\nAbdominal discomfort\t4 (6.3)\t\nFlatulence\t3 (4.8)\t\nHeadache\t3 (4.8)\t\nHypertension\t3 (4.8)\t\nSerious adverse events\t6 (9.5)\t\nPatiromer‐related serious adverse events\t0 (0)\t\nAdverse event leading to study discontinuation\t4 (6.3)\t\na Adverse events were coded to the preferred terms listed above using the Medical Dictionary for Regulatory Activities Version 12.0, except for worsening of renal function, which includes the preferred terms of renal failure acute (three patients), renal impairment (three patients), and renal failure (two patients).\n\nDuring the treatment period through follow‐up, six (9.5%) patients had a total of nine serious AEs (SAEs); three patients had a single, non‐fatal SAE: acute renal failure in two patients (see Supporting Information, \nTable S3\n) and subcutaneous abscess in one patient. Three patients, all diabetic, experienced fatal SAEs. One patient died because of sudden cardiac death on Day 29 of the study. This patient's last measured (on Day 28) serum K+ was 4.6 mEq/L and serum magnesium was 1.7 mg/dL. Two patients died after stopping patiromer: one sudden death 5 days after completing study treatment and one sudden cardiac death 26 days after prematurely discontinuing patiromer treatment due to non‐fatal SAEs, including acute renal failure (see Supporting Information, \nTable S3\n). The narratives for the three patients with fatal SAEs are provided in \nTable S4\n of the Supporting Information. None of the SAEs, including the fatal events, were considered by the study investigators as related to patiromer, and the SAEs of acute renal failure for two patients were considered to be related to spironolactone. Two of the three deaths were considered by the Safety Review Board as unlikely to be due to hypokalaemia or hyperkalaemia, and the relationship to hypokalaemia or hyperkalaemia for the one death that occurred 26 days after prematurely discontinuing patiromer treatment could not be determined.\n\nOne (1.6%) patient developed hypokalaemia (3.1 mEq/L at the Week 3 visit) based on prespecified criteria (serum K+ <3.5 mEq/L); patiromer was downtitrated, while the spironolactone dose was maintained, and at the next visit 8 days later, the serum K+ was 3.9 mEq/L. No patient discontinued the study because of hypokalaemia. A total of 15 (24%) patients developed hyperkalaemia (serum K+ >5.5 mEq/L): nine (14%) patients had an isolated event before or at the end of treatment; six (10%) patients had more than one serum K+ value >5.5 mEq/L. Serum K+ was normalized with individualized dose titration of patiromer in all but one of these patients, with the exception being the patient who was prematurely withdrawn from the study owing to hyperkalaemia. Six patients had a total of seven episodes of serum K+ >6.0 mEq/L, with the highest being 6.6 mEq/L in one patient.\n\nMean serum magnesium levels were slightly lower (−0.17 to −0.18 mg/dL) at all treatment visits (Week 4, Week 8, and end‐of‐treatment visits) than at baseline; however, mean levels remained within the normal range (1.8–2.4 mg/dL). At Week 8, the mean [standard error (SE)] change from baseline in serum magnesium was −0.18 (0.04) (range: −1.00 to 0.30). Eight (12.7%) patients had serum magnesium levels <1.8 mg/dL [lower limit of normal (LLN)] during the treatment period (with one having baseline level below the LLN); of these, two (3.2%) patients had levels <1.4 mg/dL (none <1.2 mg/dL). One patient with serum magnesium of 1.5 mg/dL reported moderate myalgia with onset on Day 29, which was resolved within a week after the patient received a magnesium supplement. Mean serum magnesium returned to near‐baseline values 7 days post‐treatment (change from baseline, 0.03 mg/dL). No AEs of hypomagnesaemia were reported.\n\nThere were no clinically relevant or statistically significant changes in mean serum creatinine or eGFR values at Week 8. Mean (SE) change from baseline to Week 8 was +0.04 (0.04) mg/dL (range: −0.84 to 0.97) for serum creatinine and −0.21 (1.11) mL/min/1.73 m2 (range: −16.0 to 18.0) for eGFR. At baseline, 35 (55.6%) patients had micro‐albuminuria or macro‐albuminuria [albumin‐to‐creatinine ratio (ACR) ≥30 mg/g], with a mean (SD) ACR of 750 (1342) mg/g. The mean (SE) ACR decreased from baseline to Week 8 by 291 (142) mg/g (range: −2536 to 1189; n = 30; P <0.05).\n\nSix patients were noted to have an eGFR of <30 mL/min/1.73 m2 (range: 14–29 mL/min/1.73 m2) by central laboratory results at baseline. All of these patients were successfully uptitrated to spironolactone 50 mg/day (four at Week 1 and one at Week 2) and five were able to maintain this dose of spironolactone throughout their participation in the study. One patient was terminated early from the study because of hyperkalaemia (serum K+ 6.0 and 5.6 mEq/L at Weeks 6 and 7, respectively) while on spironolactone 50 mg/day and patiromer 8.4 g/day, and another patient was withdrawn from the study at Day 25 because of an AE of diarrhoea. From baseline to the end of treatment, there were no meaningful changes in blood pressure, heart rate, ECG intervals or findings, or physical examinations.\n\nDiscussion\nPatiromer is a novel K+‐binding polymer approved to treat hyperkalaemia.10 Patiromer uses calcium, rather than sodium, as the counterion for K+ exchange.11 This avoids the potential for increases in sodium absorption and retention in patients with volume overload who may not tolerate even a small increase in sodium load, such as those with hypertension, CKD, and/or HF.18, 19 Patiromer has recently been shown to reduce serum aldosterone levels in patients with CKD and hyperkalaemia who are on RAASi.20 A previous trial, PEARL‐HF, demonstrated that, compared with placebo, a 25.2 g/day fixed dose of patiromer prevented the development of hyperkalaemia and was relatively well tolerated in patients with HF receiving standard therapy and initiating spironolactone (25–50 mg/day)16 but was associated with a 7% incidence of hypokalaemia (serum K+ <3.5 mEq/L).\n\nThe present study extends previous literature by showing that patiromer initiated at a lower starting dose of 16.8 g/day followed by individual dose titration maintained serum K+ within the target range in nearly all study patients. The study population had characteristics that may make spironolactone initiation clinically desirable but challenging: HFrEF or HF with preserved EF (HFpEF) patients with CKD and high rates of other cardiovascular risk factors, such as diabetes (43%) and hypertension (94%), all but one of whom were on one or more RAASi at baseline. Spironolactone was initiated at 25 mg/day, uptitrated to 50 mg/day to meet the target doses used in HF trials1, 4, 5; in the present trial, all participants achieved the 50 mg/day dose. At the end of the treatment period, 90.5% of patients had serum K+ in the range of 3.5–5.5 mEq/L, and 84.1% had serum K+ in the range of 4.0–5.1 mEq/L.\n\nApproximately one‐third of the patients did not require patiromer dose uptitration to maintain their serum K+ in the range of 3.5–5.5 mEq/L. Among patients who did require patiromer dose titrations, the majority needed only one or two titrations to maintain their serum K+ levels within the target range, despite having CKD and receiving spironolactone 50 mg/day in addition to their standard therapy, including one or more RAASi. Patiromer's efficacy in preventing hyperkalaemia occurred against a background of diuretic therapy in over 80% of patients; however, a previously published analysis of OPAL‐HK data showed a similar magnitude and time course of reductions in serum K+ in CKD patients with hyperkalaemia on and not on diuretics.21\n\n\nPatiromer was generally well tolerated, with only mild to moderate GI side effects in most patients and low rates of discontinuation. Furthermore, the incidence of hypokalaemia (1.6%) and serum magnesium below the LLN (12.7%) in the present study was lower compared with the rates in PEARL‐HF (7% and 24%, respectively) that used a fixed higher dose of patiromer, suggesting that patiromer initiated at a dose of 16.8 g/day with subsequent individualized dose titrations may be a more effective strategy for avoiding hypokalaemia and serum magnesium <LLN than the 25.2 g/day fixed‐dose strategy used in PEARL‐HF.16 There was a low incidence (4.8%) of renal dysfunction, and in most patients, events of hyperkalaemia were isolated, including in the six patients with serum K+ measurements ≥6.0 mEq/L; none were above 6.6 mEq/L. There were no ECG abnormalities or serious cardiovascular events associated with either hypokalaemia or hyperkalaemia.\n\nSelect patients with HF and CKD have potential to derive significant benefit from RAASi, especially MRAs,22 and MRAs have a Class Ia recommendation from the ESC to reduce the risk of HF hospitalization and death in HFrEF patients who remain symptomatic on ACEi or beta‐blocker therapy.6 In addition, spironolactone has also been shown to be effective in reducing atrial natriuretic peptide levels in HF patients on an ACEi or an ARB and in overcoming diuretic resistance in patients with HF.23, 24 However, RAASi agents are frequently not initiated or may be discontinued because of potential risk for hyperkalaemia.25, 26, 27 A prospective analysis from BIOSTAT‐CHF showed that patients with HFrEF receiving less than 50% of the recommended doses of ACEi, ARBs, and/or BBs displayed more risk of death or hospitalization for HF compared with those who receive ≥100%.28\n\n\nIn HFpEF or HF with mid‐range EF (HFmrEF) patients, however, no RAASi has been shown to reduce morbidity and mortality.6 Nonetheless, RAASi therapies, including MRAs, are often used in clinical practice in HFpEF and HFmrEF patients to manage coexisting conditions, such as hypertension, diabetes, and CKD and/or to provide symptom relief. In the large European Society of Cardiology Heart Failure Registry, approximately 23% of ambulatory patients with chronic HF had EF above 45%. Among these patients, 80% were prescribed an ACEi or ARB, and 41% were prescribed an MRA.27\n\n\nThe present study enrolled patients with HF, 47% of whom had EF >40%, and with CKD already receiving background therapy of an ACEi, ARB, and/or a BB and challenged them with a dosing regimen of spironolactone. The role of spironolactone in HFpEF patients remains uncertain,29, 30, 31 although MRAs received a Class IIb recommendation in the recently updated American Heart Association/American College of Cardiology HF guidelines to reduce hospitalization in appropriately selected patients with HFpEF.4 Nonetheless, the results of this study suggest that, in HF patients who, in the opinion of their treating physician, may benefit from spironolactone initiation and uptitration to 50 mg, patiromer was able to maintain serum K+ in the target range in the majority of patients; this was achieved with improved control of hyperkalaemia and a low incidence of hypokalaemia and hypomagnesaemia, as well as acceptable tolerability. The ability to manage or prevent hyperkalaemia may remove one obstacle to the use of MRAs in HF patients who have an indication for such therapy.\n\nLimitations\nThe most important limitation in the present study is the lack of a control group. However, there was a control group in the PEARL‐HF study,16 which demonstrated a significant reduction in the incidence of hyperkalaemia in patients on patiromer vs. placebo who were initiated on spironolactone 25 mg/day with subsequent uptitration to 50 mg/day.\n\nIn addition to the inclusion of patients with HFpEF and HFmrEF, several patients in the present study who received spironolactone in an attempt to test the effectiveness of patiromer in preventing hyperkalaemia did not conform to current guidelines for the use of an MRA due to an eGFR <30 mL/min/1.73 m2. The inclusion of only six patients with an eGFR <30 mL/min/1.73 m2 in the present study was likely related to the current guidelines, which recommend initiating spironolactone in HF patients with eGFR >30 mL/min/1.73 m2.4, 6 Nonetheless, results of this study provide useful information for the development of future trials to evaluate patiromer in a broad group of patients who might be at risk for the development of hyperkalaemia if administered an ACEi or ARB and an MRA. Many of these patients, while at significantly increased risk for cardiovascular death and hospitalization for HF, are currently not treated with an MRA due to the fear of inducing hyperkalaemia.\n\nConclusions\nPatiromer initiated at a dose of 16.8 g/day with subsequent individualized dose titrations (needed by two‐thirds of patients) maintained serum K+ within the target range in the majority of patients with HF and CKD in the present open‐label study, all of whom were uptitrated to spironolactone 50 mg/day, with a relatively low incidence of hyperkalaemia. This strategy was accomplished with a low incidence of hypokalaemia, hypomagnesaemia, and renal dysfunction. With a dose‐titration strategy, patiromer appears to be effective and safe, and our findings should allow development of further prospective, randomized controlled trials to evaluate this strategy in high‐risk patients such as those with HFrEF and eGFR <30 mL/min/1.73 m2.\n\nConflict of interest\nDr Bertram Pitt reports personal fees for consulting with Sanofi, Relypsa, Merck, Bayer, AstraZeneca, Boehringer Ingelheim, Forest Laboratories, scPharmaceuticals, PharmaIN, Tricida, DaVinci Therapeutics, KBP Biosciences, Stealth Peptides, and AuraSense. He has stock options with scPharmaceuticals, PharmaIN, DaVinci Therapeutics, Tricida, KBP Biosciences, and AuraSense. He serves on a data safety monitoring committee for and receives personal fees from Johnson & Johnson, Novartis, and Tenax Pharmaceuticals. He serves on a clinical events committee and receives personal fees from Juventas Therapeutics. In addition, he has a pending patent EFS ID 14916043, application number 61762661/UM‐33001/US‐1PRO for the site‐specific delivery of eplerenone to the myocardium.\n\nDr Bushinsky reports personal fees from Relypsa, Amgen, Sanofi/Genzyme, OPKO Health, Tricida, and Fresenius Medical Care. He also has stock options in Tricida. Dr Bushinsky reports research support from the National Institutes of Health and from the Renal Research Institute outside of the submitted work.\n\nDr Kitzman reports personal fees and other from Relypsa. He also reports personal fees from AbbVie, Merck, AstraZeneca, and Bayer, as well as grants from Bayer, AstraZeneca, and Novartis.\n\nDr Ruschitzka reports personal fees from SJM, Servier, Zoll, AstraZeneca, Sanofi, Cardiorentis, Novartis, Amgen, BMS, Pfizer, Fresenius, Vifor, Roche, Bayer, and Abbott and grants from SJM and Novartis. He also reports serving on the steering committee meetings of clinical trials for Cardiorentis, Fresenius, and Vifor and participating at advisory board meetings for AstraZeneca, Sanofi, Amgen, BMS, Pfizer, and Roche.\n\nDr Metra reports consulting honoraria from Amgen, Novartis, Relypsa, and Servier.\n\nDr Filippatos reports committee fees from Novartis, Bayer, Servier, and Vifor.\n\nDr Rossignol reports personal fees (consulting) from Bayer, Novartis, Relypsa, AstraZeneca, Stealth Peptides, Fresenius, Grünenthal, Vifor Fresenius Medical Care Renal Pharma, and CTMA; lecture fees from CVRx; being a cofounder of CardioRenal.\n\nDrs Du Mond, Garza, and Berman report employment with Relypsa, Inc., a Vifor Pharma Group Company. Dr Berman also has a patent (WO 2014/058905) pending.\n\nDr Lainscak reports personal fees from Relypsa and other from Relypsa and personal fees from Novartis, Relypsa, and Pfizer outside the submitted work.\n\nFunding\nThis study was funded by Relypsa, Inc., a Vifor Pharma Group Company.\n\nSupporting information\n\nFigure S1. Patient disposition.\n\n\nTable S1. Patiromer and spironolactone dosing algorithm.\n\n\nTable S2. Percentage of patients on each dose level of patiromer as last prescribed.\n\n\nTable S3. Summary of non‐serious and serious adverse events related to worsening renal function in eight patients.\n\n\nTable S4. Narratives of deaths.\n\n\nTable S5. Investigator list.\n\nClick here for additional data file.\n\n Acknowledgements\nEditorial assistance was provided by Narender Dhingra, MBBS, PhD, of AlphaBioCom, LLC, and funded by Relypsa, Inc., a Vifor Pharma Group Company.\n==== Refs\nReferences\n1 \n\nPitt \nB \n, \nZannad \nF \n, \nRemme \nWJ \n, \nCody \nR \n, \nCastaigne \nA \n, \nPerez \nA \n, \nPalensky \nJ \n, \nWittes \nJ \n. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators . N Engl J Med \n1999 ; 341 : 709 –717 .10471456 \n2 \n\nPitt \nB \n, \nRemme \nW \n, \nZannad \nF \n, \nNeaton \nJ \n, \nMartinez \nF \n, \nRoniker \nB \n, \nBittman \nR \n, \nHurley \nS \n, \nKleinman \nJ \n, \nGatlin \nM \n, \nEplerenone Post‐Acute Myocardial Infarction Heart Failure Efficacy and Survival Study Investigators \n. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction . 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J Am Coll Cardiol \n2016 ; 27 : 1476 –1488 .\n6 \n\nPonikowski \nP \n, \nVoors \nAA \n, \nAnker \nSD \n, \nBueno \nH \n, \nCleland \nJG \n, \nCoats \nAJ \n, \nFalk \nV \n, \nGonzalez‐Juanaty \nJR \n, \nHarjola \nVP \n, \nJankowska \nEA \n, \nJessup \nM \n, \nLinde \nC \n, \nNihoyannopoulos \nP \n, \nParissis \nJT \n, \nPieske \nB \n, \nRiley \nJP \n, \nRosano \nGP \n, \nRuilope \nLM \n, \nRuschitzka \nF \n, \nRutten \nFH \n, \nvan der Meer \nP \n, \nAuthors/Task Force Members; Document Reviewers \n. ESC guidelines for the diagnosis and treatment of acute and chronic heart failure: the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC . Eur J Heart Fail \n2016 ; 18 : 891 –975 .27207191 \n7 \n\nEinhorn \nLM \n, \nZhan \nM \n, \nHsu \nVD \n, \nWalker \nLD \n, \nMoen \nMF \n, \nSeliger \nSL \n, \nWeir \nMR \n, \nFink \nJC \n. 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Mechanism of action and pharmacology of patiromer, a nonabsorbed cross‐linked polymer that lowers serum potassium concentration in patients with hyperkalemia . J Cardiovasc Pharmacol Ther \n2016 ; 21 : 456 –165 .26856345 \n12 \nEuropean Medicines Agency \n. Veltassa . http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/004180/human_med_002141.jsp&mid=WC0b01ac058001d124 (9 January 2018).\n13 \n\nBakris \nGL \n, \nPitt \nB \n, \nWeir \nMR \n, \nFreeman \nMW \n, \nMayo \nMR \n, \nGarza \nD \n, \nStasiv \nY \n, \nZawadski \nR \n, \nBeerman \nL \n, \nBushinsky \nDA \n, \nAMETHYST‐DA Investigators \n. Effect of patiromer on serum potassium level in patients with hyperkalemia and diabetic kidney disease: the AMETHYST‐DN randomized clinical trial . JAMA \n2015 ; 314 : 151 –161 .26172895 \n14 \n\nWeir \nMR \n, \nBakris \nGL \n, \nBushinsky \nDA \n, \nMayo \nMR \n, \nGarza \nD \n, \nStasiv \nY \n, \nWittes \nJ \n, \nChrist‐Schmidt \nH \n, \nBerman \nL \n, \nPitt \nB \n, \nOPAL‐HK Investigators \n. Patiromer in patients with kidney disease and hyperkalemia receiving RAAS inhibitors . N Engl J Med \n2015 ; 372 : 211 –221 .25415805 \n15 \n\nPitt \nB \n, \nBakris \nGL \n, \nBushinsky \nDA \n, \nGarza \nD \n, \nMayo \nMR \n, \nStasiv \nY \n, \nChrist‐Shmidt \nH \n, \nBerman \nL \n, \nWeir \nMR \n. Effect of patiromer on reducing serum potassium and preventing recurrent hyperkalaemia in patients with heart failure and chronic kidney disease on RAAS inhibitors . Eur J Heart Fail \n2015 ; 17 : 1057 –1065 .26459796 \n16 \n\nPitt \nB \n, \nAnker \nSD \n, \nBushinsky \nDA \n, \nKitzman \nDW \n, \nZannad \nF \n, \nHuang \nIZ \n, \nPEARL‐HF Investigators \n. Evaluation of the efficacy and safety of RLY5016, a polymeric potassium binder, in a double‐blind, placebo‐controlled study in patients with chronic heart failure (the PEARL‐HF) trial . Eur Heart J \n2011 ; 32 : 820 –828 .21208974 \n17 \n\nLevey \nAS \n, \nBosch \nJP \n, \nLewis \nJB \n, \nGreene \nT \n, \nRogers \nN \n, \nRoth \nD \n. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group . Ann Intern Med \n1999 ; 130 : 461 –470 .10075613 \n18 \n\nBushinsky \nDA \n, \nSpiegel \nDM \n, \nGross \nC \n, \nBenton \nWW \n, \nFogli \nJ \n, \nHill Gallant \nKM \n, \nDu Mond \nC \n, \nBlock \nGA \n, \nWeir \nMR \n, \nPitt \nB \n. Effect of patiromer on urinary ion excretion in healthy adults . Clin J Am Soc Nephrol \n2016 ; 11 : 1769 –1776 .27679518 \n19 \n\nEpstein \nM \n, \nPitt \nB \n. Recent advances in pharmacological treatments of hyperkalemia: focus on patiromer . Expert Opin Pharmacother \n2016 ; 17 : 1435 –1448 .27180623 \n20 \n\nWeir \nMR \n, \nBakris \nGL \n, \nGross \nC \n, \nMayo \nMR \n, \nGarza \nD \n, \nStasiv \nY \n, \nYuan \nJ \n, \nBerman \nL \n, \nWilliams \nGH \n. Treatment with patiromer decreases aldosterone in patients with chronic kidney disease and hyperkalemia on renin–angiotensin system inhibitors . Kidney Int \n2016 ; 90 : 696 –704 .27350174 \n21 \n\nWeir \nMR \n, \nMayo \nMR \n, \nGarza \nD \n, \nArthur \nSA \n, \nBerman \nL \n, \nBushinsky \nD \n, \nWilson \nDJ \n, \nEpstein \nM \n. Effectiveness of patiromer in the treatment of hyperkalemia in chronic kidney disease patients with hypertension on diuretics . J Hypertens \n2017 ; 35 : S57 –S63 .28129247 \n22 \n\nZannad \nF \n, \nAlla \nF \n, \nDousset \nB \n, \nPerez \nA \n, \nPitt \nB \n, \nRALES Investigators \n. Limitation of excessive extracellular matrix turnover may contribute to survival benefit of spironolactone therapy in patients with congestive heart failure: insights from the randomized aldactone evaluation study (RALES) . Circulation \n2000 ; 102 : 2700 –2706 .11094035 \n23 \nRALES Investigators \n. Effectiveness of spironolactone added to an angiotensin‐converting enzyme inhibitor and a loop diuretic for severe chronic congestive heart failure (the Randomized Aldactone Evaluation Study [RALES]) . Am J Cardiol \n1996 ; 78 : 902 –907 .8888663 \n24 \n\nHensen \nJ \n, \nAbraham \nWT \n, \nDurr \nJA \n, \nSchrier \nRW \n. Aldosterone in congestive heart failure: analysis of determinants and role in sodium retention . Am J Nephrol \n1991 ; 11 : 441 –446 .1840232 \n25 \n\nPerazella \nMA \n. Drug‐induced hyperkalemia: old culprits and new offenders . Am J Med \n2000 ; 109 : 307 –314 .10996582 \n26 \n\nPalmer \nBF \n. Managing hyperkalemia caused by inhibitors of the renin–angiotensin–aldosterone system . N Engl J Med \n2004 ; 351 : 585 –592 .15295051 \n27 \n\nMaggioni \nAP \n, \nAnker \nSD \n, \nDahlstrom \nU \n, \nFilippatos \nG \n, \nPonikowski \nP \n, \nZannad \nF \n, \nAmir \nO \n, \nChioncel \nO \n, \nLeiro \nMC \n, \nDrozdz \nJ \n, \nErglis \nA \n, \nFazlibegovic \nE \n, \nFonseca \nC \n, \nFruhwald \nF \n, \nGatzov \nP \n, \nGoncalvesova \nE \n, \nHassanein \nM \n, \nHradec \nJ \n, \nKavoliunine \nA \n, \nLainscak \nM \n, \nLogeart \nD \n, \nMerkley \nB \n, \nMetra \nM \n, \nPersson \nH \n, \nSeferovic \nP \n, \nTemizhan \nA \n, \nTousoulis \nD \n, \nTavazzi \nL \n, \nHeart Failure Association of the ESC \n. Are hospitalized or ambulatory patients with heart failure treated in accordance with European Society of Cardiology guidelines? Evidence from 12440 patients of the ESC Heart Failure Long‐Term Registry . Eur J Heart Failure \n2013 ; 15 : 1173 –1184 .\n28 \n\nOuwerkerk \nW \n, \nVoors \nAA \n, \nAnker \nSD \n, \nCleland \nJG \n, \nDickstein \nK \n, \nFilippatos \nG \n, \nvan der Harst \nP \n, \nHillege \nHL \n, \nLang \nCC \n, \nTer Maaten \nJM \n, \nNg \nLL \n, \nPonikowski \nP \n, \nSamani \nNJ \n, \nvan Veldhuisen \nDJ \n, \nZannad \nF \n, \nMetra \nM \n, \nZinderman \nAH \n. Determinants and clinical outcome of uptitration of ACE‐inhibitors and beta‐blockers in patients with heart failure: a prospective European study . 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"fulltext_license": "CC BY-NC",
"issn_linking": "2055-5822",
"issue": "5(3)",
"journal": "ESC heart failure",
"keywords": "Chronic kidney disease; Heart failure; Mineralocorticoid receptor antagonist; Patiromer; Potassium-binding polymer",
"medline_ta": "ESC Heart Fail",
"mesh_terms": "D000368:Aged; D015415:Biomarkers; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D005260:Female; D005500:Follow-Up Studies; D006333:Heart Failure; D006801:Humans; D006947:Hyperkalemia; D008297:Male; D000451:Mineralocorticoid Receptor Antagonists; D011108:Polymers; D011188:Potassium; D051436:Renal Insufficiency, Chronic; D012189:Retrospective Studies; D013148:Spironolactone; D016896:Treatment Outcome",
"nlm_unique_id": "101669191",
"other_id": null,
"pages": "257-266",
"pmc": null,
"pmid": "29369537",
"pubdate": "2018-06",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": "24716680;12668699;26172895;26459796;10471456;10075613;28461007;25406305;27207191;27216111;15295051;27679518;17023204;29369537;22342847;1840232;21208974;21073363;11094035;8888663;26856345;23978433;24865962;25415805;19546417;10996582;28329163;27350174;27180623;28129247",
"title": "Evaluation of an individualized dose titration regimen of patiromer to prevent hyperkalaemia in patients with heart failure and chronic kidney disease.",
"title_normalized": "evaluation of an individualized dose titration regimen of patiromer to prevent hyperkalaemia in patients with heart failure and chronic kidney disease"
} | [
{
"companynumb": "US-MYLANLABS-2019M1001597",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
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"actiondrug": "1",
"activesubstance": {
"activesubstancename": "SPIRONOLACTONE"
},
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{
"abstract": "BACKGROUND\nBelimumab (Benlysta) is currently approved for the treatment of active Lupus despite standard therapy. Few data are available on the efficacy of this drug in lupus nephritis (LN).\n\n\nMETHODS\n17 LN female followed in two Nephrology Italian Unit received belimumab for a median period of 36 months (range 6-42 months). The indications were: arthralgia in 3 patients, cutaneous manifestations in 2, residual proteinuria in 8, and the need to reduce steroids for severe side effects in 4. Of interest, 1 patient started therapy during Peritoneal Dialysis and continued after kidney transplantation due to non-responsive arthralgias.\n\n\nRESULTS\nArthralgia and skin manifestations resolved in all patients. Proteinuria normalized in three patients and stabilized in all but one of the others. Steroids were indefinitely stopped in six patients (35%) and reduced to around 40% of the basal dosage in the other patients. During belimumab therapy, three extrarenal and one renal SLE flares were diagnosed accounting for a rate of renal flares of 0.02/patient/year. No major adverse events leading to therapy withdrawal occurred.\n\n\nMETHODS\nArthralgia resolved, immunological parameters improved and prednisone could be reduced within few months in the patient who started belimumab during peritoneal dialysis. After kidney transplantation belimumab was stopped but due to arthralgias unresponsive to standard immunosuppressive therapy it was restarted with success.\n\n\nCONCLUSIONS\nBelimumab allows the achievement of complete response together with the withdrawal or the reduction of corticosteroids in almost all our patients. Of interest its satisfactory use in a patient in peritoneal dialysis and after kidney transplantation.",
"affiliations": "Divisione Di Nefrologia E Dialisi-Padiglione Croff, Fondazione Ca' Granda IRCCS Ospedale Maggiore Policlinico Di Milano, via della Commenda 15, 20122, Milan, Italy. valentina.binda@policlinico.mi.it.;Nephrology Unit, Department of Medicine and Surgery, University of Milano-Bicocca and ASST Monza, Monza, Italy.;U.O.C. Day Hospital Reumatologia, ASST G. Pini-CTO, Milan, Italy.;Referral Center for Systemic Autoimmune Diseases, Fondazione Ca' Granda IRCCS Ospedale Maggiore Policlinico Di Milano, Milan, Italy.;Divisione Di Nefrologia E Dialisi-Padiglione Croff, Fondazione Ca' Granda IRCCS Ospedale Maggiore Policlinico Di Milano, via della Commenda 15, 20122, Milan, Italy.;Divisione Di Nefrologia E Dialisi-Padiglione Croff, Fondazione Ca' Granda IRCCS Ospedale Maggiore Policlinico Di Milano, via della Commenda 15, 20122, Milan, Italy.;Nephrology Unit, Department of Medicine and Surgery, University of Milano-Bicocca and ASST Monza, Monza, Italy.;Rheumatology Unit, ASST-Monza, Monza, Italy.;Divisione Di Nefrologia E Dialisi-Padiglione Croff, Fondazione Ca' Granda IRCCS Ospedale Maggiore Policlinico Di Milano, via della Commenda 15, 20122, Milan, Italy.;Nephrology Unit, Department of Medicine and Surgery, University of Milano-Bicocca and ASST Monza, Monza, Italy.;Divisione Di Nefrologia E Dialisi-Padiglione Croff, Fondazione Ca' Granda IRCCS Ospedale Maggiore Policlinico Di Milano, via della Commenda 15, 20122, Milan, Italy.",
"authors": "Binda|Valentina|V|;Trezzi|Barbara|B|;Del Papa|Nicoletta|N|;Beretta|Lorenzo|L|;Frontini|Giulia|G|;Porata|Giulia|G|;Fabbrini|Paolo|P|;Pozzi|Maria Rosa|MR|;Messa|Piergiorgio|P|;Sinico|Renato Alberto|RA|;Moroni|Gabriella|G|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D005938:Glucocorticoids; D007166:Immunosuppressive Agents; C511911:belimumab",
"country": "Italy",
"delete": false,
"doi": "10.1007/s40620-020-00706-3",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1121-8428",
"issue": "33(5)",
"journal": "Journal of nephrology",
"keywords": "Belimumab; Kidney transplantation; Lupus nephritis; SLE; Systemic lupus erythematosus",
"medline_ta": "J Nephrol",
"mesh_terms": "D061067:Antibodies, Monoclonal, Humanized; D005260:Female; D005938:Glucocorticoids; D006801:Humans; D007166:Immunosuppressive Agents; D008180:Lupus Erythematosus, Systemic; D008181:Lupus Nephritis; D006435:Renal Dialysis; D016896:Treatment Outcome",
"nlm_unique_id": "9012268",
"other_id": null,
"pages": "1019-1025",
"pmc": null,
"pmid": "32002799",
"pubdate": "2020-10",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Belimumab may decrease flare rate and allow glucocorticoid withdrawal in lupus nephritis (including dialysis and transplanted patient).",
"title_normalized": "belimumab may decrease flare rate and allow glucocorticoid withdrawal in lupus nephritis including dialysis and transplanted patient"
} | [
{
"companynumb": "IT-GLAXOSMITHKLINE-IT2020GSK027502",
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"abstract": "We present a case of diltiazem overdose in which the patient ingested 5.6 g in an apparent suicide attempt. She was admitted in the emergency department 2 hours postingestion with cardiodepressive syndrome. She was treated with gastric lavage, activated charcoal, intravenous fluids, calcium, and epinephrine, without improvement in vital signs. We gave her an infusion of 20% intralipid, leading to a favorable evolution. The patient was stable hemodynamically and metabolic in the following 24 hours. She was alert and oriented and was extubated in the second day. She was discharged after 4 days in a good state and without any neurologic deficits.",
"affiliations": "Internal Medicine Department, II Internal Medical Clinic, Sf. Spiridon Clinical Emergency Hospital, Gr.T.Popa University of Medicine and Pharmacy, Iasi, Romania. crisbologa@yahoo.com",
"authors": "Bologa|Cristina|C|;Lionte|Catalina|C|;Coman|Adorata|A|;Sorodoc|Laurentiu|L|",
"chemical_list": "D002121:Calcium Channel Blockers; D005217:Fat Emulsions, Intravenous; D004110:Diltiazem",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0735-6757",
"issue": "31(7)",
"journal": "The American journal of emergency medicine",
"keywords": null,
"medline_ta": "Am J Emerg Med",
"mesh_terms": "D000369:Aged, 80 and over; D001145:Arrhythmias, Cardiac; D002121:Calcium Channel Blockers; D004110:Diltiazem; D062787:Drug Overdose; D005217:Fat Emulsions, Intravenous; D005260:Female; D006801:Humans; D013406:Suicide, Attempted; D013577:Syndrome",
"nlm_unique_id": "8309942",
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"pages": "1154.e3-4",
"pmc": null,
"pmid": "23685061",
"pubdate": "2013-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Lipid emulsion therapy in cardiodepressive syndrome after diltiazem overdose--case report.",
"title_normalized": "lipid emulsion therapy in cardiodepressive syndrome after diltiazem overdose case report"
} | [
{
"companynumb": "RO-SANOFI-AVENTIS-2013SA094920",
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{
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"activesubstance": {
"activesubstancename": "INDAPAMIDE"
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... |
{
"abstract": "In this report, we present a patient whose positive symptoms did not improve despite being treated with clozapine monotherapy at a therapeutic dose for 4 months, and whose symptoms began to resolve after aripiprazole long-acting injection adjunction to clozapine. A 22-year-old man was diagnosed as having schizophrenia last year in his first admission, with symptoms of auditory hallucinations, persecutory delusions, and associated social withdrawal. His positive symptoms did not improve despite being treated with risperidone, olanzapine, and paliperidone. Oral clozapine monotherapy was planned, and the daily dose was increased to provide a therapeutic plasma clozapine concentration and measured as effective (545 mg/dL). Aripiprazole long-acting injection 400 mg monthly was combined with the ongoing clozapine treatment for augmentation. One week after the third injection, a psychiatric examination revealed a significant improvement in the positive symptoms, and his caregivers confirmed an increase in the social interaction of the patient. Although we cannot postulate on a single exact mechanism for the increased efficacy of clozapine and aripiprazole combination, we may suggest that, at least for a subgroup of patients with schizophrenia who respond clinically to clozapine at a suboptimal level, combination with aripiprazole may be an effective therapeutic strategy.",
"affiliations": "Department of Psychiatry, Bakirkoy Prof Mazhar Osman Training and Research Hospital for Psychiatry, Neurology, and Neurosurgery.;Department of Psychiatry, University of Health Sciences, Bagcilar Training and Research Hospital, Istanbul, Turkey.;Department of Psychiatry, Bakirkoy Prof Mazhar Osman Training and Research Hospital for Psychiatry, Neurology, and Neurosurgery.",
"authors": "Balcioglu|Yasin Hasan|YH|;Gokcay|Hasan|H|;Yesilkaya|Umit Haluk|UH|",
"chemical_list": "D014150:Antipsychotic Agents; D003692:Delayed-Action Preparations; D000068180:Aripiprazole; D003024:Clozapine",
"country": "United States",
"delete": false,
"doi": "10.1097/WNF.0000000000000404",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0362-5664",
"issue": "43(5)",
"journal": "Clinical neuropharmacology",
"keywords": null,
"medline_ta": "Clin Neuropharmacol",
"mesh_terms": "D014150:Antipsychotic Agents; D000068180:Aripiprazole; D003024:Clozapine; D003692:Delayed-Action Preparations; D004351:Drug Resistance; D004359:Drug Therapy, Combination; D006801:Humans; D007267:Injections; D008297:Male; D012559:Schizophrenia; D012565:Schizophrenic Psychology; D000083505:Social Interaction; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "7607910",
"other_id": null,
"pages": "166-168",
"pmc": null,
"pmid": "32947430",
"pubdate": "2020",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "One Plus One Sometimes Equals More Than Two: Long-acting Injectable Aripiprazole Adjunction in Clozapine-Resistant Schizophrenia.",
"title_normalized": "one plus one sometimes equals more than two long acting injectable aripiprazole adjunction in clozapine resistant schizophrenia"
} | [
{
"companynumb": "TR-MYLANLABS-2020M1103771",
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"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "ARIPIPRAZOLE"
},
"drugadditional": null,
... |
{
"abstract": "Interval debulking surgery (IDS) after neoadjuvant chemotherapy (NAC) is currently one of the preferred treatment options for advanced ovarian, fallopian tube or peritoneal cancer. This study was conducted to evaluate the clinical efficacy and safety of dose-dense paclitaxel plus carboplatin therapy (ddTC therapy) as NAC for these cancers.\nA retrospective study was conducted in 25 patients with Stage III/IV ovarian, fallopian tube or peritoneal cancer who received ddTC therapy as NAC. For ddTC therapy, paclitaxel (80 mg/m2) was administered intravenously on Days 1, 8 and 15 and carboplatin (AUC 6.0 mg/ml × min) was administered intravenously on Day 1 every 3 weeks. IDS was performed after three cycles of ddTC therapy, and ddTC therapy was also continued after surgery.\nWith ddTC therapy as NAC, the response rate was 92% and disease progression did not occur in any patient. Grade 4 hematologic toxicity and ≥Grade 3 non-hematologic toxicity both occurred in 8% of the patients, but no patient discontinued NAC because of adverse events. When IDS was performed, the complete surgery rate was 64% and the optimal surgery rate was 96%. ≥Grade 3 perioperative complications occurred in 16% of the patients, but there were no perioperative deaths. Median overall survival was 35.7 months and median progression-free survival was 17.7 months.\nThis study showed that ddTC therapy was considerably effective and tolerable as NAC. The complete surgery rate was high with IDS, and perioperative complications were acceptable.",
"affiliations": "Department of Obstetrics and Gynecology, Keio University School of Medicine, Tokyo, Japan.;Department of Obstetrics and Gynecology, Keio University School of Medicine, Tokyo, Japan.;Department of Obstetrics and Gynecology, Keio University School of Medicine, Tokyo, Japan.;Department of Obstetrics and Gynecology, Keio University School of Medicine, Tokyo, Japan.;Department of Obstetrics and Gynecology, Keio University School of Medicine, Tokyo, Japan.;Department of Obstetrics and Gynecology, Keio University School of Medicine, Tokyo, Japan.;Department of Obstetrics and Gynecology, Keio University School of Medicine, Tokyo, Japan.;Department of Obstetrics and Gynecology, Keio University School of Medicine, Tokyo, Japan.;Department of Obstetrics and Gynecology, Keio University School of Medicine, Tokyo, Japan.;Department of Obstetrics and Gynecology, Keio University School of Medicine, Tokyo, Japan.;Department of Obstetrics and Gynecology, Keio University School of Medicine, Tokyo, Japan.",
"authors": "Yoshihama|Tomoko|T|;Nomura|Hiroyuki|H|;Iwasa|Naomi|N|;Kataoka|Fumio|F|;Hashimoto|Shiho|S|;Nanki|Yoshiko|Y|;Hirano|Takuro|T|;Makabe|Takeshi|T|;Sakai|Kensuke|K|;Yamagami|Wataru|W|;Hirasawa|Akira|A|;Aoki|Daisuke|D|",
"chemical_list": "D016190:Carboplatin; D017239:Paclitaxel",
"country": "England",
"delete": false,
"doi": "10.1093/jjco/hyx118",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0368-2811",
"issue": "47(11)",
"journal": "Japanese journal of clinical oncology",
"keywords": "dose-dense TC; interval debulking surgery; neoadjuvant chemotherapy; ovarian cancer",
"medline_ta": "Jpn J Clin Oncol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D016190:Carboplatin; D018572:Disease-Free Survival; D005185:Fallopian Tube Neoplasms; D005260:Female; D006801:Humans; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D010051:Ovarian Neoplasms; D017239:Paclitaxel; D010534:Peritoneal Neoplasms; D012189:Retrospective Studies",
"nlm_unique_id": "0313225",
"other_id": null,
"pages": "1019-1023",
"pmc": null,
"pmid": "28973541",
"pubdate": "2017-11-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Efficacy and safety of dose-dense paclitaxel plus carboplatin as neoadjuvant chemotherapy for advanced ovarian, fallopian tube or peritoneal cancer.",
"title_normalized": "efficacy and safety of dose dense paclitaxel plus carboplatin as neoadjuvant chemotherapy for advanced ovarian fallopian tube or peritoneal cancer"
} | [
{
"companynumb": "JP-TEVA-2017-JP-839124",
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"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "CARBOPLATIN"
},
"drugadditional": null,
... |
{
"abstract": "Timolol maleate is a non-selective beta-adrenergic receptor blocking agent with demonstrated efficacy in the treatment of open-angle glaucoma. A 76 year old female who presented with productive cough, progressive dyspnea and hypoxia after starting timolol maleate opthalamic drops following glaucoma surgery. The patient was diagnosed with interstitial lung disease secondary to timolol treatment and after cessation of the offending agent along with corticosteroid treatment, symptoms improved drastically. Elimination of other possible causes of disease along with evolution of radiological and functional signs left us with a diagnosis of timolol-induced interstitial lung disease. To our knowledge, this is the second reported case of timolol-induced interstitial lung disease.",
"affiliations": "Division of Critical Care and Pulmonary Diseases, Florida Hospital Orlando, Orlando, FL, USA.;Division of Critical Care and Pulmonary Diseases, Florida Hospital Orlando, Orlando, FL, USA.;Division of Critical Care and Pulmonary Diseases, Florida Hospital Orlando, Orlando, FL, USA.",
"authors": "Patel|Hetain|H|;Wilches|Lina Vanessa|LV|;Guerrero|Jorge|J|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1016/j.rmcr.2015.02.006",
"fulltext": "\n==== Front\nRespir Med Case RepRespir Med Case RepRespiratory Medicine Case Reports2213-0071Elsevier S2213-0071(15)00010-610.1016/j.rmcr.2015.02.006Case ReportTimolol-induced interstitial lung disease Patel Hetain Wilches Lina Vanessa Guerrero Jorge jguerrero@cfpulmonary.com∗Division of Critical Care and Pulmonary Diseases, Florida Hospital Orlando, Orlando, FL, USA∗ Corresponding author. Division of Critical Care and Pulmonary Diseases, Florida Hospital Orlando, Central Florida Pulmonary Group, P.A., 326 N Mills Ave, Orlando, FL 32803, USA. Tel.: +1 (407) 841 1100; fax: +1 (407) 680 1191. jguerrero@cfpulmonary.com02 3 2015 2015 02 3 2015 15 30 32 © 2015 Published by Elsevier Ltd.2015This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Timolol maleate is a non-selective beta-adrenergic receptor blocking agent with demonstrated efficacy in the treatment of open-angle glaucoma. A 76 year old female who presented with productive cough, progressive dyspnea and hypoxia after starting timolol maleate opthalamic drops following glaucoma surgery. The patient was diagnosed with interstitial lung disease secondary to timolol treatment and after cessation of the offending agent along with corticosteroid treatment, symptoms improved drastically. Elimination of other possible causes of disease along with evolution of radiological and functional signs left us with a diagnosis of timolol-induced interstitial lung disease. To our knowledge, this is the second reported case of timolol-induced interstitial lung disease.\n\nKeywords\nInterstitial lung diseaseTimolol maleateDrug-induced\n==== Body\nIntroduction\nSeveral types of drugs can cause drug-induced interstitial lung disease (DILD). Currently more than 300 medications are known to cause DILD and this number will undoubtedly continue to increase as the newer therapeutic agents hit the market. DILD is generally described in terms of its clinical/histopathological features and thus can be difficult to diagnose as diagnosis is often possible by exclusion alone [1]. Timolol maleate is a non-selective beta-adrenergic receptor blocking agent used in treatment of open-angle glaucoma and is a relatively well-tolerated drug. Little is known about the adverse pulmonary effects associated with Timolol maleate. It is important that health care providers be familiar with possible adverse effects of medications they prescribe as prompt recognition of the disease along with cessation of the offending agent will minimize the risk morbidity and potential mortality. We report a case of timolol-induced interstitial lung disease along with a review of the literature.\n\nCase report\nA 76 year old Caucasian female of French ethnicity with past medical history of hypertension and glaucoma presented with a three month history of productive cough and progressive dyspnea. Patient was seen by her primary care physician when symptoms first started and was diagnosed with bronchitis and treated with a course of antibiotics. With no resolution of symptoms, patient was treated with another course of antibiotics along with medrol dose pack. Still with progressive symptoms patient underwent allergy testing which was negative. Patient decided to seek treatment in the emergency room. She denied a history of fevers, chills, weight loss, chest pain, palpitations, chronic cough, hemoptysis, abdominal pain, nausea, vomiting, diarrhea, asthma, rash, arthritis, recreational drug abuse, exposure to pigeons or other birds, and exposure to silicon, berillym, or asbestos. Patient denied family history of pulmonary or cardiac problems. Other ambulatory medicines included losartan and protonix. Upon examination, blood pressure was 128/68 mm Hg, heart rate was 72 beats per minute (bpm) and regular, a respiratory rate of 20 breaths per minute, and temperature of 98.8°. Pulmonary examination revealed bibasilar rales with evidence of hypoxia with oxygen saturation of 84% on room air. Cardiovascular, abdominal, and neurological examinations were unremarkable. Complete blood counts and chemistry panels were within normal limits. Blood cultures were negative x 5 days. Sputum cultures were negative for acid-fast bacilli, fungal, or pneumococcal growth. Chest CT revealed a slight mosaic attenuation pattern of the lungs suggestive of air trapping (Fig. 1A). A high resolution CT (HRCT) chest was recommended. HRCT chest imaging revealed groundglass opacities and mosaic pattern suggestive of bronchial air-trapping (Fig. 2). Bronchoscopy with bronchoalveolar lavage was hypercellular with 89% neutrophils, 8% lymphocytes, 2% monocytes, and 1% macrophages. Transbronchial biopsy showed evidence of focal giant cell reaction and negative for malignancy. CD4:CD8 ratio 2.8:1. Pulmonary function test revealed FEV1 75% and decreased DLCO suggestive of restrictive disease. The diagnosis of interstitial lung disease secondary to the use of timolol maleate was suspected and the medication was stopped. The patient was started on methylprednisolone treatment at a dose of 60 mg every 6 h with gradual tapering to 5 mg oral daily over a 3 month period. Upon followup, the patients symptoms had resolved. Repeat CT of the chest revealed no evidence of parenchymal infiltrates with complete resolution of any signs of air trapping (Fig. 1B). The patients with oxygen saturation was noted to be 96% on room air.\n\nDiscussion\nAdverse drug reactions are the seventh most common cause of death [2]. Drug induced pulmonary disease is an underdiagnosed issue. The global incidence of interstitial lung disease is not clearly known, but 2.5–3% of cases are drug induced [3,4]. Disparities in incidence regarding drug-induced interstitial lung disease in different ethnic groups have been reported. Recent studies have shown timolol maleate is metabolized by CYP2D6, a member of the cytochrome P450 family. In patients who are CYP2D6 poor metabolizers, systemic timolol concentrations may be high enough to cause respiratory and cardiovascular adverse effects (5–10% Caucasians, 1–2% Asians) [5]. Timolol maleate is a non-selective beta-adrenergic receptor blocking agent used in treatment of open-angle glaucoma. Unlike the oral route which undergoes extensive first pass hepatic metabolism, the topical route drains into the lacrimal ducts where systemic absorption occurs via facial and opthalamic veins which results in higher concentrations reaching systemic circulation [6]. Drugs in the same therapeutic class can induce similar pulmonary toxicity patterns [7]. Opthalamic administration of beta-adrenergic receptor blockers cause similar effects to those reported with oral beta-adrenergic receptor blockers with the most frequent being bronchospasm. Also reported are bradycardia, pleural and perdicardial effusion, bronchiolitis obiterans organizing pneumonia, and interstitial lung disease.\n\nAlthough based on recent guidelines, clinical history and HRCT imaging of the chest is deemed sufficient enough for diagnosis of interstitial lung disease [8] bronchoalveolar lavage is generally indicated to exclude an infection and to support a drug etiology [9] A lymphocytic predominance is most frequently seen in analysis although neutrophilic, mixed lymphocytic and neutrophilic and or eosinophilic pattern has been reported less frequently [10] There has not been a risk-benefit analysis regarding lung biopsy vs conservative management in regards to drug-induced lung disease however in regards to drug induced interstitial pneumonitis, lung biopsy is rarely needed to confirm the diagnosis as it is not pathognomonic for drug toxicity and most cases tend to respond to withdrawal of the offending agent with or without corticosteroid therapy [11]. Transbronchial lung biopsy has been shown to have a diagnostic rate of 76% in drug induced lung disease cases [12] Pulmonary function testing demonstrates restrictive lung disease pattern with decreased total lung capacity, residual volume, forced vital capacity, and diffusion capacity, with the latter suggestive of an alveolar–capillary interface disturbance [13]. Although drug provocation testing may be the most convincing test to confirm drug induced interstitial lung disease, rechallenged patients run the risk of severe or fatal interstitial lung disease following re-exposure and is generally considered unethical [1].\n\nThe pathophysiology of timolol induced interstitial lung disease is still unknown. The physiological mechanisms underlying iatrogenic lung disease include direct cellular toxicity, cellular edema, alveo-capillary membrane leakage, activation of the inflammatory cascade and immunological phenomenon [14].\n\nTreatment needs to be individualized based on response to therapy and presence or absence of side-effects, with the endpoint being to prevent deposition of fibrotic tissue via suppression of the inflammatory response. There is a paucity of data regarding treatment agents, dosing, or duration of therapy in interstitial lung disease, thus firm recommendations cannot be made. Steroids are indicated in patients with extensive opacities on imaging, patients with significant hypoxemia, or in patients in whom drug withdrawal fails to translate into a definite improvement [9] Based on published case studies, recommendations of high dose methylprednisoline (1 g daily for 3 days) for patients with respiratory failure and lower doses of methylprednisolone (1 mg/kg every 6 h) for less severe cases have been reported with successful results [15,16].\n\nThe diagnosis of drug induced interstitial lung disease depends on a temporal association between exposure to causative agent and development of respiratory signs and symptoms [1]. We believe timolol maleate is responsible for the development of interstitial lung disease in our patient due to the following reasons:\n\nFirst and foremost, other causes of lung damage were excluded including infectious, collagen vascular diseases, occupational exposures, other medication exposures, and malignancy. Lipoid pneumonia has been associated with angiotensin converting enzyme inhibitor drugs but has not been demonstrated with use of angiotensin receptor blocking agents [17]. Furthermore, there is no lipid excipients in timolol eyedrops, there was no lipid density in scanner, and no fat inclusions seen in bronchoalveolar lavage marcrophages. The Naranjo adverse drug reaction probability scale with a final score of six, indicated a probable relation between timolol and development of lung disease [18]. The removal of opthalamic treatment brought about resolution of symptoms and radiographic findings (with the addition of corticosteroid treatment).\n\nConclusions\nTo our knowledge, this is the second literature report of interstitial lung disease related to timolol maleate treatment. This report is similar to the prior literature report in regards to presentation and workup leading to the diagnosis of timolol maleate induce lung disease but differs in treatment. We decided to use steroids as a treatment option in addition to stopping the offending agent. This decision was based on more recent anecodotal case reports which have shown a beneficial effect of steroids in ameliorating symptoms and resolution of interstitial lung disease. In the clinical setting, the persistence of dyspnea after timolol usage should urge the physician to order a CT scan of the chest. Interstitial lung disease should be considered in the differential diagnosis and the suspected offending agent should be withheld. Drug induced interstitial lung disease carries a good prognosis and the development of lung fibrosis following early recognition and treatment of this condition is rare.\n\nFunding\nNo funding was used.\n\nFig. 1 A. Chest CT revealing mosaic pattern of the lungs with air trapping. B. Chest CT post-treatment reveals resolution of air trapping along with homogenous lung density.\n\nFig. 2 HRCT chest revealing presence of areas of heterogeneous with increase in lung density and multiple areas of air trapping.\n==== Refs\nReferences\n1 Matsuno Drug-induced interstitial lung disease mechanisms and best diagnostic approaches Respir Res 13 2012 9 22296774 \n2 Wester K. Johnson A. Sigset O. Incidence of fatal adverse reactions: a population based study Br J Clin Pharmacol 65 2008 573 579 18070216 \n3 Thommer M. Costabel U. Rizzato G. Comparison of registries of interstitial lung diseases in three European countries Eur Respir J 18 2001 114s 118s \n4 Coultas D. Zumwalt R. Black W. The epidemiology of interstitial lung diseases Am J Respir Crit Care Med 150 1994 967 972 7921471 \n5 Volotinen M. Hakkola J. Pelkonen O. Metabolism of ophthalmic timolol: new aspects of an old drug Basic & Clin Pharmacol Toxicol 108 2011 297 303 \n6 Juzych M.S. Zimmerman T.J. b-Blockers 1997 Lippincott-Raven Philadelphia, PA \n7 Denman J. Gilbar P. Abdi E. Hypersensitivity reaction to doetoxel after previous hypersensitivity reaction to paclitaxel J Oncol 20 2002 2760 2761 \n8 Hodnett P.A. Naidich D.P. Fibrosing interstitial lung disease. A practical high-resolution computed tomography-based approach to diagnosis and management and a review of the literature Am J Respir Crit Care Med 188 2 2013 141 149 23672718 \n9 Camus P. Famton A. Bonniaud P. Camus C. Foucher P. Interstitial lung disease induced by drugs and radiation Respiration 71 2004 301 326 15316202 \n10 Costabel U. Uzaslan E. Guzman J. Bronchoalveolar lavage in drug-induced lung disease Clin Chest Med 25 2004 25 36 15062594 \n11 Malhotra A. Muse V.V. Mark E.J. Case reports of Massachusetts General Hospital. Weekly clinicopathological exercises. Case 22-2003. An 82 year-old man with dyspnea and pulmonary abnormalities N Engl J Med 348 2003 1574 1585 12700378 \n12 Romagnoli M. Bigliazzi C. Casoni G. The role of transbronchial lung biopsy for diagnosis of diffuse drug induced lung disease: a case series of 44 patients Sarcoidosis Vasc Diffuse Lung Dis 25 2008 36 45 19070259 \n13 Chetta A. Marangio E. Olivieri D. Pulmonary function testing in interstitial lung diseases Respiration 71 2004 209 213 15133338 \n14 Fraser-Parg. Synopsis of disease of the chest: 2nd ed. p. 687.\n15 Flaherty K.R. Toews G.B. Travis W.D. Colby T.V. Kazerooni E.A. Gross B.H. Clinical significance of histological classification of idiopathic interstitial pneumonia Eur Respir J 19 2002 275 283 11866008 \n16 Nagai S. Kitaichi M. Itoh H. Nishimura K. Izumi T. Colby T.V. Idiopathic nonspecific interstitial pneumonia/fibrosis: comparison with idiopathic pulmonary fibrosis and BOOP Eur RespirJ 12 1998 1010 1019 9863989 \n17 Prakash U.S. Rosenow E.C. III Pulmonary complications from opthalmic preperations Mayo Clin Proc 65 1990 521 529 2332993 \n18 Naranjo C.A. Busto U. Sellers E.M. A method for estimating the probability of adverse drug reactions Clin Pharmacol Ther 30 1981 239 245 7249508\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2213-0071",
"issue": "15()",
"journal": "Respiratory medicine case reports",
"keywords": "Drug-induced; Interstitial lung disease; Timolol maleate",
"medline_ta": "Respir Med Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101604463",
"other_id": null,
"pages": "30-2",
"pmc": null,
"pmid": "26236595",
"pubdate": "2015",
"publication_types": "D002363:Case Reports",
"references": "22651223;12039945;19070259;7921471;15062594;11866008;11816817;9863989;21385322;18070216;15316202;7249508;2332993;23672718;15133338;12700378",
"title": "Timolol-induced interstitial lung disease.",
"title_normalized": "timolol induced interstitial lung disease"
} | [
{
"companynumb": "PHHY2015US073541",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
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{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "TIMOLOL"
},
"drugadditional": null,
"drugadm... |
{
"abstract": "BACKGROUND\nLive-attenuated influenza vaccines (LAIVs) have the potential to be affordable, effective, and logistically feasible for immunization of children in low-resource settings.\n\n\nMETHODS\nWe conducted a phase II, randomized, double-blind, parallel group, placebo-controlled trial on the safety of the Russian-backbone, seasonal trivalent LAIV among children aged 24 through 59 months in Dhaka, Bangladesh in 2012. After vaccination, we monitored participants for six months with weekly home visits and study clinic surveillance for solicited and unsolicited adverse events, protocol-defined wheezing illness (PDWI), and serious adverse events (SAEs), including all cause hospitalizations.\n\n\nRESULTS\nThree hundred children were randomized and administered LAIV (n=150) or placebo (n=150). No immediate post-vaccination reactions occurred in either group. Solicited reactions were similar between vaccine and placebo groups during the first 7 days post-vaccination and throughout the entire trial. There were no statistically significant differences in participants experiencing PDWI between LAIV and placebo groups throughout the trial (n=13 vs. n=16, p=0.697). Of 131 children with a history of medical treatment or hospitalization for asthma or wheezing at study entry, 65 received LAIV and 66 received placebo. Among this subset, there was no statistical difference in PDWI occurring throughout the trial between the LAIV or placebo groups (7.7% vs. 19.7%, p=0.074). While there were no related SAEs, LAIV recipients had six unrelated SAEs and placebo recipients had none. These SAEs included three due to traumatic injury and bone fracture, and one each due to accidental overdose of paracetamol, abdominal pain, and acute gastroenteritis. None of the participants with SAEs had laboratory-confirmed influenza, wheezing illness, or other signs of acute respiratory illness at the time of their events.\n\n\nCONCLUSIONS\nIn this randomized, controlled trial among 300 children aged 24 through 59 months in urban Bangladesh, Russian-backbone LAIV was safe and well tolerated. Further evaluation of LAIV safety and efficacy in a larger cohort is warranted.",
"affiliations": "PATH, Seattle, WA, USA; University of Washington, Departments of Global Health and Medicine, Seattle, WA, USA. Electronic address: jrortiz@uw.edu.;International Centre for Diarrhoeal Disease Research, Bangladesh (ICDDR,B), Dhaka, Bangladesh.;PATH, Seattle, WA, USA.;International Centre for Diarrhoeal Disease Research, Bangladesh (ICDDR,B), Dhaka, Bangladesh.;International Centre for Diarrhoeal Disease Research, Bangladesh (ICDDR,B), Dhaka, Bangladesh.;International Centre for Diarrhoeal Disease Research, Bangladesh (ICDDR,B), Dhaka, Bangladesh.;International Centre for Diarrhoeal Disease Research, Bangladesh (ICDDR,B), Dhaka, Bangladesh.;PATH, Seattle, WA, USA.;PATH, Seattle, WA, USA; University of Washington, Departments of Global Health and Medicine, Seattle, WA, USA.;International Centre for Diarrhoeal Disease Research, Bangladesh (ICDDR,B), Dhaka, Bangladesh; Johns Hopkins University, Baltimore, MD, USA.",
"authors": "Ortiz|Justin R|JR|;Goswami|Doli|D|;Lewis|Kristen D C|KD|;Sharmeen|Amina Tahia|AT|;Ahmed|Moshtaq|M|;Rahman|Mustafizur|M|;Rahman|Mohammed Z|MZ|;Feser|Jodi|J|;Neuzil|Kathleen M|KM|;Brooks|W Abdullah|WA|",
"chemical_list": "D007252:Influenza Vaccines; D010919:Placebos; D014613:Vaccines, Attenuated",
"country": "Netherlands",
"delete": false,
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"issn_linking": "0264-410X",
"issue": "33(29)",
"journal": "Vaccine",
"keywords": "Clinical trial; Live attenuated influenza vaccine",
"medline_ta": "Vaccine",
"mesh_terms": "D001459:Bangladesh; D002675:Child, Preschool; D004311:Double-Blind Method; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D006760:Hospitalization; D006801:Humans; D007252:Influenza Vaccines; D007251:Influenza, Human; D008297:Male; D010919:Placebos; D012135:Respiratory Sounds; D014613:Vaccines, Attenuated",
"nlm_unique_id": "8406899",
"other_id": null,
"pages": "3415-21",
"pmc": null,
"pmid": "25917680",
"pubdate": "2015-06-26",
"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Safety of Russian-backbone seasonal trivalent, live-attenuated influenza vaccine in a phase II randomized placebo-controlled clinical trial among children in urban Bangladesh.",
"title_normalized": "safety of russian backbone seasonal trivalent live attenuated influenza vaccine in a phase ii randomized placebo controlled clinical trial among children in urban bangladesh"
} | [
{
"companynumb": "US-JNJFOC-20150620920",
"fulfillexpeditecriteria": "1",
"occurcountry": "BD",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ACETAMINOPHEN"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nOxygen is an essential element of life in aerobic organisms. However, if not controlled, inhalation of oxygen under increased pressure in conditions of hyperbaric oxygen therapy can lead to serious damage and even death.\n\n\nMETHODS\nWe presented a 20-year-old male who had begun exhibiting symptoms of epilepsy during diving test in a hyperbaric chamber while inhaling 100% oxygen. He was immediately taken off oxygen mask and started breathing air and began rapid decompression. He lost consciousness, began foaming at the mouth, and had a series of tonic spasms. The patient was previously completely healthy and not on any medications. He was admitted for emergency treatment in our hospital, where he was treated for epilepsy. On admission, he complained of muscle and joint pain, and had erythematous changes on the forehead, neck and chest. All these changes occurred after leaving the hyperbaric chamber. Bloodwork revealed leukocytosis with neutrophil (Leukocytosis 16.0 x 10(9)/L (reference values 4.00-11.00 x 10(9)/L), Neutrophili 13 x 10(9)/L (reference values 1.9-8.0 x 10(9)/L), with elevated enzymes aspartate aminotransferase (AST) 56 U/L (reference values 0-37 U/L), alanin aminotransferase (ALT) 59 U/L, (reference values 25-65 U/L), creatine kinase (CK) 649 U/L, (reference values 32-300 U /L), lactate dehydrogenase (LDH) 398 U/L (reference values 85-227 U/L). Because of pain and his condition we began treatment in a hyperbaric chamber at a pressure of 2.0 ATA for 70 minutes, resulting in a reduction of symptoms and objective recovery of the patient. Within 24 h, repeated laboratory tests showed a reduction of leukocytosis (13 x 109/L and neutrophils (7.81 x 109/L), and the gradual reduction of the enzymes AST (47 U/L), ALT (50 U/L, CK (409 U/L), LDH (325 U/L). Since head CT and EEG were normal, epilepsy diagnosis was ruled out. This fact, along with medical tests, facilitated the differential diagnosis and confirmed that this was a case of neurotoxic effects of oxygen while the patient was in a hyperbaric chamber, not epileptic seizures.\n\n\nCONCLUSIONS\nThis case report suggests that in patients with symptoms of epileptic seizures while undergoing treatment in a hyperbaric chamber, it is always important to think of neurotoxic effects of pure oxygen which occurs at higher pressures and with a longer inhalation of 100% oxygen. In these patients, reexposure to hyperbaric conditions leads to recovery. This effect is important in daily inhalation of 100% oxygen under hyperbaric conditions which is why the use of pure oxygen is controlled and diving is allowed in shallow depths and for a limited time.",
"affiliations": null,
"authors": "Rabrenović|Milorad|M|;Trešnjić|Saša|S|;Rabrenović|Violeta|V|;Čikiriz|Nikola|N|;Mašić|Siniša|S|;Matunović|Radomir|R|",
"chemical_list": "D010100:Oxygen",
"country": "Serbia",
"delete": false,
"doi": "10.2298/vsp140312059r",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0042-8450",
"issue": "72(9)",
"journal": "Vojnosanitetski pregled",
"keywords": null,
"medline_ta": "Vojnosanit Pregl",
"mesh_terms": "D003937:Diagnosis, Differential; D004827:Epilepsy; D006801:Humans; D006931:Hyperbaric Oxygenation; D018496:Hyperoxia; D008297:Male; D009460:Neurologic Examination; D020258:Neurotoxicity Syndromes; D010100:Oxygen; D055815:Young Adult",
"nlm_unique_id": "21530700R",
"other_id": null,
"pages": "827-30",
"pmc": null,
"pmid": "26554116",
"pubdate": "2015-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Neurotoxic effects of oxygen in hyperbaric environment: A case report.",
"title_normalized": "neurotoxic effects of oxygen in hyperbaric environment a case report"
} | [
{
"companynumb": "RS-LINDE GAS NORTH AMERICA LLC-RS-LHC-2015126",
"fulfillexpeditecriteria": "2",
"occurcountry": "RS",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "OXYGEN"
},
"drugaddition... |
{
"abstract": "OBJECTIVE\nLacosamide (LCM) is an effective antiepileptic drug (AED) approved for the treatment of focal epilepsy in both children and adults. The aim of this observational study was to review our centre's experience with LCM and to characterise its efficacy and tolerability as an adjunct therapy in children with refractory focal epilepsy.\n\n\nMETHODS\nWe retrospectively reviewed the medical records of 12 paediatric patients who underwent treatment with LCM from January 2014 to December 2015. We recorded the treatment response at three time points: at 3 and 6 months after LCM therapy and at the final follow-up visit. Children showing seizure reduction ≥ 50% were considered responders.\n\n\nRESULTS\nWe included 12 patients (five boys), and their mean age was 13.8 years (range: 6.2-17.6 years) at the end of LCM treatment. The average length of follow-up after starting LCM was 23 months (11-37 months). Eight patients (66%) had > 50% reduction in seizures at the 3-month follow-up visit, and seven (58%) had > 50% reduction at the 6-month follow-up visit. Six patients (50%) maintained ≥ 50% reduction in seizures at the final follow-up visit. Two patients (16.6%) were seizure free at the 6-month and final follow-up visits. Common adverse side effects included dizziness, ataxia, nausea, and vomiting. Two patients developed status epilepticus (SE), one each at 3 and 11 days after the first LCM dose; they both discontinued treatment.\n\n\nCONCLUSIONS\nOur study points to the efficacy of LCM in a small paediatric group. Furthermore, it was important to report status epilepticus after LCM administration in the paediatric population for the first time.",
"affiliations": "Istanbul Faculty of Medicine, Division of Pediatric Neurology, Department of Pediatrics, Istanbul University, Millet cd. Fatih, 34093, Istanbul, Turkey. edibepembegul@hotmail.com.;Istanbul Faculty of Medicine, Division of Pediatric Neurology, Department of Pediatrics, Istanbul University, Millet cd. Fatih, 34093, Istanbul, Turkey.;Istanbul Faculty of Medicine, Division of Pediatric Neurology, Department of Pediatrics, Istanbul University, Millet cd. Fatih, 34093, Istanbul, Turkey.;Istanbul Faculty of Medicine, Division of Pediatric Neurology, Department of Pediatrics, Istanbul University, Millet cd. Fatih, 34093, Istanbul, Turkey.;Istanbul Faculty of Medicine, Division of Pediatric Neurology, Department of Pediatrics, Istanbul University, Millet cd. Fatih, 34093, Istanbul, Turkey.;Istanbul Faculty of Medicine, Division of Pediatric Neurology, Department of Pediatrics, Istanbul University, Millet cd. Fatih, 34093, Istanbul, Turkey.;Istanbul Faculty of Medicine, Division of Pediatric Neurology, Department of Pediatrics, Istanbul University, Millet cd. Fatih, 34093, Istanbul, Turkey.",
"authors": "Yildiz|Edibe Pembegul|EP|;Ozkan|Melis Ulak|MU|;Bektas|Gonca|G|;Uzunhan|Tuğçe Aksu|TA|;Aydinli|Nur|N|;Caliskan|Mine|M|;Ozmen|Meral|M|",
"chemical_list": "D000081:Acetamides; D000927:Anticonvulsants; D000078334:Lacosamide",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00381-017-3586-8",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0256-7040",
"issue": "33(11)",
"journal": "Child's nervous system : ChNS : official journal of the International Society for Pediatric Neurosurgery",
"keywords": "Childhood; Focal epilepsy; Lacosamide; Status epilepticus",
"medline_ta": "Childs Nerv Syst",
"mesh_terms": "D000081:Acetamides; D000293:Adolescent; D000927:Anticonvulsants; D002648:Child; D000069279:Drug Resistant Epilepsy; D004828:Epilepsies, Partial; D005260:Female; D006801:Humans; D000078334:Lacosamide; D008297:Male; D012189:Retrospective Studies; D016896:Treatment Outcome",
"nlm_unique_id": "8503227",
"other_id": null,
"pages": "2023-2027",
"pmc": null,
"pmid": "28884208",
"pubdate": "2017-11",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": "23948372;21555051;25266613;23143718;22370116;21406334;21924653;23298605;25628098;10660394;23859801;23193979;23258963;22467791;26609635;24129195",
"title": "Lacosamide treatment of childhood refractory focal epilepsy: the first reported side effect in paediatric patients.",
"title_normalized": "lacosamide treatment of childhood refractory focal epilepsy the first reported side effect in paediatric patients"
} | [
{
"companynumb": "TR-UCBSA-2017038255",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "LACOSAMIDE"
},
"drugadditional": null,
"d... |
{
"abstract": "Stress fractures are uncommon and often occur in young athletes with high intensity physical activity. These stress fractures occur in weight bearing long bones. Recent literature suggests association of thigh pain, tension side cortical thickening of femoral shaft or a femoral subtrochanteric atypical stress fractures in patients on long term bisphosphonate therapy. The reports of peri-implant bisphosphonate associated atypical stress fractures are very rare. We describe a series of three cases of femoral shaft stress phenomenon around orthopaedic implants who presented with similar prodromal thigh pain and tension side cortical thickening. Two patients sustained fractures as the condition was not recognised despite presenting with prodromal symptoms and one patient with a stress riser who was treated prophylactically. Thus this series aims to highlight the importance of identifying the stress phenomenon around orthopaedic implants, be it intra or extra-medullary implants. The location of these fractures is just distal to the implants and are classically transverse fractures. The treatment of peri-implant stress fractures needs a personalised approach in every case with appropriate choice of implants.",
"affiliations": "Department of Orthopaedics, Royal Liverpool and Broadgreen University Hospitals NHS Trust, UK.;Department of Orthopaedics, Royal Liverpool and Broadgreen University Hospitals NHS Trust, UK.",
"authors": "Kumar|Gunasekaran|G|;Dhamangaonkar|Anoop C|AC|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.1016/j.jcot.2019.01.006",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0976-5662",
"issue": "10(Suppl 1)",
"journal": "Journal of clinical orthopaedics and trauma",
"keywords": "Bisphosphonate; Dynamic hip screw; Stress fracture; Total hip replacement",
"medline_ta": "J Clin Orthop Trauma",
"mesh_terms": null,
"nlm_unique_id": "101559469",
"other_id": null,
"pages": "S112-S114",
"pmc": null,
"pmid": "31695269",
"pubdate": "2019-10",
"publication_types": "D002363:Case Reports",
"references": "14846496;29252422;17356148;22733959;19670917;19419297;20148064;21542743;20101130;25817305;18448990;18222447;19884427;10926246;12143987;30280425;19198962",
"title": "Bisphosphonate associated femoral stress fracture distal to an orthopaedic implant: They are predictable!",
"title_normalized": "bisphosphonate associated femoral stress fracture distal to an orthopaedic implant they are predictable"
} | [
{
"companynumb": "GB-MYLANLABS-2019M1099492",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ALENDRONATE SODIUM"
},
"drugadditional": "3",... |
{
"abstract": "BACKGROUND\nDrug-induced hypersensitivity reactions attributed to the immunosuppressive agent tacrolimus after an organ transplant are rare in the literature. We present 3 cases of male adult patients grafted with a cadaveric liver who developed delayed hypersensitivity reactions to tacrolimus in the form of the prolonged-release capsules (Advagraf). Furthermore, the appropriate drug concentration solutions used for allergy testing are proposed.\n\n\nMETHODS\nAll patients received a liver transplant (LT) because of cirrhosis of various etiologies. They were immunosuppressed with tacrolimus once daily. Several months after they had been placed on an immunosuppressive regimen with tacrolimus in the form of prolonged-release capsules (Advagraf), the patients presented with delayed hypersensitivity reactions and torturous pruritic rash that affected the whole body and was unresponsive to treatment with oral ursodeoxycholic acid, cholestyramine, or levocetirizine. Allergy testing that was performed by skin prick testing was negative. Nevertheless, intradermal testing yielded positive results in all 3 patients. Management was by interruption of the culprit agent, which was followed by symptom resolution. The immunosuppressive treatment was continued with alternative drugs.\n\n\nRESULTS\nAppropriate nonirritating drug concentration solutions of the drug used for intradermal testing were highly sensitive and confirmed the clinical diagnosis of tacrolimus allergy in all the affected patients.\n\n\nCONCLUSIONS\nImmunosuppressive treatment with tacrolimus in the form of prolonged-release capsules may cause a drug hypersensitivity reaction. A suspicion of allergy warrants a referral for allergy testing. Pruritic rash refractory to treatment in liver transplanted patients should be evaluated by an allergist for possible drug allergy when bile stasis and graft disease have been excluded. Intradermal testing has proven a highly sensitive method for confirming a drug allergy diagnosis, whereas skin prick testing did not.",
"affiliations": "Allergy Unit, Hippokration Hospital, Aristotle University of Thessaloniki, Greece. Electronic address: antigonemavrudi@gmail.com.;Organ Transplantation Unit, Aristotle University of Thessaloniki, Greece.;3rd Pediatric Department, Hippokration Hospital, Aristotle University of Thessaloniki, Greece.;Department of Pediatrics, Democritus University of Thrace, Greece.;Organ Transplantation Unit, Aristotle University of Thessaloniki, Greece.;2nd Propaedeutic Department of Internal Medicine, Gastroenterology Section, Aristotle University of Thessaloniki, Hippokration Hospital, Thessaloniki, Greece.",
"authors": "Mavroudi|Antigoni|A|;Imvrios|George|G|;Xinias|Ioannis|I|;Cassimos|Dimitrios|D|;Vagiotas|Lampros|L|;Giouleme|Olga|O|",
"chemical_list": "D003692:Delayed-Action Preparations; D007166:Immunosuppressive Agents; D016559:Tacrolimus",
"country": "United States",
"delete": false,
"doi": "10.1016/j.transproceed.2021.03.031",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1345",
"issue": "53(5)",
"journal": "Transplantation proceedings",
"keywords": null,
"medline_ta": "Transplant Proc",
"mesh_terms": "D000368:Aged; D003692:Delayed-Action Preparations; D004342:Drug Hypersensitivity; D005076:Exanthema; D006801:Humans; D007166:Immunosuppressive Agents; D008103:Liver Cirrhosis; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D016559:Tacrolimus",
"nlm_unique_id": "0243532",
"other_id": null,
"pages": "1731-1735",
"pmc": null,
"pmid": "33962771",
"pubdate": "2021-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Tacrolimus Immunosuppression Causes Drug-Induced Hypersensitivity Reactions in Liver-Transplant Patients: A 3-Case Report.",
"title_normalized": "tacrolimus immunosuppression causes drug induced hypersensitivity reactions in liver transplant patients a 3 case report"
} | [
{
"companynumb": "GR-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-298956",
"fulfillexpeditecriteria": "1",
"occurcountry": "GR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "URSODIOL"
},
"drugad... |
{
"abstract": "Glioblastoma multiforme (GBM) treatment consists of surgery, radiotherapy and chemotherapy with Temozolomide (TMZ). After subtotal resection (STR), residual tumors rarely undergo spontaneous regression. Overall survival (OS) and progression-free survival (PFS) are reduced when compared with gross total resection. There is evidence that adding Tumor Treating Fields (TTFields) to standard management may lead to a significant increase in PFS and OS. In 2015 and 2016, STR was performed in 27 patients with GBM. Of these, four subsequently received TTFields therapy in addition to chemotherapy. The present study presents a series of three patients with GBM (44-54 years; isocitrate dehydrogenase wild-type, methylated O6-methylguanine-DNA methyltransferase promoter) that were treated with radiochemotherapy and TTFields after STR. Therapy with TTFields started concomitantly to TMZ following radiotherapy and was maintained for 14, 24 and 37 months. TTFields were used as monotherapy in one case, as TMZ treatment had to be stopped due to toxicity for 1 month. In all patients, TTFields therapy was well tolerated at high compliance levels, resulting in complete response (CR) after 4, 5 and 7 months, respectively. Two patients remain tumor-free at 16 and 40 months after STR. One patient exhibited multifocal recurrence 11 months after the beginning of TTFields treatment but remains alive, presenting a mild neurological decline 24 months after starting TTFields. All three presented patients gave written informed consent for their data to be published. In conclusion, the current report detailed three patients with GBM who underwent STR and were subsequently treated with TMZ and TTFields. TTFields treatment was tolerated well and was applied accurately and with high compliance by these patients, which may have contributed to the complete response. Four of the 27 patients treated with STR received additional TTFields treatment. Three of these 4 showed a CR, while a CR was observed only 2 of the remaining 23 patients without TTFields. The current series supports the effects in clinical practice, as demonstrated in recent clinical trials. The results also demonstrated that adjuvant TTFields therapy can structurally affect residual tumors after STR.",
"affiliations": "Department of Neurosurgery, University Hospital of Würzburg, Würzburg 97080, Germany.;Department of Neurosurgery, University Hospital of Würzburg, Würzburg 97080, Germany.;Department of Neurosurgery, University Hospital of Würzburg, Würzburg 97080, Germany.;Department of Neurosurgery, University Hospital of Würzburg, Würzburg 97080, Germany.;Department of Neurosurgery, University Hospital of Würzburg, Würzburg 97080, Germany.;Department of Neuropathology, Institute of Pathology, University of Würzburg, Würzburg 97080, Germany.;Department of Neurosurgery, University Hospital of Würzburg, Würzburg 97080, Germany.;Department of Neurosurgery, University Hospital of Würzburg, Würzburg 97080, Germany.;Department of Neurosurgery, University Hospital of Würzburg, Würzburg 97080, Germany.;Department of Neurosurgery, University Hospital of Würzburg, Würzburg 97080, Germany.",
"authors": "Kessler|Almuth Friederike|AF|;Linsenmann|Thomas|T|;Westermaier|Thomas|T|;Wolber|Wanja|W|;Weiland|Judith|J|;Monoranu|Camelia-Maria|CM|;Breun|Maria|M|;Hagemann|Carsten|C|;Ernestus|Ralf-Ingo|RI|;Löhr|Mario|M|",
"chemical_list": null,
"country": "Greece",
"delete": false,
"doi": "10.3892/ol.2019.11110",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1792-1074",
"issue": "19(1)",
"journal": "Oncology letters",
"keywords": "Tumor Treating Fields; complete response; glioblastoma multiforme; incomplete resection; subtotal resection",
"medline_ta": "Oncol Lett",
"mesh_terms": null,
"nlm_unique_id": "101531236",
"other_id": null,
"pages": "557-561",
"pmc": null,
"pmid": "31897171",
"pubdate": "2020-01",
"publication_types": "D016428:Journal Article",
"references": "23039151;27526690;21910919;24484232;19352386;24130262;24305719;21417701;25213870;29260225;17551011;15758009;29644485;29392280;19747048;23757294;22608262;11780887;20231676;26503470",
"title": "Complete radiological response following subtotal resection in three glioblastoma patients under treatment with Tumor Treating Fields.",
"title_normalized": "complete radiological response following subtotal resection in three glioblastoma patients under treatment with tumor treating fields"
} | [
{
"companynumb": "DE-009507513-2001DEU002682",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "TEMOZOLOMIDE"
},
"drugadditional": null,
... |
{
"abstract": "We describe four cases of histoplasmosis indigenous to Himachal Pradesh (India) that will be of considerable public health interest. A 48-year-old human immunodeficiency virus (HIV)-negative man with cervical and mediastinal lymphadenopathy, hepatosplenomegaly, adrenal mass, and bone marrow involvement was treated as disseminated tuberculosis without benefit. Progressive disseminated histoplasmosis was diagnosed from the fungus in smears from adrenal mass. Another 37-year-old HIV-positive man was on treatment of suspected pulmonary tuberculosis. He developed numerous erythema nodosum leprosum-like mucocutanous lesions accompanied by fever, generalized lymphadenopathy, and weight loss. Pulmonary histoplasmosis with cutaneous dissemination was diagnosed when skin lesions showed the fungus in smears, histopathology, and mycologic culture. Both were successfully treated with amphotericin B/itraconazole. Third patient, a 46-year-old HIV-negative man, had oropharyngeal lesions, cervical lymphadenopathy, intermittent fever, hepatosplenomegaly, and deteriorating general health. Progressive disseminated oropharyngeal histoplasmosis was diagnosed from the fungus in smears and mycologic cultures from oropharyngeal lesions and cervical lymph node aspirates. He died despite initiating treatment with oral itraconazole. Another 32-year-old man 3 months after roadside trauma developed a large ulcer with exuberant granulation tissue over left thigh without evidence of immunosuppression/systemic involvement. He was treated successfully with surgical excision of ulcer under amphotericin B/itraconazole coverage as primary cutaneous histoplasmosis confirmed pathologically and mycologically. A clinical suspicion remains paramount for early diagnosis of histoplasmosis particularly in a nonendemic area. Most importantly, with such diverse clinical presentation and therapeutic outcome selection of an appropriate and customized treatment schedule is a discretion the treating clinicians need to make.",
"affiliations": "Department of Dermatology, Venereology and Leprosy, Dr. R. P. Govt. Medical College, Kangra (Tanda), Himachal Pradesh, India.;Department of Pathology, Dr. R. P. Govt. Medical College, Kangra (Tanda), Himachal Pradesh, India.;Department of Pathology, Dr. R. P. Govt. Medical College, Kangra (Tanda), Himachal Pradesh, India.;Department of Dermatology, Venereology and Leprosy, Dr. R. P. Govt. Medical College, Kangra (Tanda), Himachal Pradesh, India.;Department of Microbiology, Dr. R. P. Govt. Medical College, Kangra (Tanda), Himachal Pradesh, India.;Department of Dermatology, Venereology and Leprosy, Dr. R. P. Govt. Medical College, Kangra (Tanda), Himachal Pradesh, India.;Department of Dermatology, Venereology and Leprosy, Dr. R. P. Govt. Medical College, Kangra (Tanda), Himachal Pradesh, India.;Department of Dermatology, Venereology and Leprosy, Dr. R. P. Govt. Medical College, Kangra (Tanda), Himachal Pradesh, India.;Department of Dermatology, Venereology and Leprosy, Dr. R. P. Govt. Medical College, Kangra (Tanda), Himachal Pradesh, India.",
"authors": "Mahajan|Vikram K|VK|;Raina|Rashmi Kaul|RK|;Singh|Suman|S|;Rashpa|Rattan Sagar|RS|;Sood|Anuradha|A|;Chauhan|Pushpinder S|PS|;Mehta|Karaninder S|KS|;Rawat|Ritu|R|;Sharma|Vikas|V|",
"chemical_list": "D000935:Antifungal Agents; D017964:Itraconazole; D000666:Amphotericin B",
"country": "United States",
"delete": false,
"doi": "10.4269/ajtmh.17-0432",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0002-9637",
"issue": "97(6)",
"journal": "The American journal of tropical medicine and hygiene",
"keywords": null,
"medline_ta": "Am J Trop Med Hyg",
"mesh_terms": "D000328:Adult; D000666:Amphotericin B; D000935:Antifungal Agents; D017809:Fatal Outcome; D005334:Fever; D015658:HIV Infections; D006658:Histoplasma; D006660:Histoplasmosis; D006801:Humans; D007194:India; D017964:Itraconazole; D008168:Lung; D008172:Lung Diseases, Fungal; D008297:Male; D008875:Middle Aged; D016896:Treatment Outcome",
"nlm_unique_id": "0370507",
"other_id": null,
"pages": "1749-1756",
"pmc": null,
"pmid": "29016342",
"pubdate": "2017-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "25780970;15679662;28273974;25960856;10234082;20606964;27512207;24432229;14629354;22707773;19293507;27722134;19040507;27248851;27166049;17806045;11837763;25514986;19142453;15926599;21200187;23547881;20877062;7774966",
"title": "Case Report: Histoplasmosis in Himachal Pradesh (India): An Emerging Endemic Focus.",
"title_normalized": "case report histoplasmosis in himachal pradesh india an emerging endemic focus"
} | [
{
"companynumb": "IN-ALKEM LABORATORIES LIMITED-IN-ALKEM-2017-01052",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ITRACONAZOLE"
},
"dru... |
{
"abstract": "We present the unusual case of a \"disappearing\" aortic valve in an infant with hypoplastic left heart syndrome (mitral and aortic stenosis) that underwent Norwood palliation at birth and subsequently a Glenn operation. Angiographic images at the time of operation showed no apparent insufficiency of the native aortic valve. Over the course of 14 months following operation, the patient developed significant cardiomegaly with a workup revealing severe native aortic valve insufficiency. Following orthotopic heart transplantation, examination of the explanted heart revealed a complete absence of native aortic valve leaflets.",
"affiliations": "Pediatric Cardiothoracic Surgery, University of Utah, Salt Lake City, UT, USA.",
"authors": "Loftus|Patrick D|PD|;Erickson|Lance K|LK|;Everitt|Melanie D|MD|;Kaza|Aditya K|AK|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1177/2150135113512137",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2150-1351",
"issue": "5(2)",
"journal": "World journal for pediatric & congenital heart surgery",
"keywords": "aortic valve; congenital heart disease; hypoplastic left heart syndrome; neonate; repair",
"medline_ta": "World J Pediatr Congenit Heart Surg",
"mesh_terms": "D001021:Aortic Valve; D001022:Aortic Valve Insufficiency; D017023:Coronary Angiography; D004108:Dilatation, Pathologic; D005355:Fibrosis; D006333:Heart Failure; D016027:Heart Transplantation; D006801:Humans; D018636:Hypoplastic Left Heart Syndrome; D007231:Infant, Newborn; D008297:Male; D009206:Myocardium; D014463:Ultrasonography",
"nlm_unique_id": "101518415",
"other_id": null,
"pages": "334-7",
"pmc": null,
"pmid": "24668988",
"pubdate": "2014-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Heart failure due to \"disappearing\" aortic valve in hypoplastic left heart syndrome.",
"title_normalized": "heart failure due to disappearing aortic valve in hypoplastic left heart syndrome"
} | [
{
"companynumb": "US-BAYER-2020-042144",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "VANCOMYCIN"
},
"drugadditional": null,
... |
{
"abstract": "Sunitinib-associated hyperammonemic encephalopathy has not been previously reported in the emergency medicine literature. As newer treatments for cancer become more widespread and patients live longer, the emergence of previously unreported or rare adverse effects is expected to increase. Here we report the case of a 71-year-old woman with infiltrating ductal carcinoma of the breast with metastasis to the liver who developed hyperammonemic encephalopathy after taking sunitinib for 12 days. She presented to the emergency department (ED) with confusion and the initial workup revealed an elevated ammonia level (202 μmol/L; reference range, 11-51 μmol/L) without evidence of cirrhosis or portal hypertension. The patient was started on lactulose and admitted to the hospital, where her ammonia levels and mental status waxed and waned throughout her 12-day hospitalization. Further workup with magnetic resonance imaging and an electroencephalogram were negative. After 12 days, her ammonia level normalized and she was discharged without re-initiating Sunitinib. The patient was followed for three months post hospitalization without recurrence of symptoms. Patients on sunitinib should have their ammonia levels checked when presenting to the ED with altered mentation for early identification of hyperammonemic encephalopathy and its potential complications, such as seizures, brain edema, and death. Emergent management in the ED should include initiation of lactulose and consultation with the gastroenterology team.",
"affiliations": "Department of Emergency Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States of America. Electronic address: dnlipe@mdanderson.org.;Department of Emergency Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States of America.;Department of General Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States of America.",
"authors": "Lipe|Demis N|DN|;Hoxha|Besim|B|;Sahai|Sunil K|SK|",
"chemical_list": "D000970:Antineoplastic Agents; D000077210:Sunitinib",
"country": "United States",
"delete": false,
"doi": "10.1016/j.ajem.2020.07.079",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0735-6757",
"issue": "46()",
"journal": "The American journal of emergency medicine",
"keywords": null,
"medline_ta": "Am J Emerg Med",
"mesh_terms": "D000368:Aged; D000970:Antineoplastic Agents; D001943:Breast Neoplasms; D005260:Female; D006801:Humans; D022124:Hyperammonemia; D008113:Liver Neoplasms; D020258:Neurotoxicity Syndromes; D000077210:Sunitinib",
"nlm_unique_id": "8309942",
"other_id": null,
"pages": "282-283",
"pmc": null,
"pmid": "32811710",
"pubdate": "2021-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Sunitinib-associated hyperammonemic encephalopathy.",
"title_normalized": "sunitinib associated hyperammonemic encephalopathy"
} | [
{
"companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-311182",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "SUNITINIB"
},
"druga... |
{
"abstract": "Germline DICER1 mutations have been described in individuals with pleuropulmonary blastoma (PPB), ovarian Sertoli-Leydig cell tumor (SLCT), sarcomas, multinodular goiter, thyroid carcinoma, cystic nephroma and other neoplastic conditions. Early results from the International Ovarian and Testicular Stromal Tumor Registry show germline DICER1 mutations in 48 % of girls and women with SLCT. In this report, a young woman presented with ovarian undifferentiated sarcoma. Four years later, she presented with SLCT. She was successfully treated for both malignancies. Sequence results showed a germline intronic mutation in DICER1. This mutation results in an exact duplication of the six bases at the splice site at the intron 23 and exon 24 junction. Predicted improper splicing leads to inclusion of 10 bases of intronic sequence, frameshift and premature truncation of the protein disrupting the RNase IIIb domain. A second individual with SLCT was found to have an identical germline mutation. In each of the ovarian tumors, an additional somatic mutation in the RNase IIIb domain of DICER1 was found. In rare patients, germline intronic mutations in DICER1 that are predicted to cause incorrect splicing can also contribute to the pathogenesis of SLCT.",
"affiliations": "International Ovarian and Testicular Stromal Tumor Registry, Children's Hospital and Clinics of Minnesota, 2530 Chicago Ave. S. CSC-175, Minneapolis, MN, 55404, USA. krisann.schultz@childrensmn.org.;International Ovarian and Testicular Stromal Tumor Registry, Children's Hospital and Clinics of Minnesota, 2530 Chicago Ave. S. CSC-175, Minneapolis, MN, 55404, USA.;International Ovarian and Testicular Stromal Tumor Registry, Children's Hospital and Clinics of Minnesota, 2530 Chicago Ave. S. CSC-175, Minneapolis, MN, 55404, USA.;Department of Oncology, Children's Hospitals and Clinics of Minnesota, Minneapolis, MN, USA.;Virginia Piper Cancer Institute, Allina Health, Minneapolis, MN, USA.;Lauren V. Ackerman Division of Surgical Pathology, Washington University Medical Center, St. Louis, MO, USA.;Division of Anatomic Pathology and Center for Genetic Medicine Research, Children's National Medical Center, George Washington University School of Medicine & Health Sciences, Washington, DC, USA.",
"authors": "Schultz|Kris Ann P|KA|;Harris|Anne|A|;Messinger|Yoav|Y|;Sencer|Susan|S|;Baldinger|Shari|S|;Dehner|Louis P|LP|;Hill|D Ashley|DA|",
"chemical_list": "C408087:DICER1 protein, human; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases",
"country": "Netherlands",
"delete": false,
"doi": "10.1007/s10689-015-9831-y",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1389-9600",
"issue": "15(1)",
"journal": "Familial cancer",
"keywords": "DICER1; MiRNA; Ovarian cancer; Sarcoma; Sertoli-Leydig cell tumor",
"medline_ta": "Fam Cancer",
"mesh_terms": "D000293:Adolescent; D000595:Amino Acid Sequence; D002648:Child; D053487:DEAD-box RNA Helicases; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007438:Introns; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D010051:Ovarian Neoplasms; D012042:Registries; D043244:Ribonuclease III; D013736:Testicular Neoplasms",
"nlm_unique_id": "100898211",
"other_id": null,
"pages": "105-10",
"pmc": null,
"pmid": "26289771",
"pubdate": "2016-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "21882293;24821309;26925222;19556464;24136150;22180160;21156700;24659465;24090359;22187960;21221095;23620094;25356068;22517427;17137906;8382107;25118636;25022261;21266384;24909177;21205968;8280234;18605764;23625684;24481001;20717847",
"title": "Ovarian tumors related to intronic mutations in DICER1: a report from the international ovarian and testicular stromal tumor registry.",
"title_normalized": "ovarian tumors related to intronic mutations in dicer1 a report from the international ovarian and testicular stromal tumor registry"
} | [
{
"companynumb": "US-RECORDATI RARE DISEASES-US-R13005-16-00008",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "DACTINOMYCIN"
},
"drugad... |
{
"abstract": "Camptocormia, a condition that involves the abnormal flexion of the trunk and results in a forward-bending posture, is relatively common during the course of Parkinson disease (PD). Despite this, there is ongoing controversy concerning its mechanisms and no consensus regarding the underlying etiology. This report demonstrates a case in which a dopaminergic agonist (DA) was implicated in the onset of camptocormia episodes in a non-PD patient who developed camptocormia after the start of DA treatment. Over a course of 8 years, the patient experienced intermittent camptocormia, which resulted in multiple falls. After cessation of the DA, the patient showed decreased camptocormia symptoms. This case report suggests that clinicians should consider the possibility of DA-induced camptocormia in patients with PD and non-PD patients receiving DA treatments, and serves to caution clinicians regarding the administration of DAs.",
"affiliations": "Departments of Neuromodulation and Neurosurgery, Osaka University Graduate School of Medicine; and †Center for Information and Neural Networks (CiNet), Osaka University, Suita, Osaka, Japan.",
"authors": "Mano|Tomoo|T|",
"chemical_list": "D018491:Dopamine Agonists; D050483:Dopamine Plasma Membrane Transport Proteins; D007211:Indoles; C046649:ropinirole",
"country": "United States",
"delete": false,
"doi": "10.1097/WNF.0000000000000266",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0362-5664",
"issue": "41(2)",
"journal": "Clinical neuropharmacology",
"keywords": null,
"medline_ta": "Clin Neuropharmacol",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D018491:Dopamine Agonists; D050483:Dopamine Plasma Membrane Transport Proteins; D005260:Female; D006801:Humans; D007211:Indoles; D009134:Muscular Atrophy, Spinal; D013121:Spinal Curvatures; D014202:Tremor",
"nlm_unique_id": "7607910",
"other_id": null,
"pages": "70-72",
"pmc": null,
"pmid": "29401068",
"pubdate": "2018",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Camptocormia Induced by a Dopaminergic Agonist.",
"title_normalized": "camptocormia induced by a dopaminergic agonist"
} | [
{
"companynumb": "JP-ORCHID HEALTHCARE-2046802",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ROPINIROLE HYDROCHLORIDE"
},
"drugaddition... |
{
"abstract": "The US Food and Drug Administration (FDA) has approved multiple systemic vascular endothelial growth factor (VEGF) inhibitors since 2004 to treat various malignancies. Inhibition of the VEGF signaling pathway can result in impairment of vascular wall integrity through medial degeneration and endothelial dysfunction, potentially resulting in arterial (including aortic) aneurysm/dissection. We performed a postmarketing review to evaluate arterial aneurysm/dissection as a potential safety risk for patients with cancer treated with VEGF inhibitors. We searched the FDA Adverse Event Reporting System (FAERS) database and literature for reports of arterial (including aortic) aneurysm/dissection with VEGF inhibitors currently approved by the FDA for a cancer indication. We identified 240 cases of arterial aneurysm/dissection associated with VEGF inhibitors. The median time to onset of an arterial aneurysm/dissection event from the initiation of a VEGF inhibitor was 94 days (range 1-1955 days). Notably, 22% (53/240) of cases reported fatal outcomes related to arterial aneurysm/dissection. We determined the drug-event association as probable in 15 cases that lacked relevant confounding factors for arterial aneurysm/dissection, which is supported by unremarkable computed tomography (CT) findings prior to starting VEGF inhibitor therapy, despite nondrug-associated background arterial aneurysm/dissection generally demonstrating preexisting arterial abnormalities. FAERS and literature case-level evidence suggests that VEGF inhibitors may have contributed to arterial aneurysm/dissection, as a class effect, based on short onset relative to natural history of disease and biologic plausibility. Cardiovascular and oncology healthcare professionals should be aware of this rare, but life-threatening safety risk associated with VEGF inhibitors.",
"affiliations": "Division of Pharmacovigilance, Office of Surveillance and Epidemiology, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA.;Division of Pharmacovigilance, Office of Surveillance and Epidemiology, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA.;Division of Pharmacovigilance, Office of Surveillance and Epidemiology, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA.;Division of Pharmacovigilance, Office of Surveillance and Epidemiology, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA.;Division of Oncology, Office of Oncologic Diseases, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA.;Division of Oncology, Office of Oncologic Diseases, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA.;Division of Oncology, Office of Oncologic Diseases, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA.;Division of Pharmacovigilance, Office of Surveillance and Epidemiology, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA.",
"authors": "Cheng|Connie|C|https://orcid.org/0000-0002-4201-4457;Nguyen|Michelle Nadeau|MN|https://orcid.org/0000-0002-2620-1885;Nayernama|Afrouz|A|;Jones|S Christopher|SC|https://orcid.org/0000-0002-0478-0978;Brave|Michael|M|;Agrawal|Sundeep|S|;Amiri-Kordestani|Laleh|L|;Woronow|Daniel|D|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1177/1358863X211006470",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1358-863X",
"issue": "26(5)",
"journal": "Vascular medicine (London, England)",
"keywords": "arterial aneurysm; arterial dissection; vascular endothelial growth factor (VEGF)",
"medline_ta": "Vasc Med",
"mesh_terms": null,
"nlm_unique_id": "9610930",
"other_id": null,
"pages": "526-534",
"pmc": null,
"pmid": "33840328",
"pubdate": "2021-10",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Arterial aneurysm and dissection with systemic vascular endothelial growth factor inhibitors: A review of cases reported to the FDA Adverse Event Reporting System and published in the literature.",
"title_normalized": "arterial aneurysm and dissection with systemic vascular endothelial growth factor inhibitors a review of cases reported to the fda adverse event reporting system and published in the literature"
} | [
{
"companynumb": "US-BAYER-2021A243854",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "SORAFENIB"
},
"drugadditional": null,
"... |
{
"abstract": "We encountered two cases of macular infarction that occurred after vitrectomy performed for mild endophthalmitis, which, on culture, yielded Staphylococcus epidermidis. At the end of each vitrectomy, 0.4 mg of gentamicin, 1.0 mg of cefazolin, and 0.32 mg of dexamethasone were injected into the vitreous cavity. We are concerned that the macular lesion was a retinal toxic effect of gentamicin because of the recent description of similar lesions occurring after the inadvertent intraocular injection of massive doses of this drug.",
"affiliations": null,
"authors": "Conway|B P|BP|;Campochiaro|P A|PA|",
"chemical_list": "D005839:Gentamicins",
"country": "United States",
"delete": false,
"doi": "10.1001/archopht.1986.01050150067028",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0003-9950",
"issue": "104(3)",
"journal": "Archives of ophthalmology (Chicago, Ill. : 1960)",
"keywords": null,
"medline_ta": "Arch Ophthalmol",
"mesh_terms": "D000328:Adult; D009877:Endophthalmitis; D005131:Eye Injuries; D005260:Female; D005451:Fluorescein Angiography; D005839:Gentamicins; D006801:Humans; D007238:Infarction; D008266:Macula Lutea; D008297:Male; D008875:Middle Aged; D011183:Postoperative Complications; D012164:Retinal Diseases; D013203:Staphylococcal Infections; D013212:Staphylococcus epidermidis; D014821:Vitrectomy; D014822:Vitreous Body",
"nlm_unique_id": "7706534",
"other_id": null,
"pages": "367-71",
"pmc": null,
"pmid": "3485422",
"pubdate": "1986-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Macular infarction after endophthalmitis treated with vitrectomy and intravitreal gentamicin.",
"title_normalized": "macular infarction after endophthalmitis treated with vitrectomy and intravitreal gentamicin"
} | [
{
"companynumb": "US-BAUSCH-BL-2016-028351",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "DEXAMETHASONE PHOSPHATE"
},
"drugadditional":... |
{
"abstract": "Originally developed for treatment of human immunodeficiency virus (HIV), the antiviral combination lopinavir/ritonavir (LPV/r) is being repurposed for treating the novel coronavirus disease (COVID-19) despite minimal experience in this markedly different population and an in-vitro derived EC50 against SARS-CoV-2 several hundred-fold greater than for HIV. We present a case series including a case of severe hyponatremia and a 32-fold overdose raising safety and effectiveness concerns in COVID-19 patients.\n\n\n\nWe measured LPV trough concentrations in 12 patients and reviewed their clinical charts for side effects known to occur in HIV patients.\n\n\n\nCompared to established LPV trough concentrations in HIV patients, concentrations in COVID-19 patients were 3-fold greater (19.37 ± 10.12 mcg/mL versus 6.25 mcg/mL). In addition, cholestasis and dyslipidemia toxicity thresholds were exceeded in 12/12 and 11/12 patients respectively. No patients achieved the presumed therapeutic concentration. Side effects included gastrointestinal symptoms (5/12), electrolyte imbalances (4/12), liver enzyme disturbances (5/12) and triglyceride elevations (2/12).\n\n\n\nNo patients reached presumed therapeutic LPV concentrations despite experiencing side effects and exceeding cholestasis and dyslipidemia toxicity thresholds. This raises concerns for the safety and effectiveness of LPV/r. Clinicians should consider closely monitoring for side effects and not necessarily attribute them to COVID-19.",
"affiliations": "McGill University Health Centre, Montreal, Canada.;McGill Faculty of Medecine and Health Sciences, Montreal, Canada.;McGill University Health Centre, Montreal, Canada.;McGill University Health Centre, Montreal, Canada.",
"authors": "Lepage|Marc-Antoine|MA|0000-0002-7518-185X;Rozza|Nicholas|N|;Kremer|Richard|R|0000-0002-7053-2139;Grunbaum|Ami|A|0000-0001-8745-0036",
"chemical_list": "D000998:Antiviral Agents; D004338:Drug Combinations; C558899:lopinavir-ritonavir drug combination; D061466:Lopinavir; D019438:Ritonavir",
"country": "England",
"delete": false,
"doi": "10.1080/15563650.2020.1842882",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1556-3650",
"issue": "59(7)",
"journal": "Clinical toxicology (Philadelphia, Pa.)",
"keywords": "COVID-19; Lopinavir/ritonavir; SARS-CoV-2; case series; safety profile",
"medline_ta": "Clin Toxicol (Phila)",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000998:Antiviral Agents; D000086382:COVID-19; D004338:Drug Combinations; D016903:Drug Monitoring; D062787:Drug Overdose; D005260:Female; D054884:Host-Pathogen Interactions; D006801:Humans; D007010:Hyponatremia; D061466:Lopinavir; D008297:Male; D008875:Middle Aged; D061214:Patient Safety; D012189:Retrospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D019438:Ritonavir; D000086402:SARS-CoV-2; D013997:Time Factors; D016896:Treatment Outcome",
"nlm_unique_id": "101241654",
"other_id": null,
"pages": "644-647",
"pmc": null,
"pmid": "33641562",
"pubdate": "2021-07",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Safety and effectiveness concerns of lopinavir/ritonavir in COVID-19 affected patients: a retrospective series.",
"title_normalized": "safety and effectiveness concerns of lopinavir ritonavir in covid 19 affected patients a retrospective series"
} | [
{
"companynumb": "CA-B.BRAUN MEDICAL INC.-2109550",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "SODIUM CHLORIDE"
},
"drugadditional": ... |
{
"abstract": "BACKGROUND\nContrast-induced encephalopathy (CIE) is a well-known complication of iodinated contrast agents during angiography and vascular interventions. It can manifest as hemiparesis, cortical blindness, speech changes, Parkinsonism, confusion, seizure, and coma. Most of the reported CIE cases have been transient and reversible. Irreversible fatal CIE cases have been rarely reported. All the fatal CIE cases reported involved the use of ionic high osmolar contrast agents. Here, we document a heretofore unreported fatal CIE after digital subtraction angiography (DSA) using iopamidol, which is a type of non-ionic monomer low osmolar contrast agent.\n\n\nMETHODS\nA 71-year-old woman was admitted to our Department of Neurology for tinnitus in the head. The cerebral magnetic resonance angiography (MRA) detected atherosclerotic cerebral arteries and bilateral stenosis of the middle cerebral arteries. The patient underwent DSA for further diagnostic work-up. The total amount of iopamidol used during the procedure was 110 ml. The patient experienced headache during the procedure, followed by dizziness with nausea and vomiting. Despite treatment with anti-oedema medications, her clinical status was gradually deteriorating and ended up with deep coma due to irreversible cerebral oedema which was confirmed by cerebral computed tomography (CT). Finally, the patient died 56 days after the procedure due to irreversible fatal cerebral oedema.\n\n\nCONCLUSIONS\nThis report documents that iopamidol-induced encephalopathy may not always have a benign outcome and can result in irreversible fatal cerebral oedema.",
"affiliations": "Department of Neurology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, 250014, China.;Department of Neurology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, 250014, China.;Department of Neurology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, 250014, China.;Department of Neurology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, 250014, China.;Department of Neurology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, 250014, China.;Department of Neurology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, 250014, China.;Department of Neurology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, 250014, China.;Department of Neurology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, 250014, China.;Department of Neurology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, 250014, China. hanjujack@163.com.",
"authors": "Zhao|Wei|W|;Zhang|Jinping|J|;Song|Yun|Y|;Sun|Lili|L|;Zheng|Meimei|M|;Yin|Hao|H|;Zhang|Jun|J|;Wang|Wei|W|;Han|Ju|J|",
"chemical_list": "D003287:Contrast Media",
"country": "England",
"delete": false,
"doi": "10.1186/s12883-019-1279-5",
"fulltext": "\n==== Front\nBMC NeurolBMC NeurolBMC Neurology1471-2377BioMed Central London 127910.1186/s12883-019-1279-5Case ReportIrreversible fatal contrast-induced encephalopathy: a case report Zhao Wei weiwei5405sdu@163.com Zhang Jinping zhangjinping@sdhospital.com.cn Song Yun songyunjn@163.com Sun Lili sunlili1818@126.com Zheng Meimei 1986zhengminmin@163.com Yin Hao shenlan6869@163.com Zhang Jun zhangjunada@163.com Wang Wei wangoowei@163.com Han Ju +86 13791120710hanjujack@163.com 0000 0004 1761 1174grid.27255.37Department of Neurology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, 250014 China 28 3 2019 28 3 2019 2019 19 4613 12 2018 21 3 2019 © The Author(s). 2019Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nContrast-induced encephalopathy (CIE) is a well-known complication of iodinated contrast agents during angiography and vascular interventions. It can manifest as hemiparesis, cortical blindness, speech changes, Parkinsonism, confusion, seizure, and coma. Most of the reported CIE cases have been transient and reversible. Irreversible fatal CIE cases have been rarely reported. All the fatal CIE cases reported involved the use of ionic high osmolar contrast agents. Here, we document a heretofore unreported fatal CIE after digital subtraction angiography (DSA) using iopamidol, which is a type of non-ionic monomer low osmolar contrast agent.\n\nCase presentation\nA 71-year-old woman was admitted to our Department of Neurology for tinnitus in the head. The cerebral magnetic resonance angiography (MRA) detected atherosclerotic cerebral arteries and bilateral stenosis of the middle cerebral arteries. The patient underwent DSA for further diagnostic work-up. The total amount of iopamidol used during the procedure was 110 ml. The patient experienced headache during the procedure, followed by dizziness with nausea and vomiting. Despite treatment with anti-oedema medications, her clinical status was gradually deteriorating and ended up with deep coma due to irreversible cerebral oedema which was confirmed by cerebral computed tomography (CT). Finally, the patient died 56 days after the procedure due to irreversible fatal cerebral oedema.\n\nConclusions\nThis report documents that iopamidol-induced encephalopathy may not always have a benign outcome and can result in irreversible fatal cerebral oedema.\n\nKeywords\nDigital subtraction angiographyIodinated contrast agentsComplicationsContrast-induced encephalopathyissue-copyright-statement© The Author(s) 2019\n==== Body\nBackground\nContrast-induced encephalopathy (CIE) is a known but rare complication of angiography and endovascular interventions. The presentations may include hemiparesis, cortical blindness, speech changes, Parkinsonism, confusion, seizure, and coma [1, 2]. In most reported cases, the symptoms are reversible, and fatal encephalopathy following iodinated contrast administration has been rarely reported. Only 8 cases of autopsy-proven fatal cerebral oedema due to contrast neurotoxicity in the early stage of angiography have been reported [1, 3, 4]. All these reported fatal cases involved the use of high osmolar contrast agents. Iopamidol is a non-ionic monomer low osmolar contrast agent, which has been reported in cases of reversible contrast-induced encephalopathy [5–9]. Here, we describe a patient who suffered irreversible fatal encephalopathy after DSA using iopamidol.\n\nCase presentation\nA 71-year-old woman with a history of hypertension, hyperlipemia, and angina was admitted to our Department of Neurology for tinnitus in the head. On physical examination, bilateral hearing impairment was found. The cerebral magnetic resonance imaging (MRI) detected signal changes consisted with multiple cerebral infarctions and bilateral demyelination in the centrum semiovale. And the cerebral MRA detected atherosclerotic cerebral arteries and bilateral stenosis of the middle cerebral arteries (Fig. 1a, b). For further diagnosis, the patient underwent DSA subsequently. The total amount of iopamidol (Bracco Imaging Italia S.r.L.) administered during the procedure was 110 ml. The DSA showed that the patient had bilateral embryonic posterior cerebral arteries, 40% stenosis of the left middle cerebral artery and tortuous vertebral arteries bilaterally. There was no obvious calcification of the aortic arch; angiography of the arch using 25 ml iopamidol was performed only once. Ten minutes after the aortic arch angiography, the patient experienced mild headache. The pain was bearable, and the patient could cooperate during the remainder of the procedure. The DSA was completed 20 min later. No haemorrhage or vasospasm was detected during the procedure. The headache was continuous, and the patient suffered nausea and vomiting. The immediate physical examination showed no obvious abnormal sign. The patient was treated with 8 mg ramosetron and 10 mg dexamethasone. After 20 min of observation, the symptoms were relieved. Her cerebral CT scan at the time was normal (Fig. 2a, b, c). Two hours later, the patient manifested dizziness with nausea and vomiting and was treated with 8 mg ondansetron and 20 mg diphenhydramine. Meanwhile, compound sodium chloride injection was used to facilitate the elimination of the contrast agent. The treatment alleviated her symptoms. Four hours after the procedure, the patient re-experienced dizziness; thus 5 mg dexamethasone was administered but resulted in no alleviation until after 11 h wherein dizziness was relived but her blood pressure was 183/92 mmHg. The patient was drowsy but could answer questions correctly. The pupil were symmetric and reactive, and limb movements were preserved. To manage hypertension, 30 mg nimodipine tablets were used. Fourteen hours after the procedure, the patient fell asleep, but at 17 h, respiratory failure progressed and oxygen saturation dropped to 88%. The patient was in a coma state, with sighing respiration. Anisocoria with non-reactive pupils developed, limb drop test was positive along with flexor plantar and Babinski sign was negative. Therefore, cerebral hernia was considered. The patient was treated with 20% mannitol, nikethamide, lobeline and diprophylline, and was transferred to the intensive care unit for further treatment after cardio-pulmonary resuscitation, endotracheal intubation and mechanical ventilation. Two days after the procedure, cerebral CT scan indicated diffuse cerebral oedema, loss of grey-white differentiation, effacement of the cerebral sulci and decrease in cerebrospinal fluid space (Fig. 2d, e, f). The patient was treated with dehydration, mechanical ventilation, and anti-infectious agent, but the diffuse cerebral oedema did not improve. Nine days after the procedure, the third cerebral CT scan showed that the cerebral oedema had become much more severe, the ventricles had disappeared and there was hyperdense signal in the subarachnoid space, which was considered to be indicative of a pseudo-subarachnoid haemorrhage due to the severe cerebral oedema [10] (Fig. 2g, h, i). Fifteen days after the procedure, the cerebral CT scan detected unrelieved diffuse cerebral oedema, and the hyperdense signal in the subarachnoid space persisted (Fig. 2j, k, l). None of these cerebral CT scans showed intracerebral haemorrhage or infarct in this patient. The patient remained in a continuous deep coma state, and the brainstem reflexes had disappeared; she died 56 days after that sudden deterioration.Fig. 1 The cerebral MRA detected atherosclerotic cerebral arteries and bilateral stenosis of the middle cerebral arteries (a, b arrowheads), the stenosis of the left middle cerebral artery was serious\n\nFig. 2 Cerebral CT immediately after DSA did not indicate any obvious abnormal sign (a, b, c); 2 days after the procedure, a repeat cerebral CT revealed diffuse cerebral oedema, loss of grey-white differentiation, effacement of the cerebral sulci and decrease in cerebrospinal fluid space (d, e, f); 9 days after the procedure, the cerebral CT showed more severe diffuse oedema of the brain, loss of grey-white differentiation, effacement of the cerebral sulci and subarachnoid space, disappearance of the cerebral ventricles, enhancement of the subarachnoid space, and darkened brain tissue in Hounsfield units (g, h, i); 15 days after the procedure, the cerebral CT showed persistent diffuse oedema of the brain with effacement of the cerebral ventricles and sulci, darkened brain tissue in Hounsfield units, and enhancement of the subarachnoid space (j, k, l)\n\n\n\nDiscussion and conclusions\nThe prognosis of most CIE is generally reported to be good with a rapid recovery, and only rare cases with the persistent deficits have been reported [2]. Notably, there were 8 cases of autopsy-proven fatal cerebral oedema due to contrast neurotoxicity in the early stage of angiography [1, 3, 4]. The 8 deaths included 6 infants; 5 of these patients underwent cardiac angiography, and the other 3 received aortography. All fatal cerebral oedema cases reported involved the use of ionic high osmolar contrast agents, and ionic high osmolar contrast agents are no longer used in routine angiography and intervention procedures. The case which we report here may be the first fatal cerebral oedema after DSA using iopamidol. This case highlights the potential for other types of iodinated contrast agents to induce fatal encephalopathy.\n\nThe diagnosis of CIE is important, as its presentation may be similar to embolism, and haemorrhagic complications following angiography or endovascular interventions. Typical radiological findings include abnormal cortical contrast enhancement and cerebral oedema, subarachnoid contrast enhancement and striatal contrast enhancement [2, 11]. CT or MRI of the brain helps us to differentiate CIE from haemorrhage or infarct. In the case which we report here, none of the CT scans of the brain after DSA (immediately, 2 days, 9 days and 15 days after the procedure) indicated intracerebral haemorrhage or infarct. Therefore, the possibility of multiple embolisms was not considered in this case. The hyperdense signal in the subarachnoid space in the cerebral CT scans was considered to be due to the severe diffuse cerebral oedema. The hyperdense appearance results from a combination of loss of grey-white differentiation, narrowing and effacement of the subarachnoid spaces, and corresponding engorgement of superficial pial veins [10].\n\nThe patient experienced headache 10 minutes after the aortic arch angiography during the DSA procedure, and suffered nausea, vomiting and dizziness after the procedure. The symptoms were continuous, the patient was comatose at 17 h with respiratory failure. Anisocoria with non-reactive pupils developed, the limb drop test was positive, and Babinski sign was negative. All these symptoms supported the diffuse lesion of the brain, there was no sign of focal brain lesion. The cerebral CT scans detected diffuse unrelieved cerebral oedema after the severe deterioration. Therefore, cerebral hernia was considered due to severe cerebral oedema. The sudden respiratory failure was due to cerebral oedema leading to cerebral hernia. Hence the anoxic brain injury was not considered in this case. And the history, symptoms and cerebral CT scans did not support the diagnoses of secondary viral encephalitis, secondary cerebral vein thrombosis and metabolic causes.\n\nThe mechanism of CIE is controversial. The temporary disruption of the blood-brain barrier (BBB) after injection of the iodinated contrast agent is widely accepted [2, 11–15]. Experimental studies have demonstrated that contrast agents can penetrate the altered BBB and that this is dependent on the contact time, anions and dosage [1, 12, 13, 15]. Both the hyperosmolality and chemotoxicity of the contrast agents contribute to the disruption of the BBB. Hyperosmolality of the contrast medium is hypothesised to cause shrinkage of endothelial cells and disrupt tight junctions [12]. Other studies suggest that the alteration of the BBB is due to the physical or chemical effects of the contrast medium on the BBB instead of the hyperosmolality [14]. The expression of endothelin, which can be induced by radiocontrast agents, can increase human brain endothelial cell permeability and has been implicated in the pathophysiology of disorders associated with BBB injury [2, 15].\n\nStudies have indicated that opening of the BBB may be accompanied by brain oedema, resulting from the flux of proteins, electrolytes, and water across the abnormally permeable cerebral vessels into the extracellular space [4]. An idiosyncratic response to small doses of contrast agent, which may be related to the areas of incompleteness of their BBB, has been reported [1]. We postulate that the idiosyncratic response to contrast agents may have contributed to the patient’s prolonged and progressive brain oedema. Contrast agents can produce direct neurotoxic effects on the neurons and astrocytes when they penetrate the altered BBB. Experimental studies have shown that ionised contrast agents can severely alter neuronal function when directly introduced into the nervous system [1, 12, 13, 15]. We hypothesised that the direct neurotoxic effect of the contrast agent also contributed to the patient’s progressive and fatal brain oedema.\n\nAll types of iodinated contrast agents can induce the development of neurotoxicity, but the occurrence of fatal cerebral oedema is very rare. Unfortunately, there is no currently available effective treatment for such a severe fatal CIE. In the case reported by L. Junck and W.H. Marshall [4], the post mortem tissue iodine concentrations were the highest in the urine, serum and kidney. The use of continuous renal replacement therapy and continuous blood purification may be potential treatments for cases of fatal CIE.\n\nIn summary, although CIE has typically been associated with benign outcomes in previous studies, we present a case of fatal cerebral oedema after DSA using iopamidol. This case illustrates the potential to cause severe complications, even fatal cerebral oedema, with all types of iodinated contrast agents. The doctors performing angiography and interventions should be aware of this severe potentially harmful effect. The rare occurrence of severe contrast-induced complications renders their prevention very difficult. Further studies are needed to define the risk factors and the mechanism of the iodinated contrast agent neurotoxicity, which may help minimise the occurrence of severe complications.\n\nAbbreviations\nBBBBlood-brain barrier\n\nCIEContrast-induced encephalopathy\n\nCTComputed tomography\n\nDSADigital subtraction angiography\n\nMRAMagnetic resonance angiography\n\nMRIMagnetic resonance imaging\n\nAcknowledgements\nNone.\n\nFunding\nNone.\n\nAvailability of data and materials\nAll data generated and analysed during this study are included in this article.\n\nAuthors’ contributions\nWZ designed and wrote the manuscript. JPZ, YS, and LLS examined the patient. MMZ, HY, JZ and WW analysed the neuroimages. JH examined the patient, designed the case report and helped draft the manuscript. All authors read and approved the final manuscript.\n\nEthics approval and consent to participate\nThe Institutional Review Board of Qianfoshan Hospital affiliated to Shandong University approved the study.\n\nConsent for publication\nA signed informed consent was obtained from the patient’s guardian for publication of this case report and accompanying neuroimages.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Lalli AF Contrast media reactions: data analysis and hypothesis Radiology 1980 134 1 1 12 10.1148/radiology.134.1.6985735 6985735 \n2. Leong S Fanning NF Persistent neurological deficit from iodinated contrast encephalopathy following intracranial aneurysm coiling. A case report and review of the literature Interv Neuroradiol 2012 18 1 33 41 10.1177/159101991201800105 22440599 \n3. Shrivastava S Mohan JC Chopra P Fatal cerebral edema following angiocardiography: a case report Int J Cardiol 1985 8 4 490 491 10.1016/0167-5273(85)90127-5 4030150 \n4. Junck L Marshall WH Fatal brain edema after contrast-agent overdose AJNR Am J Neuroradiol 1986 7 3 522 525 3085459 \n5. Parry R Rees JR Wilde P Transient cortical blindness after coronary angiography Br Heart J 1993 70 6 563 564 10.1136/hrt.70.6.563 8280526 \n6. Kamata J Fukami K Yoshida H Mizunuma Y Moriai N Takino T Transient cortical blindness following bypass graft angiography. A case report Angiology 1995 46 10 937 946 10.1177/000331979504601009 7486215 \n7. Uchiyama Y Abe T Hirohata M Tanaka N Kojima K Nishimura H Blood brain-barrier disruption of nonionic iodinated contrast medium following coil embolization of a ruptured intracerebral aneurysm AJNR Am J Neuroradiol 2004 25 10 1783 1786 15569746 \n8. Gellen B Remp T Mayer T Milz P Franz WM Cortical blindness: a rare but dramatic complication following coronary angiography Cardiology 2003 99 1 57 59 10.1159/000068443 12589125 \n9. Merchut MP Richie B Transient visuospatial disorder from angiographic contrast Arch Neurol 2002 59 5 851 854 10.1001/archneur.59.5.851 12020271 \n10. Hasan TF Duarte W Akinduro OO Goldstein ED Hurst R Haranhalli N Nonaneurysmal \"pseudo-subarachnoid hemorrhage\" computed tomography patterns: challenges in an acute decision-making heuristics J Stroke Cerebrovasc Dis 2018 27 9 2319 2326 10.1016/j.jstrokecerebrovasdis.2018.04.016 29884521 \n11. Lantos G Cortical blindness due to osmotic disruption of the blood-brain barrier by angiographic contrast material: CT and MRI studies Neurology 1989 39 4 567 571 10.1212/WNL.39.4.567 2927682 \n12. Junck L Marshall WH Neurotoxicity of radiological contrast agents Ann Neurol 1983 13 5 469 484 10.1002/ana.410130502 6347033 \n13. Torvik A Walday P Neurotoxicity of water-soluble contrast media Acta Radiol Suppl 1995 399 221 229 10.1177/0284185195036S39927 8610520 \n14. Wilson AJ Evill CA Sage MR Effects of nonionic contrast media on the blood-brain barrier. Osmolality versus chemotoxicity Investig Radiol 1991 26 12 1091 1094 10.1097/00004424-199112000-00012 1765444 \n15. Heyman SN Clark BA Kaiser N Spokes K Rosen S Brezis M Radiocontrast agents induce endothelin release in vivo and in vitro J Am Soc Nephrol 1992 3 1 58 65 1391709\n\n",
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"abstract": "A 30-year-old woman underwent laparotomy and was placed on a seven-day course of metronidazole and ampicillin postoperatively. Chloroquine therapy for malaria was instituted on the sixth day and the patient developed acute dystonic reactions after a single dose. Diphenhydramine therapy before chloroquine administration did not prevent the development of the dystonic reactions. The extrapyramidal symptoms subsided upon diazepam administration and chloroquine withdrawal even though metronidazole therapy was continued. The mechanism of this adverse drug reaction based on the pharmacodynamic interaction between chloroquine and metronidazole is discussed. It is suggested that the combination of pyrimethamine and sulfadoxine be used in place of chloroquine for malaria chemotherapy in patients on metronidazole therapy.",
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"abstract": "We evaluated a 39-year-old pregnant woman with right temporal lobe epilepsy. During the second trimester, seizure deterioration was responsive to an increased daily dose of levetiracetam (LEV). However, immediately after delivery, new non-habitual seizures emerged along with a sharply increased LEV concentration. The frequency of habitual seizures also slightly increased. The non-habitual seizures completely disappeared, and the frequency of the habitual seizures improved to the baseline level after the LEV dosage was reduced. Thus, a paradoxical effect of an increased LEV blood concentration was assumed to be a potential cause of these events. Peripartum pharmacokinetic fluctuations in LEV levels should be monitored carefully.",
"affiliations": "Department of Clinical Neuroscience and Therapeutics, Hiroshima University Graduate School of Biomedical and Health Sciences, Japan.;Department of Clinical Neuroscience and Therapeutics, Hiroshima University Graduate School of Biomedical and Health Sciences, Japan.;Department of Clinical Neuroscience and Therapeutics, Hiroshima University Graduate School of Biomedical and Health Sciences, Japan.;Department of Clinical Neuroscience and Therapeutics, Hiroshima University Graduate School of Biomedical and Health Sciences, Japan.;Department of Clinical Neuroscience and Therapeutics, Hiroshima University Graduate School of Biomedical and Health Sciences, Japan.;Epilepsy Center, Hiroshima University Hospital, Japan.;Department of Clinical Neuroscience and Therapeutics, Hiroshima University Graduate School of Biomedical and Health Sciences, Japan.",
"authors": "Kikumoto|Mai|M|;Neshige|Shuichiro|S|;Shishido|Takeo|T|;Ueno|Hiroki|H|;Aoki|Shiro|S|;Iida|Koji|K|;Maruyama|Hirofumi|H|",
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"fulltext": "\n==== Front\nIntern Med\nIntern Med\nInternal Medicine\n0918-2918\n1349-7235\nThe Japanese Society of Internal Medicine\n\n34615824\n10.2169/internalmedicine.8173-21\nCase Report\nSeizure Deterioration with Increased Levetiracetam Blood Concentration during the Postpartum Period in Refractory Temporal Lobe Epilepsy\nKikumoto Mai 1\nNeshige Shuichiro 12\nShishido Takeo 123\nUeno Hiroki 124\nAoki Shiro 1\nIida Koji 25\nMaruyama Hirofumi 12\n1 Department of Clinical Neuroscience and Therapeutics, Hiroshima University Graduate School of Biomedical and Health Sciences, Japan\n2 Epilepsy Center, Hiroshima University Hospital, Japan\n3 Department of Neurology, Hiroshima City Asa Citizens Hospital, Japan\n4 Department of Neurology, Hiroshima City Hiroshima Citizens Hospital, Japan\n5 Department of Neurosurgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, Japan\nCorrespondence to Dr. Shuichiro Neshige, s-neshige@hiroshima-u.ac.jp\n\n5 10 2021\n15 4 2022\n61 8 12371240\n18 6 2021\n17 8 2021\nCopyright © 2022 by The Japanese Society of Internal Medicine\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ The Internal Medicine is an Open Access journal distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (https://creativecommons.org/licenses/by-nc-nd/4.0/).\nWe evaluated a 39-year-old pregnant woman with right temporal lobe epilepsy. During the second trimester, seizure deterioration was responsive to an increased daily dose of levetiracetam (LEV). However, immediately after delivery, new non-habitual seizures emerged along with a sharply increased LEV concentration. The frequency of habitual seizures also slightly increased. The non-habitual seizures completely disappeared, and the frequency of the habitual seizures improved to the baseline level after the LEV dosage was reduced. Thus, a paradoxical effect of an increased LEV blood concentration was assumed to be a potential cause of these events. Peripartum pharmacokinetic fluctuations in LEV levels should be monitored carefully.\n\nfocal impaired awareness seizure\nlevetiracetam\npregnancy\n==== Body\npmcIntroduction\n\nLevetiracetam (LEV) often exhibits dramatic pharmacokinetic fluctuations due to the glomerular filtration rate change during the peripartum period (1). Thus, patients with epilepsy require titration of the LEV dose during pregnancy because of the increased renal excretion.\n\nWe encountered a patient with epilepsy who continued to take high-dose LEV after delivery, resulting in postpartum seizure exacerbation. This event was considered to have been associated with elevated serum LEV concentrations after delivery. One of the potential underlying mechanisms included not only adverse effects but also a paradoxical effect (PE) caused by the elevation of the LEV concentration (2).\n\nContinuing to take the high-dose LEV after delivery can lead to a postpartum increase in the serum concentration and may risk seizure exacerbation.\n\nCase Report\n\nA 39-year-old right-handed pregnant woman with medically refractory mesial temporal lobe epilepsy (MTLE) visited our hospital during the sixth week of gestation to manage her seizures. She had experienced natural childbirth once before the first visit. She had no history of any initial precipitating injury, such as febrile seizure. Her familial history of epilepsy was negative.\n\nShe had suffered from focal aware non-motor seizures (FNMS) characterized by fatigue lasting for less than a minute 8 times a month since she was 34 years old. There were no other forms of FNMS that were related to the temporal region, such as fear, auditory or olfactory hallucinations, or an epigastric rising sensation. Her FNMS was occasionally followed by loss of awareness, i.e. focal impaired awareness seizures (FIAS) accompanied by oral automatism, and lasted for less than a minute every week. She had never experienced any generalized seizures.\n\nNeurological abnormalities were negative except for her left emotional facial paresis (3). Blood examinations, which included autoimmune-related parameters (anti-nuclear antibody, anti-neutrophil cytoplasmic antibody, anti-SS-A/B antibody, and antithyroid antibody, or anti-GAD antibody), were negative. An interictal electroencephalogram (EEG) revealed repetitive temporal spikes on the right (T2 and A2 max in the amplitude) (Fig. 1). There was no induction of a paroxysmal photic response, and magnetic resonance imaging (MRI) did not reveal any hippocampal sclerosis. A subsequent ictal EEG showed that her habitual seizures arose from the right temporal region. Thus, she was diagnosed with right MTLE.\n\nFigure 1. An interictal electroencephalogram (EEG) recorded before the pregnancy. Continuous repetitive spikes are visible in the right anterior to basal temporal regions every second during the drowsy state (yellow arrowheads).\n\nThe patient was able to avoid any seizure deterioration during the first trimester by continuing her LEV (2,500 mg/day) and lacosamide (LCM; 200 mg/day) treatments that had been administered prior to her pregnancy (Fig. 2). However, the FIAS frequency gradually increased from 4 times a month to 7 times a month during the second trimester (20th week of pregnancy). Given her body weight, the number of weeks of gestation, and the potential decrease in the LEV blood concentration, we increased the LEV dosage to 3,000 mg/day. This titration subsequently decreased the seizure frequency to the same level as before the second trimester, with the LEV blood concentration reaching 39.5 μg/mL at 3 weeks after the titration.\n\nFigure 2. Clinical course, including the peripartum period. The clinical courses of habitual seizures (FNMS and FIAS) and non-habitual seizures are illustrated. Bars indicate the frequency of each type of seizure, and the numbers in the bars indicate the frequency per month. The line graphs indicate changes in the body weight and blood concentration of the antiepileptic drugs during the peripartum period. Due to the long duration between the first and second examinations of the LEV blood concentration, the concentration changes during this period are shown by a red dashed line. FIAS: focal impaired awareness seizure, FNMS: focal aware non-motor seizure, LEV: levetiracetam, LCM: lacosamide\n\nShe gave birth to her child through normal labor at term (36 weeks) in a different hospital. The child was healthy with a normal condition. The patient continued to take her anti-epilepsy drugs (AEDs) at the same dose level even after delivery.\n\nHowever, within a few days after delivery, a new non-habitual seizure characterized by a sense of rotation lasting for ten seconds appeared. The frequency of FIAS also slightly increased to more than four times a month. Conversely, as this was her second childbirth, she exhibited no marked fatigue, depression, or stress during the postpartum period. Thus, she revisited our hospital.\n\nAt the time of this visit (36 days after delivery), the serum LEV concentration had reached 61.7 μg/mL. The non-habitual seizure completely disappeared after reducing the LEV daily dosage (Fig. 2). Follow-up EEG showed no epileptic discharges. The LCM concentration remained stable during the pregnancy.\n\nDiscussion\n\nThe present case with MRI-negative medically refractory right MTLE showed the emergence of new non-habitual seizures after delivery under the high-dose administration of LEV. The non-habitual seizures immediately disappeared after decreasing the dose. Given the clinical course of seizure and LEV blood concentration, this event was likely to be associated with a postpartum elevation of the LEV blood concentration that was attributed to the continuation of the high-dose LEV even after delivery. Thus, PE related to the elevated LEV concentration can be a potential factor causing habitual seizure frequency increase and a new non-habitual seizure appearance, as previously reported (2,4,5).\n\nIt should be noted that LEV can also cause a sense of rotation as an adverse event (6), similar to that observed with non-habitual seizures. This makes it difficult to discriminate between new non-habitual seizures and side effects of LEV. However, several facts supported the possibility of PE in the present case. First, although the sense of rotation might have been an adverse event of LEV, other typical adverse events of LEV, such as drowsiness, were absent in the present case. In addition, the duration of the sense of rotation was comparable to that seen in epileptic focal seizures (7). Second, while the sense of rotation emerged, the frequency of habitual seizures also slightly increased, suggesting that the epileptic condition had deteriorated. Finally, the semiology of non-habitual seizures was also comparable to that of epileptic seizures arising from the lateral temporal region (8).\n\nThe habitual FNMS in the present case was consistent with seizures that originated from the mesial temporal lobe. The location of epileptic discharges in the ictal and interictal EEG was also consistent with this diagnosis. In contrast, the non-habitual seizure was characterized by a sense of rotation in the horizontal plane around the patient's body axis, or Yaw plane illusions. The superior and mid temporal gyri, the opercular region, and parietal lobe are potentially responsible regions (8). The interictal epileptic discharge was prominent in the right anterior temporal region (T2); however, the lateral temporal region (T4 and T6) was also involved. These findings suggested that the epileptogenic lesion included a broad area that was centered at the temporal lobe, with the mesial temporal region having the lowest seizure threshold within the area, i.e. the seizure onset zone. The superior temporal cortex and surrounding cortices likely had the second-lowest threshold, i.e. probably the irritative zone (11). Thus, PE might reduce the seizure threshold of these areas which thus results in the non-habitual seizure being subsequently generated from the irritative zone, which normally does not generate a seizure with the LEV blood concentration at the appropriate level.\n\nUnderstanding the peripartum pharmacodynamics of LEV is essential to clarify the relationship between the blood concentration of LEV and the timing of the event. LEV has a broad spectrum for seizure types among patients with epilepsy, including pregnant patients (1,9). However, the LEV serum concentration fluctuates during the perinatal period. LEV is primarily eliminated through renal excretion (1,10). Since the glomerular filtration rate increases by approximately 50% during pregnancy, the serum concentration can be 40% of the baseline value, thereby resulting in a marked decrease in the serum concentration/dose (C/D) ratio (1). Within the first two weeks after delivery, the C/D ratio immediately increases to the baseline level. As the present patient continued to take high-dose LEV throughout the second trimester and during the postpartum period, there may have been a sharp increase in the LEV serum concentration after delivery due to the reduced renal LEV clearance.\n\nAlthough the present patient reported no substantial increase in postpartum stress, several peripartum factors can influence one's seizure control, e.g. hormone levels and breast vs. formula feeding.\n\nThe present case with MTLE exhibited a new non-habitual seizure immediately after delivery. Her clinical course suggested that the continuation of LEV at the same dose before and after delivery dramatically increased the blood LEV concentration, thereby potentially leading to a deteriorated seizure condition. Therefore, clinicians should keep managing seizures carefully after delivery, depending on peripartum metabolic changes in patients with epilepsy. Inter-departmental cooperation is also critical in such cases.\n\nThe authors state that they have no Conflict of Interest (COI).\n==== Refs\n1. Westin AA , Reimers A , Helde G , Nakken KO , Brodtkorb E . Serum concentration/dose ratio of levetiracetam before, during and after pregnancy. Seizure 17 : 192-198, 2008.18180176\n2. Nakken KO , Eriksson AS , Lossius R , Johannessen SI . A paradoxical effect of levetiracetam may be seen in both children and adults with refractory epilepsy. Seizure 12 : 42-46, 2003.12495648\n3. Ross RT , Mathiesen R . Volitional and emotional supranuclear facial weakness. N Engl J Med 338 : 1515, 1998.9593790\n4. Szucs A , Clemens Z , Jakus R , et al . The risk of paradoxical levetiracetam effect is increased in mentally retarded patients. Epilepsia 49 : 1174-1179, 2008.18479387\n5. Elger CE , Bauer J , Scherrmann J , Widman G . Aggravation of focal epileptic seizures by antiepileptic drugs. Epilepsia 39 : S15-S18, 1998.9593231\n6. Thacker AK , Misra P , Gupta PP . Exacerbations of seizures by levetiracetam. Epilepsia 49 : 177, 2008.\n7. Cook MJ , Karoly PJ , Freestone DR , et al . Human focal seizures are characterized by populations of fixed duration and interval. Epilepsia 57 : 359-368, 2016.26717880\n8. Kahane P , Hoffmann D , Minotti L , Berthoz A . Reappraisal of the human vestibular cortex by cortical electrical stimulation study. Ann Neurol 54 : 615-624, 2003.14595651\n9. Cereghino JJ , Biton V , Abou-Khalil B , et al . Levetiracetam for partial seizures: results of a double-blind, randomized clinical trial. Neurology 55 : 236-242, 2000.10908898\n10. Wright C , Downing J , Mungall D , et al . Clinical pharmacology and pharmacokinetics of levetiracetam. Front Neurol 4 : 1-6, 2013.23355832\n11. Lüders HO , Najm I , Nair D , Widdess-Walsh P , Bingman W . The epileptogenic zone: general principles. Epileptic Disord 8 : S1-S9, 2006.17012067\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0918-2918",
"issue": null,
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": "focal impaired awareness seizure; levetiracetam; pregnancy",
"medline_ta": "Intern Med",
"mesh_terms": null,
"nlm_unique_id": "9204241",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34615824",
"pubdate": "2021-10-05",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Seizure Deterioration with Increased Levetiracetam Blood Concentration During the Postpartum Period in Refractory Temporal Lobe Epilepsy.",
"title_normalized": "seizure deterioration with increased levetiracetam blood concentration during the postpartum period in refractory temporal lobe epilepsy"
} | [
{
"companynumb": "JP-ACI HealthCare Limited-2122249",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "LEVETIRACETAM"
},
"drugadditional": "... |
{
"abstract": "Background: The clinical presentation of hereditary spherocytosis varies from no symptoms to severe hemolytic anemia requiring splenectomy. Splenectomy imposes the risk of hypercoagulability and acute pulmonary embolism. Catheter-directed thrombolysis is an established treatment for submassive pulmonary embolism in adults. However, the literature regarding its use in children is limited. Case Report: We present the case of a 12-year-old male with hereditary spherocytosis who was diagnosed with pulmonary embolism and successfully treated with catheter-directed thrombolysis. The patient was initially treated with 10.5 mg of recombinant tissue plasminogen activator (r-tPA) delivered over 8 hours. However, because of minimal clinical and hemodynamic improvement, a second course of thrombolytic was administered for an additional 24 hours (25 mg of r-tPA), and the treatment resulted in marked clinical and hemodynamic improvement. Clot resolution was confirmed via angiography. The patient was discharged on enoxaparin and with regular follow-up. One year later, the patient was asymptomatic on enoxaparin. Conclusion: This case demonstrates that catheter-based treatment of submassive pulmonary embolism restores hemodynamic stability and thus is an alternative to surgery or systemic thrombolysis, even in the pediatric setting. While catheter-directed thrombolysis is a safe and effective alternative to systemic thrombolysis, further research is needed to establish appropriate dosing and indications in the adolescent population.",
"affiliations": "Department of Internal Medicine, Wayne State University School of Medicine, Detroit Medical Center Heart Hospital, Detroit, MI.;Department of Interventional Cardiology, Wayne State University School of Medicine, Detroit Medical Center, Detroit MI.;Department of Interventional Cardiology, Wayne State University School of Medicine, Detroit Medical Center, Detroit MI.;Department of Cardiology, Wayne State University School of Medicine, Children's Hospital of Michigan, Detroit, MI.;Department of Cardiology, Wayne State University School of Medicine, Children's Hospital of Michigan, Detroit, MI.;Department of Interventional Cardiology, Ascension St. John Hospital, Detroit, MI.;Department of Interventional Cardiology, Wayne State University School of Medicine, Detroit Medical Center, Detroit MI.;Department of Interventional Cardiology, Wayne State University School of Medicine, Detroit Medical Center, Detroit MI.;Department of Interventional Cardiology, Ascension St. John Hospital, Detroit, MI.",
"authors": "Kajy|Marvin|M|;Blank|Nimrod|N|;Alraies|M Chadi|MC|;Akam-Venkata|Jyothsna|J|;Aggarwal|Sanjeev|S|;Kaki|Amir|A|;Mohamad|Tamam|T|;Elder|Mahir|M|;Schreiber|Theodore|T|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.31486/toj.18.0147",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1524-5012",
"issue": "19(3)",
"journal": "The Ochsner journal",
"keywords": "Endovascular procedures; mechanical thrombolysis; pulmonary embolism; spherocytosis–hereditary; thrombolytic therapy; tissue plasminogen activator; vascular access devices",
"medline_ta": "Ochsner J",
"mesh_terms": null,
"nlm_unique_id": "101125795",
"other_id": null,
"pages": "264-270",
"pmc": null,
"pmid": "31528140",
"pubdate": "2019",
"publication_types": "D002363:Case Reports",
"references": "10227218;10608028;14517746;15262836;15480387;15635472;16020800;17854065;18940465;19373154;19388926;19919804;20696966;21422387;22961946;24226805;24698774;24716681;24917641;25524824;25704224;25856269;26315743;27051541;28811305;28882336;29248101;29270396;30025734;352100",
"title": "Treatment of a Child With Submassive Pulmonary Embolism Associated With Hereditary Spherocytosis Using Ultrasound-Assisted Catheter-Directed Thrombolysis.",
"title_normalized": "treatment of a child with submassive pulmonary embolism associated with hereditary spherocytosis using ultrasound assisted catheter directed thrombolysis"
} | [
{
"companynumb": "US-ROCHE-2459274",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ALTEPLASE"
},
"drugadditional": null,
"druga... |
{
"abstract": "Dupilumab is a relatively new and quite effective medication for recalcitrant atopic dermatitis in patients over 6 years of age. Here, we present a 12-year-old girl with progressively worsening episodic facial swelling and erythema while treated with dupilumab. This case highlights the possibility of angioedema as an adverse effect of dupilumab treatment.",
"affiliations": "Department of Dermatology, University of North Carolina, Chapel Hill, NC, USA.;Department of Dermatology, University of North Carolina, Chapel Hill, NC, USA.;Department of Dermatology, University of North Carolina, Chapel Hill, NC, USA.",
"authors": "Fritz|Andrea L|AL|https://orcid.org/0000-0003-1222-9913;Lacy|Frank A|FA|;Morrell|Dean S|DS|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; C582203:dupilumab",
"country": "United States",
"delete": false,
"doi": "10.1111/pde.14434",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0736-8046",
"issue": "38(1)",
"journal": "Pediatric dermatology",
"keywords": "angioedema; atopic dermatitis; biologic; drug reaction; dupilumab",
"medline_ta": "Pediatr Dermatol",
"mesh_terms": "D000799:Angioedema; D061067:Antibodies, Monoclonal, Humanized; D002648:Child; D003876:Dermatitis, Atopic; D004485:Eczema; D005260:Female; D006801:Humans",
"nlm_unique_id": "8406799",
"other_id": null,
"pages": "237-238",
"pmc": null,
"pmid": "33099796",
"pubdate": "2021-01",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Angioedema: A potential complication of dupilumab in atopic dermatitis.",
"title_normalized": "angioedema a potential complication of dupilumab in atopic dermatitis"
} | [
{
"companynumb": "US-SA-2020SA308461",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "DUPILUMAB"
},
"drugadditional": "1",
"drug... |
{
"abstract": "The introduction of biological agents, especially the tumor necrosis factor inhibitors (anti-TNF), for the treatment of rheumatic diseases increased the risk of developing tuberculosis (TB). Screening for latent TB infection (LTBI) is strongly recommended before starting therapy with anti-TNF agents. The objective of this study was to identify the prevalence of LTBI and TB among patients with rheumatic diseases on anti-TNF agents. This is a cross-sectional study. The electronic medical records of all adult patients (≥18 years old) undergoing anti-TNF treatment were reviewed. Every patient underwent tuberculin skin test (TST) before starting anti-TNF treatment. In total, 176 patients were included; the mean age was 51.9 ± 12.4 years, 34.7% were males, and 90.9% were white. The underlying diseases were rheumatoid arthritis (RA) in 50.6% (N = 89), ankylosing spondylitis (AS) in 27.8% (N = 49), and psoriatic arthritis (PsA) in 17.6% (N = 31). The prevalence of positive TST was 29.5%. Household contact with TB was significantly associated with a positive TST (p = 0.020). RA patients had lower TST reactions than AS patients (p = 0.022). There were six cases of TB (3.4%) diagnosed during anti-TNF therapy. We demonstrated a high prevalence of positive TST (29.5%) among patients with rheumatic diseases in a region with high TB prevalence. Our data corroborates the ACR's recommendation that patients who live in high TB incidence settings should be tested annually for LTBI.",
"affiliations": "Programa de Pós-Graduação em Ciências Pneumológicas, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.;Rhematology Division, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil.;Faculdade de Medicina, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.;Faculdade de Medicina, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.;Rhematology Division, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil.;Rhematology Division, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil.;Programa de Pós-Graduação em Ciências Pneumológicas, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil. denise.rossato@terra.com.br.",
"authors": "Garziera|Giovana|G|;Morsch|André Luis Bittencourt|ALB|;Otesbelgue|Felipe|F|;Staub|Fernanda Luiza|FL|;Palominos|Penélope Esther|PE|;Brenol|Claiton Viegas|CV|;Silva|Denise Rossato|DR|",
"chemical_list": "D001688:Biological Products; D014409:Tumor Necrosis Factor-alpha",
"country": "Germany",
"delete": false,
"doi": "10.1007/s10067-017-3714-6",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0770-3198",
"issue": "36(8)",
"journal": "Clinical rheumatology",
"keywords": "Anti-TNF therapy; Latent tuberculosis; Mantoux; Mycobacterium tuberculosis; Rheumatoid arthritis; Tuberculin skin test; Tumor necrosis factor-alpha",
"medline_ta": "Clin Rheumatol",
"mesh_terms": "D000328:Adult; D001688:Biological Products; D003430:Cross-Sectional Studies; D005260:Female; D006801:Humans; D055985:Latent Tuberculosis; D008297:Male; D008875:Middle Aged; D012216:Rheumatic Diseases; D014374:Tuberculin Test; D014376:Tuberculosis; D014409:Tumor Necrosis Factor-alpha",
"nlm_unique_id": "8211469",
"other_id": null,
"pages": "1891-1896",
"pmc": null,
"pmid": "28589321",
"pubdate": "2017-08",
"publication_types": "D016428:Journal Article",
"references": "24725559;18025446;19918635;2261703;24707285;22858451;18723065;22021896;19407047;24608401;11396095;16100342;21412605;15986370;17417991;18795393;19017449;22473917;23103667;25199003;22863801;12858438;21273108;6430250;21846592;22782640;16572442;17309133;24930647;24790412",
"title": "Latent tuberculosis infection and tuberculosis in patients with rheumatic diseases treated with anti-tumor necrosis factor agents.",
"title_normalized": "latent tuberculosis infection and tuberculosis in patients with rheumatic diseases treated with anti tumor necrosis factor agents"
} | [
{
"companynumb": "BR-JNJFOC-20170809583",
"fulfillexpeditecriteria": "1",
"occurcountry": "BR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "INFLIXIMAB"
},
"drugadditional": "3",
"... |
{
"abstract": "Giant cell myocarditis is a rare but often devastating diagnosis. Advances in cardiac imaging and mechanical circulatory support have led to earlier and more frequent diagnoses and successful management. This disease state has wide variation in acuity of presentation, and consequently, optimal treatment ranging from intensity and type of immunosuppression to mechanical circulatory support is not well defined. The following case describes the management of a patient with an unusual presentation of giant cell myocarditis over a 10 year course of advanced heart failure therapies and immunomodulatory support. This case highlights emerging concepts in the management of giant cell myocarditis including sub-acute presentations, challenges in diagnosis, and treatment modalities in the modern era.",
"affiliations": "Department of Pharmacy, Cleveland Clinic, Cleveland, OH.;Division of Cardiology, University of Florida Health, Gainesville, FL, USA.;Department of Pharmacy, University of Virginia Health System, Charlottesville, VA, USA.;Division of Cardiology, University of California San Francisco, San Francisco, CA, USA.",
"authors": "Fallon|Julianne M|JM|;Parker|Alex M|AM|;Dunn|Steven P|SP|;Kennedy|Jamie L W|JLW|",
"chemical_list": "D007166:Immunosuppressive Agents",
"country": "England",
"delete": false,
"doi": "10.1002/ehf2.12564",
"fulltext": "\n==== Front\nESC Heart Fail\nESC Heart Fail\n10.1002/(ISSN)2055-5822\nEHF2\nESC Heart Failure\n2055-5822 John Wiley and Sons Inc. Hoboken \n\n10.1002/ehf2.12564\nEHF212564\nESCHF-19-00173\nCase Report\nCase Report\nA giant mystery in giant cell myocarditis: navigating diagnosis, immunosuppression, and mechanical circulatory support\nA giant mystery in giant cell myocarditis: navigating diagnosis, immunosuppression, and mechanical circulatory supportJ.M. Fallon et al.Fallon Julianne M. \n1\nfallonjmb@gmail.com Parker Alex M. \n2\n Dunn Steven P. \n3\n Kennedy Jamie L.W. \n4\n \n1 \nDepartment of Pharmacy\nCleveland Clinic\nCleveland\nOH\n\n\n2 \nDivision of Cardiology\nUniversity of Florida Health\nGainesville\nFL\nUSA\n\n\n3 \nDepartment of Pharmacy\nUniversity of Virginia Health System\nCharlottesville\nVA\nUSA\n\n\n4 \nDivision of Cardiology\nUniversity of California San Francisco\nSan Francisco\nCA\nUSA\n\n* \nCorrespondence to: Julianne M. Fallon, Department of Pharmacy, Cleveland Clinic, 9500 Euclid Ave. (HB‐105), Cleveland, OH 44195, USA.\n\nEmail: fallonjmb@gmail.com\n\n24 12 2019 \n2 2020 \n7 1 10.1002/ehf2.v7.1315 319\n16 7 2019 02 10 2019 04 11 2019 © 2019 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.Abstract\nGiant cell myocarditis is a rare but often devastating diagnosis. Advances in cardiac imaging and mechanical circulatory support have led to earlier and more frequent diagnoses and successful management. This disease state has wide variation in acuity of presentation, and consequently, optimal treatment ranging from intensity and type of immunosuppression to mechanical circulatory support is not well defined. The following case describes the management of a patient with an unusual presentation of giant cell myocarditis over a 10 year course of advanced heart failure therapies and immunomodulatory support. This case highlights emerging concepts in the management of giant cell myocarditis including sub‐acute presentations, challenges in diagnosis, and treatment modalities in the modern era.\n\nGiant cell myocarditismechanical circulatory supportimmunosuppression source-schema-version-number2.0cover-dateFebruary 2020details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:5.7.8 mode:remove_FC converted:20.03.2020\n\n\nFallon , J. M. \n, \nParker , A. M. \n, \nDunn , S. P. \n, and \nKennedy , J. L. W. \n (2020 ) A giant mystery in giant cell myocarditis: navigating diagnosis, immunosuppression, and mechanical circulatory support\n. ESC Heart Failure , 7 : 315 –319\n. 10.1002/ehf2.12564 .\n==== Body\n1 Introduction\nGiant cell myocarditis (GCM) is a rare, incompletely understood disease. Severe, rapidly progressive heart failure in young to middle‐aged adults characterizes the most frequently reported presentation of GCM.1 Prognostic differences have been suggested on the basis of initial presentation of myocarditis, with patients in fulminant myocarditis and histologically proven GCM both highly associated with short‐term mortality.2 Early reports of GCM demonstrated survival rates around 5 1/2 months after diagnosis; however, modern reports have shown 5 year survival free from death or heart transplant of 52–72% with immunosuppression.3, 4, 5 Some patients respond to immunosuppression; many require transplantation for long‐term survival.4 Increased use of mechanical circulatory support (MCS) over the past decade has played a pivotal role in improving survival and time to transplant. The optimal balance between immunosuppression, MCS, and heart transplant has not been fully elucidated in GCM. The following case describes an atypical presentation of GCM managed with a combination of immunosuppression, left ventricular assist device (LVAD), and eventually orthotopic heart transplantation (OHT).\n\n2 Case report\nA 54‐year‐old Caucasian woman presented with symptoms of chest tightness, palpitations, and non‐sustained ventricular tachycardia (VT). Her past medical history was significant for supraventricular tachycardia; she took no prescription medications and lived in an area with high prevalence of tick‐borne illnesses. Cardiovascular family history included heart failure (mother) and supraventricular tachycardia (daughter). Her physical examination was notable for clear lungs and no jugular venous distension, gallops, or murmurs. Vitals included a heart rate of 68 beats per minute, blood pressure of 100/60 mmHg, height of 64 inches, and weight of 62.5 kg. Her admission electrocardiogram showed biventricular bigeminy and Q waves in leads V1 and V2. Her labs were normal except for B‐type natriuretic peptide of 237 pg/mL (reference range < 100 pg/mL) and troponin I 0.16 ng/mL (reference range < 0.08 ng/mL). Transthoracic echocardiogram demonstrated normal biventricular function, mild mitral regurgitation, mild pulmonary hypertension, and an estimated left ventricular ejection fraction (LVEF) of 60%. Coronary angiography revealed no coronary disease, and she was discharged on metoprolol, lisinopril, and mexiletine.\n\nShe was admitted three times the following year for VT with persistently elevated troponin levels (0.12–0.42 ng/mL). Her LVEF had declined to 30–35%, and a dual chamber implantable cardioverter‐defibrillator was implanted. Cardiac magnetic resonance imaging found subepicardial hyper‐enhancement along the mid‐anterior wall of the left ventricle compatible with myocarditis and LVEF of 32.8% (Figure\n1). Her metoprolol was increased on discharge.\n\nFigure 1 Cardiac magnetic resonance imaging. (A) Mid short axis late gadolinium enhancement (LGE) image. (B) Two‐chamber LGE image. There is a distinctive pattern of diffusely located “patchy” transmural delayed hyper‐enhancement compatible with infiltrative cardiomyopathy and fibrosis of the left ventricle. This pattern is not indicative of ischaemic cardiomyopathy. There is subepicardial LGE along the mid‐anterior wall, which can be seen in myocarditis.\n\nShe was referred to an academic medical center for endomyocardial biopsy, which showed inflammatory findings thought to be most consistent with Lyme carditis, staining for amyloid was unrevealing (Figure\n2). Serologies for Lyme disease were negative. Treatment consisted of doxycycline, corticosteroid taper, and mycophenolate mofetil. A depiction of pharmacological therapy received during the patient's course is summarized in Figure 3. She had gradual improvement in LVEF that correlated with corticosteroid treatment and declined when corticosteroids were stopped. Despite treatment, her clinical status declined with recurrent heart failure admissions requiring inotropes, inability to tolerate evidence‐based medical therapy, worsening LVEF, and recurrent VT, leading to consideration of advanced heart failure therapies.\n\nFigure 2 Endomyocardial biopsy. (A) High‐power hematoxyylin and eosin (H&E) stained image showing markedly damaged myocardium with intermyocyte fibrosis and a diffuse infiltrate of lymphocytes. (B) High‐power H&E stained image showing a capillary surrounded with lymphocytic infiltrate. (C) Low power H&E stained image showing endocardium with a predominantly lymphocytic infiltrate. Black arrows indicate lymphocytic infiltrate and white arrows indicate damaged myocardium.\n\nFigure 3 Timeline of case report showing LVEF over the 10 year follow‐up, treatment regimens, and time of LVAD and OHT relative to initial presentation. ATG, anti‐thymocyte globulin; IVIG, intravenous immunoglobulin; LVAD, left ventricular assist device; LVEF, left ventricular ejection fraction; PLEX, plasmapheresis; QOD, every other day.\n\nFigure 4 Left ventricular apex core biopsy. Both views are high‐power hematoxyylin and eosin (H&E) stained images showing markedly damaged myocytes with a lymphocytic infiltrate with the addition of multinucleated giant cells, not associated with granulomas. Black arrows indicate lymphocytic infiltrate, white arrows represent necrotic myocardium, and giant cells are circled in black.\n\nTwo years after initial presentation, a HeartMate II LVAD (Thoratec, Pleasanton, CA) was implanted as a bridge to transplant. Left ventricular apex core biopsy demonstrated a focal chronic lymphocytic infiltrate notable for multiple multinucleated cells and absence of granulomas, consistent with GCM (Figure 4). Additionally, staining for mycobacteria, atypical mycobacteria, bacteria, and fungi was negative. After LVAD implantation, she restarted mycophenolate mofetil for approximately 1 year, transitioned to azathioprine for a few days, and then antimetabolites were withdrawn because of leukopenia. Time to transplant was prolonged because of the presence of high levels of preformed antibodies. She received antibody reduction therapy with rituximab and intravenous immunoglobulin 4 months following LVAD implant; plasma exchange was added 4 months later because of persistently high levels of preformed antibodies. During this time, she experienced an improvement in symptoms and left ventricular function; however, she was unable to tolerate a trial wean of LVAD support to 8400 rpm, with a VO2 max of 10 mL/kg/min and peak respiratory exchange ratio of 1.3. More aggressive immunosuppression regimens targeting GCM were ultimately not pursued because of infection risk.\n\nA suitable donor with negative prospective crossmatch became available, and she underwent an OHT at age 60. Her induction immunosuppression included three doses of rabbit anti‐thymocyte globulin, methylprednisolone 1 g followed by 250 mg every 8 h for six doses, and mycophenolate 1 g intraoperatively followed by 1 g twice/day. Maintenance immunosuppression included tacrolimus, prednisone, and mycophenolate. She is now 4 years post‐transplant, doing well without cellular or antibody‐mediated rejection or evidence of recurrent GCM.\n\n3 Discussion\nClassic reports of GCM include patients with acute onset heart failure rapidly progressing to cardiogenic shock and death within weeks to months of initial presentation.4, 6, 7, 8 GCM is often associated with refractory ventricular arrhythmias or other conduction abnormalities.4, 7, 9, 10 Only 14–29% of patients initially present with VT compared with more than 75% of patients presenting with acutely decompensated heart failure.1 These figures are likely a reflection of historical findings when GCM was only identified at the time of autopsy. A change in the acuity of patients diagnosed with GCM may be seen with increasing utilization of prospective endomyocardial biopsy and apex biopsy at the time of LVAD implantation. This sub‐acute case managed with immunosuppression and LVAD, followed by OHT with no GCM recurrence after 4 years, likely represents an example of possible benefit of early GCM diagnosis.\n\nDiagnosis of GCM is often challenging because of the focal nature of the disease and similarities with other infiltrative cardiomyopathies; this is demonstrated in our patient who had definitive evidence of GCM only after left ventricular apex biopsy. Prospective endomyocardial biopsy has been the gold standard for the diagnosis of GCM since the 1980s because of the similarity in clinical features with other etiologies of myocarditis, particularly sarcoidosis, with the caveat that repeat biopsies are often necessary.1, 5 Targeted biopsies based on the findings of cardiac magnetic resonance imaging and other imaging studies may lead to increased diagnosistic accuracy of initial endomyocardial biopsy. The pathologic diagnosis of GCM requires exclusion of other causes of myocarditis including infectious diseases, amyloidosis, and sarcoidosis. GCM pathophysiology is linked to a T‐cell‐mediated process, characterized by infiltration of cardiomyocytes by lymphocytes, histocytes, multinucleated giant cells, eosinophils with necrosis of cardiomyocytes, and notable absence of granulomas.1, 4, 11, 12, 13\n\n\nSaltykow first described GCM in 1905, and the role of immunosuppression was reported in 1987.14, 15 There are no prospective clinical trials to guide management of this rare disease; however, retrospective reports and case series suggest maintenance immunosuppressive therapy with or without induction. Induction regimens may include high dose steroids, muromonab CD3, or ATG, while maintenance therapy typically includes a corticosteroid, antimetabolite, and calcineurin inhibitor.4, 16 Survival beyond 1 year after diagnosis of GCM is rare without treatment; however, use of immunosuppression has been associated with extended survival.3, 4 Choosing an optimal evidence‐based immunosuppression regimen is challenging because of overall paucity of evidence because of the small number of reports and absence of data from randomized clinical trials. On the other hand, descriptions of successful use of MCS in patients with GCM have followed the increasing use of this modality in heart failure.17, 18, 19 Antibody reduction therapy with mycophenolate, rituximab, intravenous immunoglobulin, and plasma exchange coincided with improvement in our patient's symptoms and cardiac function, which offers an area for future study as T cells are traditionally thought to be the main GCM etiology.\n\nGoals of GCM treatment have been to control symptoms, prolong life, and delay transplant. Heart transplantation is not necessarily a curative treatment, with approximately 20–25% of patients experiencing recurrence.3, 20 There may be a prognostic difference between symptomatic and asymptomatic biopsy proven recurrence and consequently management of each may vary.17 Fortunately, our patient has not had recurrence to date. Contemporary reports on survival in GCM have described survival after OHT at 1, 5, and 10 years as similar to other forms of myocarditis (94%, 82%, and 68%; P = 0.11). 21 Our patient highlights an example of an uncomplicated post‐transplant course after GCM diagnosis.\n\n4 Conclusions\nAdvances in diagnostic modalities and treatment options are leading to earlier diagnosis and improved outcomes in GCM. Rare diseases are challenging to study with prospective clinical trials and clinicians often seek retrospective reports for guidance; registry data have filled this void in other uncommon conditions and may be beneficial in GCM. This case demonstrates a slowly progressive course, requiring durable MCS 2 years after presentation at which time the diagnosis of GCM was made. Intriguingly, cardiac function improved during antibody reduction therapy, though MCS could not be weaned and OHT was ultimately pursued. This suggests an area for further research into alternative methods to treat GCM. This case provides considerations for the utilization of synergistic imaging and treatment modalities for patients with GCM in order to promote early identification and ultimately reduce symptoms and improve functional status.\n\nConflict of interest\nNone declared.\n==== Refs\nReferences\n1 \n\nXu \nJ \n, \nBrooks \nEG \n. Giant cell myocarditis: a brief review\n. Arch Pathol Lab Med \n2016 ; 140 : 1429 –1434\n.27922771 \n2 \n\nAmmirati \nE \n, \nVeronese \nG \n, \nBrambatti \nM \n, \nMerlo \nM \n, \nCipriani \nM \n, \nPotena \nL \n, \nSormani \nP \n, \nAoki \nT \n, \nSugimura \nK \n, \nSawamura \nA \n, \nOkumura \nT \n, \nPinney \nS \n, \nHong \nK \n, \nShah \nP \n, \nBraun \nÖ \n, \nVan de Heyning \nCM \n, \nMontero \nS \n, \nPetrella \nD \n, \nHuang \nF \n, \nSchmidt \nM \n, \nRaineri \nC \n, \nLala \nA \n, \nVarrenti \nM \n, \nFoà \nA \n, \nLeone \nO \n, \nGentile \nP \n, \nArtico \nJ \n, \nAgostini \nV \n, \nPatel \nR \n, \nGarascia \nA \n, \nVan Craenenbroeck \nEM \n, \nHirose \nK \n, \nIsotani \nA \n, \nMurohara \nT \n, \nArita \nY \n, \nSionis \nA \n, \nFabris \nE \n, \nHashem \nS \n, \nGarcia‐Hernando \nV \n, \nOliva \nF \n, \nGreenberg \nB \n, \nShimokawa \nH \n, \nSinagra \nG \n, \nAdler \nED \n, \nFrigerio \nM \n, \nCamici \nPG \n. Fulminant versus acute nonfulminant myocarditis in patients with left ventricular systolic dysfunction\n. J Am Coll Cardiol \n2019 ; 74 : 299 –311\n.31319912 \n3 \n\nMaleszewski \nJJ \n, \nOrellana \nVM \n, \nHodge \nDO \n, \nKuhl \nU \n, \nSchultheiss \nHP \n, \nCooper \nLT \n. Long‐term risk of recurrence, morbidity and mortality in giant cell myocarditis\n. Am J Cardiol \n2015 ; 115 : 1733 –1738\n.25882774 \n4 \n\nCooper \nLT \n, \nBerry \nGJ \n, \nShabetai \nR \n. Idiopathic giant‐cell myocarditis—natural history and treatment. Multicenter Giant Cell Myocarditis Study Group Investigators\n. N Engl J Med \n1997 ; 336 : 1860 –1866\n.9197214 \n5 \n\nKandolin \nR \n, \nLehtonen \nJ \n, \nSalmenkivi \nK \n, \nRäisänen‐Sokolowski \nA \n, \nLommi \nJ \n, \nKupari \nM \n. Diagnosis, treatment, and outcome of giant‐cell myocarditis in the era of combined immunosuppression\n. Circ Heart Fail \n2013 ; 6 : 15 –22\n.23149495 \n6 \n\nCooper \nLT \n, \nBerry \nGJ \n, \nRizeq \nM \n, \nSchroeder \nJS \n. Giant cell myocarditis\n. J Heart Lung Transplant \n1995 ; 14 : 394 –401\n.7779862 \n7 \n\nGleber \nC \n, \nYoruk \nA \n, \nEastburg \nL \n, \nGoldman \nBI \n, \nCameron \nSJ \n. Conduction dysfunction and near expunction: giant cell myocarditis\n. Am J Med \n2018 ; 131 : 1317 –1320\n.29729236 \n8 \n\nDavidoff \nR \n, \nPalacios \nI \n, \nSouthern \nJ \n, \nFallon \nJT \n, \nNewell \nJ \n, \nDec \nGW \n. Giant cell versus lymphocytic myocarditis. A comparison of their clinical features and long‐term outcomes\n. Circulation \n1991 ; 83 : 953 –961\n.1999043 \n9 \n\nPazdernik \nM \n, \nNetuka \nI \n, \nMaly \nJ \n, \nKettner \nJ \n, \nVoska \nL \n, \nRiha \nH \n, \nPirk \nJ \n, \nMelenovsky \nV \n, \nKautzner \nJ \n. A complex heart team's approach to a patient with giant cell myocarditis\n. Can J Cardiol \n2017 ; 33 : 1335.e5 –1335.e7\n.\n10 \n\nPanchal \nA \n, \nOkojie \nO \n, \nSlagle \nB \n, \nTawfik \nO \n. Giant cell myocarditis causing refractory ventricular tachycardia in a pediatric patient\n. Clin Case Rep \n2018 ; 6 : 617 –620\n.29636926 \n11 \n\nKodama \nM \n, \nHanawa \nH \n, \nSaeki \nM \n, \nHosono \nH \n, \nInomata \nT \n, \nSuzuki \nK \n, \nShibata \nA \n. Rat dilated cardiomyopathy after autoimmune giant cell myocarditis\n. Circ Res \n1994 ; 75 : 278 –284\n.8033341 \n12 \n\nKodama \nM \n, \nMatsumoto \nY \n, \nFujiwara \nM \n, \nMasani \nF \n, \nIzumi \nT \n, \nShibata \nA \n. A novel experimental model of giant cell myocarditis induced in rats by immunization with cardiac myosin fraction\n. Clin Immunol Immunopathol \n1990 ; 57 : 250 –262\n.2208806 \n13 \n\nFrantz \nS \n, \nFalcao‐Pires \nI \n, \nBalligand \nJL \n, \nBauersachs \nJ \n, \nBrutsaert \nD \n, \nCiccarelli \nM \n, \nDawson \nD \n, \nde Windt \nLJ \n, \nGiacca \nM \n, \nHamdani \nN \n, \nHilfiker‐Kleiner \nD \n, \nHirsch \nE \n, \nLeite‐Moreira \nA \n, \nMayr \nM \n, \nThum \nT \n, \nTocchetti \nCG \n, \nvan der Velden \nJ \n, \nVarricchi \nG \n, \nHeymans \nS \n. The innate immune system in chronic cardiomyopathy: a European Society of Cardiology (ESC) scientific statement from the Working Group on Myocardial Function of the ESC\n. Eur J Heart Fail \n2018 ; 20 : 445 –459\n.29333691 \n14 \n\nCostanzo‐Nordin \nMR \n, \nSilver \nMA \n, \nO'Connell \nJB \n, \nScanlon \nPJ \n, \nRobinson \nJA \n. Giant cell myocarditis: dramatic hemodynamic and histological improvement after immunosuppressive therapy\n. Eur Heart J \n1987 ; 8 : 271 –274\n.3582386 \n15 \n\nSaltykow \nS \n. Uber diffuse myocarditis\n. Arch Pathol Anat \n1905 ; 182 : 1 –39\n.\n16 \n\nCooper \nLT \n, \nHare \nJM \n, \nTazelaar \nHD \n, \nEdwards \nWD \n, \nStarling \nRC \n, \nDeng \nMC \n, \nMenon \nS \n, \nMullen \nGM \n, \nJaski \nB \n, \nBailey \nKR \n, \nCunningham \nMW \n, \nDec \nGW \n, \nInvestigators \nGCMTT \n. Usefulness of immunosuppression for giant cell myocarditis\n. Am J Cardiol \n2008 ; 102 : 1535 –1539\n.19026310 \n17 \n\nDavies \nRA \n, \nVeinot \nJP \n, \nSmith \nS \n, \nStruthers \nC \n, \nHendry \nP \n, \nMasters \nR \n. Giant cell myocarditis: clinical presentation, bridge to transplantation with mechanical circulatory support, and long‐term outcome\n. J Heart Lung Transplant \n2002 ; 21 : 674 –679\n.12057701 \n18 \n\nOoka \nJ \n, \nTanaka \nH \n, \nHatani \nY \n, \nTsuji \nY \n, \nTakeshige \nR \n, \nMori \nS \n, \nMatsumoto \nK \n, \nHara \nS \n, \nOkita \nY \n, \nHirata \nKI \n. Treatment of fulminant giant cell myocarditis associated with polymyositis using a left ventricular assist device and subsequent corticosteroid and immunosuppressive therapy leading to remission\n. Intern Med \n2017 ; 56 : 2155 –2158\n.28781324 \n19 \n\nEid \nSM \n, \nSchamp \nD \n, \nHalushka \nMK \n, \nBarouch \nLA \n. Resolution of giant cell myocarditis after extended ventricular assistance\n. Arch Pathol Lab Med \n2009 ; 133 : 138 –141\n.19123727 \n20 \n\nGries \nW \n, \nFarkas \nD \n, \nWinters \nGL \n, \nCostanzo‐Nordin \nMR \n. Giant cell myocarditis: first report of disease recurrence in the transplanted heart\n. J Heart Lung Transplant \n1992 ; 11 : 370 –374\n.1576144 \n21 \n\nElamm \nCA \n, \nAl‐Kindi \nSG \n, \nBianco \nCM \n, \nDhakal \nBP \n, \nOliveira \nGH \n. Heart transplantation in giant cell myocarditis: analysis of the United Network for Organ Sharing Registry\n. J Card Fail \n2017 ; 23 : 566 –569\n.28449952\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2055-5822",
"issue": "7(1)",
"journal": "ESC heart failure",
"keywords": "Giant cell myocarditis; immunosuppression; mechanical circulatory support",
"medline_ta": "ESC Heart Fail",
"mesh_terms": "D001706:Biopsy; D005260:Female; D015726:Giant Cells; D006333:Heart Failure; D006353:Heart-Assist Devices; D006801:Humans; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents; D019028:Magnetic Resonance Imaging, Cine; D008875:Middle Aged; D009205:Myocarditis; D009206:Myocardium; D012008:Recurrence",
"nlm_unique_id": "101669191",
"other_id": null,
"pages": "315-319",
"pmc": null,
"pmid": "31872976",
"pubdate": "2020-02",
"publication_types": "D002363:Case Reports; D013485:Research Support, Non-U.S. Gov't",
"references": "1576144;31319912;29333691;29729236;31872976;19123727;9197214;28449952;8033341;25882774;12057701;1999043;29636926;2208806;19026310;27922771;28822649;23149495;7779862;28781324",
"title": "A giant mystery in giant cell myocarditis: navigating diagnosis, immunosuppression, and mechanical circulatory support.",
"title_normalized": "a giant mystery in giant cell myocarditis navigating diagnosis immunosuppression and mechanical circulatory support"
} | [
{
"companynumb": "NVSC2020US103009",
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"abstract": "OBJECTIVE\nHyperthermic intraperitoneal chemotherapy (HIPEC) is an intriguing method of delivery wherein the cytotoxic agent is continuously heated and circulated throughout the peritoneum in an attempt to bolster drug efficacy. Despite HIPEC's potential, ascertaining the optimal dose without compromising patient tolerability remains indeterminate.\n\n\nMETHODS\nWe retrospectively evaluated 52 advanced stage ovarian cancer patients who were treated with consolidation HIPEC with carboplatin at varying doses (e.g., AUC 6, 8 or 10) subsequent to optimal debulking surgery and the attainment of a clinical complete response to their primary chemotherapy regimen. The following patient and operative characteristics were abstracted: demographics, surgery and pathology data, chemotherapy regimen, intraoperative results, toxicity, postoperative complications, length of hospital stay and survival data.\n\n\nRESULTS\nTwelve patients received HIPEC carboplatin at an AUC 6, 15 subjects were treated with carboplatin at an AUC 8 and 25 underwent carboplatin at an AUC 10. There were no intraoperative complications during the administration of HIPEC; mean estimated blood loss was 50 mL and length of hospital stay was 1.65 days. In the overall study population, 5 patients developed grade 3/4 anemia and 33 subjects exhibited grade ≤2 thrombocytopenia and neutropenia. Thirteen patients also developed grade ≤2 nausea on postoperative day 1, which was successfully addressed with anti-emetic therapy; there were no hospital readmissions.\n\n\nCONCLUSIONS\nThe results from the current evaluation suggest that consolidation hyperthermic intraperitoneal chemotherapy with carboplatin is both feasible and reasonably tolerated, even at an AUC of 10. However, additional, randomized study of this procedure incorporating chemotherapy dose escalation with a more extensive patient population is warranted.",
"affiliations": "Gynecologic Oncology Associates, 351 Hospital Road, Suite 507, Newport Beach, CA, 92663, USA.",
"authors": "Rettenmaier|Mark A|MA|;Mendivil|Alberto A|AA|;Abaid|Lisa N|LN|;Brown|John V|JV|;Micha|John P|JP|;Wilcox|Amber M|AM|;Goldstein|Bram H|BH|",
"chemical_list": "D000932:Antiemetics; D000970:Antineoplastic Agents; D016190:Carboplatin",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00404-014-3590-0",
"fulltext": null,
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"issn_linking": "0932-0067",
"issue": "291(6)",
"journal": "Archives of gynecology and obstetrics",
"keywords": null,
"medline_ta": "Arch Gynecol Obstet",
"mesh_terms": "D000368:Aged; D000932:Antiemetics; D000970:Antineoplastic Agents; D016190:Carboplatin; D005260:Female; D006801:Humans; D008875:Middle Aged; D009503:Neutropenia; D010051:Ovarian Neoplasms; D012189:Retrospective Studies",
"nlm_unique_id": "8710213",
"other_id": null,
"pages": "1381-6",
"pmc": null,
"pmid": "25516177",
"pubdate": "2015-06",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "The feasibility of administering varying high-dose consolidation hyperthermic intraperitoneal chemotherapy with carboplatin in the treatment of ovarian carcinoma.",
"title_normalized": "the feasibility of administering varying high dose consolidation hyperthermic intraperitoneal chemotherapy with carboplatin in the treatment of ovarian carcinoma"
} | [
{
"companynumb": "US-CIPLA LTD.-2014US02918",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PACLITAXEL"
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"drugadditional": null,
... |
{
"abstract": "Bone regeneration and remodeling are crucial to healing after surgical interventions. Local and systemic factors impact healing. Some well-known medications actively alter bone remodeling. The objective of this report was to increase awareness of less commonly recognized medications that may delay the integration of bone grafts. This case report presents the delayed integration of a bone graft after tooth removal, socket preservation, and ridge augmentation procedures in a patient taking various medications that may have affected bone remodeling. The literature review enables the discussion of evidence regarding delayed bone remodeling associated with selective serotonin reuptake inhibitors (SSRIs), sodium-glucose cotransporter 2 (SGLT2) inhibitors, metformin, and nonsteroidal anti-inflammatory drugs (NSAIDs), and the clinical implications for patients taking these medications.",
"affiliations": null,
"authors": "Nicolaev|Nikoletta|N|;Romanos|Georgios E|GE|;Malmstrom|Hans|H|;Elad|Sharon|S|",
"chemical_list": "D015921:Dental Implants; D004364:Pharmaceutical Preparations",
"country": "Germany",
"delete": false,
"doi": "10.3290/j.qi.b2053577",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0033-6572",
"issue": "52(10)",
"journal": "Quintessence international (Berlin, Germany : 1985)",
"keywords": "bone remodeling; delayed osseointegration; dental implant; medication; bone grafting",
"medline_ta": "Quintessence Int",
"mesh_terms": "D000540:Alveolar Ridge Augmentation; D016723:Bone Remodeling; D016025:Bone Transplantation; D003758:Dental Implantation, Endosseous; D015921:Dental Implants; D006801:Humans; D004364:Pharmaceutical Preparations; D014081:Tooth Extraction; D020390:Tooth Socket",
"nlm_unique_id": "0342677",
"other_id": null,
"pages": "880-886",
"pmc": null,
"pmid": "34595911",
"pubdate": "2021-10-19",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Commonly used systemic drugs interfering with bone remodeling: a case report and literature review.",
"title_normalized": "commonly used systemic drugs interfering with bone remodeling a case report and literature review"
} | [
{
"companynumb": "US-STRIDES ARCOLAB LIMITED-2022SP006538",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "IBUPROFEN"
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"drugadditional":... |
{
"abstract": "In December 2019, a novel coronavirus (SARS-CoV-2) emerged in China and rapidly spread globally including India. The characteristic clinical observations and outcomes of this disease (COVID-19) have been reported from different countries. The present study was aimed to describe the clinico-demographic characteristics and in-hospital outcomes of a group of COVID-19 patients in north India.\nThis was a prospective, single-centre collection of data regarding epidemiological, demographic, clinical and laboratory parameters, management and outcome of COVID-19 patients admitted in a tertiary care facility in north India. Patient outcomes were recorded as death, discharge and still admitted.\nData of 144 patients with COVID-19 were recorded and analyzed. The mean age of the patients was 40.1±13.1 yr, with 93.1 per cent males, and included 10 (6.9%) foreign nationals. Domestic travel to or from affected States (77.1%) and close contact with COVID-19 patients in congregations (82.6%) constituted the most commonly documented exposure. Nine (6.3%) patients were smokers, with a median smoking index of 200. Comorbidities were present in 23 (15.9%) patients, of which diabetes mellitus (n=16; 11.1%) was the most common. A significant proportion of patients had no symptoms (n=64; 44.4%); among the symptomatic, cough (34.7%) was the most common symptom followed by fever (17.4%) and nasal symptoms (2.15%). Majority of the patients were managed with supportive treatment with hydroxychloroquine and azithromycin given on a case-to-case basis. Only five (3.5%) patients required oxygen supplementation, four (2.8%) patients had severe disease requiring intensive care, one required mechanical ventilation and mortality occurred in two (1.4%) patients. The time to reverse transcription-polymerase chain reaction (RT-PCR) negativity was 16-18 days.\nIn this single-centre study of 144 hospitalized patients with confirmed COVID-19 in north India, the characteristic findings included younger age, high proportion of asymptomatic patients, long time to PCR negativity and low need for intensive care unit care.",
"affiliations": "Department of Pulmonary, Critical Care & Sleep Medicine, All India Institute of Medical Sciences, New Delhi, India.;Department of Pulmonary, Critical Care & Sleep Medicine, All India Institute of Medical Sciences, New Delhi, India.;Department of Onco-Anaesthesia & Palliative Medicine, All India Institute of Medical Sciences, New Delhi, India.;Department of Pulmonary, Critical Care & Sleep Medicine, All India Institute of Medical Sciences, New Delhi, India.;Department of Pulmonary, Critical Care & Sleep Medicine, All India Institute of Medical Sciences, New Delhi, India.;Department of Microbiology, All India Institute of Medical Sciences, New Delhi, India.;Department of Pulmonary, Critical Care & Sleep Medicine, All India Institute of Medical Sciences, New Delhi, India.;Department of Onco-Anaesthesia & Palliative Medicine, All India Institute of Medical Sciences, New Delhi, India.;Department of Onco-Anaesthesia & Palliative Medicine, All India Institute of Medical Sciences, New Delhi, India.;Department of Laboratory Oncology, National Cancer Institute, All India Institute of Medical Sciences, Jhajjar, Haryana, India.;Department of Hospital Administration, National Cancer Institute, All India Institute of Medical Sciences, Jhajjar, Haryana, India.;Department of Medicine, All India Institute of Medical Sciences, New Delhi, India.;Department of Onco-Anaesthesia & Palliative Medicine, All India Institute of Medical Sciences, New Delhi, India.;Department of Onco-Anaesthesia & Palliative Medicine, All India Institute of Medical Sciences, New Delhi, India.;Department of Pulmonary, Critical Care & Sleep Medicine, All India Institute of Medical Sciences, New Delhi, India.;Department of Pulmonary, Critical Care & Sleep Medicine, All India Institute of Medical Sciences, New Delhi, India.;Department of Pulmonary, Critical Care & Sleep Medicine, All India Institute of Medical Sciences, New Delhi, India.;Department of Laboratory Oncology, National Cancer Institute, All India Institute of Medical Sciences, Jhajjar, Haryana, India.;Department of Microbiology, All India Institute of Medical Sciences, New Delhi, India.;Department of Microbiology, All India Institute of Medical Sciences, New Delhi, India.;Department of Medicine, All India Institute of Medical Sciences, New Delhi, India.;All India Institute of Medical Sciences, New Delhi, India.;Department of Onco-Anaesthesia & Palliative Medicine, All India Institute of Medical Sciences, New Delhi, India.;Department of Onco-Anaesthesia & Palliative Medicine, All India Institute of Medical Sciences, New Delhi, India.;Department of Onco-Anaesthesia & Palliative Medicine, All India Institute of Medical Sciences, New Delhi, India.;Department of Otolaryngology & Head-Neck Surgery, All India Institute of Medical Sciences, New Delhi, India.;Department of Hospital Administration, All India Institute of Medical Sciences, New Delhi, India.;Department of Hospital Administration, National Cancer Institute, All India Institute of Medical Sciences, Jhajjar, Haryana, India.;Department of Hospital Administration, National Cancer Institute, All India Institute of Medical Sciences, Jhajjar, Haryana, India.",
"authors": "Mohan|Anant|A|;Tiwari|Pawan|P|;Bhatnagar|Sushma|S|;Patel|Ankit|A|;Maurya|Abhishek|A|;Dar|Lalit|L|;Pahuja|Sourabh|S|;Garg|Rakesh|R|;Gupta|Nishkarsh|N|;Sahoo|Biswajeet|B|;Gupta|Ritu|R|;Meena|Ved Prakash|VP|;Vig|Saurabh|S|;Pandit|Anuja|A|;Mittal|Saurabh|S|;Madan|Karan|K|;Hadda|Vijay|V|;Dwivedi|Tanima|T|;Choudhary|Aashish|A|;Brijwal|Megha|M|;Soneja|Manish|M|;Guleria|Randeep|R|;Ratre|Brajesh|B|;Kumar|Balbir|B|;Bhopale|Shweta|S|;Panda|Smriti|S|;Singh|Angel Rajan|AR|;Singh|Sheetal|S|;Wundavalli|Laxmitej|L|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.4103/ijmr.IJMR_1788_20",
"fulltext": "\n==== Front\nIndian J Med Res\nIndian J Med Res\nIJMR\nThe Indian Journal of Medical Research\n0971-5916 0975-9174 Wolters Kluwer - Medknow India \n\n32773414\nIJMR-152-61\n10.4103/ijmr.IJMR_1788_20\nOriginal Article\nClinico-demographic profile & hospital outcomes of COVID-19 patients admitted at a tertiary care centre in north India\nMohan Anant 1 Tiwari Pawan 1 Bhatnagar Sushma 2 Patel Ankit 1 Maurya Abhishek 1 Dar Lalit 3 Pahuja Sourabh 1 Garg Rakesh 2 Gupta Nishkarsh 2 Sahoo Biswajeet 7 Gupta Ritu 8 Meena Ved Prakash 4 Vig Saurabh 2 Pandit Anuja 2 Mittal Saurabh 1 Madan Karan 1 Hadda Vijay 1 Dwivedi Tanima 7 Choudhary Aashish 3 Brijwal Megha 3 Soneja Manish 4 Guleria Randeep † Ratre Brajesh 2 Kumar Balbir 2 Bhopale Shweta 2 Panda Smriti 5 Singh Angel Rajan 6 Singh Sheetal 8 Wundavalli Laxmitej 8 1 Department of Pulmonary, Critical Care & Sleep Medicine, All India Institute of Medical Sciences, New Delhi, India\n2 Department of Onco-Anaesthesia & Palliative Medicine, All India Institute of Medical Sciences, New Delhi, India\n3 Department of Microbiology, All India Institute of Medical Sciences, New Delhi, India\n4 Department of Medicine, All India Institute of Medical Sciences, New Delhi, India\n5 Department of Otolaryngology & Head-Neck Surgery, All India Institute of Medical Sciences, New Delhi, India\n6 Department of Hospital Administration, All India Institute of Medical Sciences, New Delhi, India\n7 Department of Laboratory Oncology, National Cancer Institute, All India Institute of Medical Sciences, Jhajjar, Haryana, India\n8 Department of Hospital Administration, National Cancer Institute, All India Institute of Medical Sciences, Jhajjar, Haryana, India\n† All India Institute of Medical Sciences, New Delhi, India\nFor correspondence: Dr Anant Mohan, Department of Pulmonary, Critical Care & Sleep Medicine, All India Institute of Medical Sciences, New Delhi 110 029, India e-mail: anantmohan@yahoo.com\nJul-Aug 2020 \n152 1-2 61 69\n06 5 2020 Copyright: © 2020 Indian Journal of Medical Research2020This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.Background & objectives:\nIn December 2019, a novel coronavirus (SARS-CoV-2) emerged in China and rapidly spread globally including India. The characteristic clinical observations and outcomes of this disease (COVID-19) have been reported from different countries. The present study was aimed to describe the clinico-demographic characteristics and in-hospital outcomes of a group of COVID-19 patients in north India.\n\nMethods:\nThis was a prospective, single-centre collection of data regarding epidemiological, demographic, clinical and laboratory parameters, management and outcome of COVID-19 patients admitted in a tertiary care facility in north India. Patient outcomes were recorded as death, discharge and still admitted.\n\nResults:\nData of 144 patients with COVID-19 were recorded and analyzed. The mean age of the patients was 40.1±13.1 yr, with 93.1 per cent males, and included 10 (6.9%) foreign nationals. Domestic travel to or from affected States (77.1%) and close contact with COVID-19 patients in congregations (82.6%) constituted the most commonly documented exposure. Nine (6.3%) patients were smokers, with a median smoking index of 200. Comorbidities were present in 23 (15.9%) patients, of which diabetes mellitus (n=16; 11.1%) was the most common. A significant proportion of patients had no symptoms (n=64; 44.4%); among the symptomatic, cough (34.7%) was the most common symptom followed by fever (17.4%) and nasal symptoms (2.15%). Majority of the patients were managed with supportive treatment with hydroxychloroquine and azithromycin given on a case-to-case basis. Only five (3.5%) patients required oxygen supplementation, four (2.8%) patients had severe disease requiring intensive care, one required mechanical ventilation and mortality occurred in two (1.4%) patients. The time to reverse transcription-polymerase chain reaction (RT-PCR) negativity was 16-18 days.\n\nInterpretation & conclusions:\nIn this single-centre study of 144 hospitalized patients with confirmed COVID-19 in north India, the characteristic findings included younger age, high proportion of asymptomatic patients, long time to PCR negativity and low need for intensive care unit care.\n\nClinico-epidemiologiccoughCOVID-19north Indiaoutcomeprospective\n==== Body\nIn December 2019, an outbreak of cases of pneumonia of unknown aetiology was identified at Wuhan city in Hubei province of China. In the early January 2020, the Chinese authorities identified a new strain of coronavirus which was later named as 2019 novel coronavirus (2019-nCoV)1. This virus spread rapidly across the globe, and the WHO subsequently declared COVID-19 (coronavirus disease 2019) as a pandemic on March 11, 20202. As per the WHO data, as on May 5, 2020, a total of 3,517,345 confirmed cases and 243,401 deaths had been reported worldwide3. Countries such as the USA, Spain, Italy and France bore the maximum brunt of disease load3.\n\nCoronavirus has caused large respiratory outbreaks previously in the form of severe acute respiratory syndrome (SARS) outbreak in 2003 and Middle East respiratory syndrome (MERS) in 2012 which has caused >10,000 cases globally and mortality around 10 and 37 per cent for SARS and MERS, respectively45. In India, the first case of COVID-19 was identified on January 30, 20206 and the number has been increasing steadily due to local transmission and foci of community transmission. As of April 14, 2020, the number of cases in India was 11,485 with overall reported mortality of 3967. Delhi recorded 1,561 cases till April 14, with 30 deaths8.\n\nThe clinical presentation and outcomes of patients with COVID-19 have been variable in different countries910111213141516. Therefore, it is important to analyze and document the clinical behaviour of this disease in the local population. Herein, we report the clinical profile, exposure characteristics and outcomes of the first 144 COVID-19 patients admitted to a tertiary care facility in north India.\n\nMaterial & Methods\nData on epidemiological, demographic, clinical and laboratory parameters, management and outcome from consecutive patients with microbiological diagnosis of COVID-19 admitted to the All India Institute of Medical Sciences (AIIMS), New Delhi, India, from March 23 till April 15, 2020, were collected prospectively. The AIIMS, New Delhi, has dedicated COVID-19 facilities at the National Cancer Institute, Jhajjhar (AIIMS-NCI, Jhajjhar) and AIIMS Trauma Center, catering to COVID-19 patients across all severity spectra. Our centre was designated as a referral facility for COVID-19 patients from nodal public sector hospital, as per government policy17. Patients of all severity were referred for admission; the hospital had no control over patient selection. Patients were received in a screening area, evaluated on arrival and triaged to isolation facility, ward, high-dependency unit or intensive care unit (ICU) as per clinical assessment. A focussed history including travel and exposure history and comorbidities were recorded. After initial clinical evaluation, patients with dyspnoea, respiratory rate (RR) >20/min, or oxygen saturation (SpO2) <94 per cent on room air, clinical diagnosis of pneumonia and those deemed to be at risk for severe disease were subjected to chest radiography. Baseline haemogram and liver and kidney function tests were done for all symptomatic patients, and those at risk of severe disease. Patients with age >60 years and those with cardiovascular risk factors (hypertension, coronary artery disease); diabetes mellitus; immunocompromised state and chronic respiratory, liver or kidney diseases, were considered at high-risk for progression to severe disease. Severe disease was defined as either of these, i.e., RR >24/min, SpO2<94 per cent on room air, confusion, drowsiness, hypotension, sepsis, septic shock or admission to ICUs1718.\n\nDates of symptom onset and resolution were recorded. Time elapsed between the onset and resolution of symptoms was taken as time to clinical resolution. Treatment protocol was followed as per the international18 and local institutional guidelines.\n\nAll patients received symptomatic treatment and were continued on treatment for pre-existing diseases. Azithromycin was prescribed to patients with respiratory symptoms with or without fever. Patients with a clinical diagnosis of pneumonia received a combination of beta-lactam with a beta-lactamase inhibitor along with azithromycin. Hydroxychloroquine (HCQ) was prescribed to symptomatic patients at high-risk of progression to severe disease, and to those with a clinical diagnosis of pneumonia, if there were no contraindications, based on the treating clinician's judgement. Baseline electrocardiogram (ECG) was performed in patients as indicated, and in all patients prior to initiation of HCQ. Follow up ECG was done as clinically indicated. Oxygen supplementation was given with the help of a nasal prong, a face mask and a non-rebreathing mask as clinically indicated. Eligible patients were applied with prone positioning under supervision.\n\nThroat and nasopharyngeal samples were collected using dacron swabs from patients suspected of having SARS-CoV-2 infection. Samples were immediately immersed in viral transport medium (VTM, Hank's balanced salt solution) and transported in triple layered packaging to virology laboratory, where these were processed in a biological safety cabinet (BSC-type IIb). RNA was extracted from VTM fluid followed by real-time reverse transcription-polymerase chain reaction (RT-PCR) using the standardized National Institute of Virology, Pune, protocol as reported earlier19. Qualitative RT-PCR targeting the envelope (E), open reading frame 1b (ORF-1b) and RNA-dependent RNA polymerase (RdRp2)genes of beta coronaviruses and SARS-CoV-2 virus were utilized for diagnosis19.\n\nThe duration of infectivity was calculated based on the duration between the first positive real-time RT-PCR to the first negative RT-PCR. As per the hospital policy at that time, follow up nasopharyngeal and throat swab for RT-PCR was sent after four days of resolution of symptoms, or after seven days of symptom onset, whichever was later, subject to the availability of viral transport media. If the follow up RT-PCR was positive, another sample was sent after 4-7 days. Patients were discharged after two consecutive negative RT-PCR tests, along with normal chest examination findings or improvement in chest radiograph. Outcomes were recorded as death, discharge or still admitted.\n\nStatistical analysis: Continuous data were presented as mean±standard deviation (SD), if normally distributed, and median [interquartile range (IQR)], if data were non-normal. Categorical variables were presented as frequency and percentages (n; %). Comparability of groups was analyzed by Chi-square test, Student's t test or Mann-Whitney test as appropriate. IBM SPSS Statistics version 26 (IBM Corp., Armonk, NY, USA) software was used for statistical analyses.\n\nResults\nA total of 144 patients were studied, of whom 134 (93.1%) were males and the overall mean age was 40.1±13.1 yr, with 10 (6.9%) patients being foreign nationals. The State-wise distribution of patients is shown in Table I. Recent domestic travel to or from affected States (n=111; 77.1%) and close contact with COVID-19 patients in congregations (n=119; 82.6%) constituted the most common exposure characteristic. Other exposure characteristics included foreign travel to an affected country (n=20; 13.9%), and household close contact with a known COVID-19 patient (n=7; 4.9%). Two (1.4%) patients were healthcare workers treating COVID-19 patients, and one was a public official with close contact with a patient during work. Nine patients were smokers, with two (1.4%) being current smokers and seven (4.9%) being reformed smokers; the median smoking index was 200 [interquartile range (IQR): 125-250]. Comorbidities were present in 23 (15.9%) patients, of which diabetes mellitus (n=16; 11.1%) was the most common comorbidity observed, while one patient each had asthma and concomitant pulmonary tuberculosis. Two (1.4%) patients were receiving angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs). Based on age and previously identified risk factors, 31 (21.5%) patients were considered to be at risk of progression to severe disease. Table I describes the baseline characteristics of the admitted COVID-19 patients.\n\nTable I Baseline characteristics of the admitted patients with COVID-19 (n=144)\n\nParameter\tn (%)\t\nAge in years*\t40.1±13.1\t\nSex\t\t\nMale\t134 (93.1)\t\nFemale\t10 (7.2)\t\nIndian nationals\t134 (93.1)\t\nState of residence\t\t\nAndaman and Nicobar Islands\t6 (4.5)\t\nAndhra Pradesh\t12 (9.0)\t\nAssam\t2 (1.5)\t\nBihar\t1 (0.8)\t\nDelhi\t26 (19.4)\t\nHaryana\t1 (0.8)\t\nMaharashtra\t6 (4.7)\t\nPuducherry\t4 (3.0)\t\nRajasthan\t1 (0.8)\t\nTamil Nadu\t74 (55.2)\t\nTelangana\t1 (0.8)\t\nCountry of residence (foreign nationals) (n=10)\t\t\nFiji\t3 (2.1)\t\nKyrgyzstan\t1 (0.7)\t\nMalaysia\t2 (1.4)\t\nThailand\t4 (2.8)\t\nExposure characteristics\t\t\nRecent foreign travel within 14 days of symptoms\t20 (13.9)\t\nRecent domestic travel to affected States\t111 (77.1)\t\nClose contact with COVID-19 patients\t7 (4.9)\t\nHealthcare worker treating COVID-19 patients\t2 (1.4)\t\nPublic service personnel with exposure to COVID-19 patients\t1 (0.7)\t\nPublic congregation\t119 (82.6)\t\nSmoking status\t\t\nCurrent smoker\t2 (1.4)\t\nReformed smoker\t7 (4.9)\t\nNever smoker\t135 (93.8)\t\nSmoking index (n=6)#\t200 (125-250)\t\nComorbidities\t23 (15.9)\t\nDiabetes mellitus\t16 (11.1)\t\nHypertension\t3 (2.1)\t\nCoronary artery disease\t1 (0.7)\t\nHypothyroidism\t3 (2.1)\t\nNeurologic (parkinsonism)\t1 (0.7)\t\nChronic respiratory diseases\t2 (1.4)\t\nBronchial asthma\t1 (0.7)\t\nConcomitant pulmonary tuberculosis\t1 (0.7)\t\nPatients receiving ACEIs or ARBs\t2 (1.4)\t\nTime from first symptom appearance to admission (days)#\t3 (2-6)\t\n*Values expressed as mean (SD); #Values expressed as median (IQR). ACEIs, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; SD, standard deviation; IQR, interquartile range\n\nSixty four (44.4%) patients were asymptomatic and remained so during the hospital stay. In others, the most common symptoms were cough (n=50; 34.7%), fever (n=25; 17.4%), nasal symptoms (n=31; 21.5%) and throat irritation (n=31; 21.5%). Only eight (5.6%) patients complained of dyspnoea, while gastrointestinal symptoms in the form of nausea or vomiting were reported by three (2.1%) patients; diarrhoea was reported by four (2.8%) patients (Table II). The median duration of onset of symptoms before admission was three days (IQR: 2-6 days). There was no significant difference in age, sex or frequency of comorbidities between asymptomatic and symptomatic patients.\n\nTable II Symptom profile of the admitted COVID-19 patients (n=144)\n\nSymptom profile\tn (%)\tDuration in days*\t\nAsymptomatic\t64 (44.4)\t-\t\nSymptomatic\t80 (55.6)\t-\t\nFever\t25 (17.4)\t5 (3-7)\t\nNasal symptoms\t31 (21.5)\t3 (3-4)\t\nThroat irritation\t31 (21.5)\t3 (3-4)\t\nCough\t50 (34.7)\t3 (2-7)\t\nSputum\t5 (3.5)\t4 (2.5-8.0)\t\nDyspnea\t8 (5.6)\t2 (2-3)\t\nFatigue\t2 (1.4)\t6 (4-6)\t\nMyalgia\t5 (3.5)\t3 (1-6)\t\nDiarrhoea\t4 (2.8)\t2 (1-2)\t\nNausea/vomiting\t3 (2.1)\t2 (1-2)\t\nOther symptoms\t\t\t\nChest pain\t1 (0.7)\tNR\t\nEarache\t1 (0.7)\tNR\t\nGiddiness\t1 (0.7)\tNR\t\nHeadache\t2 (1.4)\tNR\t\n*Median (IQR). NR, not recorded\n\nAt admission, 16 (11.1%) patients had fever >37.3°C. Only four (2.8%) patients had severe disease at admission. Anaemia was present in five (3.5%) patients; no patient had leucopenia; however, leucocytosis [total leucocyte count (TLC) >11,000/μl] was present in 15 (10.4%) patients and lymphopenia (absolute lymphocyte count <1500/μl; or lymphocytes <5%) in nine (6.3%) patients. There was no significant difference in baseline laboratory parameters such as haemoglobin, TLC, lymphopenia, neutrophil-lymphocyte (NL) ratio, platelet counts, urea, creatinine, total protein, albumin, bilirubin, alanine aminotransferase, aspartate aminotransferase or alkaline phosphatase between symptomatic and asymptomatic patients. Among the 144 patients, four (2.8%) had severe disease, whereas the remaining 140 (97.2%) had mild-to-moderate disease. There was no significant association between severe disease with respect to age, sex, smoking status, TLC grading or lymphopenia. However, a significant association was observed between severe disease at presentation and NL ratio (P<0.05). Table III depicts the baseline clinical and laboratory parameters of the COVID-19 patients included in this study.\n\nTable III Baseline vitals, laboratory parameters, hospital course, treatment details and outcomes of the admitted COVID-19 patients (n=144)\n\nParameter at admission\tn (%)\t\nFever (≥37.3°C)\t16 (11.1)\t\nRR (breaths/min)#\t18 (16-18)\t\nSpO2(%)*\t95.6±13.8\t\nHeart rate (beats/min)*\t85.0±14.0\t\nSystolic blood pressure (mmHg)*\t111.6±15.6\t\nDiastolic blood pressure (mmHg)*\t78.1±11.7\t\nHeart rate >110/min\t4 (2.8)\t\nRR >24 breaths per minute\t4 (2.8)\t\nSpO2<94% \t3 (2.1)\t\nSystolic blood pressure <90 mmHg\t1 (0.7)\t\nDisease severity status at baseline\t\t\nMild to moderate\t140 (97.2)\t\nSevere\t4 (2.8)\t\nLaboratory findings\t\t\nHb (g %)*\t14.1±1.4\t\nPlatelet count (105/μl)#\t3.3 (2.9-4.0)\t\nAnaemia\t5 (3.5)\t\nTLC (per μl)#\t8460 (6900-9790)\t\nTLC grading (per µl)\t\t\n4,000-11,000 \t121 (84)\t\n>11,000\t15 (10.4)\t\nNeutrophil: lymphocyte ratio#\t1.9 (1.5-2.6)\t\nLymphopenia\t9 (6.3)\t\nSerum proteins (g/dl)*\t6.9±0.7\t\nSerum albumin (g/dl)*\t4.3±0.5\t\nBilirubin (mg/dl)#\t0.5 (0.4-0.7)\t\nALT (units/l)#\t28.3 (24.8-38.8)\t\nAST (units/l)#\t30.5 (21.0-46.7)\t\nAlkaline phosphatase (units/l)#\t79 (67.7-97.5)\t\nRadiologic findings (n=18)\t\t\nNormal\t9 (50)\t\nLobar consolidation with bilateral interstitial infiltrates\t4 (22.2)\t\nPatchy bilateral infiltrates\t3 (16.6)\t\nCavitation along with bilateral interstitial infiltrates\t2 (11.1)\t\nDrugs received\t\t\nParacetamol\t30 (20.8)\t\nAntihistamines\t70 (48.6)\t\nOral vitamin C\t68 (47.2)\t\nAzithromycin\t29 (20.1)\t\nHCQ\t27 (18.7)\t\nBoth azithromycin and HCQ\t11 (7.6)\t\nBeta-lactam/beta-lactamase inhibitor\t7 (4.9)\t\nTeicoplanin\t1 (0.7)\t\nAntitubercular treatment\t1 (0.7)\t\nHospital course and outcome\t\t\nTime to RT-PCR negativity (days)*\t16.9±2.9\t\nImproved\t139 (96.5)\t\nWorsening requiring shifting to ICU/high-dependency unit\t5 (3.5)\t\nMV\t1 (0.7)\t\nOutcome\t\t\nTransferred out\t1 (0.7)\t\nDeath\t2 (1.4)\t\nCured\t125 (86.8)\t\nStill admitted\t16 (11.1)\t\n*Values in mean±SD; #Values in median (IQR). SpO2, oxygen saturation; RR, respiratory rate; TLC, total leucocyte count; ALT, alanine aminotransferase; AST, aspartate aminotransferase; MV, mechanical ventilation; RT-PCR, reverse transcription-polymerase chain reaction; Hb, haemoglobin; HCQ, hydroxychloroquine; ICU, intensive care unit\n\nMajority of the patients were treated with supportive care and required only symptomatic treatment i.e., antihistamines (48.6%), vitamin C (47.2%) and paracetamol (20.8%). Azithromycin was prescribed to 29 (20.1%) patients, HCQ was administered to 27 (18.7%) patients and 11 (7.6%) received both HCQ and azithromycin. One patient was prescribed antitubercular therapy on a clinico-radiological basis. Table III summarizes the treatment details of patients. Only one (0.7%) patient required mechanical ventilation. Five (3.5%) patients required oxygen supplementation. None of the patients were treated with non-invasive ventilation or high-flow nasal cannula.\n\nTwo of 144 patients died, giving a mortality of 1.4 per cent. These two deaths were among the severe group, amounting the mortality to 50 per cent in that group. One of these was a 35 yr old male with diabetic ketoacidosis, multilobar consolidation and septic shock, who required cardiopulmonary resuscitation immediately on arrival to the hospital and died within the next three hours. The second was an emaciated, malnourished patient with bicytopenia, bilateral lung infiltrates and right upper zone cavitation, who died on the fifth day of admission due to refractory acute respiratory distress syndrome.\n\nThe disease severity at baseline did not show any significant association with age, sex, smoking history, smoking index, baseline TLC, TLC grading, percentage lymphocyte count, lymphopenia or time to RT-PCR negativity. Till the time of data analysis, 125 (86.8%) patients had achieved two consecutive negative RT-PCR reports. The median time to RT-PCR negativity, calculated as the duration from the first positive report to the first negative report, was 18 days (IQR: 17-18). There was no significant difference in the median time to RT-PCR negativity between symptomatic (18; IQR: 17.5-18) and asymptomatic (18; IQR: 15-18) patients in our cohort. The median time to RT-PCR negativity was 16 days (IQR: 14.5-18) in patients receiving HCQ, as compared to 18 (IQR: 17.3-18) days in those who did not receive it (P <0.001). Time to RT-PCR positivity did not vary significantly in patients receiving azithromycin or combination of azithromycin along with HCQ as compared to those not receiving these drugs. However, both deaths occurred in patients who were receiving azithromycin and HCQ.\n\nDiscussion\nWe reported the clinical characteristics, hospital course and outcome of the first 144 patients admitted to a COVID-19-dedicated hospital from north India. Compared to previously published reports from other countries (Table IV), the mean age of our patients was significantly lower (40.1 vs. 47-63 yr)910111213141520. Our patients had large male preponderance compared to global data (93 vs. 54.3-73%). However, this may be related to the fact that the majority of our patients were part of a public congregation mainly attended by males, which was identified as a COVID-19 hotspot, and patients were identified on active screening. Of note, two patients were healthcare workers treating COVID-19 patients, and one was a public official with close contact with a COVID-19 patient during work, highlighting the risk associated within healthcare and law enforcement work during an ongoing pandemic. Severe disease was seen in only 2.8 per cent subjects, a much lower figure compared to that of other studies where 15.7-29 per cent of all patients had severe disease9101112131415. Another observation was that a significant proportion of our patients (44.4%) was asymptomatic at admission, and remained so throughout the hospital course. This may be a cause of concern as these asymptomatic patients are potential carriers or transmitters of infection in the community. Most symptomatic patients had mild respiratory symptoms such as nasal symptoms, throat irritation and cough, which was different from the reported symptoms in other studies. Fever was present in only 17 per cent of our patients, which was far less compared to other reports across the globe, including the Chinese cohort in whom 44 per cent had fever at the time of presentation and 88 per cent developed fever during the hospital stay9. Thus, overemphasis on fever as a predominant symptom may lead to several cases being missed. The differences in symptom profile in our study may be due to the selection bias, as most patients were identified on active screening. Lymphopenia, commonly associated with severe disease in reported studies910, was not found to be significantly associated with severe disease in our study. However, higher NL ratio was significantly associated with severe disease in our study, as has been reported in a recent meta-analysis of published COVID-19 studies21.\n\nTable IV Comparison of present study with published descriptive studies on COVID-19\n\nStudy\tGuan et al9 (n=1099)\tChen et al13 (n=99)\tHuang et al10 (n=41)\tWang et al11 (n=138)\tRichardson et al20 (n=5700)\tCurrent study (n=144)\t\nAge (yr)\t47\t55.5\t49\t56\t63 (52-75)#\t40.1 (13.1)*\t\nMales, n (%)\t637 (58.1)\t67 (68)\t30 (73)\t75 (54.3)\t3437 (60.3)\t134 (93.1)\t\nExposure characteristics, n (%)\t\t\t\t\t\t\t\nLiving in Wuhan\t483 (43.9)\tNR\tNR\tNR\tNR \tCommunity hotspots 119 (82.6) Domestic travel to affected areas 111 (77.1)\t\nContact with wildlife\t13 (1.9)\t49 (49)\t27 (66)\t12 (8.7)\tNR\t\t\nRecently visited Wuhan\t193 (31.3)\tNR\tNR\tNR\tNR\t\t\nContact with Wuhan residents\t442 (72.3)\tNR\tNR\tNR\tNR\t\t\nSmoking history, n (%)\t158 (14.6)\tNR\t3 (7)\tNR\t558 (15.6)\t9 (6.3)\t\nComorbidities, n (%)\t\t\t\t\t\t\t\nAny\t261 (23.7)\t50 (51)\t13 (32)\t64 (46.4)\tNR\tNR\t\nCardiovascular\t27 (2.5)\t40 (40)\t6 (15)\t20 (14.5)\tNR\t1 (0.7)\t\nNeurological\t15 (1.4)\t1 (1)\tNR\t7 (2.9)\tNR\t1 (0.7)\t\nHypertension\t165 (15)\tNR\t6 (15)\t43 (31.2)\t3026 (56.6)\t3 (2.1)\t\nDigestive system disease\t23 (2.1)\t11 (11)\t1 (2)\t4 (2.9)\tNR\tNR\t\nEndocrine system disease\t81 (7.4)\t13 (13)\t8 (20)\t14 (10.1)\t1808 (33.8)\t16 (11.1)\t\nMalignant tumour\t10 (0.9)\t1 (1)\t1 (2)\t10 (7.2)\tNR\tNR\t\nPulmonary disease\t12 (1.1)\t1 (1)\t1 (2)\t4 (2.9)\tNR\t3 (2.1)\t\nObesity\tNR\tNR\tNR\tNR\t1737 (41.7)\tNR\t\nFever, n (%)\t975 (88.7)\t82 (83)\t40 (98)\t136 (98.6)\t1734 (30.7)\t25 (17.4)\t\nCough, n (%)\t745 (67.8)\t81 (82)\t31 (76)\t82 (59.4)\tNR\t50 (34.7)\t\nNasal symptoms/throat irritation, n (%)\t153 (13.9)\t5 (5)\tNR\t24 (17.4)\tNR\t31 (21.5)\t\nSputum, n (%)\tNR\tNR\t11 (28)\t37 (26.8)\tNR\t5 (3.5)\t\nDyspnoea, n (%)\t205 (18.7)\t31 (31)\t22 (55)\t43 (31.2)\tNR\t8 (5.6)\t\nDiarrhoea, n (%)\t42 (3.8)\t2 (2)\t1 (3)\t14 (10.1)\tNR\t4 (2.8)\t\nSevere disease, n (%)\t173 (15.74)\t23 (23)\t12 (29)\t36 (26)\t1584 (27.8)\t4 (2.8)\t\nLymphopenia, n (%)\t731 (83.2)\t35 (35)\t26 (63)\tNR\t3387 (60)\t9 (6.3)\t\nProgression to severe disease, n (%)\t173 (15.74)\t23 (23)\t13 (32)\t36 (26)\tNR\t5 (3.5)\t\nOxygen supplementation, n (%)\t454 (41.3)\t75 (76)\t27 (66)\t106 (76.81)\t1584 (27.8)\t5 (3.5)\t\nMechanical ventilation, n (%)\t67 (6.1)\t17 (17)\t14 (34)\t32 (23.2)\t320 (12.2)\t1 (0.8)\t\nHCQ administration, n (%)\tNR\tNR\tNR\tNR\tNR\t27 (18.7)\t\nOther specific drugs (%)\tOseltamivir (35.8) Antifungals (2.8) Steroids (18.6)\tAntivirals (76) Antifungal (15) Steroids (19) Antibiotics (71) IVIg (27)\tAntivirals (93) Antibiotics (100) Steroids (22)\tAntivirals (89.9) Steroids (44.9)\tNR\tAzithromycin (20.1)Antitubercular therapy (0.7)\t\nMortality (%)\t1.4\t11\t15\t4.3\t21\t1.4\t\nAll values expressed as number (%); median (IQR)#or mean (SD)*. IVIg, intravenous immunoglobin\n\nTwo consecutive negative RT-PCR tests performed 24 h apart were required for discharge from the hospital. The mean time to RT-PCR conversion was 16.9±2.9 days even though most patients had mild-to-moderate disease. This was similar to the findings of other studies where the median duration for which SARS-CoV-2 RNA remained detectable by PCR in nasopharyngeal swabs was 12.5 and 14 days, respectively1622.\n\nHCQ has demonstrated variable results in RT-PCR conversion and time-to-clinical resolution232425. In our study, all patients with severe disease, or significant comorbidities, deemed to be at high-risk of progression to severe disease were given HCQ. Although HCQ reduced median time to RT-PCR negativity from 18 to 16 days, the clinical significance of this observation remained uncertain because this was not a randomized comparison. Azithromycin possesses anti-inflammatory and immunomodulatory properties extending beyond their antibacterial activity. A review of literature by Min and Jang26 showed that macrolides could be considered a promising treatment option for respiratory viral infections. Among patients administered azithromycin, no significant change in time to RT-PCR conversion was noted.\n\nOnly nine patients were smokers, and all improved with treatment. None of them had severe disease, or worsening during the hospital course. Due to the low number of smokers and the low frequency of adverse events, we could not evaluate the correlation of smoking with the severity of disease or adverse outcome. However, according to a recent systematic review and meta-analysis, smoking appears to be a risk factor for COVID-19 progression with higher prevalence of smoking among COVID-19 patients with severe, progressive disease or intensive care admission2728.\n\nIn previous studies91011121320, 15.7-29 per cent of patients were reported to have severe disease; however, only 2.8 per cent patients in our study had severe disease at admission. Furthermore, the mortality in our study was 1.4 per cent (2/144). Only one patient required mechanical ventilation and five required oxygen supplementation. This was possibly due to the fact that our health centre was primarily prepared as a facility for the relatively less-sick patients initially. Our observed mortality was similar to that reported from China9, but far less than reported from Europe or the USA1520. A recent descriptive case series of 21 patients has been published from New Delhi, India29. Although we reported only 144 patients in this study, the age distribution, severity and mortality statistics in our study were similar to those reported from Delhi and national level7829. At this juncture, no definitive conclusions with respect to reasons for differences in disease severity and outcome can be drawn; however, it is possible that an overall younger age distribution, combined with low frequency of comorbidities, lymphopenia and hypoxemia, may be the contributing factors for some characteristic features in our patients.\n\nIn conclusion, our study highlights some important differences in Indian patients from those already reported in literature from China, Europe and the USA. This study was limited to the in-hospital clinical course only and follow up details were not available; thus, information of relapses was not reported. Furthermore, by virtue of being a referral centre and not accepting patients directly, majority of the patients had mild-to-moderate disease; the spectrum of severe illness was underrepresented.\n\nFinancial support & sponsorship: None.\n\nConflicts of Interest: None.\n==== Refs\n1 Zhu N Zhang D Wang W Li X Yang B Song J A novel coronavirus from patients with pneumonia in China, 2019 N Engl J Med 2020 382 727 33 31978945 \n2 World Health Organization WHO Director-General's opening remarks at the media briefing on COVID-19 - 11 March 2020 accessed on June 1, 2020 Available from: https://wwwwhoint/dg/speeches/detail/who-director-general-s-opening-remarks-at-the-media-briefing-on-covid-19---11-march-2020 \n3 World Health Organization Coronavirus Disease 2019 (COVID-19) Situation Report - 94 2020 Geneva WHO \n4 World Health Organization Middle East respiratory syndrome coronavirus (MERS-CoV) assessed on June 1, 2020 Available from: https://wwwwhoint/news-room/fact-sheets/detail/middle-east-respiratory-syndrome-coronavirus-(mers-cov) \n5 World Health Organization Summary of probable SARS cases with onset of illness from 1 November 2002 to 31 July 2003 accessed on assessed on June 1, 2020 Available from: https://wwwwhoint/csr/sars/country/table2004_04_21/en/ \n6 Andrews M A Areekal B Rajesh K R Krishnan J Suryakala R Krishnan B First confirmed case of COVID-19 infection in India: A case report Indian J Med Res 2020 151 490 2 32611918 \n7 COVID19 INDIA Coronavirus in India: latest map and case count assessed on June 1, 2020 Available from: https://wwwcovid19indiaorg \n8 Directorate General of Health Services Delhi State Health bulletin for containment of COVID-19 (No 41/April 14, 2020) Government of NCT of Delhi 2020 accessed on June 1, 2020 Available from: http://healthdelhigovtnicin/wps/wcm/connect/2fb1fa004df2d858b9affbd194e333e1/HB14ApdfMOD =AJPERES&lmod=-2048803167&CACHEID=2fb1fa004df2d858b9affbd194e333e1 \n9 Guan WJ Ni ZY Hu Y Liang WH Ou CQ He JX Clinical characteristics of coronavirus disease 2019 in China N Engl J Med 2020 382 1708 20 32109013 \n10 Huang C Wang Y Li X Ren L Zhao J Hu Y Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China Lancet 2020 395 497 506 31986264 \n11 Wang D Hu B Hu C Zhu F Liu X Zhang J Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China JAMA 2020 323 1061 9 32031570 \n12 Wang X Fang J Zhu Y Chen L Ding F Zhou R Clinical characteristics of non-critically ill patients with novel coronavirus infection (COVID-19) in a Fangcang Hospital Clin Microbiol Infect 2020 S1198-743X 20 30177 4 \n13 Chen N Zhou M Dong X Qu J Gong F Han Y Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: A descriptive study Lancet 2020 395 507 13 32007143 \n14 COVID-19 National Emergency Response Center E, Case Management Team KCfDC, Prevention Coronavirus disease-19: The first 7,755 cases in the Republic of Korea Osong Public Health Res Perspect 2020 11 85 90 32257774 \n15 Grasselli G Pesenti A Cecconi M Critical care utilization for the COVID-19 outbreak in Lombardy, Italy: Early experience and forecast during an emergency response JAMA 2020 323 1545 6 32167538 \n16 Young BE Ong SWX Kalimuddin S Low JG Tan SY Loh J Epidemiologic features and clinical course of patients infected with SARS-CoV-2 in Singapore JAMA 2020 323 1488 94 32125362 \n17 Directorate General of Health Services (EMR Division), Ministry of Health & Family Welfare, Government of India Guidance document on appropriate management of suspect/confirmed cases of COVID-19 accessed on July 13, 2020 Available from: https://www.mohfw.gov.in/pdf/FinalGuidanceonMangaementofCovidcasesversion2.pdf \n18 World Health Organization Clinical management of COVID-19 accessed on June 9, 2020 Available from: https://www.who.int/publicationsdetail-redirect/clinical-management-of-covid-19 \n19 ICMR COVID Study Group, COVID Epidemiology & Data Management Team, COVID Laboratory Team, VRDLN Team Laboratory surveillance for SARS-CoV-2 in India: Performance of testing & descriptive epidemiology of detected COVID-19, January 22 - April 30, 2020 Indian J Med Res 2020 151 424 37 32611914 \n20 Richardson S Hirsch JS Narasimhan M Crawford JM McGinn T Davidson KW Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the New York city area JAMA 2020 323 2052 9 32320003 \n21 Lagunas-Rangel FA Neutrophil-to-lymphocyte ratio and lymphocyte-to-C-reactive protein ratio in patients with severe coronavirus disease 2019 (COVID-19): A meta-analysis J Med Virol 2020 101002/jmv25819 \n22 Wölfel R Corman VM Guggemos W Seilmaier M Zange S Müller MA Virological assessment of hospitalized patients with COVID-2019 Nature 2020 581 465 9 32235945 \n23 Molina JM Delaugerre C Le Goff J Mela-Lima B Ponscarme D Goldwirt L No evidence of rapid antiviral clearance or clinical benefit with the combination of hydroxychloroquine and azithromycin in patients with severe COVID-19 infection Med Mal Infect 2020 50 384 32240719 \n24 Gautret P Lagier JC Parola P Hoang VT Meddeb L Mailhe M Hydroxychloroquine and azithromycin as a treatment of COVID-19: Results of an open-label non-randomized clinical trial Int J Antimicrob Agents 2020 105949 32205204 \n25 Chen J Liu D Liu L Liu P Xu Q Xia L Ling Y A pilot study of hydroxychloroquine in treatment of patients with common coronavirus disease-19 (COVID-19) Zhejiang Da Xue Xue Bao Yi Xue Ban 2020 49 215 9 32391667 \n26 Min JY Jang YJ Macrolide therapy in respiratory viral infections Mediators Inflamm 2012 2012 649570 22719178 \n27 Vardavas CI Nikitara K COVID-19 and smoking: A systematic review of the evidence Tob Induc Dis 2020 18 20 32206052 \n28 Patanavanich R Glantz SA Smoking is associated with COVID-19 progression: A meta-analysis medRxiv 2020 doi: 101101/2020041320063669 \n29 Gupta N Agrawal S Ish P Mishra S Gaind R Usha G Clinical and epidemiologic profile of the initial COVID-19 patients at a tertiary care centre in India Monaldi Arch Chest Dis 2020 10 90\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0971-5916",
"issue": "152(1 & 2)",
"journal": "The Indian journal of medical research",
"keywords": "COVID-19; Clinico-epidemiologic; cough; north India; outcome; prospective",
"medline_ta": "Indian J Med Res",
"mesh_terms": "D000328:Adult; D000073640:Betacoronavirus; D000086382:COVID-19; D002681:China; D015897:Comorbidity; D018352:Coronavirus Infections; D005260:Female; D006760:Hospitalization; D006761:Hospitals; D006801:Humans; D007194:India; D008297:Male; D008875:Middle Aged; D058873:Pandemics; D011024:Pneumonia, Viral; D000086402:SARS-CoV-2; D062606:Tertiary Care Centers",
"nlm_unique_id": "0374701",
"other_id": null,
"pages": "61-69",
"pmc": null,
"pmid": "32773414",
"pubdate": "2020",
"publication_types": "D016428:Journal Article",
"references": "32031570;32320003;32251842;32235945;32611914;32240719;32125362;32290644;32007143;32206052;32257774;32399563;32242950;32391667;31978945;32109013;22719178;31986264;32167538;32205204;32611918",
"title": "Clinico-demographic profile & hospital outcomes of COVID-19 patients admitted at a tertiary care centre in north India.",
"title_normalized": "clinico demographic profile hospital outcomes of covid 19 patients admitted at a tertiary care centre in north india"
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"abstract": "Ibrutinib (IBR) covalently binds to the active site of Bruton's tyrosine kinase (BTK) and is used for the treatment of relapsed/refractory chronic lymphocytic leukemia (CLL). Approximately 5-10% of CLL is complicated by autoimmune cytopenia (AIC), such as autoimmune hemolytic anemia (AIHA). Several cases of AIC have reportedly demonstrated improvement during IBR treatment. However, in our case, the patient developed AIHA during oral IBR treatment. As AIHA is exacerbated by the increased number of CLL cells in the peripheral blood, it may have developed because of disease progression rather than IBR use. This phenomenon may also be attributed to the production of autoantibodies due to increased number of CD5+ B cells. In this case, withdrawal of IBR and administration of rituximab improved hemolysis. If AIHA develops during treatment, its etiology must be examined to confirm the effects of treatment.",
"affiliations": null,
"authors": "Suzuki|Takaharu|T|;Miyakoshi|Shukuko|S|;Nanba|Ayako|A|;Uchiyama|Takayoshi|T|;Kawamoto|Keisuke|K|;Aoki|Sadao|S|",
"chemical_list": "D001323:Autoantibodies; D010880:Piperidines; D011720:Pyrazoles; D011743:Pyrimidines; C551803:ibrutinib; D000069283:Rituximab; D000225:Adenine",
"country": "Japan",
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"doi": "10.3960/jslrt.18012",
"fulltext": "\n==== Front\nJ Clin Exp HematopJ Clin Exp HematopjslrtJournal of Clinical and Experimental Hematopathology : JCEH1346-42801880-9952JSLRT 300129211801210.3960/jslrt.18012Case ReportA case of chronic lymphocytic leukemia complicated by autoimmune hemolytic\nanemia due to ibrutinib treatment Suzuki Takaharu \n1\n\n2\nMiyakoshi Shukuko \n1\n\n2\nNanba Ayako \n1\nUchiyama Takayoshi \n3\nKawamoto Keisuke \n1\nAoki Sadao \n2\n\n 3\n1)Department of Hematology,\nEndocrinology and Metabolism, Faculty of Medicine, Niigata\nUniversity, Niigata, Japan,\n2)Niigata Minami Hospital,\nNiigata, Japan, 3)Department of Pathophysiology,\nNiigata University of Pharmacy and Applied Life Sciences,\nNiigata, JapanCorresponding author: Sadao Aoki, 265-1, Higashijima, Akiha-ku, Niigata,\nNiigata 956-8603, Japan. E-mail: saoki@nupals.ac.jp14 7 2018 9 2018 58 3 136 140 05 4 2018 30 5 2018 19 6 2018 © 2018 by The Japanese Society for Lymphoreticular Tissue\nResearch2018The Japanese Society for Lymphoreticular Tissue\nResearchThis is an open-access article distributed under the terms of the Creative Commons Attribution ShareAlike (CC BY-NC-SA) 4.0 License.Ibrutinib (IBR) covalently binds to the active site of Bruton’s tyrosine kinase (BTK) and\nis used for the treatment of relapsed/refractory chronic lymphocytic leukemia (CLL).\nApproximately 5-10% of CLL is complicated by autoimmune cytopenia (AIC), such as\nautoimmune hemolytic anemia (AIHA). Several cases of AIC have reportedly demonstrated\nimprovement during IBR treatment. However, in our case, the patient developed AIHA during\noral IBR treatment. As AIHA is exacerbated by the increased number of CLL cells in the\nperipheral blood, it may have developed because of disease progression rather than IBR\nuse. This phenomenon may also be attributed to the production of autoantibodies due to\nincreased number of CD5+ B cells. In this case, withdrawal of IBR and administration of\nrituximab improved hemolysis. If AIHA develops during treatment, its etiology must be\nexamined to confirm the effects of treatment.\n\nKeywords:\nChronic lymphocytic leukemiaAutoimmune hemolytic anemiaIbrutinib\n==== Body\nINTRODUCTION\nChronic lymphocytic leukemia (CLL) is the most common type of leukemia in adults in Europe\nand the United States.1 However, its\nincidence is lower in East Asia, including Japan.2 Therapeutic agents for the treatment of CLL have been developed,\nincluding the introduction of alkylating agents (chlorambucil, and cyclophosphamide) in\n1960, purine analogs (fludarabine, pentostatin, and cladribine) in 1980, and combination\ntherapy of purine analogs and alkylating agents in 2000.3 Chemoimmunotherapy (CIT) that uses employing anti-CD20 antibody in\naddition to chemotherapy has become common in recent years.3 Furthermore, since 2010, new molecular targeted drugs that can be\norally administered have been developed.3\nIbrutinib (IBR) covalently binds to the active site of Bruton’s tyrosine kinase (BTK) and\nexerts antitumor effects via the inhibition of survival/proliferation signal\ntransduction,4 and is used for the\ntreatment of relapsed/refractory CLL.\n\nApproximately 5-10% of CLL cases are complicated by autoimmune cytopenia (AIC) such as\nautoimmune hemolytic anemia (AIHA).5 AIHA\noccurs in any risk classification and is not associated with prognostic factors.5 IBR is effective for the treatment of CLL\ncomplicated by AIHA.6 However, in this\nreport, we describe a case of CLL that became complicated by AIHA during IBR treatment.\n\nCASE REPORT\nA 75-year-old Japanese woman was diagnosed with CLL (Rai classification: 0, and Binet\nclassification: A) 10 years ago and was followed-up at our hospital. The patient presented\nwith progressive lymphadenopathy, splenomegaly, peripheral blood lymphocytosis, and\nthrombocytopenia 4 years and 1 month ago, for which fludarabine treatment was started.\nAlthough partial response to fludarabine was observed, she repeatedly relapsed. Partial\nresponse was achieved with ofatumumab or bendamustine and rituximab (BR) therapy. Due to\nrelapse, the patient was admitted to our hospital to initiate IBR treatment. The clinical\ncourse during hospitalization is shown in Fig. 1. Blood\ntest results upon admission revealed anemia, thrombocytopenia, peripheral blood lymphocyte\nproliferation, and an increased lactate dehydrogenase (LDH) level (Table 1). As her reticulocyte count was low and direct bilirubin was\nwithin the normal range, hemolysis was excluded. Computed tomography (CT) demonstrated\nintraperitoneal lymph node swelling and splenomegaly (Fig.\n2A). On the bone marrow examination, 95% heteromorphic lymphocytes were observed,\nand numerous round lymphocytes with a smooth nuclear membrane and fine granular chromatin\nwere noted (Fig. 3A). On flow cytometry analysis of\nperipheral blood using CD19 gating, CLL cells were positive for CD5 and CD23, weakly\npositive for CD20, and negative for CD22 (Fig. 3B). The\nMatutes score7 was 4, consistent with CLL.\nMutation TP53 was not investigated because the remaining specimen was inadequate, but 17p13\ndeletion was negative on fluorescence in situ hybridization.\n\nFig. 1 Clinical course\n\nOn day 3, ibrutinib (IBR; 420 mg/day) was started. On day 5, the following results were\nobtained: direct Coombs test, +; anti-human IgG, 4+; and anti-complement C3b and C3d.\nThe patient had no symptoms, and was thus followed-up. On day 8, she exhibited\npalpitations, dyspnea upon walking, and dizziness. She received RBC transfusion on days\n8, 15, 20, 21, 22, 24, and 27. IBR treatment was continued, but the number of WBC\nincreased. On day 23, IBR treatment was discontinued, and on day 23, PSL was started. We\nused rituximab for AIHA on days 31 and 38. AIHA was improved, and the number of WBC\ndecreased. On day 59, she was discharged from the hospital.\n\nTable 1 Laboratory findings on admission\nPeripheral blood\tChemistry\tSeroimmunological test\t\nWBC\nSeg\nEo\nBas\nLym\nMono\nRBC\nRet\nHb\nHt\nMCV\nPlt\t31870\n/μL\n5.0%\n0.5%\n0.0%\n94.5%\n0.0%\n241×104\n/μL\n0.25%\n7.9 g/dL\n23.1%\n95.9%\n5.3×104\n/μL\tTP\nAlb\nBUN\nCre\nT-Bil\nD-Bil\nALP\nAST\nALT\nLDH\nγ-GTP\nAmy\nNa\nK\nCl\nCa\t5.9 g/dL\n4.3 g/dL\n19.9 g/dL\n0.89\ng/dL\n1.2 g/dL\n0.3 g/dL\n162 g/dL\n39 IU/L\n29\nIU/L\n349 IU/L\n16 IU/L\n72 IU/L\n148 mEq/L\n4.4\nmEq/L\n107 mEq/L\n8.8 mg/dL\tIgG\nIgA\nIgM\nSoluble\nIL-2R\nCRP\t5339 IU/mL\n176 mg/dL\n< 10 mg/dL\n7\nmg/dL\n< 0.30 IU/mL\t\nFig. 2 Intra-abdominal CT scan\n\nA)On day 2, CT was carried out, showing swelling of intraperitoneal\nlymph nodes and splenomegaly.\n\nB)After discharge, repeat CT was performed, revealing decreased\nswelling of the intraperitoneal lymph nodes and spleen.\n\nFig. 3 A)On day 1, bone marrow aspiration was performed. Numerous round\nlymphocytes with a smooth nuclear membrane and fine granular chromatin were\nobserved.\n\nB)On flow cytometry, CLL cells were positive for CD5 and CD23, weakly\npositive for CD20, and negative for CD22. The Matutes score was 4.\n\nBased on these results, IBR treatment (420 mg/body) was started. However, after initiating\nIBR treatment, peripheral blood lymphocyte proliferation (highest count at 165169/μL on day\n19) was observed. However, treatment was continued because there was no overt organopathy.\nOn day 3, the hemoglobin (Hb) level was 6.4 g/dL. The test results were as follows: direct\nCoombs test, +; anti-human IgG, 4+; and anti-complement C3b and C3d. As no subjective\nsymptom of anemia was observed, follow-up observation was performed. On day 5, her Hb level\nwas 6.6 g/dL, and she presented with palpitations, dyspnea upon walking, and dizziness. One\nhundred milligrams of hydrocortisone was administered, and 2 units of red blood cells (RBC)\nwere transfused. On day 21, her haptoglobin level decreased to < 2 mg/dL. The following\nlaboratory test results indicated hemolysis: RBC level, 194 × 104/μL; Ret, 3.79%; LDH level,\n248 IU/L; and T-Bil, 4.5 mg/dL. The patient was thus diagnosed with AIHA. As IBR was\nsuspected as a cause of AIHA, it was discontinued on day 21. Prednisolone (PSL) (50 mg/day)\nwas started on day 23. Sustained hemolysis was prolonged, and two units of RBC were\ntransfused on days 15, 20, 21, 22, 24, and 27. However, PSL was not effective and was\ndiscontinued. We administered rituximab (RIT) as a single agent on days 31 and 38. After RIT\ntreatment, peripheral blood lymphocyte proliferation and hemolysis improved, and\npalpitations and dyspnea disappeared. Her Hb level increased, and T-Bil and LDH levels were\nwithin the normal range (Fig. 1). Considering AIHA to\nhave improved, the patient was discharged on day 59, but CT revealed swelling in the lymph\nnodes and spleen (Fig. 2B).\n\nDISCUSSION\nApproximately 5-10% of CLL cases are complicated by AIC, which may be developed in any risk\nclassification.5 Approximately 90% of\nAIC-complicated CLL cases are due to high affinity IgG antibodies against\nerythrocytes-/-platelets that are produced by non-malignant B cells.8 Several studies have demonstrated that IBR treatment improves\nAIC.9,10 Molica reported that AIHA was suppressed during IBR\ntreatment and worsened as IBR was withdrawn when pneumonia developed.11 Rider found that AIHA developed at initial IBR treatment,\nbut did not develop during re-treatment.12\nIn our case, the patient did not previously develop AIHA, and onset was observed during IBR\ntreatment. Therefore, these reports differ from our case. Although the cause of AIHA during\nIBR treatment is unknown, the following possibilities have been considered:\n\nFirst, IBR itself causes AIHA. Fludarabine causes AIHA during CLL treatment.13 This drug causes autoimmune tolerance due\nto the destruction of regulatory T cells.14 Therefore, AIHA may be induced by the administration of\nfludarabine.14 A small number (1.28%) of\nAIHA cases with AIHA attributed to the use of IBR has been reported.6 Although IBR has immunological activity, pharmacological\neffects similar to those of fludarabine have not been observed by IBR. Thus, the probability\nof IBR causing AIHA is low.\n\nSecond, a rapid increase in lymphocytes due to IBR is involved. As shown in Fig. 1, white blood cells (WBC) in the peripheral blood\nsignificantly increased after administration of IBR, exacerbating AIHA. In general, after\nIBR treatment, CLL cells are released from lymph nodes,15,16\nwhich causes transient lymphocytosis. These lymphocytes then undergo apoptosis. If the\ndisease is not PD, follow-up is considered sufficient. In this case, AIHA was observed 4\nweeks after IBR treatment. Moreover, AIHA was exacerbated by the increase in the peripheral\nblood lymphocyte count. Thus, lymphocytes may promote autoantibody production.\n\nThird, the efficacy of IBR was delayed. Administration of IBR to patients with CLL and\ndiabetes reportedly decreases insulin and GAD antibody levels.17 As such, IBR may have suppressed autoantibody production.\nThe delayed effects of inhibiting autoantibody production by IBR can worsen the condition of\npatients with AIHA.\n\nWe believe that the most likely reason for why AIHA was not controlled in this case was the\namount of time required for the effects of IBR to develop. Based on RIT treatment,\nlymphocytes in the peripheral blood rapidly decreased and AIHA was also improved. RIT may\nhave more immediate effects than IBR. Rituximab is considered to be effective for AIHA.18 In conclusion, when AIHA develops during\nIBR treatment, RIT should be administered immediately.\n\nCONFLICT OF INTEREST: The authors declare no conflicts of interest.\n==== Refs\nREFERENCES\n1 Scarfò L Ferreri AJM Ghia P .\nChronic lymphocytic leukaemia. \nCrit Rev Oncol Hematol . 2016 ; 104 :\n169 -182 . 10.1016/j.critrevonc.2016.06.003 27370174 \n2 Ruchlemer R Polliack A .\nGeography, ethnicity and “roots” in chronic lymphocytic\nleukemia. \nLeuk Lymphoma . 2013 ; 54 :\n1142 -1150 . 10.3109/10428194.2012.740670 23121522 \n3 Rai KR Jain P .\nChronic lymphocytic leukemia (CLL)-Then and now. \nAm J Hematol . 2016 ; 91 :\n330 -340 . 10.1002/ajh.24282 26690614 \n4 Dubovsky JA Beckwith KA Natarajan G \nIbrutinib is an irreversible molecular inhibitor of ITK driving a\nTh1-selective pressure in T lymphocytes. \nBlood . 2013 ; 122 :\n2539 -2549 . 10.1182/blood-2013-06-507947 23886836 \n5 Zent CS Kay NE .\nAutoimmune complications in chronic lymphocytic leukaemia\n(CLL). \nBest Pract Res Clin Haematol . 2010 ; 23 :\n47 -59 . 10.1016/j.beha.2010.01.004 20620970 \n6 Rogers KA Ruppert AS Bingman A \nIncidence and description of autoimmune cytopenias during treatment with\nibrutinib for chronic lymphocytic leukemia. \nLeukemia . 2016 ; 30 :\n346 -350 . 10.1038/leu.2015.273 26442611 \n7 Matutes E Owusu-Ankomah K Morilla R \nThe immunological profile of B-cell disorders and proposal of a scoring\nsystem for the diagnosis of CLL. \nLeukemia . 1994 ; 8 :\n1640 -1645 .7523797 \n8 Visco C Barcellini W Maura F \nAutoimmune cytopenias in chronic lymphocytic leukemia. \nAm J Hematol . 2014 ; 89 :\n1055 -1062 . 10.1002/ajh.23785 24912821 \n9 Manda S Dunbar N Marx-Wood CR \nIbrutinib is an effective treatment of autoimmune haemolytic anaemia in\nchronic lymphocytic leukaemia. \nBr J Haematol . 2015 ; 170 :\n734 -736 . 10.1111/bjh.13328 25716177 \n10 Galinier A Delwail V Puyade M .\nIbrutinib is effective in the treatment of autoimmune haemolytic anaemia\nin mantle cell lymphoma. \nCase Rep Oncol . 2017 ; 10 :\n127 -129 . 10.1159/000456002 28203175 \n11 Molica S Polliack A .\nAutoimmune hemolytic anemia (AIHA) associated with chronic lymphocytic\nleukemia in the current era of targeted therapy. \nLeuk Res . 2016 ; 50 :\n31 -36 . 10.1016/j.leukres.2016.09.002 27657651 \n12 Rider TG Grace RJ Newman JA .\nAutoimmune haemolytic anaemia occurring during ibrutinib therapy for\nchronic lymphocytic leukaemia. \nBr J Haematol . 2016 ; 173 :\n326 -327 . 10.1111/bjh.13602 26195269 \n13 Myint H Copplestone JA Orchard J \nFludarabine-related autoimmune haemolytic anaemia in patients with chronic\nlymphocytic leukaemia. \nBr J Haematol . 1995 ; 91 :\n341 -344 . 10.1111/j.1365-2141.1995.tb05300.x 8547072 \n14 Beyer M Kochanek M Darabi K \nReduced frequencies and suppressive function of CD4+CD25hi regulatory T\ncells in patients with chronic lymphocytic leukemia after therapy with\nfludarabine. \nBlood . 2005 ; 106 :\n2018 -2025 . 10.1182/blood-2005-02-0642 15914560 \n15 Burger JA .\nNurture versus nature: the microenvironment in chronic lymphocytic\nleukemia. \nHematology . 2011 ; 2011 :\n96 -103 . 10.1182/asheducation-2011.1.96 22160019 \n16 Woyach JA Smucker K Smith LL \nProlonged lymphocytosis during ibrutinib therapy is associated with\ndistinct molecular characteristics and does not indicate a suboptimal response to\ntherapy. \nBlood . 2014 ; 123 :\n1810 -1817 . 10.1182/blood-2013-09-527853 24415539 \n17 Skrabs C Pickl WF Perkmann T \nRapid decline in insulin antibodies and glutamic acid decarboxylase\nautoantibodies with ibrutinib therapy of chronic lymphocytic leukaemia. \nJ Clin Pharm Ther . 2018 ; 43 :\n145 -149 . 10.1111/jcpt.12602 28753229 \n18 Peñalver FJ Alvarez-Larrán A Díez-Martin JL Multi-institutional\nRetrospective Study on the use of rituximab in refractory\nAIHA \nRituximab is an effective and safe\ntherapeutic alternative in adults with refractory and severe autoimmune hemolytic\nanemia. \nAnn Hematol . 2010 ; 89 :\n1073 -1080 . 10.1007/s00277-010-0997-y 20526716\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "1346-4280",
"issue": "58(3)",
"journal": "Journal of clinical and experimental hematopathology : JCEH",
"keywords": "Autoimmune hemolytic anemia; Chronic lymphocytic leukemia; Ibrutinib",
"medline_ta": "J Clin Exp Hematop",
"mesh_terms": "D000225:Adenine; D000368:Aged; D000744:Anemia, Hemolytic, Autoimmune; D001323:Autoantibodies; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell; D008297:Male; D010880:Piperidines; D011720:Pyrazoles; D011743:Pyrimidines; D000069283:Rituximab",
"nlm_unique_id": "101141257",
"other_id": null,
"pages": "136-140",
"pmc": null,
"pmid": "30012921",
"pubdate": "2018-09-19",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "15914560;20526716;20620970;22160019;23121522;23886836;24415539;24912821;25716177;26195269;26442611;26690614;27370174;27657651;28203175;28753229;7523797;8547072",
"title": "A case of chronic lymphocytic leukemia complicated by autoimmune hemolytic anemia due to ibrutinib treatment.",
"title_normalized": "a case of chronic lymphocytic leukemia complicated by autoimmune hemolytic anemia due to ibrutinib treatment"
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"abstract": "Nicolau syndrome (NS) is a rare iatrogenic syndrome usually following intramuscular (IM) injection of various described medications. The typical presentation involves immediate injection site pain and development of a livedoid reticular patch, which can progress to muscle necrosis requiring surgical debridement. The pathophysiology is unclear, although vasoconstrictive etiologies have been implicated. Treatment ranges from supportive care to surgical debridement. The authors present a case report of this syndrome as well as a review of the literature and introduction to a new treatment modality. NS in a 52-year-old woman following IM injection of Demerol and Phenergan to address pain and nausea before discharge is reported. This occurred in the post-anesthesia care unit after aesthetic breast surgery in an ambulatory surgery center. Our patient had immediate injection site pain and a hemorrhagic patch was evident on her physical examination the following day. With local care and hyperbaric oxygen therapy, her lesion improved in appearance. However, she continued to have debilitating pain and was referred to a specialist for osteopathic manipulative therapy (OMT), which had the greatest impact on her pain level. After multi-modal therapy was initiated, the syndrome ultimately resolved without the need for surgical debridement. However, she continues to experience pain and ambulates with a limp due to muscle atrophy. NS is a rare diagnosis that can have devastating complications that can be averted by early recognition and initiation of treatment modalities. In this case, the authors introduced OMT as a new treatment modality, with the potential to improve the progression of this syndrome.",
"affiliations": "Oregon Health and Science University, Portland, OR.;Oregon Health and Science University, Portland, OR.;Oregon Health and Science University, Portland, OR.",
"authors": "Gal|Shaili|S|;Dart|Paul E|PE|;Movassaghi|Kiya|K|",
"chemical_list": null,
"country": "England",
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"doi": "10.1093/asjof/ojaa027",
"fulltext": "\n==== Front\nAesthet Surg J Open Forum\nAesthet Surg J Open Forum\nasjopenforum\nAesthetic Surgery Journal. Open Forum\n2631-4797\nOxford University Press US\n\n10.1093/asjof/ojaa027\nojaa027\nBreast Surgery\nCase Reports\nAsj/2\nAcademicSubjects/MED00987\nA Case Report of Nicolau Syndrome After Aesthetic Breast Surgery: A Review of the Literature and Introduction to a New Treatment Modality\nGal Shaili MD\nDart Paul E MD, FCA\nMovassaghi Kiya MD, DMD, FACS Assistant Clinical Professor\nOregon Health and Science University, Portland, OR\nCorresponding Author: Dr Kiya Movassaghi, Movassaghi Plastic Surgery, 330 S. Garden Way Suite 100, Eugene, OR 97401, USA. E-mail: kiya@drmovassaghi.com; Instagram: @movassaghiplasticsurgery\nDr Gal is an aesthetic plastic surgeon in private practice in Peoria, AZ.\n\nDr Dart is an osteopathic manipulative medicine specialist in private practice in Eugene, OR.\n\n9 2020\n24 6 2020\n24 6 2020\n2 3 ojaa02705 5 2020\n10 8 2020\n© 2020 The Aesthetic Society.\n2020\nThis 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.com\n\nAbstract\n\nNicolau syndrome (NS) is a rare iatrogenic syndrome usually following intramuscular (IM) injection of various described medications. The typical presentation involves immediate injection site pain and development of a livedoid reticular patch, which can progress to muscle necrosis requiring surgical debridement. The pathophysiology is unclear, although vasoconstrictive etiologies have been implicated. Treatment ranges from supportive care to surgical debridement. The authors present a case report of this syndrome as well as a review of the literature and introduction to a new treatment modality. NS in a 52-year-old woman following IM injection of Demerol and Phenergan to address pain and nausea before discharge is reported. This occurred in the post-anesthesia care unit after aesthetic breast surgery in an ambulatory surgery center. Our patient had immediate injection site pain and a hemorrhagic patch was evident on her physical examination the following day. With local care and hyperbaric oxygen therapy, her lesion improved in appearance. However, she continued to have debilitating pain and was referred to a specialist for osteopathic manipulative therapy (OMT), which had the greatest impact on her pain level. After multi-modal therapy was initiated, the syndrome ultimately resolved without the need for surgical debridement. However, she continues to experience pain and ambulates with a limp due to muscle atrophy. NS is a rare diagnosis that can have devastating complications that can be averted by early recognition and initiation of treatment modalities. In this case, the authors introduced OMT as a new treatment modality, with the potential to improve the progression of this syndrome.\n\nLevel of Evidence: 5\n==== Body\nNicolau syndrome (NS) was first described in the 1920s following intramuscular injection of bismuth salts for the treatment of syphilis.1 Since then, there have been about a hundred case reports written describing this iatrogenic complication. It is a rare syndrome following intramuscular, subcutaneous, intravenous, as well as intra-articular injection of multiple different drugs leading to ischemic necrosis of the skin, soft tissue, and muscle, which arises locoregionally at the injection site.1\n\nThe pathophysiology is not well understood and so treatment and prevention are not well elucidated.1 Here, we present a case report as well as a review of the literature of this rare syndrome following intramuscular injection of Phenergan and Demerol postoperatively after an outpatient aesthetic breast surgery procedure. From this, we hope to increase awareness of NS and to suggest the utility of hyperbaric oxygen (HBO) and introduce osteopathic manipulative treatment (OMT) as a useful treatment for this rare syndrome.\n\nCASE REPORT\n\nA 52-year-old female underwent bilateral breast implant exchange and mastopexy on July 9, 2018 by the senior author (K.M.) at an outpatient surgery center without adverse events from her procedure. After discontinuation of her intravenous access, she was given an intramuscular injection of 12.5 mg of Demerol and 12.5 mg of Phenergan to address pain and nausea for outpatient control before discharge. The injection was made with a 25 gauge needle, 3 cm in length, and was placed at her left anterolateral thigh. She immediately experienced severe injection site pain as well as noted a violaceous patch at the site. Along with pain, she had left lower extremity swelling, but no parasthesias. She was seen in the clinic the following day and the purplish patch appeared less pronounced and appeared ecchymotic with slight induration beneath the skin, along with swelling of her left lower extremity and pain over the lesion (Figure 1). As her pain continued to worsen, she was evaluated in the emergency room later that day. A computed tomography (CT) scan with contrast of her left lower extremity was done and revealed interfascial fluid in the anterior compartment of her proximal thigh and hypodensity within the vastus lateralis and some soft tissue swelling (Figure 2). Labs drawn that same day showed a mild white blood cell count elevation of 13.8 and the complete metabolic panel was within normal limits. She was discharged home under the assumption that this was an extravasation injury. She was encouraged to keep her lower extremity elevated and apply heat or ice for comfort. On postoperative day 2, she was evaluated by dermatology and was treated expectantly for suspected NS and told she should not apply ice to the lesion. Her pain continued to worsen, and she required hospital admission for pain control and expectant management of NS on postoperative day 4. Magnetic resonance imaging obtained in the hospital showed concern for myositis and necrosis in the vastus lateralis and to a lesser degree in the rectus femoris and vastus medialis. All her bloodwork including complete metabolic panel and complete blood count were within normal limits. While in the hospital, an ultrasound-assisted muscle biopsy was also performed, and final pathology showed viable skeletal muscle with focal granulation tissue and limited muscle fiber injury. Microbiology of the specimen showed no growth. She was discharged from the hospital on postoperative day 7 on a pain regimen to include narcotics, nonsteroidal anti-inflammatory drugs (NSAIDs), muscle relaxants, and Lyrica along with antibiotics. As the lesion became increasingly hemorrhagic, violaceous and ischemic appearing with less blanching, it was thought she would benefit from HBO treatment. Thus, on postoperative day 8, she was started on HBO twice daily for a total of 10 treatments (Figure 3). There was an immediate and dramatic improvement in the lesion’s appearance as well as a decrease in size upon initiation of HBO therapy. At her 2-week postoperative visit, the lesion was noted to be shrinking and epidermolysis was noted. There was only superficial desquamation of the skin. At her 2.5-week visit, after completion of 10 HBO treatments, her left thigh lesion was noted to be even smaller with continued epidermolysis and decreased ischemic patches (Figure 4). Although the lesion continued to improve in appearance, she continued to have exquisite, debilitating pain at the site.\n\nFigure 1. A 52-year-old female with a classic pattern of livedoid reticular patch to left lateral thigh seen on post-operative day 1.\n\nFigure 2. Computed tomography (CT) scan of the left lower extremity (LLE) with contrast done on post-operative day 1 with reactive changes noted to vastus lateralis muscle (circled in red above).\n\nFigure 3. Appearance of lesion before hyperbaric oxygen treatment (post-operative day 8).\n\nAt this point, she was referred to an osteopathic physician for further pain management. Our patient’s pain likely stemmed from the initial injection producing a strong enough afferent autonomic pain signal to trigger a very strong efferent sympathetic nervous system (SNS) response causing spasm in one or more arterioles surrounding the injection site in her thigh. The ensuing hypoxic tissue damage produced enough additional pain to perpetuate the strong autonomic response in a vicious cycle of hyper sympathetic activity. Essentially, this is reflex sympathetic dystrophy or complex regional pain syndrome but acted out on a more focal level.\n\nThe patient was given OMT using gentle indirect soft tissue techniques to reduce spasm both locally (in the cutaneous and subcutaneous tissues at and around the lesion site, and in the underlying muscle tissues), regionally (in the upper leg, hip, and pelvis), and more centrally at the involved levels of the spinal cord. Her perceived pain reduced immediately after the first treatment and decreased more markedly over the next 2 treatments. This was accompanied by a significant improvement in vascular perfusion of the lesion area, as evidenced by the rapid reduction in her perceived pain and by observation of improved changes in skin perfusion made at her second osteopathic visit 5 days later (Figure 5). She was recommended further osteopathic treatments; however, she stopped going after her third treatment session (Figure 6).\n\nFigure 4. Appearance of lesion before initiation of osteopathic manipulative therapy (post-operative day 17).\n\nUltimately, on her most recent postoperative visit on postoperative month (POM) 9, her pain was significantly improved but she continues to experience a constant ache. On physical examination, she continues to have contour irregularities and hyperpigmentation at the site of her lesion (Figure 7). She no longer requires ambulatory assistance but continues to walk with a slight limp. She is continuing to see physical therapy and a pain specialist and remains on daily Lyrica and oxycontin for pain.\n\nFigure 5. Appearance of lesion 5 days after first osteopathic manipulative therapy visit (postoperative day 22).\n\nDISCUSSION\n\nFirst described by Freudenthal in 1924 and subsequently by Nicolau in 1925, NS (also known as embolia cutis medicamentosa, livedo-like dermatitis) is a rare complication most commonly following intramuscular injection of a drug.2-4 While intramuscular injection is the most frequent underlying event, it has also been reported after other parenteral routes of administration, such as subcutaneous, intravenous, intra-articular, subacromial, and even intramatricial.2,5 Along with various routes of administration, multiple drugs have been associated with this syndrome, most notably, NSAIDs, antibacterials, antihistamines, local anesthetics, corticosteroids, antipsychotics, interferons, and even vaccinations.2,6\n\nAlthough the pathophysiology of NS remains unclear, there are several theories connecting the syndrome to ischemia caused by thromboembolic occlusion or vascular injury and compression followed by occlusion after injection.2 One theory poses that after peri-arterial or intra-arterial injection, the sympathetic nerve stimulation due to pain leads to vasospasm and ischemia.7,8 Another theory, specific to NSAIDs, depicts vasospasm and ischemia due to blockade of prostaglandin synthesis.9-12 A third theory is based around accidental intra-arterial injection leading to embolic occlusion.13,14 A fourth theory emphasizes perivascular inflammation due to cytotoxic reaction from the injected medication.1,11 Finally, a fifth theory postulates physical obstruction of blood vessels due to lipophilic drugs, which inadvertently penetrated the vessel.9,11,15 Since the pathophysiology is not well understood and the route of administration as well as the drug administered has no apparent correlation, it seems that the injection itself is the common variable leading to this syndrome.2\n\nSince NS is fairly rare and the pathophysiology remains unknown, there are no set diagnostic criteria. However, the common feature of the syndrome is severe injection site pain, which our patient stated she had immediately post-injection. Along with this, is pain out of proportion to physical examination findings, which was also seen in our patient.16 Aside from pain, there is usually rapid development of edema and erythema with a livedoid reticular patch at the injection site. These patches progress to a hemorrhagic appearance with plaques that ultimately may culminate with cutaneous, subcutaneous, and possibly intramuscular necrosis.2 Not all cases develop in this manner, and thus, clinical diagnosis is difficult. The main differential diagnosis that needs to be ruled out is necrotizing fasciitis.2 Diagnosis is mainly based on clinical findings and early recognition is key to allow the implementation of specific therapeutic measures in order to prevent some of the dreaded complications described in the literature.\n\nMost cases describe a somewhat benign course with a resolution with remaining atrophic scar or pigmentation. In some cases of muscular necrosis, surgical debridement is required. However, there have been reports of hypoesthesia and even paraplegia.1 There have also been reports of compartment syndrome of the limb, hyperkalemia, renal failure, sepsis, and even death.16\n\nThere are many proposed treatment strategies for NS, but there is no standardized treatment protocol. Most reports utilize conservative measures to treat symptoms such as multi-modal pain control, antibiotics, dressing changes, and surgical debridement if required. Other measures include anticoagulants, intravenous or topical corticosteroids, and vasoactive therapy (such as nifedipine and pentoxifylline) to relieve vasospasm.1,16 Some cases required fasciotomy for compartment syndrome.10 Other measures to help improve vascularity such as HBO have also been reported. To our knowledge, the use of HBO to treat NS has been reported in 3 other cases in the literature with good results.17-19 In our patient’s case, there was a dramatic improvement in her lesion’s appearance after the institution of HBO and she sustained no complications from her HBO treatments.\n\nThe therapeutic basis of HBO is based on its mechanical effect of increasing environmental pressure on gas containing spaces in the body and the physiologic changes induced by hyperoxia. Due to this hyperoxygenated state, hypoxic tissues are oxygenated, vasoconstrictive effects lessen the edema, leukocyte activation is boosted, and neo-angiogenesis is started, leading to the recovery. Since NS may be due to acute vascular damage and tissue ischemia, HBO therapy may yield its effects by improving tissue oxygen tensions. Even though the mechanism of action of HBO therapy is well elucidated, since the acute vascular response in NS is still unclear, the effect of HBO therapy on patients with NS remains unclear.17 However, based on our observation in our patient, HBO can play a role in the treatment of NS.\n\nFinally, another modality utilized for our patient was OMT. To our knowledge, there is no previous report of using OMT as a treatment for NS. In this form of treatment, the primary goal was reducing the hyperactivity in the SNS, which was causing spasm in one or more arterioles surrounding the injection site in her thigh. At the level of the spinal SNS ganglion, sufficient nociceptive afferent signaling will produce a reflex efferent response that generalizes to the entire segmental autonomic distribution at that level. The vasospasm and other effects produced by a strong SNS motor output will occur in both somatic and visceral structures, and this can result in a stronger and more persistent nociceptive response, resulting in a vicious cycle of pain and spasm (Figure 8).20\n\nFigure 6. Appearance of lesion 12 days after third and last osteopathic manipulative therapy visit (post-operative day 35).\n\nFigure 7. Appearance of lesion at most recent office visit (POM9).\n\nFigure 8. Target cycle of osteopathic manual medicine. (1) Visceral pain sensor, (2) dorsal root ganglion, (3) sympathetic preganglionic neuron, (4) vertebral ganglion, (5) sympathetic postganglionic neuron, (6) arteriole, and (7) somatic pain sensors.\n\nWe hypothesized that this patient’s reaction to the IM injection (needle ± injected material) produced enough afferent autonomic pain signal to trigger a very strong efferent SNS motor response, which caused severe vasospasm in one or more arterioles perfusing the involved area. The ensuing hypoxic tissue damage then produced enough additional pain to perpetuate the strong autonomic response in a vicious cycle of hypersympathetic activity. Essentially, this is reflex sympathetic dystrophy or complex regional pain syndrome, but acted out on a more focal level.\n\nIn osteopathic terminology, the structural and/or physiologic changes caused by this sort of hyperactive SNS feedback loop are called “somatic dysfunction.” This impaired or altered function is not simply a result of static restriction in the compliance of these structures. It is produced and actively maintained by a heightened level of SNS reflex activity at the segmental level of innervation of the involved visceral and anatomic structures.21-29\n\nThe osteopathic approach to treating somatic dysfunction involves working to reduce spasm in soft tissue components both locally at the site of injury and regionally at the structural level of the segmental spinal response. Reducing spasm removes some of the nociceptive input to the feedback loop and improves the flow of fluids into and out of the involved tissues. Better fluid movement leads to better peripheral oxygenation and allows better tissue repair and normalization of local physiology, which further reduces nociceptive input. With enough reduction in nociceptive signaling, the positive feedback is removed from the system, and reflex functions can reestablish their normal equilibriums.\n\nAfter our patient was given osteopathic manipulative treatment, her perceived pain reduced immediately after the first treatment and continued to decrease over the next 2 treatments. This was correlated with a dramatic improvement in vascular perfusion of the lesion area, as noted by the healing rate of her skin lesion thereafter. Furthermore, since our patient discontinued her osteopathic manipulative treatments prematurely, before what was recommended, and was not medically stationary with regard to osteopathic medical treatment, we propose that she may well be in a significantly better shape today if she had continued to receive this form of treatment. Due to the multiple treatments utilized and their subsequent promotion of healing, it is our observation that multi-modal therapy is the key to this syndrome’s resolution as treatment is mainly based on symptomatology.\n\nSome limitations to our study are centered on the rarity of this syndrome. No direct conclusions can be made to the utility of OMT or otherwise, as this study was based on observation of a single patient and multiple modalities were used to treat our patient. Thus, since we cannot run a two-armed study with multiple patients, we can only surmise from our single patient observations.\n\nCONCLUSION\n\nNS is a rare iatrogenic complication due to injection of multiple drugs reported in the literature. It is important to recognize the diagnosis early, so that appropriate treatment modalities can be initiated to help prevent some of the potential dreaded outcomes of this syndrome. We introduce osteopathic manipulative treatment as a new possible treatment modality, with the potential to improve the progression of this syndrome.\n\nPresented at: The Aesthetic Meeting (ASAPS) Residents and Fellows Forum Program 2019 in New Orleans, LA.\n\nDisclosures\n\nThe authors declared no potential conflicts of interest with respect to the research, authorship, and publication of this article.\n\nFunding\n\nThe authors received no financial support for the research, authorship, and publication of this article.\n==== Refs\nREFERENCES\n\n1. Kim SK , Kim TH , Lee KC Nicolau syndrome after intramuscular injection: 3 cases. Arch Plast Surg. 2012;39 (3 ):249-252.22783535\n2. Tabor D , Bertram CG , Williams AJK , Mathers ME , Biswas A Nicolau syndrome (Embolia Cutis Medicamentosa): a rare and poorly recognized iatrogenic cause of cutaneous thrombotic vasculopathy. Am J Dermatopathol. 2018;40 (3 ):212-215.28816739\n3. Freudenthal W Lokales embolisches bismugenol exanthema, sitzungsbericht der schlesischen dermatologischen gesellschaft vom (in German). Geschlechtskr. 1924;11 :400.\n4. Nicolau P Dermite livedoide et gangreneuse de la fesse consecutive aux injections intramusculaire de la syphilis (in French). Ann Venereol Mal Venereol. 1925;20 :321.\n5. Grover C , Kharghoria G , Daulatabad D , Bhattacharya SN Nicolau syndrome following intramatricial triamcinolone injection for nail lichen planus. Indian Dermatol Online J. 2017;8 (5 ):350-351.28979869\n6. Nischal K , Basavaraj H , Swaroop M , Agrawal D , Sathyanarayana B , Umashankar N Nicolau syndrome: an iatrogenic cutaneous necrosis. J Cutan Aesthet Surg. 2009;2 (2 ):92-95.20808597\n7. Kılıç İ , Kaya F , Özdemir AT , Demirel T , Çelik İ Nicolau syndrome due to diclofenac sodium (Voltaren®) injection: a case report. J Med Case Rep. 2014;8 :404.25471251\n8. Hatefi M , Pirabadi NR , Khajavikhan J , Jaafarpour M Claudication due to sciatic nerve palsy following Nicolau syndrome: a case report. J Clin Diagn Res. 2015;9 (10 ):RD01-RD02.\n9. Rygnestad T , Kvam AM Streptococcal myositis and tissue necrosis with intramuscular administration of diclofenac (Voltaren). Acta Anaesthesiol Scand. 1995;39 (8 ):1128-1130.8607323\n10. Enshaei A , Afshar A Compartment syndrome of the calf due to Nicolau syndrome. Arch Bone Jt Surg. 2016;4 (1 ):87-89.26894227\n11. Faucher L , Marcoux D What syndrome is this? Nicolau syndrome. Pediatr Dermatol. 1995;12 (2 ):187-190.7659650\n12. Lie C , Leung F , Chow SP Nicolau syndrome following intramuscular diclofenac administration: a case report. J Orthop Surg (Hong Kong). 2006;14 (1 ):104-107.16598099\n13. Saputo V , Bruni G [Nicolau syndrome caused by penicillin preparations: review of the literature in search for potential risk factors]. Pediatr Med Chir 1998;20 (2 ):105-123.9706633\n14. Stiehl P , Weissbach G , Schröter K [Nicolau syndrome. Pathogenesis and clinical aspects of penicillin-induced arterial embolism]. Schweiz Med Wochenschr. 1971;101 (11 ):377-385.5558551\n15. Okan G , Canter HI Nicolau syndrome and perforator vessels: a new viewpoint for an old problem. Cutan Ocul Toxicol. 2010;29 (1 ):70-72.20038267\n16. Memarian S , Gharib B , Gharagozlou M , Alimadadi H , Ahmadinejad Z , Ziaee V Nicolau syndrome due to penicillin injection: a report of 3 cases without long-term complication. Case Rep Infect Dis. 2016;2016 :9082158.27882254\n17. Ergul Y , Soydemir D , Tastan Y , Omeroglu RE Does early hyperbaric oxygen therapy prevent extremity necrosis in Nicolau syndrome? Pediatr Int. 2012;54 (3 ):e15-e18.22631583\n18. Ocak S , Ekici B , Cam H , Taştan Y Nicolau syndrome after intramuscular benzathine penicillin treatment. Pediatr Infect Dis J. 2006;25 (8 ):749.16874179\n19. Yildiz C , Ozkan H , Ay H A case of Nicolau syndrome treated with hyperbaric oxygen. Cent Eur J Med. 2009;4 :262-264.\n20. Korr IM The neural basis of the osteopathic lesion. J Am Osteopath Assoc. 1947;47 (4 ):191-198.18910957\n21. American Association of Colleges of Osteopathic Medicine. Glossary of Osteopathic Terminology. Association of Colleges of Osteopathic Medicine 2003 Updated October 2011. https://www.aacom.org/docs/default-source/insideome/got2011ed.pdf?sfvrsn=2. Accessed April 2019.\n22. Korr IM , ed. The Neurobiologic Mechanisms in Manipulative Therapy, 1st ed. New York, NY and England: Plenum Press; 1978.\n23. Korr IM Proprioceptors and somatic dysfunction. J Am Osteopath Assoc. 1975;74 (7 ):638-650.124754\n24. Korr IM The spinal cord as organizer of disease processes: some preliminary perspectives. J Am Osteopath Assoc. 1976;76 (1 ):35-45.1048965\n25. Korr IM The spinal cord as organizer of disease processes: II. The peripheral autonomic nervous system. J Am Osteopath Assoc. 1979;79 (2 ):82-90.\n26. Korr IM The spinal cord as organizer of disease processes: III. Hyperactivity of sympathetic innervation as a common factor in disease. J Am Osteopath Assoc. 1979;79 (4 ):232-237.583147\n27. Korr IM The spinal cord as organizer of disease processes: IV. Axonal transport and neurotrophic function in relation to somatic dysfunction. J Am Osteopath Assoc. 1981;80 (7 ):451-459.6263830\n28. Korr IM Somatic dysfunction, osteopathic manipulative treatment, and the nervous system: a few facts, some theories, many questions. J Am Osteopath Assoc. 1986;86 (2 ):109-114.3753964\n29. Liem T Intuitive judgement in the context of osteopathic clinical reasoning. J Am Osteopath Assoc 2017;117 (9 ):586-594.28846125\n\n",
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"title": "A Case Report of Nicolau Syndrome After Aesthetic Breast Surgery: A Review of the Literature and Introduction to a New Treatment Modality.",
"title_normalized": "a case report of nicolau syndrome after aesthetic breast surgery a review of the literature and introduction to a new treatment modality"
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"abstract": "Tourette syndrome is a complex neuropsychiatric disorder with a wide phenotypic spectrum, including tics and psychiatric comorbidities, such as obsessive-compulsive disorder and attention-deficit disorder. Often considered a neurodevelopmental disorder, it is most prevalent during childhood and treatment strategies can vary according to degree of severity and patient-specific symptom manifestations. This review focuses on established and emerging management options for tics, including behavioral interventions and nonpharmacologic therapies, medication management, and promising surgical approaches.",
"affiliations": "Movement Disorders Neuromodulation & Brain Circuit Therapeutics, Neurology, Icahn School of Medicine at Mount Sinai, Mount Sinai West, 1000 10th Avenue, Suite 10C, New York, NY 10019, USA. Electronic address: Joohi.Jimenez-Shahed@mountsinai.org.",
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"abstract": "Posterior reversible encephalopathy syndrome (PRES) and human herpesvirus (HHV)-6 encephalitis are both serious neurological complications post hematopoietic stem cell transplantation. Although infection is one of the important causes of PRES, only few cases have reported the relation between PRES and viral infection. Herein, we report the first adult case of PRES concurrent with HHV-6 encephalitis after allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia. This case suggests that HHV-6 reactivation is associated with the pathogenesis of PRES. Also, PRES and HHV-6 encephalitis cause similar symptoms, and switching the immunosuppressant from calcineurin inhibitor to prednisolone for treating PRES may worsen HHV-6 encephalitis. Therefore, we should pay attention to the complication of HHV-6 encephalitis even after PRES is diagnosed.",
"affiliations": "Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo, Japan.;Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo, Japan.;Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo, Japan.;Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo, Japan.;Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo, Japan.;Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo, Japan; Department of Cell Therapy and Transplantation Medicine, The University of Tokyo Hospital, Japan. Electronic address: kurokawa-tky@umin.ac.jp.",
"authors": "Ito|Yusuke|Y|;Toyama|Kazuhiro|K|;Honda|Akira|A|;Nakazaki|Kumi|K|;Arai|Shunya|S|;Kurokawa|Mineo|M|",
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"mesh_terms": "D000998:Antiviral Agents; D018792:Encephalitis, Viral; D017245:Foscarnet; D018380:Hematopoietic Stem Cell Transplantation; D015654:Herpesvirus 6, Human; D006801:Humans; D007166:Immunosuppressive Agents; D008297:Male; D008875:Middle Aged; D054038:Posterior Leukoencephalopathy Syndrome; D019349:Roseolovirus Infections; D014184:Transplantation, Homologous; D016896:Treatment Outcome",
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"title": "Posterior reversible encephalopathy syndrome concurrent with human herpesvirus-6B encephalitis after allogeneic hematopoietic stem cell transplantation.",
"title_normalized": "posterior reversible encephalopathy syndrome concurrent with human herpesvirus 6b encephalitis after allogeneic hematopoietic stem cell transplantation"
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"abstract": "A recent increase in the incidence of ventricular arrhythmias has been observed with the consumption of large dosages of the anti-diarrheal agent, loperamide. Our case is unique in that our patient not only displayed ventricular tachycardia (VT) but sustained VT (known as a VT storm). In this era of the opioid crisis, clinicians should be aware of all of the over-the-counter medications that have opioid-like side effects.",
"affiliations": "Internal Medicine, University of Kansas School of Medicine, Wichita, USA.;Internal Medicine, University of Kansas School of Medicine, Wichita, USA.;Cardiology, University of Kansas School of Medicine, Wichita, USA.;Internal Medicine, University of Kansas School of Medicine, Wichita, USA.",
"authors": "Al-Khatib|Jihad|J|;Vindhyal|Shravani R|SR|;Boppana|Venkata S|VS|;Vindhyal|Mohinder R|MR|",
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"fulltext": "\n==== Front\nCureusCureus2168-8184Cureus2168-8184Cureus Palo Alto (CA) 10.7759/cureus.3981CardiologyInternal MedicineVentricular Tachycardia Storm Induced by Loperamide Abuse Muacevic Alexander Adler John R Al-khatib Jihad 1Vindhyal Shravani R 1Boppana Venkata S 2Vindhyal Mohinder R 1\n1 \nInternal Medicine, University of Kansas School of Medicine, Wichita, USA \n2 \nCardiology, University of Kansas School of Medicine, Wichita, USA \nMohinder R. Vindhyal mvindhyal@hotmail.com29 1 2019 1 2019 11 1 e398116 1 2019 29 1 2019 Copyright © 2019, Al-khatib et al.2019Al-khatib et al.This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.This article is available from https://www.cureus.com/articles/17447-ventricular-tachycardia-storm-induced-by-loperamide-abuseA recent increase in the incidence of ventricular arrhythmias has been observed with the consumption of large dosages of the anti-diarrheal agent, loperamide. Our case is unique in that our patient not only displayed ventricular tachycardia (VT) but sustained VT (known as a VT storm). In this era of the opioid crisis, clinicians should be aware of all of the over-the-counter medications that have opioid-like side effects. \n\nventricular tachycardialoperamideopioid crisisThe content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus.\n==== Body\nIntroduction\nLoperamide is a commonly used and relatively safe anti-diarrheal agent that is available over-the-counter. The drug primarily works as an opioid receptor agonist within the gastrointestinal tract to decrease intestinal motility. In recent years, substance abusers have exploited the drug's agonizing opioid properties by ingesting large amounts of the drug to induce symptoms of euphoria. We present a case with a ventricular tachycardia storm following ingestion of large doses of loperamide. \n\nCase presentation\nA 43-year-old female patient with a past medical history of substance use disorder (SUD) was brought to the hospital by emergency medical services (EMS) presenting with multiple episodes of dizziness, shortness of breath, and palpitations. EMS reported ventricular tachycardia (VT) while in transit to the hospital for which she was externally defibrillated 10 times without any resolution of the ventricular arrhythmia. The patient’s past medical history was positive for depression and substance abuse of hydrocodone dating back to 2007. The patient’s husband denied any history of cardiac arrhythmias, structural heart disease, or ischemic heart disease. The patient’s husband denied using any medications, including herbal supplements, but reported drug allergies to amoxicillin and erythromycin. The patient’s social history revealed that she worked at a consignment store and had a history of alcohol and marijuana abuse. The patient’s husband also revealed recreational usage of loperamide at approximately 400 mg in the last 24 hours before the presentation. On physical exam in the emergency department, she appeared to be in moderate distress with pain from the external defibrillations. Her vital signs consisted of an elevated pulse of > 200 beats per minute (bpm), an elevated blood pressure of 157/80, and an increased respiratory rate at 24/minute. The pulmonary exam revealed decreased breath sounds bilaterally with symmetrical chest wall expansion. The cardiovascular exam revealed tachycardia with no murmurs reported. Examination of the head and neck showed moist mucous membranes with no jugular venous distension. The gastrointestinal exam was negative for distention, tenderness, rebound, guarding, hepatomegaly, or splenomegaly. The musculoskeletal exam revealed warm and well-perfused upper and lower extremities free of clubbing, cyanosis, and edema. In the processes of placing the electrocardiogram (EKG) electrodes onto the patient in the emergency room, the patient became unresponsive and the two lead EKG monitors showed polymorphic VT with a heart rate of 220 per minute and blood pressure of 84/58. The patient was immediately defibrillated once again before being sedated, intubated, and started on an amiodarone drip. The patient’s vitals were stabilized for 15 minutes before she went into another episode of polymorphic VT despite the amiodarone drip. The patient underwent synchronized cardioversion, and once her vitals stabilized, she underwent a cardiac catheterization which showed patent coronaries and a normal ejection fraction. The patient got transferred to the Medical Intensive Care Unit (MICU) for continuous monitoring and was started on a lidocaine drip in addition to the amiodarone drip. Her EKG in the MICU is shown below in Figure 1.\n\nFigure 1 Electrocardiogram showing polymorphic ventricular tachycardia\nIn the MICU, the patient continued to have polymorphic VT episodes despite medical management and went in and out of VT episodes approximately 16 times with each episode lasting between 30 seconds to two minutes. Subsequently, the patient had a transvenous cardiac pacer placed which stabilized her vital signs. After 72 hours, the pacer was removed, and the patient remained stable on amiodarone and lidocaine. Transthoracic echocardiogram in the MICU revealed a normal ejection fraction with no valvular abnormality. Serum electrolytes were within normal limits, and the urine drug screen was also negative. After the temporary pacer was removed, the patient subsequently remained in sinus rhythm with a heart rate of 70 bpm, QRS duration of 98 ms, and a QTc interval of 456 ms as seen in Figure 2.\n\nFigure 2 Electrocardiogram showing normal sinus rhythm (NSR) and normal QTc\nAfter five days of hospitalization, the effects of the loperamide had completely resolved, and the patient remained in normal sinus rhythm on amiodarone until discharge and followed up a month later.\n\nDiscussion\nThe number of published case reports with regards to loperamide toxicity has been gradually increasing [1]. A total of 54 case reports have been published from 1985 to 2016, with 21 of those cases occurring between 1985 to 2013 and the remaining 33 cases occurring between 2014 and 2016. [1] Aside from published case reports, the National Poison Database System reports a total of 179 cases of intentional loperamide misuse between 2008 - 2016 with over half of those cases occurring after 2014 [1]. Consequently, the increasing trend in the misuse of the anti-diarrheal agent has shed light on its life-threatening cardiotoxic effects and arrhythmias, such as ventricular tachycardia storm (VTS). Ventricular tachycardia is a life-threatening cardiac arrhythmia brought on by those with structural heart disease, ischemic heart disease, and serum electrolyte abnormalities [2]. VTS is characterized by greater than or equal to three episodes of sustained VT, ventricular fibrillation (VF), or implantable cardioverter-defibrillator therapy within a 24-hour timeframe [3]. Loperamide is an anti-diarrheal agent that can be purchased over-the-counter and is commonly used and relatively inexpensive. The drug is a is a synthetic opiate that acts on peripheral µ opioid receptors primarily located within the gastrointestinal tract to decrease intestinal transit time and increase rectal tone [4]. Due to the drug's rapid metabolism and its inability of crossing the blood-brain barrier at therapeutic doses (2 - 16 mg), it is unable to precipitate the sought-after side effect of euphoria amongst substance abusers [5]. However, in recent years, substance abusers have exploited the drug's potent opioid agonizing properties by ingesting large doses (50 - 300 mg) of the drug to induce symptoms of euphoria [6-8]. Investigative studies have looked into loperamide’s inhibitory effects on L-type cardiac calcium channels which could, in turn, cause QT prolongation and lead to polymorphic VT [9]. However, the exact mechanism for loperamide’s cardiotoxicity associated with ventricular arrhythmias, QTc prolongation, and QRS prolongation are not clearly understood [10]. Our patient reported ingesting close to 400 mg per day and presented with sustained VT despite 10 attempts of external cardiac defibrillation. The uniqueness of our case is that our patient not only experienced one episode of VT but also had sustained and recurrent polymorphic VT with loperamide.\n\nConclusions\nAbrupt resolution of the VT, normalization of the patient's heart rate, QRS duration, and QTc interval without the need for an anti-arrhythmic after discontinuation of loperamide makes us believe a causal relationship exists, but the pathogenesis remains unclear. Future studies should focus on the cardiotoxic mechanisms associated with loperamide.\n\nThe authors have declared that no competing interests exist.\n\nHuman Ethics\nConsent was obtained by all participants in this study\n==== Refs\nReferences\n1 Ventricular tachycardia and sudden cardiac death Mayo Clin Proc Koplan BA Stevenson WG 289 297 84 2009 19252119 \n2 Loperamide misuse and abuse J Am Pharm Assoc (2003) Miller H Panahi L Tapia D Tran A Bowman JD 0 57 2017 \n3 The evaluation and management of electrical storm Tex Heart Inst J Eifling M Razavi M Massumi A 111 121 38 2011 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3066819/ 21494516 \n4 Loperamide induced life threatening ventricular arrhythmia Case Rep Cardiol Upadhyay A Bodar V Malekzadegan M Singh S Frumkin W Mangla A Doshi K 5040176 2016 2016 27547470 \n5 FDA Drug Safety Communication: FDA warns about serious heart problems with high doses of the antidiarrheal medicine loperamide (Imodium), including from abuse and misuse 10 2018 2016 http://www.fda.gov/Drugs/DrugSafety/ucm504617.htm \n6 Abuse of prescription drugs in the context of novel psychoactive substances (NPS): a systematic review Brain Sci Schifano F Chiappini S Corkery JM Guirguis A 0 8 2018 \n7 Not your regular high: cardiac dysrhythmias caused by loperamide Clin Toxicol (Phila) Wightman RS Hoffman RS Howland MA Rice B Biary R Lugassy D 454 458 54 2016 27022002 \n8 Cardiac conduction disturbance after loperamide abuse Clin Toxicol (Phila) Marraffa JM Holland MG Sullivan RW Morgan BW Oakes JA Wiegand TJ Hodgman MJ 952 957 52 2014 25345436 \n9 Loperamide blocks high voltage-activated calcium channels and N-methyl-D-aspartate-evoked responses in rat and mouse cultured hippocampal pyramidal neurons Mol Pharmacol Church J Fletcher EJ Abdel-Hamid K MacDonald JF 747 757 45 1994 http://molpharm.aspetjournals.org/content/45/4/747 8183255 \n10 Proarrhythmic mechanisms of the common anti-diarrheal medication loperamide: revelations from the opioid abuse epidemic Naunyn Schmiedebergs Arch Pharmacol Kang J Compton DR Vaz RJ Rampe D 1133 1137 389 2016 27530870\n\n",
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"issue": "11(1)",
"journal": "Cureus",
"keywords": "loperamide; opioid crisis; ventricular tachycardia",
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"title": "Ventricular Tachycardia Storm Induced by Loperamide Abuse.",
"title_normalized": "ventricular tachycardia storm induced by loperamide abuse"
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"abstract": "Bilateral enlarged adrenal glands are rare, and as diagnostic delay may have serious consequences for the patient, we recommend a multidisciplinary approach of specialists in the field of endocrinology, oncology, radiology, and clinical chemistry prior to the start of the diagnostic work-up.",
"affiliations": "Department of Internal Medicine Rijnstate Hospital Arnhem the Netherlands.;Department of Internal Medicine Rijnstate Hospital Arnhem the Netherlands.;Department of Internal Medicine Rijnstate Hospital Arnhem the Netherlands.;Department of Internal Medicine Rijnstate Hospital Arnhem the Netherlands.",
"authors": "Drenthen|Linda C A|LCA|;Roerink|Sean H P P|SHPP|0000-0001-7407-9127;Mattijssen|Vera|V|;de Boer|Hans|H|",
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"fulltext": "\n==== Front\nClin Case RepClin Case Rep10.1002/(ISSN)2050-0904CCR3Clinical Case Reports2050-0904John Wiley and Sons Inc. Hoboken 10.1002/ccr3.1340CCR31340Case ReportCase ReportsBilaterally enlarged adrenal glands without obvious cause: need for a multidisciplinary diagnostic work‐up L. C. A. Drenthen et al.Drenthen Linda C. A. \n1\nRoerink Sean H. P. P. http://orcid.org/0000-0001-7407-9127sean.roerink@radboudumc.nl \n1\nMattijssen Vera \n1\nde Boer Hans \n1\n\n1 \nDepartment of Internal Medicine\nRijnstate Hospital\nArnhem\nthe Netherlands\n* Correspondence\n\nSean H. P. P. Roerink, Department of Internal Medicine, Rijnstate Hospital, Arnhem, the Netherlands. Tel: +3124‐3616504; E‐mail: sean.roerink@radboudumc.nl\n03 3 2018 4 2018 6 4 10.1002/ccr3.2018.6.issue-4729 734 08 6 2017 21 11 2017 28 11 2017 © 2018 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.This 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.Key clinical message\nBilateral enlarged adrenal glands are rare, and as diagnostic delay may have serious consequences for the patient, we recommend a multidisciplinary approach of specialists in the field of endocrinology, oncology, radiology, and clinical chemistry prior to the start of the diagnostic work‐up.\n\nAdrenal glandsbilateraldiagnostic delaymultidisciplinary source-schema-version-number2.0component-idccr31340cover-dateApril 2018details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:version=5.3.4 mode:remove_FC converted:06.04.2018\n\nClinical Case Reports \n2018 ; 6 (4 ): 729 –734\n==== Body\nIntroduction\nAlthough bilateral adrenal masses without obvious cause are rare, their incidence is increasing due to the improvement of radiological detection techniques and their frequent use 1, 2. Epidemiological studies focusing on this subject have been mainly performed in Asia, which limits generalization to the Western population. One retrospective analysis carried out in a tertiary center in India included 70 patients with bilateral adrenal masses of which 87.1% had a symptomatic presentation. The remaining 13.9% was incidentally detected. The underlying pathology was found to be a pheochromocytoma (40%), tuberculosis (27.1%), primary adrenal lymphoma (PAL) (10%), metastasis (5.7%), nonfunctioning adenomas (4.3%), and macronodular adrenal hyperplasia (4.3%) 1. Another retrospective study performed in China included eighteen patients of which 78% was symptomatic and reported pheochromocytoma (33%), PAL (22%), nonfunctional cortical adenoma (22%), and metastasis (11%) as the most common causes of bilateral adrenal masses 2. It is generally believed that biochemical screening for pheochromocytoma is crucial to prevent the potentially catastrophic effects of a hypertensive crisis caused by manipulation of the adrenal mass 3, 4. The present case series reviews the diagnostic work‐up of three cases with bilateral massively enlarged adrenal glands caused by rare underlying disorders and discusses the options to reduce diagnostic delay to a minimum.\n\nCase Reports\nCase 1\nThe first patient is an 82‐year‐old woman who was referred to the oncologist because of unintended weight loss of approximately 10 kilogram (kg) over the past three months, progressive fatigue, vertigo, nausea, and aversion to meals. Her medical history was limited to hypothyroidism caused by goiter surgery 45 years ago, which was treated with levothyroxine 100 μg daily. Physical examination revealed hypotension (98/64 mmHg), without other remarkable findings. Computerized tomography (CT) scan showed a homogeneous, hypodense, massive enlargement of both adrenal glands, with a radiological density of 30 Hounsfield Units (HU) after contrast infusion and without any washout. There were no signs of lymphadenopathy or hepatosplenomegaly. Subsequently, a fluorodeoxyglucose (FDG) positron emission tomography (PET) scan showed high FDG uptake in both adrenal glands (left 7.5 × 6.4 × 4.6 cm, right 8.1 × 5.8 × 3.9 cm; Figure 1), without evidence for a primary tumor elsewhere. Laboratory examination revealed a decreased sodium level of 125 mmol/L (normal range (NR): 135–145 mmol/L) and evidence of primary adrenal insufficiency (a decreased fasting cortisol of 107 nmol/L (NR: 171–536 nmol/L) and midday cortisol of 111 nmol/L (NR: 64–327 nmol/L), with elevated ACTH levels of 241 ng/L and 225 ng/L, respectively (NR: <46 ng/L)). Thyroid‐stimulating hormone (TSH) was 1.96 mU/L (NR 0.3–4.0 mU/L) combined with a free thyroxine (FT4) of 22 pmol/L (NR 11–25 pmol/L). Treatment with hydrocortisone (10 mg in the morning, 5 mg at lunch, and 5 mg in the late afternoon) daily was started. Late‐onset bilateral hyperplasia was considered but later discarded as a possibility when plasma 17‐hydroxyprogesterone concentration was found to be normal (1.51 nmol/L, NR <6 nmol/L). Normal values of normetanephrines and metanephrines in 24‐h urine were found (normetanephrine 1.27 μmol/24 h, NR <4.4 μmol/24 h; metanephrine <0.03 μmol/24 h, NR <2.0 μmol/24 h). The interferon‐gamma release assay for mycobacterium tuberculosis was negative, and plasma chromogranine A was within the normal range (29 μg/L, NR 27–94 μg/L). A few weeks after initial presentation, the patient was admitted to the hospital because of an Addison crisis and hypercalcemia (calcium 3.21 mmol/L, NR: 2.20–2.65 mmol/L; albumin 32 g/L, NR: 35–50 g/L). There were no signs of infection on physical and laboratory examination (C‐reactive protein 8 mg/L, NR <10 mg/L; leukocytes 5.0 × 109/L, NR 4.0–11.0 × 109/L). The adrenal crisis was attributed to the erratic use of hydrocortisone because of cognitive deterioration. The combination of hypercalcemia, suppressed PTH levels (<0.3 pmol/L, NR 1.3–6.8 pmol/L) and a normal plasma 25‐hydroxyvitamin D (84 nmol/L, NR >50 nmol/L) raised the suspicion of a lymphoma or bone metastases. The patient was treated with hydration, glucocorticoids, and bisphosphonates. An adrenal biopsy was performed and led to a diagnosis of diffuse large B‐cell lymphoma (DLBCL), classified as stage IVB, with a small B‐cell lymphoma component in the bone marrow specimen. Treatment consisted of six courses rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R‐CHOP21) followed by two courses of rituximab only. Six months later, the PET scan showed complete remission. At this moment, four years after diagnosing PAL, the patient is still in complete remission of her lymphoma. She is currently adequately substituted with hydrocortisone, which was confirmed by repeated early morning cortisol measurements within the normal range. The diagnostic work‐up in this case took over four months.\n\nFigure 1 PET scan of patient 1 showing bilateral enlarged adrenal glands (left 7.5 × 6.4 × 4.6 cm, right 8.1 × 5.8 × 3.9 cm) with highfludeoxyglucose uptake.\n\nCase 2\nThe second patient is an 84‐year‐old woman who was referred to the hematologist because of malaise, progressive fatigue, five kg weight loss, and an elevated erythrocyte sedimentation rate (ESR). Sixteen years previously, she was diagnosed with breast cancer, successfully treated with surgery and radiation therapy. Physical examination at presentation was unremarkable. Blood pressure was 160/88 mmHg. Laboratory examination showed an ESR of 57 mm/h (NR: 1–30 mm/h) and an elevated lactate dehydrogenase of 614 U/L (NR: <250 U/L). No M‐protein was detected. Serum calcium was slightly elevated (2.66 mmol/L) in the face of a normal albumin level (42.2 g/L). Total body CT scan showed homogeneous bilaterally enlarged adrenal glands (left 3.2 × 4.5 cm, right 3.5 × 3.9 cm) with a radiological density of 80 HU after contrast infusion (Figure 2). Adrenal biopsy, performed without prior screening for pheochromocytoma or adrenal insufficiency and without consultation with an endocrinologist, led to the diagnosis of DLBCL, later classified as stage IVB. The patient was treated with chemotherapy consisting of six courses R‐CHOP21 and achieved complete remission. The diagnostic work‐up took over three months. Three and a half years later, the patient died from acute cardiac ischemia.\n\nFigure 2 CT scan of patient 2 showing bilateral homogeneous enlarged adrenal glands (left 3.2 × 4.5 cm, right 3.5 × 3.9 cm) and two hepatic cysts.\n\nCase 3\nThe third patient is a 52‐year‐old, homeless woman with a negative medical history, who was referred to the department of oncology because of weight loss of approximately 30 kg in nine months, generalized abdominal pain, excessive sweating, and hot flushes mainly occurring during the night. She smoked twenty cigarettes a week, but did not use alcohol or drugs. Physical examination only revealed hepatomegaly. Blood pressure was normal (133/87 mmHg), and laboratory examination revealed a severe microcytic anemia (hemoglobin 3.5 mmol/L, NR 7.4–9.9 mmol/L (equal to 5.64 g/dL; NR 12–18 g/dL); MCV 67 fL, NR 80–100 fL), elevated liver enzymes (alkaline phosphatase 405 U/L, aspartate aminotransferase 46 U/L, gamma‐glutamyl transpeptidase 109 U/L; NR: <120 U/l, <30 U/L, and <40 U/L, respectively), and a lactate dehydrogenase of 1757 U/L. Malignant lymphoma was suspected because of the presence of B‐symptoms and the enormously increased lactate dehydrogenase. The CT scan showed a massive enlargement of both adrenal glands, in particular on the left side (15.3 × 10.0 × 15.6 cm) which was a heterogeneous mass with some hypodense areas. The right adrenal gland was a lobed mass of approximately 5 cm. Subsequently, diffuse pulmonary and hepatic lesions were described as well as lymphatic lesions localized left para‐aortal, left para‐iliacal, and in the left renal hilum, suggesting metastatic disease (Figure 3). Adrenal insufficiency was excluded by a fasting plasma cortisol of 588 nmol/L. Despite the fact that the patient was normotensive, it was decided that a pheochromocytoma had to be excluded biochemically before performing a diagnostic adrenal biopsy. An incompletely collected 24‐h urine sample showed a normal normetanephrine level of 3.5 μmol/24 h, with a normal metanephrine (0.65 μmol/24 h). 1.23I‐metaiodobenzylguanidine (1.23I‐MIBG) scan turned out to be negative. The physical condition of the patient deteriorated, and after consultation with the endocrinologist, 24‐h urine was collected again, now using a urinary catheter to ensure a complete sample. This yielded an elevated normetanephrine of 9.17 μmol/24 h and a normal metanephrine level of 0.65 μmol/24 h. 5‐hydroxyindoleacetic (5‐HIAA) proved to be normal (1.1 μmol/mmol creat, NR 0.5–4.0 μmol/mmol creat). In view of the massive tumor load and the relatively mild increases in normetanephrine, it was concluded that metastatic pheochromocytoma was highly unlikely and that a diagnostic biopsy was indicated. This led to a diagnosis of chromophobe renal cell carcinoma (ChRCC). Only limited treatment options with serious adverse effects were available. The patient chose to decline medical treatment targeting her metastatic disease and went to a hospice. The whole diagnostic work‐up covered almost two months.\n\nFigure 3 CT scan of patient 3 showing metastatic disease with multiple hepatic lesions, enlargement of both adrenal glands (left 15.3 × 10.0 × 15.6 cm (arrow), right approximately 5 cm; a), and a Bosniak 2F lesion in the right kidney (arrow b). Bosniak 2F lesions are generally benign, with a malignancy rate of 3–12% 25, 26.\n\nDiscussion\nIn this small case series, we describe three cases with bilateral massively enlarged adrenal glands. The time from the first presentation to final diagnosis was two to four months which is much longer than desirable or necessary. Several aspects have played a role in this diagnostic delay, including rareness of the final diagnosis, limited analytic experience with this clinical presentation within a single subspecialism of internal medicine, suboptimal diagnostic choices, and inappropriate timing of diagnostics.\n\nCase 1 and 2 represent two patients diagnosed with a PAL. The pathology of both cases showed a DLBCL, which is with 78% of all cases the most common subtype of PAL 5. Less than 200 cases of PAL have been reported, mainly in studies performed in Asia. PAL is characterized as a highly symptomatic, large (median size 8 cm), hypodense tumor that presents as a bilateral adrenal tumor in approximately 75% of the patients 5. Review of the literature shows that 61% of the patients with PAL have adrenal insufficiency. This may be an overestimation because of publication bias, however, even small size PAL may cause adrenal insufficiency, probably due to diffuse infiltration and complete destruction of the adrenal tissue architecture 5, 6, 7.\n\nCase 3 was diagnosed with a ChRCC that accounts for only 5% of all renal cell carcinomas (RCC). Knowledge regarding ChRCC is scarce. Metastases occur in approximately 6–7% of the cases, most commonly in the liver (33–39%) or lungs (33–36%) 8, 9. The medical literature reports only one case of bilateral adrenal metastases of ChRCC, detected six years after initial nephrectomy 10. Sunitinib, a tyrosine kinase inhibitor, is one of its recommended therapies, although with potentially adverse effects and a limited response rate 8. Bilateral adrenal metastases of a RCC are described in less than twenty cases in the literature and concern in most cases a clear cell RCC 9.\n\nThe diagnostic work‐up of the adrenal masses in this case series was delayed, and this may be detrimental to patients with a treatable disease. According to current knowledge, pheochromocytoma must be excluded in case of typical signs or symptoms, when an adrenal incidentaloma is found or when there is a hereditary predisposition. Pheochromocytomas affect only 2–8 per 1,000,000 persons each year and are present in 0.2–0.6% of all hypertensive patients 3, 4, 11. Its prevalence in patients with uni‐ and bilateral adrenal enlargement is 4–5% 4, 11, 12 and 30–40%, respectively 1, 2. This high prevalence of pheochromocytoma found in patients with bilateral adrenal masses is possibly biased as only two epidemiological studies are found in literature, both of which performed in Asia and included mainly patients with a symptomatic presentation. Moreover, Lomte et al. studied patients in a tertiary hospital with two‐thirds of their patients having a familial or syndromic association of pheochromocytoma 1 and Zhou et al. studied only a limited number of eighteen patients 2.\n\nManipulation of a (unrecognized) pheochromocytoma can result in hypertensive crisis, cardiac arrhythmias, cerebral vascular accident, pulmonary edema, myocardial infarction, and multi‐organ failure 3. This may occur during surgery as well as during adrenal biopsies. Therefore, it is important to recognize the possibility of the tumor and it is recommended to exclude a pheochromocytoma biochemically before executing an adrenal biopsy in patients with adrenal masses 4, 13, 14, 15, 16. About 10% of all pheochromocytomas are malignant and may present as metastatic disease 4, 11. The classic triad of (episodic) palpitations, headache, and sweating is not always present, and hypertension may be absent 3, 4, 11.\n\nImaging characteristics may serve to raise suspicion of pheochromocytoma in case an adrenal incidentaloma is detected or may be used to localize the tumor in case a pheochromocytoma is suspected biochemically 4. The radiological density of pheochromocytomas on CT is usually greater than 10 HU, and cystic areas, calcifications, necrosis, and hemorrhage are frequently observed 4, 12, 17. Washout of contrast medium is usually delayed 12, 18. High signal intensity on T2‐weighted MRI images is characteristic of pheochromocytoma; however, it may be absent in as much as 35% of the cases 17, 18, 19. Functional imaging with 1,23I‐MIBG scanning may show focal uptake of the norepinephrine analogue 17, 20. However, up to 50% of the normal adrenal glands will also store this analogue physiologically and this may cause a high number of false positives 4. Nevertheless, for the purpose of localizing pheochromocytoma, 1.23I‐MIBG scanning is preferred over FDG‐PET scanning because of its higher sensitivity (85–94% and 76%, respectively 4). However, 68Ga‐DOTANOC PET‐CT scan can also be used because of the expression of somatostatin receptors by pheochromocytoma. It shows a high sensitivity and specificity (92% and 85%, respectively) in patients with the suspicion of pheochromocytoma and may be therefore superior to 1.23I‐MIBG scanning 21. Because the specificity of these radiological characteristics is too limited to provide a definitive diagnosis, biochemical testing is always needed for diagnosing or excluding pheochromocytomas 16.\n\nPheochromocytoma may be diagnosed by measuring fractionated metanephrines in a 24‐h urine collection or by measurement of plasma‐free metanephrines 4. Plasma‐free metanephrines may have a slightly higher sensitivity but a lower specificity compared to urinary fractionated metanephrines (96–100% relative to 91–98% and 85–89% compared to 91–98%, respectively) 12. One multicenter study confirmed the slightly higher sensitivity of plasma‐free metanephrines (99% relative to 97%), and they also found a higher specificity (89% relative to 69%) 22. Other considerations to prefer plasma measurements over 24‐h urine collections are patient convenience and no risk of incomplete urine collections.\n\nCurrent consensus is that surgical procedures or biopsies in patients with pheochromocytoma should be preceded by α‐adrenergic blockade with either phenoxybenzamine or doxazosin as the first choice, with no preference for one of the two 4, 16. While phenoxybenzamine is a non‐selective drug with more adverse effects such as reflex tachycardia and postoperative hypotension, the selective drug doxazosin may be less effective in case of large catecholamine excess and often needs the support of other antihypertensive drugs 4, 11, 23.\n\nIn conclusion, massive bilateral adrenal masses are rare, and therefore, we recommend a multidisciplinary approach of specialists in the field of endocrinology, oncology, radiology, and clinical chemistry prior to the start of the diagnostic work‐up. Oncologists have to involve an endocrinologist very early in the course of diagnostic work‐up of patients with bilaterally enlarged adrenal glands, on the one hand to exclude adrenal insufficiency and on the other hand to plan endocrine diagnostic work‐up to exclude hormone excess. Adrenal insufficiency always has to be excluded, according to the most recent endocrine society guidelines 24, as it is frequently observed in patients with PAL. According to the current guidelines 4, 22, diagnostic tests for a pheochromocytoma have to be performed, even if the patient seems to be asymptomatic. Measurement of metanephrines should be performed at short notice, and the use of a urinary catheter may be considered to avoid incomplete collection and diagnostic delay.\n\nConflict of Interest\nThe authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this study.\n\nAuthorship\nL.C.A. Drenthen: wrote the manuscript. S.H.P.P. Roerink: supervised the writing of the manuscript and changed the manuscript after review. V. Mattijssen: identified two of the patients and supervised the writing of the manuscript. H. de Boer: provided input in the writing of the manuscript from his expertise in adrenal diseases.\n\nAcknowledgment\nWe thank Dr. Frank Joosten, radiologist, and dr. Marcel van Borren, clinical chemist, for their expert advice and comments.\n==== Refs\nReferences\n1 \n\nLomte , N. \n, \nT. \nBandgar \n, \nS. \nKhare \n, \nS. \nJadhav \n, \nA. \nLila \n, \nM. \nGoroshi \n, et al. 2016 \nBilateral adrenal masses: a single‐centre experience . Endocrine Connections \n5 :92 –100 .27037294 \n2 \n\nZhou , J. \n, \nD. \nYe \n, \nM. \nWu \n, \nF. \nZheng \n, \nF. \nWu \n, \nZ. \nWang \n, et al. 2009 \nBilateral adrenal tumor: causes and clinical features in eighteen cases . International Urology and Nephrology \n41 :547 –551 .18850298 \n3 \n\nHarari , A. \n, and \nW. B. \n3rd\nInabnet \n. 2011 \nMalignant pheochromocytoma: a review . The American Journal of Surgery \n201 :700 –708 .20870212 \n4 \n\nLenders , J. W. \n, \nQ. Y. \nDuh \n, \nG. \nEisenhofer \n, \nA. P. \nGimenez‐Roqueplo \n, \nS. K. \nGrebe \n, \nM. H. \nMurad \n, et al. 2014 \nPheochromocytoma and paraganglioma: an endocrine society clinical practice guideline . The Journal of Clinical Endocrinology and Metabolism \n99 :1915 –1942 .24893135 \n5 \n\nRashidi , A. \n, and \nS. I. \nFisher \n. 2013 \nPrimary adrenal lymphoma: a systematic review . Annals of Hematology \n92 :1583 –1593 .23771429 \n6 \n\nDiamanti‐Kandarakis , E. \n, \nP. \nChatzismalis \n, \nF. \nEconomou \n, \nS. \nLazarides \n, \nA. \nAndroulaki \n, and \nG. \nKouraklis \n. 2004 \nPrimary adrenal lymphoma presented with adrenal insufficiency . Hormones \n3 :68 –73 .16982581 \n7 \n\nLam , K. Y. \n, and \nC. Y. \nLo \n. 2002 \nMetastatic tumours of the adrenal glands: a 30‐year experience in a teaching hospital . Clinical Endocrinology \n56 :95 –101 .11849252 \n8 \n\nVera‐Badillo , F. E. \n, \nE. \nConde \n, and \nI. \nDuran \n. 2012 \nChromophobe renal cell carcinoma: a review of an uncommon entity . International Journal of Urology: Official Journal of the Japanese Urological Association \n19 :894 –900 .22715810 \n9 \n\nHoffmann , N. E. \n, \nM. D. \nGillett \n, \nJ. C. \nCheville \n, \nC. M. \nLohse \n, \nB. C. \nLeibovich \n, and \nM. L. \nBlute \n. 2008 \nDifferences in organ system of distant metastasis by renal cell carcinoma subtype . The Journal of Urology \n179 :474 –477 .18076920 \n10 \n\nWu , H. Y. \n, \nL. W. \nXu \n, \nY. Y. \nZhang \n, \nY. L. \nYu \n, \nX. D. \nLi \n, and \nG. H. \nLi \n. 2010 \nMetachronous contralateral testicular and bilateral adrenal metastasis of chromophobe renal cell carcinoma: a case report and review of the literature . Journal of Zhejiang University Science B \n11 :386 –389 .20443217 \n11 \n\nAdler , J. T. \n, \nG. Y. \nMeyer‐Rochow \n, \nH. \nChen \n, \nD. E. \nBenn \n, \nB. G. \nRobinson \n, \nR. S. \nSippel \n, et al. 2008 \nPheochromocytoma: current approaches and future directions . Oncologist \n13 :779 –793 .18617683 \n12 \n\nYoung , W. F. \nJr\n. 2007 \nClinical practice. The incidentally discovered adrenal mass . The New England Journal of Medicine \n356 :601 –610 .17287480 \n13 \n\nVanderveen , K. A. \n, \nS. M. \nThompson \n, \nM. R. \nCallstrom \n, \nW. F. \nJr\nYoung \n, \nC. S. \nGrant \n, \nD. R. \nFarley \n, et al. 2009 \nBiopsy of pheochromocytomas and paragangliomas: potential for disaster . Surgery \n146 :1158 –1166 .19958944 \n14 \n\nDelivanis , D. A. \n, \nD. \nErickson \n, \nT. D. \nAtwell \n, \nN. \nNatt \n, \nS. \nMaraka \n, \nG. D. \nSchmit \n, et al. 2016 \nProcedural and clinical outcomes of percutaneous adrenal biopsy in a high‐risk population for adrenal malignancy . Clinical Endocrinology \n85 :710 –716 .27248805 \n15 \n\nPaulsen , S. D. \n, \nH. V. \nNghiem \n, \nM. \nKorobkin \n, \nE. M. \nCaoili \n, and \nE. J. \nHiggins \n. 2004 \nChanging role of imaging‐guided percutaneous biopsy of adrenal masses: evaluation of 50 adrenal biopsies . AJR. American Journal of Roentgenology \n182 :1033 –1037 .15039183 \n16 \n\nChen , H. \n, \nR. S. \nSippel \n, \nM. S. \nO'Dorisio \n, \nA. I. \nVinik \n, \nR. V. \nLloyd \n, \nK. \nPacak \n, et al. 2010 \nThe North American Neuroendocrine Tumor Society consensus guideline for the diagnosis and management of neuroendocrine tumors: pheochromocytoma, paraganglioma, and medullary thyroid cancer . Pancreas \n39 :775 –783 .20664475 \n17 \n\nLeung , K. \n, \nM. \nStamm \n, \nA. \nRaja \n, and \nG. \nLow \n. 2013 \nPheochromocytoma: the range of appearances on ultrasound, CT, MRI, and functional imaging . AJR. American Journal of Roentgenology \n200 :370 –378 .23345359 \n18 \n\nBaez , J. C. \n, \nJ. P. \nJagannathan \n, \nK. \nKrajewski \n, \nK. \nO'Regan \n, \nK. \nZukotynski \n, \nM. \nKulke \n, et al. 2012 \nPheochromocytoma and paraganglioma: imaging characteristics . Cancer Imaging : The Official Publication of the International Cancer Imaging Society \n12 :153 –162 .22571874 \n19 \n\nZeiger , M. A. \n, \nG. B. \nThompson \n, \nQ. Y. \nDuh \n, \nA. H. \nHamrahian \n, \nP. \nAngelos \n, \nD. \nElaraj \n, et al. 2009 \nAmerican association of clinical endocrinologists and American association of endocrine surgeons medical guidelines for the management of adrenal incidentalomas: executive summary of recommendations . Endocrine Practice: Official Journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists \n15 :450 –453 .\n20 \n\nMcDermott , S. \n, \nC. J. \nMcCarthy \n, and \nM. A. \nBlake \n. 2015 \nImages of pheochromocytoma in adrenal glands . Gland Surgery \n4 :350 –358 .26310999 \n21 \n\nSharma , P. \n, \nV. S. \nDhull \n, \nS. \nArora \n, \nP. \nGupta \n, \nR. \nKumar \n, \nP. \nDurgapal \n, et al. 2014 \nDiagnostic accuracy of (68)Ga‐DOTANOC PET/CT imaging in pheochromocytoma . European Journal of Nuclear Medicine and Molecular Imaging \n41 :494 –504 .24158184 \n22 \n\nLenders , J. W. \n, \nK. \nPacak \n, \nM. M. \nWalther \n, \nW. M. \nLinehan \n, \nM. \nMannelli \n, \nP. \nFriberg \n, et al. 2002 \nBiochemical diagnosis of pheochromocytoma: which test is best? \nJAMA \n287 :1427 –1434 .11903030 \n23 \n\nvan der Zee , P. A. \n, and \nA. \nde Boer \n. 2014 \nPheochromocytoma: a review on preoperative treatment with phenoxybenzamine or doxazosin . The Netherlands Journal of Medicine \n72 :190 –201 .24829175 \n24 \n\nBornstein , S. R. \n, \nB. \nAllolio \n, \nW. \nArlt \n, \nA. \nBarthel \n, \nA. \nDon‐Wauchope \n, \nG. D. \nHammer \n, et al. 2016 \nDiagnosis and treatment of primary adrenal insufficiency: an endocrine society clinical practice guideline . The Journal of Clinical Endocrinology and Metabolism \n101 :364 –389 .26760044 \n25 \n\nGraumann , O. \n, \nS. S. \nOsther \n, \nJ. \nKarstoft \n, \nA. \nHorlyck \n, and \nP. J. \nOsther \n. 2013 \nEvaluation of Bosniak category IIF complex renal cysts . Insights Into Imaging \n4 :471 –480 .23673454 \n26 \n\nMuglia , V. F. \n, and \nA. C. \nWestphalen \n. 2014 \nBosniak classification for complex renal cysts: history and critical analysis . Radiologia Brasileira \n47 :368 –373 .25741120\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2050-0904",
"issue": "6(4)",
"journal": "Clinical case reports",
"keywords": "Adrenal glands; bilateral; diagnostic delay; multidisciplinary",
"medline_ta": "Clin Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101620385",
"other_id": null,
"pages": "729-734",
"pmc": null,
"pmid": "29636949",
"pubdate": "2018-04",
"publication_types": "D002363:Case Reports",
"references": "22571874;20443217;20664475;26760044;19958944;20870212;27037294;11849252;11903030;18076920;16982581;24158184;26310999;18850298;25741120;27248805;15039183;23771429;22715810;17287480;23673454;24829175;24893135;19632968;18617683;23345359",
"title": "Bilaterally enlarged adrenal glands without obvious cause: need for a multidisciplinary diagnostic work-up.",
"title_normalized": "bilaterally enlarged adrenal glands without obvious cause need for a multidisciplinary diagnostic work up"
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"companynumb": "NL-BAUSCH-BL-2018-012609",
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"abstract": "OBJECTIVE\nWe report 3 cases of intraoperative floppy-iris syndrome (IFIS) during cataract surgery in patients without a history of selective α1-blocker use but with a long-term history of antipsychotic drug use. We reviewed previously reported cases of antipsychotic drug-associated IFIS cases.\n\n\nMETHODS\nObservational case series.\n\n\nRESULTS\nIn case 1, bilateral IFIS developed in a 39-year-old man with chronic angle-closure glaucoma. He had used several classes of antipsychotic drugs to treat schizophrenia, including the first-generation antipsychotic drugs haloperidol and chlorpromazine, the dopamine system stabilizer aripiprazole, the dopamine serotonin antagonists olanzapine and quetiapine, and the serotonin dopamine antagonists risperidone and blonanserin for 7 years. In case 2, a 63-year-old woman with schizophrenia had used aripiprazole, quetiapine, and risperidone for more than 10 years. In case 3, a 65-year-old woman with an organic mental disorder had used haloperidol for more than 10 years. At least 5 cases of antipsychotic drug-induced IFIS have been reported in the literature.\n\n\nCONCLUSIONS\nAny class of antipsychotic drugs can cause IFIS. Although antipsychotic drug-induced IFIS can be mild, surgeons should be alert to the possibility of IFIS when they treat patients with current and past use of antipsychotic drugs.",
"affiliations": "Division of Ophthalmology, Matsue Red Cross Hospital, Matsue, Japan.;Division of Ophthalmology, Matsue Red Cross Hospital, Matsue, Japan.;Division of Ophthalmology, Matsue Red Cross Hospital, Matsue, Japan.;Division of Ophthalmology, Matsue Red Cross Hospital, Matsue, Japan.;Division of Ophthalmology, Matsue Red Cross Hospital, Matsue, Japan. Electronic address: tanito-oph@umin.ac.jp.",
"authors": "Matsuo|Masato|M|;Sano|Ichiya|I|;Ikeda|Yoshifumi|Y|;Fujihara|Etsuko|E|;Tanito|Masaki|M|",
"chemical_list": "D014150:Antipsychotic Agents",
"country": "England",
"delete": false,
"doi": "10.1016/j.jcjo.2016.02.008",
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"issn_linking": "0008-4182",
"issue": "51(4)",
"journal": "Canadian journal of ophthalmology. Journal canadien d'ophtalmologie",
"keywords": null,
"medline_ta": "Can J Ophthalmol",
"mesh_terms": "D000328:Adult; D000368:Aged; D014150:Antipsychotic Agents; D002387:Cataract Extraction; D005260:Female; D015812:Glaucoma, Angle-Closure; D005902:Glaucoma, Open-Angle; D006801:Humans; D007431:Intraoperative Complications; D007499:Iris Diseases; D008297:Male; D008875:Middle Aged; D012559:Schizophrenia; D014130:Trabeculectomy; D014792:Visual Acuity",
"nlm_unique_id": "0045312",
"other_id": null,
"pages": "294-296",
"pmc": null,
"pmid": "27521670",
"pubdate": "2016-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Intraoperative floppy-iris syndrome associated with use of antipsychotic drugs.",
"title_normalized": "intraoperative floppy iris syndrome associated with use of antipsychotic drugs"
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"companynumb": "JP-JNJFOC-20160814038",
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"activesubstancename": "RISPERIDONE"
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... |
{
"abstract": "Adjuvant therapy with different bacillus Calmette-Guérin (BCG) preparations is a well-established guideline-endorsed treatment for nonmuscle invasive bladder cancer (NMIBC). Our observational study demonstrates equality between BCG and mitomycin C (MMC) treatment based on the oncological outcome. However, there were significant toxicity differences with higher rates in the BCG treatment group. The potential adverse effects of BCG in terms of a BCGitis are controversially discussed regarding their occurrence. As such, we sought to retrospectively evaluate the incidence in 106 consecutive patients. The BCG group demonstrated minor adverse effects in 78.4% and major adverse effects in 43.3%-partially coincident. Moreover, the parallel MMC group showed in 34.7% respectively 1.4% adverse events-as expected distinctly lower. In the context of this clinical discussion, we refer to alternative treatment concepts. Our data show a high clinical relevance of the patient's primary comorbidity.",
"affiliations": "Akademische Lehrpraxis für Urologie, Ärztehaus am Krankenhaus St. Joseph-Stift Dresden, Dresden, Deutschland. dr.wolf-diether.boehm@gmx.de.;Institut für Biometrie und Medizinische Statistik, Technische Universität Dresden, Dresden, Deutschland.;Klinik und Poliklinik für Urologie, Universitätsklinikum Dresden, Dresden, Deutschland.;Klinik und Poliklinik für Urologie, Universitätsklinikum Dresden, Dresden, Deutschland.;Institut für Pathologie, Universitätsklinikum Bonn, Bonn, Deutschland.",
"authors": "Böhm|W-D U|WU|;Koch|R|R|;Wenzel|S|S|;Wirth|M P|MP|;Toma|M|M|",
"chemical_list": "D000276:Adjuvants, Immunologic; D000903:Antibiotics, Antineoplastic; D001500:BCG Vaccine; D016685:Mitomycin",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00120-018-0605-7",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0340-2592",
"issue": "57(5)",
"journal": "Der Urologe. Ausg. A",
"keywords": "BCGitis; Comorbidity; Disease management; Nonmuscle invasive bladder cancer",
"medline_ta": "Urologe A",
"mesh_terms": "D000276:Adjuvants, Immunologic; D000283:Administration, Intravesical; D000903:Antibiotics, Antineoplastic; D001500:BCG Vaccine; D006801:Humans; D016685:Mitomycin; D009361:Neoplasm Invasiveness; D012189:Retrospective Studies; D001749:Urinary Bladder Neoplasms",
"nlm_unique_id": "1304110",
"other_id": null,
"pages": "568-576",
"pmc": null,
"pmid": "29500474",
"pubdate": "2018-05",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": "23711538;25794457;27056069;21893692;23665400;23351086;23536017;27756727;26218471;26578142;27637184;27324428;2744050;20034729;26945890;22328186;23141049;23545101;26243021;26803476;25398060;23372864;26077036;820877;9120912",
"title": "Development and treatment of localized/systemic BCGitis : Retrospective studies in direct comparison to mitomycin C.",
"title_normalized": "development and treatment of localized systemic bcgitis retrospective studies in direct comparison to mitomycin c"
} | [
{
"companynumb": "DE-MYLANLABS-2018M1046972",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BACILLUS CALMETTE-GUERIN ANTIGEN, UNSPECIFIED SUBSTRAIN"
... |
{
"abstract": "OBJECTIVE\nTo analyze the acute effects of sodium oxybate (SO) on polysomnographic night-time recordings (PSG) and multiple sleep latency test (MSLT) on patients with narcolepsy with cataplexy (NC).\n\n\nMETHODS\nSixteen NC adult patients were recruited, together with 16 normal controls. Two consecutive PSG followed by two MSLT sessions were carried out, before and during the first night of SO assumption, respectively.\n\n\nRESULTS\nThe administration of SO was followed by a significant decrease in number of stage shifts and awakenings, wakefulness after sleep onset, and percentage of sleep stage 1. Sleep efficiency and slow wave sleep percentage increased. REM latency decreased significantly from 73 to 12 min. Cyclic alternating pattern (CAP) rate remained unchanged but the percentage of CAP A3 subtypes decreased. The number of CAP A3 subtypes per hour of NREM sleep decreased significantly, whereas that of A1 remained unchanged. The duration of A1 and A3 subtypes was slightly increased. Chin muscle tone was not modified by SO as well as periodic leg movements during sleep, but their periodicity index decreased, becoming similar to that of controls. MSLT sleep latency also significantly improved after SO intake.\n\n\nCONCLUSIONS\nThe administration of SO in NC patients is followed by immediate important and complex effects on PSG parameters and MSLT, including an evident (over)increase in slow wave sleep, which does not display a physiological microstructure, a moderate decrease in periodic and isolated LMs, possibly mediated by a disinhibited dopaminergic neuronal activity, and an improvement on daytime mean sleep latency at the MSLT.",
"affiliations": "Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy; IRCCS Istituto delle Scienze Neurologiche, Bologna, Italy. Electronic address: giuseppe.plazzi@unibo.it.;Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy; IRCCS Istituto delle Scienze Neurologiche, Bologna, Italy.;Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy; IRCCS Istituto delle Scienze Neurologiche, Bologna, Italy.;Sleep Research Centre, Department of Neurology I.C., Oasi Institute IRCCS, Troina, Italy.;Department of Social and Developmental Psychology, Faculty of Medicine and Psychology, Sapienza University, Rome, Italy.;Department of Neurology, Hôpital Gui de Chauliac, CHU Montpellier, National Reference Network for Narcolepsy, Inserm U1061, France.;Sleep Research Centre, Department of Neurology I.C., Oasi Institute IRCCS, Troina, Italy.",
"authors": "Plazzi|Giuseppe|G|;Pizza|Fabio|F|;Vandi|Stefano|S|;Aricò|Debora|D|;Bruni|Oliviero|O|;Dauvilliers|Yves|Y|;Ferri|Raffaele|R|",
"chemical_list": "D012978:Sodium Oxybate",
"country": "Netherlands",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1389-9457",
"issue": "15(9)",
"journal": "Sleep medicine",
"keywords": "Chin EMG tone; Cyclic alternating pattern; Narcolepsy with cataplexy; Periodic limb movements during sleep; Periodicity index; REM sleep atonia index; Sodium oxybate",
"medline_ta": "Sleep Med",
"mesh_terms": "D000328:Adult; D002385:Cataplexy; D004576:Electromyography; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009290:Narcolepsy; D017286:Polysomnography; D012890:Sleep; D012894:Sleep Stages; D012978:Sodium Oxybate",
"nlm_unique_id": "100898759",
"other_id": null,
"pages": "1046-54",
"pmc": null,
"pmid": "25087195",
"pubdate": "2014-09",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Impact of acute administration of sodium oxybate on nocturnal sleep polysomnography and on multiple sleep latency test in narcolepsy with cataplexy.",
"title_normalized": "impact of acute administration of sodium oxybate on nocturnal sleep polysomnography and on multiple sleep latency test in narcolepsy with cataplexy"
} | [
{
"companynumb": "IT-JAZZ-2014-IT-010137",
"fulfillexpeditecriteria": "2",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "VENLAFAXINE HYDROCHLORIDE"
},
"drugadditional":... |
{
"abstract": "Non-uremic calciphylaxis is a rare, life-threatening condition characterized clinically by cutaneous necrosis and histologically by calcium deposition in small vessel walls. The etiology of non-uremic calciphylaxis remains the subject of ongoing speculation and debate. Herein we present a patient with calciphylaxis who had normal kidney function and numerous rheumatologic diseases, namely systemic lupus erythematosus (SLE), Sjogren syndrome (SS), and myasthenia gravis (MG). We review the pathophysiology, possible mechanisms, and management for non-uremic calciphylaxis.",
"affiliations": "Department of Dermatology, University of California, San Diego School of Medicine, La Jolla, California. akusari@ucsd.edu.",
"authors": "Kusari|Ayan|A|;Cotter|David|D|;Hinds|Brian|B|;Paravar|Taraneh|T|",
"chemical_list": "D002614:Chelating Agents; D013885:Thiosulfates; C017717:sodium thiosulfate",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1087-2108",
"issue": "25(2)",
"journal": "Dermatology online journal",
"keywords": null,
"medline_ta": "Dermatol Online J",
"mesh_terms": "D002115:Calciphylaxis; D002614:Chelating Agents; D005260:Female; D006801:Humans; D007668:Kidney; D007871:Leg Ulcer; D008180:Lupus Erythematosus, Systemic; D008875:Middle Aged; D009157:Myasthenia Gravis; D012859:Sjogren's Syndrome; D013885:Thiosulfates",
"nlm_unique_id": "9610776",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "30865406",
"pubdate": "2019-02-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Non-uremic calciphylaxis in a patient with multiple rheumatologic diseases.",
"title_normalized": "non uremic calciphylaxis in a patient with multiple rheumatologic diseases"
} | [
{
"companynumb": "US-AMGEN-USASP2019106238",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "APIXABAN"
},
"drugadditional": null,
... |
{
"abstract": "Therapeutic doses of ibuprofen (2-4'-isobutylphenyl-propionic acid) have been shown to have many deleterious effects on the nervous system. However, visual disturbances have been reported in fewer than 1% of the patients taking recommended doses of ibuprofen. The most commonly reported visual disturbances include: amblyopia, scotomata, and changes in color vision. To our knowledge, no studies have examined the effects of ibuprofen therapy on the contrast sensitivity function of an affected individual. Contrast sensitivity, Snellen visual acuity, color vision (D-15 test), and Goldmann visual fields were measured on 1 affected subject during and after ibuprofen therapy (800 mg/day for 2 days). Snellen visual acuity, color vision, and Goldmann visual fields were unaffected by the treatment. However, the contrast sensitivity was significantly depressed at low spatial frequencies while the subject was taking ibuprofen. The results, in concert with previous reports concerning the visual effects of ibuprofen, suggest that this drug can result in transient multifocal lesions of the visual pathway.",
"affiliations": "Southern California College of Optometry, Fullerton.",
"authors": "Ridder|W H|WH|;Tomlinson|A|A|",
"chemical_list": "D007052:Ibuprofen",
"country": "United States",
"delete": false,
"doi": "10.1097/00006324-199208000-00009",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1040-5488",
"issue": "69(8)",
"journal": "Optometry and vision science : official publication of the American Academy of Optometry",
"keywords": null,
"medline_ta": "Optom Vis Sci",
"mesh_terms": "D003118:Color Perception; D015350:Contrast Sensitivity; D006801:Humans; D007052:Ibuprofen; D008297:Male; D008875:Middle Aged; D014786:Vision Disorders; D014792:Visual Acuity; D014794:Visual Fields",
"nlm_unique_id": "8904931",
"other_id": null,
"pages": "652-5",
"pmc": null,
"pmid": "1513562",
"pubdate": "1992-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Effect of ibuprofen on contrast sensitivity.",
"title_normalized": "effect of ibuprofen on contrast sensitivity"
} | [
{
"companynumb": "US-STRIDES ARCOLAB LIMITED-2016SP017637",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IBUPROFEN"
},
"drugadditional":... |
{
"abstract": "Tetralogy of Fallot (TOF) with pulmonary atresia (PA) and multiple aortopulmonary collaterals (MAPCAs) is a rare and severe form of congenital heart disease with poor prognosis. Aortopulmonary collaterals expose pulmonary arterioles to systemic pressure resulting in pulmonary hypertension (PH). To date, reports regarding the role of PH medications in this population are sparse. The objective of this study was to assess the effect of PH medications in patients with TOF, PA and MAPCAs or similar anatomy, with emphasis on symptoms, echocardiography and invasive hemodynamics. A retrospective review was performed for patients at a single tertiary care pediatric center. Twelve of 66 patients were treated with PH medications (18 %), and eight of these patients had adequate follow-up for further analysis. Median age at last follow-up was 6 years (range 1.4-21 years). Median length of therapy with PH medication was 4 years (range 0.3-17 years). PH medications included sildenafil, bosentan, ambrisentan, inhaled treprostinil and prostacyclin infusion. PH therapy was associated with improvement in symptoms in all patients and improvement in PH by hemodynamic measures in the majority of patients. All patients underwent at least one cardiac intervention by catheterization or surgery while taking PH medication. Two patients died from non-PH-related causes. The remaining six patients are alive and remain on PH medication. This review indicates that PH medications are well tolerated by this patient group and provide symptomatic improvement. Further studies are required to determine whether PH medications provide long-term survival benefit for patients with complex congenital heart disease.",
"affiliations": "Division of Cardiology, Children's National Health System, 111 Michigan Avenue NW, Washington, DC, 20010, USA. egrant@childrensnational.org.;Division of Cardiology, Children's National Health System, 111 Michigan Avenue NW, Washington, DC, 20010, USA.",
"authors": "Grant|Elena K|EK|;Berger|John T|JT|",
"chemical_list": "D000959:Antihypertensive Agents; D010666:Phenylpropionates; D011724:Pyridazines; D013449:Sulfonamides; D000068677:Sildenafil Citrate; C467894:ambrisentan; D000077300:Bosentan",
"country": "United States",
"delete": false,
"doi": "10.1007/s00246-015-1278-2",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0172-0643",
"issue": "37(2)",
"journal": "Pediatric cardiology",
"keywords": "Aortopulmonary collaterals; Pulmonary atresia; Pulmonary hypertension; Tetralogy of Fallot",
"medline_ta": "Pediatr Cardiol",
"mesh_terms": "D000015:Abnormalities, Multiple; D000293:Adolescent; D000959:Antihypertensive Agents; D000077300:Bosentan; D002404:Catheterization; D002648:Child; D002675:Child, Preschool; D004219:District of Columbia; D004452:Echocardiography; D005260:Female; D006439:Hemodynamics; D006776:Hospitals, Pediatric; D006801:Humans; D006976:Hypertension, Pulmonary; D007223:Infant; D007231:Infant, Newborn; D008168:Lung; D008297:Male; D010666:Phenylpropionates; D011651:Pulmonary Artery; D018633:Pulmonary Atresia; D011724:Pyridazines; D012189:Retrospective Studies; D000068677:Sildenafil Citrate; D013449:Sulfonamides; D062606:Tertiary Care Centers; D013771:Tetralogy of Fallot; D055815:Young Adult",
"nlm_unique_id": "8003849",
"other_id": null,
"pages": "304-12",
"pmc": null,
"pmid": "26511384",
"pubdate": "2016-02",
"publication_types": "D016428:Journal Article",
"references": "24637559;18006164;23250648;22459378;21304341;21763017;7829805;19332472;19349030",
"title": "Use of Pulmonary Hypertension Medications in Patients with Tetralogy of Fallot with Pulmonary Atresia and Multiple Aortopulmonary Collaterals.",
"title_normalized": "use of pulmonary hypertension medications in patients with tetralogy of fallot with pulmonary atresia and multiple aortopulmonary collaterals"
} | [
{
"companynumb": "US-APOTEX-2017AP013093",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "SILDENAFIL"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nAntiphospholipid syndrome is an autoimmune disorder causing venous and arterial thrombosis. Acute coronary complications are rare but potentially dramatic.\n\n\nMETHODS\nWe report a 39-year-old woman who presented with an acute anterior myocardial infarction after intravenous corticosteroids as part of the treatment of lupus arthritis and revealing antiphospholipid syndrome. Emergency coronary angiography was performed with drug-eluting stent angioplasty despite the need for anticoagulation and dual antiplatelet therapy.\n\n\nCONCLUSIONS\nAntiplatelet and anticoagulant therapy management is pivotal in patients with antiphospholipid syndrome and acute coronary syndrome to prevent thrombosis recurrence.",
"affiliations": "Service de cardiologie, hôpital Sainte-Anne, BCRM, boulevard Sainte-Anne, BP 600, 83600 Toulon cedex 9, France. Electronic address: leocapilla@gmail.com.;Service de cardiologie, hôpital Sainte-Anne, BCRM, boulevard Sainte-Anne, BP 600, 83600 Toulon cedex 9, France.;Centre d'expertise médicale du personnel navigant, hôpital Sainte-Anne, BCRM, boulevard Sainte-Anne, BP 600, 83600 Toulon cedex 9, France.;Service de cardiologie, hôpital Sainte-Anne, BCRM, boulevard Sainte-Anne, BP 600, 83600 Toulon cedex 9, France.;Service de cardiologie, hôpital Sainte-Anne, BCRM, boulevard Sainte-Anne, BP 600, 83600 Toulon cedex 9, France.;Service de cardiologie, hôpital Sainte-Anne, BCRM, boulevard Sainte-Anne, BP 600, 83600 Toulon cedex 9, France.;Service de cardiologie, hôpital Sainte-Anne, BCRM, boulevard Sainte-Anne, BP 600, 83600 Toulon cedex 9, France.;Service de cardiologie, hôpital Sainte-Anne, BCRM, boulevard Sainte-Anne, BP 600, 83600 Toulon cedex 9, France.",
"authors": "Capilla-Geay|E|E|;Poyet|R|R|;Brocq|F X|FX|;Pons|F|F|;Kerebel|S|S|;Foucault|G|G|;Jego|C|C|;Cellarier|G R|GR|",
"chemical_list": "D000925:Anticoagulants",
"country": "France",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0248-8663",
"issue": "37(5)",
"journal": "La Revue de medecine interne",
"keywords": "Acute coronary syndrome; Angioplastie coronaire percutanée; Antiagrégation plaquettaire; Anticoagulation; Antiphospholipid antibody syndrome; Antiplatelet therapy; Percutaneous coronary intervention; Syndrome coronaire aigu; Syndrome des antiphospholipides",
"medline_ta": "Rev Med Interne",
"mesh_terms": "D000328:Adult; D000925:Anticoagulants; D016736:Antiphospholipid Syndrome; D001168:Arthritis; D017023:Coronary Angiography; D003937:Diagnosis, Differential; D005260:Female; D006801:Humans; D008180:Lupus Erythematosus, Systemic; D009203:Myocardial Infarction; D062645:Percutaneous Coronary Intervention",
"nlm_unique_id": "8101383",
"other_id": null,
"pages": "371-4",
"pmc": null,
"pmid": "26363818",
"pubdate": "2016-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Acute anterior myocardial infarction as presenting feature of antiphospholipid syndrome related lupus arthritis.",
"title_normalized": "acute anterior myocardial infarction as presenting feature of antiphospholipid syndrome related lupus arthritis"
} | [
{
"companynumb": "FR-SUN PHARMACEUTICAL INDUSTRIES LTD-2016R1-119838",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drug... |
{
"abstract": "OBJECTIVE\nThe purpose of this study was to compare the incidence of rescue medication utilization with up to 3 subsequent doses of paclitaxel in patients who underwent an infusion rate escalation versus those who continued on the standard infusion rate after experiencing an initial paclitaxel infusion hypersensitivity reaction (HSR) requiring rescue medications.\n\n\nMETHODS\nA retrospective, single-center review was conducted on patients who experienced a paclitaxel infusion HSR requiring rescue medications to their first or second lifetime dose of paclitaxel.\n\n\nRESULTS\nA total of 99 patients were included for analysis, and from this group, 22 patients were continued on the standard infusion rate, while 77 patients were changed to an infusion rate escalation. The rate of subsequent rescue medication utilization was 5% in patients who were continued at the standard infusion rate versus 23% in patients who were changed to an infusion rate escalation (p = 0.064). The incidence of subsequent rescue medication utilization was unrelated to disease stage (p = 0.39), the paclitaxel dosing regimen (p = 0.99), or a diagnosis of asthma (p = 0.99).\n\n\nCONCLUSIONS\nThis single-center, retrospective study suggests that while not statistically significant, there was a potentially clinically meaningful increase in the rate of subsequent rescue medication utilization in patients who were changed to an infusion rate escalation compared to those who continued on the same standard infusion rate after experiencing an initial HSR to paclitaxel.",
"affiliations": "Department of Pharmacy, The Arthur G. James Cancer Hospital and Richard J. Solove Institute at The Ohio State University, 460 W 10th Avenue, C150, Columbus, OH, 43210, USA. Kristen.Nymberg@osumc.edu.;Department of Pharmacy, The Arthur G. James Cancer Hospital and Richard J. Solove Institute at The Ohio State University, 460 W 10th Avenue, C150, Columbus, OH, 43210, USA.;Department of Pharmacy, The Arthur G. James Cancer Hospital and Richard J. Solove Institute at The Ohio State University, 460 W 10th Avenue, C150, Columbus, OH, 43210, USA.;The Ohio State University College of Pharmacy, 500 West 12h Avenue, 214A Parks Hall, Columbus, OH, 43210, USA.;The Ohio State University College of Pharmacy, 500 West 12h Avenue, 214A Parks Hall, Columbus, OH, 43210, USA.;Division of Medical Oncology, The Ohio State University Wexner Medical Center, The Stefanie Spielman Comprehensive Breast Center, 1145 Olentangy River Road, Columbus, OH, 43212, USA.;Department of Pharmacy, The Arthur G. James Cancer Hospital and Richard J. Solove Institute at The Ohio State University, 460 W 10th Avenue, C150, Columbus, OH, 43210, USA.",
"authors": "Nymberg|Kristen|K|http://orcid.org/0000-0003-0507-7237;Folan|Stephanie|S|;Berger|Michael|M|;Li|Junan|J|;Zanath|Kyle|K|;VanDeusen|Jeffrey|J|;Vargo|Craig|C|",
"chemical_list": "D017239:Paclitaxel",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00520-021-05991-7",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0941-4355",
"issue": "29(8)",
"journal": "Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer",
"keywords": "Escalation; Hypersensitivity; Paclitaxel; Rate; Rescue",
"medline_ta": "Support Care Cancer",
"mesh_terms": "D000328:Adult; D000368:Aged; D004342:Drug Hypersensitivity; D005260:Female; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D017239:Paclitaxel; D012189:Retrospective Studies",
"nlm_unique_id": "9302957",
"other_id": null,
"pages": "4423-4429",
"pmc": null,
"pmid": "33447864",
"pubdate": "2021-08",
"publication_types": "D016428:Journal Article",
"references": "25089112",
"title": "Comparison of subsequent infusion hypersensitivity reactions to paclitaxel using two different infusion strategies.",
"title_normalized": "comparison of subsequent infusion hypersensitivity reactions to paclitaxel using two different infusion strategies"
} | [
{
"companynumb": "US-TEVA-2021-US-1950089",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "SODIUM CHLORIDE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nThe severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) led to the outbreak of pneumonia in Wuhan. The virus is highly infectious. Patients with cancer might be susceptible to the viral infection because of the immunosuppressive state cause by therapies on tumors.\n\n\nMETHODS\nWe present the clinical features of four cancer patients who were infected with SARS-CoV-2 in late January of 2020 in our hospital. Cases 1 and 3 were diagnosed as mild and common type of coronavirus disease 2019 (COVID-2019) and survived from the viral infection. They acquired SARS-CoV-2 infection during their staying in hospital under radiotherapy and surgery of the tumors. Cases 2 and 4 suffered from severe type of COVID-19, and Case 2 was dead owning to the advanced age, uncontrolled chronic B cell lymphocytic leukemia and many other underlying diseases. The immunosuppressive state induced by liver transplantation and anti-rejection therapy might contribute to the severity of COVID-19 in Case 4, who suffered from hepatitis B related hepatocellular carcinoma. However, Case 4 was recovered from COVID-19 after a combination therapy against virus, bacteria and fungi, and also respiratory support. Nearly all patients showed a decrease in lymphocytes including total CD3+ T cells, B cells, and natural killer cells after infection of the virus.\n\n\nCONCLUSIONS\nThe severity of COVID-19 might be influenced by immune system state and underlying diseases in cancer patients. And the treatment of SARS-CoV-2 infection in cancer patients is challenged by the immunosuppressive state of these patients under chemotherapy or surgery.",
"affiliations": "Department of Infectious Diseases, Zhongnan Hospital of Wuhan University, Donghu road 169, Wuhan, 430071, China.;Department of Infectious Diseases, Zhongnan Hospital of Wuhan University, Donghu road 169, Wuhan, 430071, China.;Department of Infectious Diseases, Zhongnan Hospital of Wuhan University, Donghu road 169, Wuhan, 430071, China.;Department of Infectious Diseases, Zhongnan Hospital of Wuhan University, Donghu road 169, Wuhan, 430071, China.;Department of Infectious Diseases, Zhongnan Hospital of Wuhan University, Donghu road 169, Wuhan, 430071, China.;Department of Infectious Diseases, Zhongnan Hospital of Wuhan University, Donghu road 169, Wuhan, 430071, China.;Department of Infectious Diseases, Zhongnan Hospital of Wuhan University, Donghu road 169, Wuhan, 430071, China.;Department of Infectious Diseases, Zhongnan Hospital of Wuhan University, Donghu road 169, Wuhan, 430071, China.;Department of Infectious Diseases, Zhongnan Hospital of Wuhan University, Donghu road 169, Wuhan, 430071, China. mzy2001pl@163.com.",
"authors": "Song|Shi-Hui|SH|;Chen|Tie-Long|TL|;Deng|Li-Ping|LP|;Zhang|Yong-Xi|YX|;Mo|Ping-Zheng|PZ|;Gao|Shi-Cheng|SC|;Hu|Wen-Jia|WJ|;Xiong|Yong|Y|;Ma|Zhi-Yong|ZY|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/s40249-020-00707-1",
"fulltext": "\n==== Front\nInfect Dis Poverty\nInfect Dis Poverty\nInfectious Diseases of Poverty\n2095-5162 2049-9957 BioMed Central London \n\n707\n10.1186/s40249-020-00707-1\nCase Report\nClinical characteristics of four cancer patients with SARS-CoV-2 infection in Wuhan, China\nSong Shi-Hui Chen Tie-Long Deng Li-Ping Zhang Yong-Xi Mo Ping-Zheng Gao Shi-Cheng Hu Wen-Jia Xiong Yong Ma Zhi-Yong mzy2001pl@163.com grid.413247.7Department of Infectious Diseases, Zhongnan Hospital of Wuhan University, Donghu road 169, Wuhan, 430071 China \n2 7 2020 \n2 7 2020 \n2020 \n9 827 3 2020 23 6 2020 © The Author(s) 2020Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.Background\nThe severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) led to the outbreak of pneumonia in Wuhan. The virus is highly infectious. Patients with cancer might be susceptible to the viral infection because of the immunosuppressive state cause by therapies on tumors.\n\nCase presentation\nWe present the clinical features of four cancer patients who were infected with SARS-CoV-2 in late January of 2020 in our hospital. Cases 1 and 3 were diagnosed as mild and common type of coronavirus disease 2019 (COVID-2019) and survived from the viral infection. They acquired SARS-CoV-2 infection during their staying in hospital under radiotherapy and surgery of the tumors. Cases 2 and 4 suffered from severe type of COVID-19, and Case 2 was dead owning to the advanced age, uncontrolled chronic B cell lymphocytic leukemia and many other underlying diseases. The immunosuppressive state induced by liver transplantation and anti-rejection therapy might contribute to the severity of COVID-19 in Case 4, who suffered from hepatitis B related hepatocellular carcinoma. However, Case 4 was recovered from COVID-19 after a combination therapy against virus, bacteria and fungi, and also respiratory support. Nearly all patients showed a decrease in lymphocytes including total CD3+ T cells, B cells, and natural killer cells after infection of the virus.\n\nConclusions\nThe severity of COVID-19 might be influenced by immune system state and underlying diseases in cancer patients. And the treatment of SARS-CoV-2 infection in cancer patients is challenged by the immunosuppressive state of these patients under chemotherapy or surgery.\n\nKeywords\nSevere acute respiratory syndrome coronavirus 2Coronavirus disease 2019CancerWuhanMedical Science Advancement Program (Basic Medical Sciences) of Wuhan UniversityTFJC2018002Xiong Yong http://dx.doi.org/10.13039/501100001809National Natural Science Foundation of China81401663issue-copyright-statement© The Author(s) 2020\n==== Body\nBackground\nIn December 2019, a cluster of cases of pneumonia was reported by Wuhan Municipal Health Commission, China, and then a novel coronavirus was eventually identified [1, 2]. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is highly infectious and can infect all individuals. Patients infected with the virus have suffered from the coronavirus disease 2019 (COVID-19), and have had symptoms including fever, cough, shortness of breath, diarrhea and vomiting [3]. As of 19 February 2020, there were 75 204 cases globally in 25 countries and the virus has led to 2009 deaths due to its rapid spread [4].\n\nThe development of COVID-19 has caused more severe cases and deaths in older people with underlying diseases, including diabetes, cardiovascular disease, and cancer [3]. There is currently no definite effective drug against the virus, although some drugs such as remdesivir, chloroquine phosphate, arbidol, lopinavir and ritonavir have been used in clinical practice and have exerted antiviral effects in some patients [5]. However, the antiviral efficacy of these drugs needs to be verified by large-scale studies. Recent studies have demonstrated a higher frequency of severe cases and increased mortality in patients in Wuhan compared with other regions of China [6].\n\nPatients with cancer are thought to be more susceptible to infection than the general population because of their system’s immunosuppressive state cause by chemotherapy, radiotherapy, or surgery on tumors [7]. Here, we report on four cancer patients infected with SARS-CoV-2 in late January of 2020 and describe their medical history, clinical diagnosis, changes in clinical parameters, and outcomes.\n\nCase presentation\nCase 1\nA 48-year-old woman was admitted to the Department of Radiation and Medical Oncology in our hospital on 12 December 2019, because of the need for continued radiotherapy for breast cancer. She received a modified radical mastectomy of the right breast on 25 June 2019, as well as six cycles of chemotherapy with paclitaxel and doxorubicin after surgery. After 4 weeks of radiotherapy, the patient presented fever on 24 January 2020, and this was accompanied by cough. Chest computed tomographic (CT) scans found slight interstitial abnormalities in both lower lungs, indicating a possibility of viral pneumonia (Fig. 1a, b). The SARS-CoV-2 infection was confirmed by positive detection of the virus in throat swab sample using the real-time reverse transcription polymerase chain reaction (RT-PCR) method. The laboratory results revealed reductions in white blood cells (WBCs) and lymphocytes in the blood, especially CD3+CD8+ T cells, B cells, and natural killer (NK) cells (Table 2). The patient was then diagnosed as suffering from COVID-19 and transferred to an isolation ward in the Department of Infectious Diseases. The symptoms were relieved after 2 days. The antibiotic ceftriaxone was given as empirical antibacterial therapy and ceased after relief of symptoms (Table 1). The chest CT scan on 30 January 2020 also suggested recovery from COVID-19 (Fig. 1c). However, the virus was sustained in the throat swab samples for several days (Table 2). The patient was transferred to another isolation ward, which was arranged by the government after discharge from our hospital. At last, the SARS-CoV-2 was cleared from the patient on 13 February 2020 (Table 2).\nFig. 1 The chest X-ray/computed tomographic (CT) images of the four patients on different time points. a–c Images from Case 1. The patient had normal CT images on 23 December 2019 after admission (a). However, on 24 January 2020, after onset of fever, CT scan showed interstitial abnormalities in both lower lung, which revealed the possibility of viral pneumonia (b). And these changes were ameliorated after treatment and showed on 30 January 2020 (c). d–e Images from Case 2. The CT images showed bilateral patchy shadowing in the patient after admission (d), and the lesion progressed 1 week later (e). f–h Images from Case 3. The CT scans taken on different time points, showed local patchy shadowing in right lung 6 days after admission (g), which is the time point of fever onset in this patient. And the lesion was recovered after treatment and showed on 30 January 2020 (H). i–m Images from Case 4. i–j The CT scans showed the multiple HCC lesions in the liver after transcatheter arterial chemoembolization therapy. The X-ray examination of the patient revealed normal lung after admission (k). However, on 2 February 2020 the images from X-ray showed bilateral patchy shadowing, indicating viral pneumonia (l). The patient has been in remission of the pneumonia despite right pleural effusion was showed by CT scan on 18 February 2020 (m)\n\nTable 1 Clinical characteristics of the four cancer patients with SARS-CoV-2 infection\n\nClinical characteristics\tCase 1\tCase 2\tCase 3\tCase 4\t\nSex\tFemale\tFemale\tMale\tMale\t\nAge (years)\t48\t78\t54\t37\t\nDate of admission\t21 December 2019\t18 January 2020\t13 January 2020\t14 January 2020\t\nDate of COVID-19 diagnosis\t26 January 2020\t25 January 2020\t23 January 2020\t1 February 2020\t\nUnderlying diseases\t\n Hypertension\tNo\tYes\tNo\tNo\t\n Cardiovascular disease\tNo\tYes\tNo\tNo\t\n COPD\tNo\tYes\tNo\tNo\t\n HBV infection\tNo\tNo\tYes\tYes\t\nTumor type\tBreast cancer\tB-CLL\tRectal cancer\tHCC\t\nTumor related therapy\t\n Chemotherapy\tYes\tNo\tNo\tYes\t\n Radiotherapy\tYes\tNo\tNo\tNo\t\n Surgery\tYes\tNo\tYes\tYes\t\n Date of surgery\t25 June 2019\t/\t16 January 2020\t20 January 2020\t\nDates of fever (day after admission)\tDay 35, Day 36\tDay 6–Day 17\tDay 7–Day 11\tDay 17–Day 24\t\nMaximum temperature\t38 °C\t39 °C\t39.5 °C\t39 °C\t\nClinical type of COVID-19\tMild\tSevere\tCommon\tSevere\t\nAnti-microbe therapy\t\n Antiviral\tNo\tOseltamivir\tOseltamivir\tOseltamivir\n\nArbidol\n\n\t\n Antibacterial\tCeftriaxone\tCefoperazone and sulbactam\n\nLinezolid\n\n\tMeropenem\n\nMoxifloxacin\n\n\tImipenem and cilastatin\n\nMoxifloxacin\n\n\t\n Antifungal\tNo\tCaspofungin\tNo\tCaspofungin\t\nMethylprednisolone\tNo\t40 mg/day\tNo\t40 mg/day\t\nOxygen therapy\tNo\tNoninvasive ventilation\tNasal catheter\tHigh-flow oxygen\t\nMinimal oxygenation index (mmHg)\tNA\t112\tNA\t261\t\nICU admission\tNo\tYes\tNo\tYes\t\nClinical outcomes\tRecovery of COVID-19;\n\nDischarge from hospital\n\n\tDead\tRecovery of COVID-19;\n\nDischarge from hospital\n\n\tRemission of COVID-19;\n\nTherapy in hospital\n\n\t\nAbbreviations: SARS-CoV-2 severe acute respiratory syndrome coronavirus 2, COVID-19 coronavirus disease 2019, COPD chronic obstructive pulmonary disease, HBV hepatitis B virus, B-CLL chronic B cell lymphocytic leukemia, HCC hepatocellular carcinoma, ICU intensive care unit, NA not available\n\nTable 2 Laboratory and radiographic findings of the four cancer patients with SARS-CoV-2 infection\n\nRadiographic and laboratory findings\tNormal Range\tCase 1\tCase 2\tCase 3\tCase 4\t\nAfter admission\t\nWhite blood cell count, × 109/L\t3.5–9.5\t4.21\t10.91↑\t4.86\t5.46\t\nNeutrophil count, × 109/L\t1.8–6.3\t2.05\t4.11\t3.8\t3.53\t\nLymphocyte count, × 109/L\t1.1–3.2\t1.3\t5.85\t0.57↓\t1.2\t\nHemoglobin, g/L\t130–175\t101↓\t118↓\t133\t152\t\nPlatelet count, ×109/L\t125–350\t350\t202\t180\t182\t\nProcalcitonin, ng/mL\t< 0.05\t< 0.05\t0.1↑\t< 0.05\t0.25\t\nC-reactive protein, mg/L\t0–10\tNA\t36.2↑\tNA\tNA\t\nAbnormalities on chest X-ray/CT\tNo\tNo (Fig. 1a)\tBilateral patchy shadowing (Fig. 1d)\tNo (Fig. 1f)\tNo (Fig. 1k)\t\nAfter fever onset\t\nWhite blood cell count, ×109/L\t3.5–9.5\t2.86↓\t6.67\t2.7↓\t9.36\t\nNeutrophil count, ×109/L\t1.8–6.3\t1.79↓\t3.55\t1.21↓\t8.73\t\nLymphocyte count, ×109/L\t1.1–3.2\t0.4↓\t2.4\t0.88↓\t0.28↓\t\nHemoglobin, g/L\t130–175\t114↓\t112↓\t115↓\t102↓\t\nPlatelet count, ×109/L\t125–350\t156\t177\t280\t50↓\t\nProcalcitonin, ng/mL\t< 0.05\t< 0.05\t0.57↑\t< 0.05\t< 0.05\t\nC-reactive protein, mg/L\t0–10\t0.7\t77.9↑\t1.3\t18.1↑\t\nInfluenza A or B virus detection\tNegative\tNegative\tNegative\tNegative\tInfluenza A virus (+)\t\n1–3-β-D polyglucosan (pg/ml)\t(Neg.) < 60\n\n(Pos.) > 110\n\n\tNA\t< 10\tNA\t165.7↑\t\nAbnormalities on chest X-ray/CT\tNo\tInterstitial abnormalities\n\n(Fig. 1b)\n\n\tProgress of bilateral lung diseases (Fig. 1e)\tLocal patchy shadowing (Fig. 1g)\tBilateral patchy shadowing (Fig. 1l)\t\nLymphocyte subsets (count/μl)\t\nCD3+T cells\t805–4459\t435↓\t297↓\t865\t335↓\t\nCD3+CD4+T cells\t345–2350\t290↓\t115↓\t482\t148↓\t\nCD3+CD8+T cells\t345–2350\t142↓\t184↓\t341↓\t185↓\t\nB cells\t240–1317\t12↓\t4213↑\t44↓\t41↓\t\nNK cells\t210–1514\t59↓\t132↓\t154↓\t43↓\t\nBefore discharge from hospital or dead\t\nWhite blood cell count, ×109/L\t3.5–9.5\t3.12↓\t16.52↑\t4.04\t6.28\t\nNeutrophil count, ×109/L\t1.8–6.3\t2.18\t7.37↑\t2.22\t5.34\t\nLymphocyte count, ×109/L\t1.1–3.2\t0.41↓\t7.94↑\t1.07↓\t0.55↓\t\nHemoglobin, g/L\t130–175\t110.1↓\t98.7↓\t107.3↓\t133.5\t\nPlatelet count, ×109/L\t125–350\t156\t44↓\t151\t92↓\t\nProcalcitonin, ng/ml\t< 0.05\t< 0.05\t1.48↑\t< 0.05\tNA\t\nC-reactive protein, mg/L\t0–10\t0.7\t138.4↑\tNA\tNA\t\nDetection of SARS-CoV-2 in throat swab samples\t\nDates of positive results\t/\t26 January\n\n30 January\n\n3 February\n\n8 February\n\n\t25 January\n\n28 January\n\n1 February\n\n5 February\n\n\t23 January\n\n30 January\n\n3 February\n\n9 February\n\n\t1 February\n\n4 February\n\n8 February\n\n12 February\n\n\t\nNegativity time of SARS-CoV-2a\t/\t13 February\t/\t15 February\t10 March\t\nAbbreviations: SARS-CoV-2 severe acute respiratory syndrome coronavirus 2, NA not available, CT computed tomographic, NK cells natural killer cells\n\naThe negativity time of SARS-CoV-2 was defined as the first day of a negative test if the nucleic acid of SARS-CoV-2 was negative for 2 consecutive tests (the sampling interval is at least 1 day)\n\n\n\nCase 2\nA 78-year-old woman from Wuhan came to our hospital with fatigue, malaise, and poor appetite on 18 January 2020. She was admitted to the Department of Hematology because of her past medical history of chronic B cell lymphocytic leukemia (B-CLL) for 5 years. She was also suffering hypertension, cardiovascular disease, and chronic obstructive pulmonary disease (COPD) for more than 10 years. She received percutaneous coronary intervention on 23 February 2014. She took aspirin and atorvastatin orally every day, and took nifedipine sustained-release tablets and indapamide sustained-release tablets to control blood pressure. Because of the presentation of the critical underlying diseases, she did not receive any treatment for B-CLL. The chest CT images found bilateral patchy shadowing, indicating double pneumonia in this patient on 19 January 2020 (Fig. 1d). The patient was diagnosed as suffering from double pneumonia, COPD, hypertension, B-CLL, and coronary heart disease, and received antibiotic therapy with oseltamivir, cefoperazone, sulbactam, linezolid, and caspofungin. Because of the immunocompromised state and the severe pulmonary infection in this patient, the initial empirical antimicrobial treatment covered influenza virus, bacteria and also fungi. However, the pneumonia progressed, and symptoms such as fever, shortness of breath, and dyspnea appeared in the patient on 25 January 2020 (Fig. 1e). The SARS-CoV-2 was found in a throat swab sample by real-time PCR. The patient was then transferred to an intensive care unit (ICU), and high flow humidification oxygen inhalation therapy and methylprednisolone (40 mg daily) were employed as combination therapy. After 5 days of therapy in the ICU, symptoms of dyspnea and hypoxia improved, and the patient was transferred to an isolation ward in our department on 31 January 2020. We continued the combination therapy employed in the ICU. However, the patient died on 10 February 2020 due to respiratory failure, despite the noninvasive ventilation (Table 1). The lymphocyte subset analysis in this patient showed an increase in B cells, which may indicate uncontrolled B-CLL (Table 2). The older age, multiple underlying diseases, and severe pulmonary infection might have contributed to the death of the patient.\n\nCase 3\nA 54-year-old man from Wuhan was admitted to the Department of Colorectal and Anal Surgery on 13 January 2020. Six days before admission, a large polyp was found in his rectum by colonoscopy examination. He has been a hepatitis B surface antigen carrier for several years. He received a laparoscopic radical resection of rectal cancer on 16 January 2020, and the pathological result diagnosed rectal adenocarcinoma. On 19 January 2020, the patient presented fever, with no other symptoms. The fever might be caused by postoperative abdominal infection in this patient, so he received meropenem and moxifloxacin as antibacterial therapy. The chest CT scans suggested local patchy shadowing in the double lower lung, which might be the result of bacterial or viral infection (Fig. 1g). The oseltamivir was prescribed to the patient against the influenza virus. However, the SARS-CoV-2 was found in a throat swab sample by real-time PCR on 23 January 2020. The patient was then diagnosed as having COVID-19 and transferred to an isolation ward of our department. The patient also received oxygen therapy by nasal catheter in the isolation ward (Table 1). The fever stopped after 7 days of therapy, and the recovery of COVID-19 was confirmed by a chest CT scan on 30 January 2020 (Fig. 1h). The laboratory results also suggested a decrease in peripheral blood lymphocytes, such as B cells and NK cells, after SARS-CoV-2 infection (Table 2). The positive detection of SARS-CoV-2 in the throat swab samples of this patient lasted at least 18 days (Table 2). The patient was transferred to another isolation ward, which was arranged by the government after discharge from our hospital. The patient cleared the virus from throat swab sample 23 days after the first time of positive detection of SARS-CoV-2 (Table 2).\n\nCase 4\nA 37-year-old man from Wuhan had the chief complaint of upper abdominal intermittent pain for more than 3 months. One day before admission to the Department of Hepatobiliary Surgery, a space-occupying lesion was found in the liver of this patient by ultrasound. He has been a hepatitis B virus carrier for more than 19 years and does not take antiviral drugs or see a doctor regularly. After admission, he was diagnosed as suffering from chronic hepatitis B and hepatocellular carcinoma (HCC). On 16 January 2020, the patient received chemotherapy through transcatheter arterial chemoembolization. Multiple hepatic HCC lesions were found in this patient through a CT scan afterward (Fig. 1i-j). Positron emission computerized tomography and computer tomography was performed, and no HCC lesion was found outside the liver. The patient received an allogeneic liver transplantation on 20 January 2020 for a better prognosis. A combination therapy with antibiotics, antiviral treatment with entecavir, a high dose of hepatitis B immunoglobulin, and immunosuppressive agent tacrolimus were given to the patient after surgery. However, the patient began to present a fever on 30 January 2020, and this was accompanied by a cough. The nucleic acids of influenza A virus and SARS-CoV-2 were detected in throat swab samples on 31 January and 1 Febuary 2020. The patient was transferred to an ICU on 2 February 2020 due to dyspnea, and the chest X-ray showed bilateral patchy shadowing, indicating COVID-19 (Fig. 1l).\n\nIn the ICU, the patient was treated with a combination therapy including high-flow humidification oxygen inhalation, antibiotic therapy with oseltamivir, arbidol, imipenem, cilastatin, moxifloxacin, caspofungin, and methylprednisolone (40 mg daily) (Table 1). Because the patient had increased plasma level of 1–3-β-D polyglucosan, and positive detection of influenza A virus and SARS-CoV-2 (Table 2), he received a combination antimicrobial therapy. Two days later, the symptoms were relieved in this patient. The patient was transferred to an isolation ward in our department on 4 Febuary 2020, and received the same treatment employed in the ICU. On 19 Febuary 2020, we ceased all antibiotic therapy and methylprednisolone. The lung CT images showed remission of the pneumonia despite the right pleural effusion found on 18 Febuary 2020 (Fig. 1m). Consistent with laboratory findings of other patients, the lymphocytes including T cells, B cells, and NK cells decreased after infection with SARS-CoV-2 in this patient (Table 2). The virus was persistent in the samples from throat swabs in this patient, so the patient remained in the hospital (Table 2). Finally, the patient cleared SARS-CoV-2 in throat swab samples on 10 March 2020, about 39 days after the first time of positive detection of the virus (Table 2).\n\nDiscussion and conclusions\nIn the present study, we collected the clinical data from four cancer patients who were infected by SARS-CoV-2 and developed COVID-19. The diagnosis of COVID-19 was based on symptoms, lung X-ray/CT examination, and detection of the virus by real-time RT-PCR in throat swab samples from the patients. No patient was initially admitted to the Department of Infectious Diseases and Department of Respiration. Only Case 2 showed pneumonia on admission; however, she did not present a fever when she came to our hospital; therefore, she may have infected the virus at home. The other three patients showed normal lung images when they were admitted to our hospital. They developed a fever and other symptoms related to COVID-19 after radiotherapy or surgery in different departments, which might indicate that the hospital acquired SARS-CoV-2 infection. This was also demonstrated by another study conducted in our hospital [3].\n\nEarly studies have demonstrated the decrease in peripheral WBCs and lymphocytes during SARS-CoV-2 infection, and we observed the same phenomenon in these patients, except Case 2. Case 2 had an increased count of B lymphocytes in the blood, which may be attributed to her underlying disease, B-CLL. Moreover, in the other three cases, we found a reduction in all lymphocyte subsets, including CD3+CD4+ helper T cells, CD3+CD8+ cytolytic T cells, B cells, and NK cells. Peripheral lymphopenia was also observed during another coronavirus, SARS-CoV infection [8, 9]. In our study, we found that the counts of CD3+ CD4+ helper T cells were much lower in two severe cases (Cases 2 and 4) compared to patients with mild (Case 1) or common (Case 3) types of COVID-19. Recently, several groups including our group demonstrated that the reduction of peripheral lymphocytes, especially CD3+, CD4+ and CD8+ T cells, was positively correlated with severity of illness and in-hospital death in SARS-CoV-2 infection [10–12]. However, the peripheral reduction of these T cells might be the result of infiltration and sequestration of lymphocytes in lungs and other organs. The infiltrated lymphocytes were activated in the lung and secreted a lot of cytokines, which might lead the severity of the disease. In a pathological study of a patient who died due to COVID-19, interstitial mononuclear inflammatory infiltrates, dominated by lymphocytes, were found in both lungs [13]. Moreover, the study found that the counts of peripheral CD4+ and CD8+ T cells were substantially reduced, while their status was hyperactivated [13]. In consistence, a recent study demonstrated that significant decreases in the counts of T cells, especially CD8+ T cells, as well as increases in IL-6, IL-10, IL-2 and IFN-γ levels in the peripheral blood in the severe cases compared to those in the mild cases [14]. Taken together, the counts of peripheral lymphocytes, especially of CD4+ and CD8+ T cells, may be useful in predicting the severity and clinical outcomes in SARS-CoV-2 infection in both tumorous patients and general population.\n\nThe clinical outcomes of COVID-19 are determined by virous parameters such as age, underlying diseases, severity of the pneumonia, and admission to an ICU [3, 6]. In our four cancer patients, Cases 2 and 4 were diagnosed as severe cases of COVID-19, and Cases 1 and 3 were diagnosed as mild and common COVID-19, respectively, according to the diagnostic and treatment guideline for SARS-CoV-2 infection issued by Chinese National Health Committee (5th edition). Case 2 was suffering from uncontrolled B-CLL, along with many underlying diseases including COPD, hypertension, and coronary heart disease. This condition and the greater age might have caused the severity of COVID-19 and might have led to the death of the patient. Results from the laboratory showed an elevation in markers of bacterial infection, procalcitonin, and C-reactive protein, after admission and diagnosis of COVID-19. Though antibiotics were used, the contaminated bacterial infection might also have contributed to the death of this patient, which was indicated by the further increases of procalcitonin, and C-reactive protein (Table 2). Case 4 was diagnosed as having COVID-19 at 10 days after liver transplantation. The immunosuppressive agent tacrolimus, which was used for anti-rejection, might have inhibited the host immune system and might have led to the severity of COVID-19. Consistent with this, we found an extreme reduction in lymphocytes including CD3+ T cells, B cells, and NK cells in this patient. However, the patient entered into remission of COVID-19 after comprehensive therapy. Liver transplantation was also attributed to the severity of pneumonia. Cases 1 and 3 had better control of their related tumors and had a low risk of immunosuppression. This might have contributed to the success in recovery from COVID-19 after SARS-CoV-2 infection. The durations of SARS-CoV-2 RNA detection in our three survived patients were 18 days (Case 1), 23 days (Case 3) and 39 days (Case 4) as measured from the first time of positive detection of the virus in throat swab samples (Table 2). A recent study demonstrated that a median duration of SARS-CoV-2 RNA detection was 17 days as measured from illness onset in general population [15]. It seemed that the clearance of SARS-CoV-2 was delayed in our tumor patients, especially Case 4, who received immunosuppressive agent tacrolimus after liver transplantation. Thus, the immunosuppressive state in tumor patients might contribute to the delayed virus clearance. Further large-scale studies are needed to verify this hypothesis.\n\nRecently, two studies from China demonstrated a higher infection rate of SARS-CoV-2 in tumor patients than that in general population [7, 16]. Moreover, it seemed that patients with cancer have more severe COVID-19 symptoms than those without [7]. Receiving the cancer treatment such as chemotherapy or surgery in the past month was associated with severe clinical events among those with cancer [7]. In our study, we also found that the uncontrolled B-CLL comorbidity, liver transplantation and receiving immunosuppressive agent were associated with severity of illnesses in Cases 2 and 4.\n\nThis study had some limitations. Firstly, the limited numbers of cancer patients were included in our study. This led to difficulty in conduction of a comparison study between cancer patients and general population. Secondly, due to no definite effective drugs against SARS-CoV-2 during early February 2020, all the patients in this study did not receive specific antiviral treatment. It will be interesting to know whether antiviral treatment against SARS-CoV-2 may influence the severity or outcomes of COVID-19 in cancer patients. Thirdly, we speculated that the immunosuppressive state in cancer patients might lead to severity of COVID-19 after their infection of SARS-CoV-2. However, we did not find a specific marker that could reflect the suppression of immune system in cancer patients. The reduction of peripheral CD3+, CD4+ and CD8+ T cells is a universal phenomenon for all SARS-CoV-2 infected patients, not only in cancer patients.\n\nDespite the limited numbers of cancer patients in our and others’ studies, these data emphasizes that the treatment of SARS-CoV-2 infection in cancer patients is challenged by the immunosuppressive state of patients under chemotherapy or surgery [7]. Further large-scale or multicenter studies are needed to compare the clinical features of COVID-19 disease between cancer patients and the general population, and clarify whether the clearance of the virus and the recovery of COVID-19 are delayed in cancer patients.\n\nAbbreviations\nSARS-CoV-2Severe acute respiratory syndrome coronavirus 2\n\nCOVID-19Coronavirus disease 2019\n\nCTComputed tomographic\n\nRT-PCRReverse transcription polymerase chain reaction\n\nWBCsWhite blood cells\n\nNKNatural killer\n\nB-CLLB cell lymphocytic leukemia\n\nCOPDChronic obstructive pulmonary disease\n\nICUIntensive care unit\n\nHCCHepatocellular carcinoma\n\nAcknowledgements\nWe would like to acknowledge and thank the patients including in this study, and all staff in the Department of Infectious Diseases, Zhongnan Hospital of Wuhan University.\n\nAuthors’ contributions\nY.X., S.S., and Z.M. conceived the original idea and led the overall study. S.S. and Z.M. wrote the paper. Z.M. and Y.X. carefully revised the manuscript. T.C., L.D., X.Z., P.M., W.H., and S.G. collected and analyzed the clinical data. The author(s) read and approved the final manuscript.\n\nFunding\nThis research was supported by the Medical Science Advancement Program (Basic Medical Sciences) of Wuhan University, Grant No. TFJC2018002 (to Y.X.) and by a grant from the National Natural Science Foundation, China, Grant No. 81401663 (to Z.M.).\n\nAvailability of data and materials\nThe datasets supporting the conclusions of this article are included within the article. And further detailed datasets for the current study are available from the corresponding author on reasonable request.\n\nEthics approval and consent to participate\nThis study was conducted according to the principles expressed in the Declaration of Helsinki, and was approved by the ethics committee of Zhongnan Hospital of Wuhan University (No. 2020011). Written consent forms were obtained from the patients after gave them appropriate information.\n\nConsent for publication\nWritten consent forms for publication were obtained from the patients or their clients after gave them appropriate information.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n==== Refs\nReferences\n1. Hui DS Azhar EI Madani TA Ntoumi F Kock R Dar O The continuing 2019-nCoV epidemic threat of novel coronaviruses to global health - the latest 2019 novel coronavirus outbreak in Wuhan, China Int J Infect Dis 2020 91 264 266 10.1016/j.ijid.2020.01.009 31953166 \n2. Jin YH Cai L Cheng ZS Cheng H Deng T Fan YP A rapid advice guideline for the diagnosis and treatment of 2019 novel coronavirus (2019-nCoV) infected pneumonia (standard version) Mil Med Res 2020 7 1 4 32029004 \n3. Wang D Hu B Hu C Zhu F Liu X Zhang J Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China JAMA 2020 323 11 1061 1069 10.1001/jama.2020.1585 \n4. World Health Organization (WHO). Coronavirus disease (COVID-2019) situation reports. https://www.who.int/emergencies/diseases/novel-coronavirus-2019/situation-reports Accessed 19 Feb 2020.\n5. Lu H Drug treatment options for the 2019-new coronavirus (2019-nCoV) Biosci Trends 2020 14 1 69 71 10.5582/bst.2020.01020 31996494 \n6. Chen N Zhou M Dong X Qu J Gong F Han Y Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study Lancet. 2020 395 10223 507 513 10.1016/S0140-6736(20)30211-7 32007143 \n7. Liang W Guan W Chen R Wang W Li J Xu K Cancer patients in SARS-CoV-2 infection: a nationwide analysis in China Lancet Oncol 2020 21 3 335 337 10.1016/S1470-2045(20)30096-6 32066541 \n8. Li T Qiu Z Zhang L Han Y He W Liu Z Significant changes of peripheral T lymphocyte subsets in patients with severe acute respiratory syndrome J Infect Dis 2004 189 4 648 651 10.1086/381535 14767818 \n9. He Z Zhao C Dong Q Zhuang H Song S Peng G Effects of severe acute respiratory syndrome (SARS) coronavirus infection on peripheral blood lymphocytes and their subsets Int J Infect Dis 2005 9 6 323 330 10.1016/j.ijid.2004.07.014 16095942 \n10. Wang F Nie J Wang H Zhao Q Xiong Y Deng L Characteristics of peripheral lymphocyte subset alteration in COVID-19 pneumonia J Infect Dis 2020 221 11 1762 1769 10.1093/infdis/jiaa150 32227123 \n11. Xu B Fan CY Wang AL Zou YL Yu YH He C Suppressed T cell-mediated immunity in patients with COVID-19: a clinical retrospective study in Wuhan China J Infect 2020 S0163-4453 20 30223 30221 \n12. He R Lu Z Zhang L Fan T Xiong R Shen X The clinical course and its correlated immune status in COVID-19 pneumonia J Clin Virol 2020 127 104361 10.1016/j.jcv.2020.104361 32344320 \n13. Xu Z Shi L Wang Y Zhang J Huang L Zhang C Pathological findings of COVID-19 associated with acute respiratory distress syndrome Lancet Respir Med 2020 8 4 420 422 10.1016/S2213-2600(20)30076-X 32085846 \n14. Liu J Li S Liu J Liang B Wang X Wang H Longitudinal characteristics of lymphocyte responses and cytokine profiles in the peripheral blood of SARS-CoV-2 infected patients EBioMedicine. 2020 55 102763 10.1016/j.ebiom.2020.102763 32361250 \n15. Xu K, Chen Y, Yuan J, Yi P, Ding C, Wu W, et al. Factors associated with prolonged viral RNA shedding in patients with COVID-19. Clin Infect Dis. 2020; ciaa351. doi: 10.1093/cid/ciaa351.\n16. Yu J, Ouyang W, Chua MLK, Xie C. SARS-CoV-2 Transmission in Patients With Cancer at a Tertiary Care Hospital in Wuhan, China. JAMA Oncol. 2020; e200980. doi: 10.1001/jamaoncol.2020.0980.\n\n",
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"keywords": "Cancer; Coronavirus disease 2019; Severe acute respiratory syndrome coronavirus 2; Wuhan",
"medline_ta": "Infect Dis Poverty",
"mesh_terms": "D000328:Adult; D000368:Aged; D000073640:Betacoronavirus; D000086382:COVID-19; D002681:China; D018352:Coronavirus Infections; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D016867:Immunocompromised Host; D008168:Lung; D008297:Male; D008875:Middle Aged; D009369:Neoplasms; D058873:Pandemics; D011024:Pneumonia, Viral; D013902:Radiography, Thoracic; D000086402:SARS-CoV-2",
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"title": "Clinical characteristics of four cancer patients with SARS-CoV-2 infection in Wuhan, China.",
"title_normalized": "clinical characteristics of four cancer patients with sars cov 2 infection in wuhan china"
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"abstract": "The pathogenesis of rest tremor in Parkinson's disease (PD) is incompletely understood. This symptom can be resistant to typical anti-PD medications. Therefore, new treatments are needed given the concern that this symptom causes to patients and family. Limited experience suggests that clozapine can have an important antitremor effect in PD. The mechanism(s) underlying this effect is not well understood, but could provide insight and impetus to the development of more-effective and safer antitremor therapies.\nExemplifying the antitremor effects of clozapine, we describe a patient with tremor-predominant PD who obtained prominent reduction of rest tremor with clozapine treatment. We review the responses to this treatment in another 7 of our PD patients with treatment-resistant rest tremor. We also review the published literature on clozapine for tremor in PD and discuss its potential mechanisms of action and possible adverse effects. In our case series, there was a 64% reduction of tremor score after clozapine was initiated. The mechanism of tremor reduction remains unclear with possible involvement of anticholinergic, serotonergic, antihistaminergic, antiadrenergic, and antidopaminergic effects. Clozapine does have potential serious adverse effects.\nClozapine may be effective in controlling rest tremor in PD. Given the potential fatal side effects, if clozapine is to be initiated in PD patients, it has to be used cautiously with proper monitoring, preferably in specialized centers. We acknowledge that the number of patients in this case series is small. Further studies are needed to understand clozapine's mechanism of action in reducing tremor.",
"affiliations": "National Neuroscience Institute Singapore.;Morton and Gloria Shulman Movement Disorders Clinic and the Edmond J. Safra Program in Parkinson's Disease Toronto Western Hospital University of Toronto Toronto Ontario Canada.;Morton and Gloria Shulman Movement Disorders Clinic and the Edmond J. Safra Program in Parkinson's Disease Toronto Western Hospital University of Toronto Toronto Ontario Canada.",
"authors": "Yaw|Tay Kay|TK|;Fox|Susan H|SH|;Lang|Anthony E|AE|",
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"issue": "3(2)",
"journal": "Movement disorders clinical practice",
"keywords": "Parkinson's disease; adverse reaction; atypical neuroleptic; clozapine; tremor",
"medline_ta": "Mov Disord Clin Pract",
"mesh_terms": null,
"nlm_unique_id": "101630279",
"other_id": null,
"pages": "116-124",
"pmc": null,
"pmid": "30363578",
"pubdate": "2016",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": "10811238;1882209;12420151;20305597;20420765;7657912;2006003;768793;10830427;1349460;9771493;3947248;10868465;17194170;12899114;9613725;2574192;19653979;7961562;18556024;9928258;21069690;1346637;8632342;14502664;20692814;15090561;16816234;10401912;8515788;10072410;18534670;16421460;11859840;17594079;9109903;20023573;18949249;24646688;9137912;10764923;9928890;12210876;7961563;2900293;11116788;8043043;11971094;10584719;2388638;17673498;7991106;10553730;11132243;9409351;14872017;19027269;16514524;2125857;1483417;1695404;12473405;12814332;12601099;12567158;23140648;12675128;2388641;12745955;14531046;18646130",
"title": "Clozapine in Parkinsonian Rest Tremor: A Review of Outcomes, Adverse Reactions, and Possible Mechanisms of Action.",
"title_normalized": "clozapine in parkinsonian rest tremor a review of outcomes adverse reactions and possible mechanisms of action"
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"abstract": "BACKGROUND\nDiamond-Blackfan anemia (DBA) is characterized by hypoplastic anemia, congenital anomalies, and a predisposition for malignancies. Most of our understanding of this disorder stems from molecular studies combined with extensive data input from international patient registries.\n\n\nOBJECTIVE\nTo create an overview of the pediatric DBA population in the Netherlands.\n\n\nMETHODS\nForty-three patients diagnosed with DBA from all Dutch university pediatric hospitals were included in this study, and their clinical and genetic characteristics were collected from patient records.\n\n\nRESULTS\nCongenital malformations were present in 24 of 43 patients (55.8%). An underlying genetic defect was identified in 26 of 43 patients (60.5%), the majority of which were found in the RPS19 gene (12 of 43, 27.9%) with 1 patient carrying a mutation in a novel DBA candidate gene, RPL9. In 31 of 35 (88.6%) patients, an initial response to glucocorticoid treatment was observed. Six patients (14.0%) underwent hematopoietic stem cell transplantation, and eleven patients (11 of 43, 25.6%) became treatment-independent spontaneously.\n\n\nCONCLUSIONS\nIn agreement with previous reports, the Dutch pediatric DBA population is both clinically and genetically heterogeneous. National and international registries, together with more extensive genetic testing, are crucial to increase our understanding of genotype and phenotype correlations of this intriguing disorder.",
"affiliations": "Department of Pediatric Hematology, University Medical Center Utrecht, Utrecht, The Netherlands.;Department of Pediatric Hematology, Erasmus Medical Center, Rotterdam, The Netherlands.;Department of Pediatric Hematology, Leiden University Medical Center, Leiden, The Netherlands.;Department of Pediatric Hematology, University Medical Center Groningen, Groningen, The Netherlands.;Department of Pediatric Hematology, Radboud University Medical Center, Nijmegen, The Netherlands.;Department of Pediatrics, Maxima Medical Center, Veldhoven, The Netherlands.;Department of Pediatric Hematology, Academic Medical Center Amsterdam, Amsterdam, The Netherlands.;Department of Pediatric Hematology, Maastricht University Medical Center, Maastricht, The Netherlands.;Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands.;Department of Pediatric Hematology, University Medical Center Utrecht, Utrecht, The Netherlands.;Laboratory Genetic Metabolic Diseases, Academic Medical Center Amsterdam, Amsterdam, The Netherlands.;Department of Pediatric Hematology, University Medical Center Utrecht, Utrecht, The Netherlands.",
"authors": "van Dooijeweert|Birgit|B|http://orcid.org/0000-0002-8889-3362;van Ommen|C Heleen|CH|;Smiers|Frans J|FJ|;Tamminga|Rienk Y J|RYJ|;Te Loo|Maroeska W|MW|;Donker|Albertine E|AE|;Peters|Marjolein|M|;Granzen|Bernd|B|;Gille|Hans J J P|HJJP|;Bierings|Marc B|MB|;MacInnes|Alyson W|AW|;Bartels|Marije|M|",
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"issue": "100(2)",
"journal": "European journal of haematology",
"keywords": "Diamond-Blackfan anemia; bone marrow failure; genotype-phenotype correlation; patient registry; ribosomopathy",
"medline_ta": "Eur J Haematol",
"mesh_terms": "D000293:Adolescent; D029503:Anemia, Diamond-Blackfan; D002648:Child; D002675:Child, Preschool; D003131:Combined Modality Therapy; D000013:Congenital Abnormalities; D005260:Female; D005500:Follow-Up Studies; D056726:Genetic Association Studies; D005820:Genetic Testing; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D009426:Netherlands; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012042:Registries",
"nlm_unique_id": "8703985",
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"pages": "163-170",
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"pubdate": "2018-02",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Pediatric Diamond-Blackfan anemia in the Netherlands: An overview of clinical characteristics and underlying molecular defects.",
"title_normalized": "pediatric diamond blackfan anemia in the netherlands an overview of clinical characteristics and underlying molecular defects"
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"abstract": "High-dose continuous midazolam therapy has been used successfully for control of refractory status epilepticus. However, normal anion gap (AG) metabolic acidosis, a deleterious complication of this therapy is underrecognized. Even though previously reported in an isolated case report in a pediatric patient, we observed similar complication in an adult patient. Stereotyped normal AG metabolic acidosis along with hypotension developed on two occasions during high-dose continuous midazolam hydrochloride infusion that reverted rapidly following cessation of the infusion.",
"affiliations": "Department of Neuroanaesthesia, AIIMS, New Delhi, India.;Department of Neuroanaesthesia, AIIMS, New Delhi, India.;Department of Anaesthesia, Base Hospital, New Delhi, India.;Department of Neuroanaesthesia, AIIMS, New Delhi, India.;Department of Neuroanaesthesia, AIIMS, New Delhi, India.",
"authors": "Singh|Shalendra|S|;Khandelwal|Ankur|A|;Datta|Rashmi|R|;Kaushal|Ashutosh|A|;Singh|Gyaninder Pal|GP|",
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"delete": false,
"doi": "10.4103/ijccm.IJCCM_416_17",
"fulltext": "\n==== Front\nIndian J Crit Care MedIndian J Crit Care MedIJCCMIndian Journal of Critical Care Medicine : Peer-reviewed, Official Publication of Indian Society of Critical Care Medicine0972-52291998-359XMedknow Publications & Media Pvt Ltd India IJCCM-22-11910.4103/ijccm.IJCCM_416_17Case ReportRecurrent Metabolic Acidosis during High-dose Midazolam Therapy for Refractory Status Epilepticus Singh Shalendra Khandelwal Ankur Datta Rashmi 1Kaushal Ashutosh Singh Gyaninder Pal Department of Neuroanaesthesia, AIIMS, New Delhi, India1 Department of Anaesthesia, Base Hospital, New Delhi, IndiaAddress for correspondence: Dr. Shalendra Singh, Senior Resident, Department of Neuroanaesthesia, AIIMS, New Delhi, India. E-mail: drsinghafmc@gmail.com2 2018 22 2 119 121 Copyright: © 2018 Indian Journal of Critical Care Medicine2018This 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.High-dose continuous midazolam therapy has been used successfully for control of refractory status epilepticus. However, normal anion gap (AG) metabolic acidosis, a deleterious complication of this therapy is underrecognized. Even though previously reported in an isolated case report in a pediatric patient, we observed similar complication in an adult patient. Stereotyped normal AG metabolic acidosis along with hypotension developed on two occasions during high-dose continuous midazolam hydrochloride infusion that reverted rapidly following cessation of the infusion.\n\nAcidosishydrochloric acidmidazolamseizures\n==== Body\nINTRODUCTION\nDifferent antiepileptic drugs (AEDs) have been employed alone or in combinations to achieve adequate control for refractory seizure. Midazolam, because of its versatile pharmacologic profile has been used successfully in high dose as continuous infusion for treatment of refractory status epilepticus.[12] However, the association of high-dose midazolam infusion and metabolic acidosis is often belittled. Failure to recognize this complication heralds fatal prognosis. We encountered a similar scenario, in which stereotyped severe metabolic acidosis developed on two occasions during high-dose midazolam infusion.\n\nCASE REPORT\nA 21-year-old (61 kg, 175 cm) male patient arrived in the emergency department in altered sensorium following an episode of status epilepticus. Glasgow Coma Scale score on admission was 8 (E2V1M5). Initial resuscitation involved intubation of trachea, maintenance of ventilatory and circulatory parameters. The patient was a known case of epilepsy for the past 8 years and had been on multiple AED (phenytoin, levetiracetam, and clonazepam). The patient also had a history of uneventful surgery of intracranial electrode implantation a year ago.\n\nDue to ongoing seizure even after starting intravenous (IV) phenytoin, levetiracetam, clonazepam, and phenobarbitone, IV sodium thiopental infusion (0.5–4 mg/kg/h) was commenced as per the guideline. Continuous electroencephalographic (EEG) monitoring was also done. On the 3rd day of hospital admission, the patient underwent craniotomy surgery for resection of epileptogenic foci. All the drugs which the patient had been taking preoperatively were started again in the postoperative period. However, clinical seizure (5–6 episodes/day) continued in the postoperative period along with continuous EEG evidence of ictal activity. As such, due to refractory status epilepticus, IV midazolam (midazolam hydrochloride 1% + benzyl alcohol 1%) was started as continuous infusion at a rate of 120 mg/h on the 12th day of admission. However, after 24 h, the patient developed severe hyperchloremic normal anion gap (AG) metabolic acidosis (nonresponsive to IV sodium bicarbonate). It was associated with hypotension (more than 20% of baseline) which required low-dose norepinephrine IV infusion (1 mcg/min). Plasma levels of AED came to be normal. All other causes of normal AG metabolic acidosis were excluded. Suspecting midazolam to be the cause of this severe metabolic acidosis, it was stopped, and IV ketamine (2 mg/kg/h) was started. In next 24 h, the acidosis resolved and sodium bicarbonate level assumed near normal levels.[Table 1]. Norepinephrine was tapered and stopped after achieving desired hemodynamics. Since the clinical seizure frequency increased (10–12 episodes/day) as compared to before, the patient eventually underwent right hemispherectomy surgery under general anesthesia.\n\nTable 1 Progression of arterial blood gas values on two different occasions\n\nNext 8 days following hemispherectomy, the patient continued to be asymptomatic. However, yet again, the patient developed intractable seizures on the 9th day after hemispherectomy. IV midazolam 100 mg/h infusion was started again along with the continuation of other AED. In next 24 h, the patient again developed severe normal AG metabolic acidosis along with fall in blood pressure within 20% of baseline. Midazolam infusion was stopped and replaced again with ketamine infusion. Yet again, the metabolic acidosis resolved in the next 12 h following cessation of midazolam infusion [Table 1]. The patient underwent percutaneous tracheostomy due to prolonged ventilation on the 12th day and weaning done in few days with no complication and rest of the patient's hospital stay was uneventful. This time too, high-dose midazolam infusion was linked to metabolic acidosis as a diagnosis of exclusion of other causes of normal AG metabolic acidosis.\n\nDISCUSSION\nPromising results have been shown with the use of high-dose IV midazolam for the treatment of refractory status epileptics both in adults[1] and children.[2] Its water-soluble property decreases venous irritation and its lipophilic property at physiological pH accounts for its rapid onset of action.[3] Prolonged infusion of other benzodiazepine drugs such as diazepam and lorazepam is not advisable because of the inherent risk of propylene glycol (solvent) toxicity.[4] Refractory metabolic acidosis as a complication of high-dose midazolam infusion has been previously reported in pediatric status epilepticus.[5] However, this association in adults has not been reported. Conventionally, midazolam is used in intensive care units for sedation in adults in doses ranging from 2 to 5 mg/h.[6] However, in our case, due to epilepsy syndrome, high-dose midazolam infusion (up to 2 mg/kg/h) was used. Normal AG metabolic acidosis that developed on two occasions in our patient during midazolam infusion were stereotyped and reverted after cessation of infusion. Moreover, since no other cause could be found to cause hyperchloremic acidosis in our patient, we speculated that the most probable cause was due to high-dose midazolam therapy.\n\nUnlike diazepam or lorazepam, midazolam is prepared with hydrochloric acid (HCl) to achieve required solubility. In addition, 1% benzyl alcohol is added as a preservative. Benzyl alcohol toxicity has been associated with high AG metabolic acidosis.[7] However, in our case, the metabolic acidosis was associated with normal AG during both situations, and thus, benzyl alcohol toxicity seemed unlikely in our case. Therefore, the normal AG hyperchloremic metabolic acidosis in our case can be most commonly attributed to cumulative exposure to HCl.\n\nDuring the first episode, hypotension was more than 20% of baseline and thus required vasopressor (norepinephrine) support. However, hypotension during the second episode (within 20% of baseline) did not require any vasopressor support. In both situations, blood pressures returned back to its baseline values after stopping midazolam infusion. Even though literature have found a significant association between hyperchloremic metabolic acidosis and acute kidney injury,[89] but in our case, neither clinical (urine output) nor laboratory parameters showed any such association. Presumably, this could be due to transient hyperchloremia and its rapid reversibility following the cessation of the offending agent.\n\nCONCLUSION\nBenzodiazepines are used as first-line drugs for control of acute seizures. Since midazolam is short-acting with less side effects, it is utilized as a continuous infusion for the treatment of refractory status epilepticus. However, normal AG metabolic acidosis and resulting hemodynamic perturbations that accompanies high-dose midazolam infusion should always be borne in mind. Since there is no role of bicarbonate therapy, prompt cessation of infusion and maintenance of hemodynamic parameters are the only remedial measures.\n\nDeclaration of patient consent\nThe authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) 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\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n==== Refs\nREFERENCES\n1 Fernandez A Lantigua H Lesch C Shao B Foreman B Schmidt JM High-dose midazolam infusion for refractory status epilepticus Neurology 2014 82 359 65 24363133 \n2 Morrison G Gibbons E Whitehouse WP High-dose midazolam therapy for refractory status epilepticus in children Intensive Care Med 2006 32 2070 6 16977485 \n3 Reves JG Fragen RJ Vinik HR Greenblatt DJ Midazolam: Pharmacology and uses Anesthesiology 1985 62 310 24 3156545 \n4 Wilson KC Reardon C Theodore AC Farber HW Propylene glycol toxicity: A severe iatrogenic illness in ICU patients receiving IV benzodiazepines: A case series and prospective, observational pilot study Chest 2005 128 1674 81 16162774 \n5 Federman MD Kelly R Harrison RE Refractory metabolic acidosis as a complication of high-dose midazolam infusion for pediatric status epilepticus Clin Neuropharmacol 2009 32 340 1 19952873 \n6 Ulvi H Yoldas T Müngen B Yigiter R Continuous infusion of midazolam in the treatment of refractory generalized convulsive status epilepticus Neurol Sci 2002 23 177 82 12536286 \n7 Brown WJ Buist NR Gipson HT Huston RK Kennaway NG Fatal benzyl alcohol poisoning in a neonatal Intensive Care Unit Lancet 1982 1 1250 \n8 Yunos NM Bellomo R Hegarty C Story D Ho L Bailey M Association between a chloride-liberal vs.chloride-restrictive intravenous fluid administration strategy and kidney injury in critically ill adults JAMA 2012 308 1566 72 23073953 \n9 McCluskey SA Karkouti K Wijeysundera D Minkovich L Tait G Beattie WS Hyperchloremia after noncardiac surgery is independently associated with increased morbidity and mortality: A propensity-matched cohort study Anesth Analg 2013 117 412 21 23757473\n\n",
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"keywords": "Acidosis; hydrochloric acid; midazolam; seizures",
"medline_ta": "Indian J Crit Care Med",
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"pages": "119-121",
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"title": "Recurrent Metabolic Acidosis during High-dose Midazolam Therapy for Refractory Status Epilepticus.",
"title_normalized": "recurrent metabolic acidosis during high dose midazolam therapy for refractory status epilepticus"
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{
"abstract": "Immune-related adverse events in the thyroid glands (thyroid irAEs) during treatment with immune-checkpoint inhibitors (ICIs) are most frequent endocrine irAE. Thyroid irAE can be divided into that requiring continuous therapy for thyroid dysfunction (P-THY), and that requiring only temporal treatment (T-THY). However, predictive factors for those differential outcomes are unknown, and susceptibility of human leukocyte antigen (HLA) to thyroid irAE has never been investigated. This study aimed to elucidate clinical courses and prognosis of P-THY in comparison with T-THY in the aspect of thyroid immunity and HLA. Patients with P-THY (n = 15) that required L-T4 supplemental therapy for hypothyroidism for more than 3 months, and patients with T-THY who required no therapy or therapy within 1 month were enrolled in the study. Lower-value of TSH, higher-value of FT4, and lower value of TSH/FT4 were thought to be predictive markers to estimate P-THY. In addition, anti-thyroglobulin antibody (TgAb) levels were significantly higher in patients with P-THY than those in patients with T-THY. HLA-DPA1*01:03 and HLA-DPB1*02:01 allele, and their haplotype frequencies were significantly higher in patients with P-THY than those in controls. P-THY had better survival rate than T-THY. Pre-existing thyroid autoimmunity, the extent of thyroid dysfunction, and predisposing HLA were associated with the differential course of thyroid irAEs. It was suggested that thyroid function tests, TgAb, and HLA typing tests are useful for prediction of clinical course in thyroid irAEs.",
"affiliations": "The First Department of Medicine, Wakayama Medical University, Wakayama, Japan.;The First Department of Medicine, Wakayama Medical University, Wakayama, Japan.;The First Department of Medicine, Wakayama Medical University, Wakayama, Japan.;The First Department of Medicine, Wakayama Medical University, Wakayama, Japan.;The First Department of Medicine, Wakayama Medical University, Wakayama, Japan.;The First Department of Medicine, Wakayama Medical University, Wakayama, Japan.;The First Department of Medicine, Wakayama Medical University, Wakayama, Japan.;Department of Otolaryngology-Head and Neck Surgery, Wakayama Medical University, Wakayama, Japan.;The First Department of Medicine, Wakayama Medical University, Wakayama, Japan.",
"authors": "Inaba|Hidefumi|H|;Ariyasu|Hiroyuki|H|;Iwakura|Hiroshi|H|;Kurimoto|Chiaki|C|;Takeshima|Ken|K|;Morita|Shuhei|S|;Furuta|Hiroto|H|;Hotomi|Muneki|M|;Akamizu|Takashi|T|",
"chemical_list": "D000074322:Antineoplastic Agents, Immunological; D000082082:Immune Checkpoint Inhibitors",
"country": "Japan",
"delete": false,
"doi": "10.1507/endocrj.EJ20-0371",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0918-8959",
"issue": "68(2)",
"journal": "Endocrine journal",
"keywords": "Human leukocyte antigen; Immune-checkpoint inhibitors; Immune-related adverse events; Thyroid gland",
"medline_ta": "Endocr J",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000074322:Antineoplastic Agents, Immunological; D005260:Female; D006801:Humans; D000082082:Immune Checkpoint Inhibitors; D008297:Male; D008875:Middle Aged; D009369:Neoplasms; D011379:Prognosis; D013959:Thyroid Diseases; D013961:Thyroid Gland",
"nlm_unique_id": "9313485",
"other_id": null,
"pages": "231-241",
"pmc": null,
"pmid": "33012745",
"pubdate": "2021-02-28",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Distinct clinical features and prognosis between persistent and temporary thyroid dysfunctions by immune-checkpoint inhibitors.",
"title_normalized": "distinct clinical features and prognosis between persistent and temporary thyroid dysfunctions by immune checkpoint inhibitors"
} | [
{
"companynumb": "JP-BRISTOL-MYERS SQUIBB COMPANY-BMS-2018-003898",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "NIVOLUMAB"
},
"drugaddi... |
{
"abstract": "We are reporting a case of zolpidem induced multimodal hallucinations in a 22 year old female without any history of psychiatric disorders. Zolpidem, by acting on gamma-amino butyric acid type A receptor has a potential to cause a paradoxical reaction and there also exists a possibility of an induced delirium with its use. This case reports evaluates its potential to cause multimodal hallucinations. Zolpidem needs to be prescribed judiciously with the caution of potential side effects particularly in females.",
"affiliations": "Departments of Psychiatry, JSS Medical College, Mysore, India.;Departments of Psychiatry, JSS Medical College, Mysore, India.;Departments of Medicine, JSS Medical College, Mysore, India.",
"authors": "Ram|Dushad|D|;Eiman|Najla|N|;Gowdappa|Basavana|B|",
"chemical_list": null,
"country": "Korea (South)",
"delete": false,
"doi": "10.9758/cpn.2015.13.2.215",
"fulltext": "\n==== Front\nClin Psychopharmacol NeurosciClin Psychopharmacol NeurosciClinical Psychopharmacology and Neuroscience1738-10882093-4327Korean College of Neuropsychopharmacology 2624385210.9758/cpn.2015.13.2.215cpn-13-215Case ReportMultimodal Hallucination (Audio-visual, Kinaesthetic and Scenic) Associated with the Use of Zolpidem Ram Dushad 1Eiman Najla 1Gowdappa Basavana 21 Department of Psychiatry, JSS Medical College, Mysore, \nIndia2 Department of Medicine, JSS Medical College, Mysore, \nIndiaAddress for correspondence: Dushad Ram, MD, Department of Psychiatry, JSS Hospital, MG Road, Mysore, Karnataka 570004, India, Tel: +91-0821-2335501, Fax: +91-0821-2335187, E-mail: akashji1972@gmail.com8 2015 31 8 2015 13 2 215 217 22 12 2014 12 2 2015 13 2 2015 Copyright © 2015, Korean College of Neuropsychopharmacology2015This is an Open-Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.We are reporting a case of zolpidem induced multimodal hallucinations in a 22 year old female without any history of psychiatric disorders. Zolpidem, by acting on gamma-amino butyric acid type A receptor has a potential to cause a paradoxical reaction and there also exists a possibility of an induced delirium with its use. This case reports evaluates its potential to cause multimodal hallucinations. Zolpidem needs to be prescribed judiciously with the caution of potential side effects particularly in females.\n\nMultimodal hallucinationsZolpidemSleep initiation and maintenance disorders\n==== Body\nINTRODUCTION\nZolpidem (ZPD) selectively activates alpha 1 subunit of the omega-1 (BZ1) receptor of the gamma-amino butyric acid type A (GABA-A) which may account for its selective sedative effects and relative lack of muscle relaxant and anticonvulsant effects compared to benzodiaze-pines. ZPD may cause unusual perceptual experience (commonly visual and auditory) in person with history of mental illness and with or without associated distress and amnesia.1–4) Here we are reporting a case of multimodal hallucination (audio, visual, kinaesthetic, and scenic) following the use of ZPD.\n\nCASE\nA 22 year old unmarried female, a third year medical student with nil significant family history and a well adjusted premorbid personality had been experiencing sleep onset insomnia for twenty days prior to her exams. She would not sleep till 1 AM and would get up late in the morning. She bought over the counter medication tablet ZPD 10 mg after having seen her consultant prescribe the same for insomnia. After consuming a 10 mg tablet of ZPD, she sat on the floor mat along with another colleague of hers for studying till she felt sleepy. About 30 minutes later she complained to her friend that the letters appeared to be shaking and going out of order. She reported that words no longer stayed in a straight line but appeared in disarray. Few minutes later she raised her hand to alarm that she was about to sink. Following this she had a very weird experience.\n\nShe felt to be in a lake and surrounded by water; floating with her friend on a boat and her body was bouncing up and down and the surrounding had assumed a bright orange hue. She was very frightened, held her friend asking for help and requesting to park at lakeside.\n\nThey stopped studying and her friend tried to convince that no such thing is occurring, and took her to TV room. She reported that the characters are coming out of the TV (that was switched off) and she tried to approach them; was talking to them as if they were in their room and unable to delineate with her surroundings though she was oriented to time and to her friend. There was no report of unusual experience in touch, pain, temperature or other modality. The friend convinced her and took her to bed and she fell asleep after 10 minutes. The next morning she had memories of the same and could recollect the events and consulted the physician. On assessment there was no evidence of physical illness, other substance abuse, nightmare or night terror or any other psychiatric disorder or any other concomitant medication use. Assessment of causal association with World Health Organization probability scale and Naranjo’s Algorithm (score=8) revealed a “probable” association of this adverse event with ZPD.5,6) She was prescribed tablet nitrazepam 5 mg at bedtime till her examination got over. Her sleep improved without any significant adverse event. After four weeks nitrazepam was tapered off over next two weeks. She was advised to avoid use of ZPD in future, practice sleep hygiene and relaxation techniques.\n\nDISCUSSION\nThis case highlights serious side effect associated with use of ZPD in normal dose range. In this case clusters of symptoms that developed immediately after the use of ZPD raised few queries–whether it was a paradoxical reaction or delirium or whether it was just a multimodal hallucination.\n\nSymptoms profile of this case has some similarity with paradoxical reaction such as increased anxiety level, hyperactivity etc. Also that ZPD is a potential substance for paradoxical reaction as it acts on GABA A receptor that is linked to such reaction. This possibility was excluded as patient did not complaint of anxiety or inability to stay at a place but rather it was a reaction to unusual experience. Delirium was also excluded because patient was oriented to time and person and because of unusual visual experience she had difficulty in ascertaining the place. Thus finally the event was considered as ZPD induced hallucination. In this case it is unique due to presence of multiple hallucinations (audio: hearing voice of TV character, visual: lake and boat, kinaesthetic: perception of body movement up and down, and scenic: seeing a TV show with lively characters) without amnesia and re-experience with nitrazepam.\n\nThough there are case reports of visual distortion and hallucination, this case was interesting due to presence of multimodal hallucination.7) Common clinical characteristics of the patients who reported such experience were mostly female, had mental illness, were on other psychotropic medication, doses of ZPD was ≥10 mg, onset of symptoms within 20–30 minutes after ingestion, improved without treatment after several hours of discontinuation.7) Toner et al.8) suggested ZPD concentration may be more in female, low serum albumin with inhibition of CYP3A4 isoenzyme and dose higher than 5 mg may cause perceptual abnormality. It is speculated that in such phenomena GABA receptor (α1 subunit) may be over-expressed or they may be rapid activation after quick absorption in sensitive individuals.9) GABA A α1 receptor constitutes a high proportion of GABA receptors and high concentration is present in limbic brain areas that has been associated with multimodal hallucination in neuroimging studies.10–12) Reduced sleep latency with ZPD use has similarity with narcolepsy; a sleep disorder that is often associated with hallucination and dysfunction of GABAergic function is often speculated. There is a possibility that similar to other GABA A α1 agonist (e.g., muscimol) ZPD may also have hallucinogenic property. In few studies the GABA A α1 receptor agonist (e.g., muscimol) was found to increase the firing of dopaminergic neuron in the ventral tegmental area (origin of the mesolimbic and mesocortical tract) a neuroantomical structure known to be associated with psychotic symptoms in schizophrenia.4)\n\nContrary to the other report, in this case there was no amnesia for the event. Literature suggests that mood disorders, substance used disorders, concomitant medication or somatic comorbidities are significant factors in contributing to amnesia, and that were not present in this case.13) Review suggests that patient who experience amnesia were on antidepressant that can attenuate GABAergic transmission facilitating neuronal activation and the release of dopamine that can contribute to unusual perceptual experience in individuals predisposed to decreased monoaminergic neurotransmission levels.13)\n\nIn this case patient did not re-experience the symptoms with the use of nitrazepam, probably due to non-selective receptor binding profile. In conclusion, although ZPD is believed to be safe it can have rare deleterious side effects and should be used at the lowest effective dose in females.\n==== Refs\nREFERENCES\n1 Markowitz JS Rames LJ Reeves N Thomas SG Zolpidem and hallucinations Ann Emerg Med 1997 29 300 301 10.1016/S0196-0644(97)70291-9 9018205 \n2 Elko CJ Burgess JL Robertson WO Zolpidem-associated hallucinations and serotonin reuptake inhibition: a possible interaction J Toxicol Clin Toxicol 1998 36 195 203 10.3109/15563659809028939 9656974 \n3 Huang CL Chang CJ Hung CF Lin HY Zolpidem-induced distortion in visual perception Ann Pharmacother 2003 37 683 686 10.1345/aph.1C318 12708947 \n4 Garbutt JC van Kammen DP The interaction between GABA and dopamine: implications for schizophrenia Schizophr Bull 1983 9 336 353 10.1093/schbul/9.3.336 6137869 \n5 Naranjo CA Busto U Sellers EM Sandor P Ruiz I Roberts EA A method for estimating the probability of adverse drug reactions Clin Pharmacol Ther 1981 30 239 245 10.1038/clpt.1981.154 7249508 \n6 World Health Organization The use of the WHO-UMC system for standardised case causality assessment [cited 2014 Aug 24] Available from: http://who-umc.org/Graphics/24734.pdf \n7 Inagaki T Miyaoka T Tsuji S Inami Y Nishida A Horiguchi J Adverse reactions to zolpidem: case reports and a review of the literature Prim Care Companion J Clin Psychiatry 2010 12 21494350 \n8 Toner LC Tsambiras BM Catalano G Catalano MC Cooper DS Central nervous system side effects associated with zolpidem treatment Clin Neuropharmacol 2000 23 54 58 10.1097/00002826-200001000-00011 10682233 \n9 de Haas S Dingemanse J Hoever P Cohen A van Gerven J Pseudohallucinations after zolpidem intake: a case report J Clin Psychopharmacol 2007 27 728 730 10.1097/JCP.0b013e31815a5806 18004155 \n10 Pirker S Schwarzer C Wieselthaler A Sieghart W Sperk G GABA(A) receptors: immunocytochemical distribution of 13 subunits in the adult rat brain Neuroscience 2000 101 815 850 10.1016/S0306-4522(00)00442-5 11113332 \n11 Young AB Chu D Distribution of GABA, and GABA, receptors in mammalian brain: potential targets for drug development Drug Dev Res 1990 21 161 167 10.1002/ddr.430210303 \n12 Silbersweig DA Stern E Frith C Cahill C Holmes A Grootoonk S A functional neuroanatomy of hallucinations in schizophrenia Nature 1995 378 176 179 10.1038/378176a0 7477318 \n13 Cubała WJ Gabrielsson A Sleep related amnestic behaviors due to zolpidem Bull Clin Psychopharmacol 2014 24 188 194\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1738-1088",
"issue": "13(2)",
"journal": "Clinical psychopharmacology and neuroscience : the official scientific journal of the Korean College of Neuropsychopharmacology",
"keywords": "Multimodal hallucinations; Sleep initiation and maintenance disorders; Zolpidem",
"medline_ta": "Clin Psychopharmacol Neurosci",
"mesh_terms": null,
"nlm_unique_id": "101207332",
"other_id": null,
"pages": "215-7",
"pmc": null,
"pmid": "26243852",
"pubdate": "2015-08-31",
"publication_types": "D016428:Journal Article",
"references": "9018205;7477318;18004155;12708947;9656974;21494350;7249508;10682233;6137869;11113332",
"title": "Multimodal Hallucination (Audio-visual, Kinaesthetic and Scenic) Associated with the Use of Zolpidem.",
"title_normalized": "multimodal hallucination audio visual kinaesthetic and scenic associated with the use of zolpidem"
} | [
{
"companynumb": "IN-LUPIN PHARMACEUTICALS INC.-2015-02873",
"fulfillexpeditecriteria": "2",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ZOLPIDEM\\ZOLPIDEM TARTRATE"
},
... |
{
"abstract": "Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a rare delayed-type hypersensitivity reaction that causes skin abnormalities and mucosal involvement of the entire body. This is a case report of DRESS occurring in a liver transplantation recipient after taking drugs. A 57-year-old female patient with hepatocellular carcinoma underwent living donor liver transplantation in April 2019. She had no previous medical histories relevant to allergic diseases. There were no adverse events during hospitalization. She was admitted to evaluate and treat a headache occurring at one month after transplantation. However, she suffered from adverse drug reactions after taking anticonvulsants, showing skin rash, itching sense, and fever with eosinophilia. Piperacillin/Tazoperan was administered for ten days as an empirical antibiotic. Skin biopsy was performed on postoperative day 106 for erythematous maculopapular rash in the arms, legs, and torso. Her symptoms improved after discontinuation of the suspected medication with conservative skin treatment and high-dose steroid treatment. This case suggests that suspicion of drug history is essential for early diagnosis and management of DRESS.",
"affiliations": "Department of Surgery, Seoul National University College of Medicine, Seoul, Korea.;Department of Surgery, Seoul National University College of Medicine, Seoul, Korea.;Department of Surgery, Seoul National University College of Medicine, Seoul, Korea.;Department of Surgery, Seoul National University College of Medicine, Seoul, Korea.;Department of Surgery, Seoul National University College of Medicine, Seoul, Korea.;Department of Surgery, Seoul National University College of Medicine, Seoul, Korea.;Department of Surgery, Seoul National University College of Medicine, Seoul, Korea.;Department of Surgery, Seoul National University College of Medicine, Seoul, Korea.;Department of Surgery, Seoul National University College of Medicine, Seoul, Korea.",
"authors": "Cho|Ara|A|https://orcid.org/0000-0002-4609-5207;Lee|Jeong-Moo|JM|https://orcid.org/0000-0001-7806-8759;Hong|Kwangpyo|K|https://orcid.org/0000-0001-7909-8116;Han|Eui Soo|ES|https://orcid.org/0000-0001-9582-1255;Hong|Suk Kyun|SK|https://orcid.org/0000-0002-0020-6215;Choi|YoungRok|Y|https://orcid.org/0000-0003-2408-7086;Yi|Nam-Joon|NJ|https://orcid.org/0000-0002-5467-425X;Lee|Kwang-Woong|KW|https://orcid.org/0000-0001-6412-1926;Suh|Kyung-Suk|KS|https://orcid.org/0000-0002-9535-7349",
"chemical_list": null,
"country": "Korea (South)",
"delete": false,
"doi": "10.14701/ahbps.2021.25.4.551",
"fulltext": "\n==== Front\nAnn Hepatobiliary Pancreat Surg\nAnn Hepatobiliary Pancreat Surg\nAnnals of Hepato-Biliary-Pancreatic Surgery\n2508-5778\n2508-5859\nThe Korean Association of Hepato-Biliary-Pancreatic Surgery\n\n34845130\n10.14701/ahbps.2021.25.4.551\nahbps-25-4-551\nCase Report\nDrug reaction with eosinophilia and systemic symptoms (DRESS) syndrome in liver transplantation\nhttps://orcid.org/0000-0002-4609-5207\nCho Ara\nhttps://orcid.org/0000-0001-7806-8759\nLee Jeong-Moo\nhttps://orcid.org/0000-0001-7909-8116\nHong Kwangpyo\nhttps://orcid.org/0000-0001-9582-1255\nHan Eui Soo\nhttps://orcid.org/0000-0002-0020-6215\nHong Suk Kyun\nhttps://orcid.org/0000-0003-2408-7086\nChoi YoungRok\nhttps://orcid.org/0000-0002-5467-425X\nYi Nam-Joon\nhttps://orcid.org/0000-0001-6412-1926\nLee Kwang-Woong\nhttps://orcid.org/0000-0002-9535-7349\nSuh Kyung-Suk\nDepartment of Surgery, Seoul National University College of Medicine, Seoul, Korea\nCorresponding author: Jeong-Moo Lee Department of Surgery, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul 03080, Korea Tel: +82-2-2072-2817, Fax: +82-2-766-3975, E-mail: jmleetpl@gmail.com ORCID: https://orcid.org/0000-0001-7806-8759\n30 11 2021\n30 11 2021\n30 11 2021\n25 4 551555\n17 3 2021\n21 5 2021\n25 5 2021\nCopyright © 2021 by The Korean Association of Hepato-Biliary-Pancreatic Surgery\n2021\nhttps://creativecommons.org/licenses/by-nc/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.\nDrug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a rare delayed-type hypersensitivity reaction that causes skin abnormalities and mucosal involvement of the entire body. This is a case report of DRESS occurring in a liver transplantation recipient after taking drugs. A 57-year-old female patient with hepatocellular carcinoma underwent living donor liver transplantation in April 2019. She had no previous medical histories relevant to allergic diseases. There were no adverse events during hospitalization. She was admitted to evaluate and treat a headache occurring at one month after transplantation. However, she suffered from adverse drug reactions after taking anticonvulsants, showing skin rash, itching sense, and fever with eosinophilia. Piperacillin/Tazoperan was administered for ten days as an empirical antibiotic. Skin biopsy was performed on postoperative day 106 for erythematous maculopapular rash in the arms, legs, and torso. Her symptoms improved after discontinuation of the suspected medication with conservative skin treatment and high-dose steroid treatment. This case suggests that suspicion of drug history is essential for early diagnosis and management of DRESS.\n\nDrug hypersensitivity\nEosinophilia\nLiver transplantation\nSevere cutaneous adverse reaction\n==== Body\npmcINTRODUCTION\n\nSevere cutaneous adverse reaction (SCAR) can have a fatal progression in various organs after drug administration, including Steven-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS). SJS and TEN are delayed-type hypersensitivity reactions that shows skin abnormalities from several days to 4 weeks after administering causative agents. As usual, skin symptoms appear several hours to several days before other symptoms such as fever, malaise, and discomfort in eyes or throat appear [1,2]. DRESS is another delayed-type hypersensitivity reaction. In addition to skin rash, it shows systematic symptoms such as organ involvement, eosinophilia, lymphadenopathy, and high fever [2]. Similar to SJS and TEN, patients with DRESS experience prodromal symptoms. However, its incubation period is relatively more extended from two weeks to two months. In addition, 20% of patients show relapse after recovery from the acute course. Furthermore, DRESS is positively associated with reactivation of latent infection of human herpes virus (HHV), cytomegalovirus (CMV), and epstein-barr virus (EBV) [3,4]. It is sometimes difficult to accurately diagnose DRESS syndrome because its clinical features are similar to those of graft-versus-host disease (GVHD), making it difficult to determine the direction of treatment.\n\nThere is a case report about a rare SCAR in Korea occurring in a liver transplant recipient experiencing DRESS syndrome after multiple medications, including anticonvulsants, immunosuppressants, and antibiotics.\n\nCASE\n\nA 57-year-old female hepatocellular carcinoma patient underwent liver transplantation from a living donor on April 15, 2019. She had no previous medical histories relevant to allergic diseases. There were no adverse events during hospitalization. She was discharged on a postoperative day (POD) 25 and readmitted because of a fever up to 38.4°C and a headache on POD 25. Based on results of neurological examination and spinal tapping, treatment was started under suspicion of viral meningitis. For persistent neuropathic pain, carbamazepine was prescribed by a neurologist from POD 32 to POD 40. She complained of drug rashes starting from hands and feet on POD 34. There were erythematous macular patches on the trunk and extremities, especially on the palmoplantar area. Laboratory findings were: white blood cell, 4,190/μL; hemoglobin, 8.2 g/dL; platelet, 89,000/μL; eosinophil, 0%; and lymphocyte, 18.4%. The drug was discontinued on POD 41 due to suspicion of drug rash caused by carbamazepine. From POD 41, she started taking trimethoprim-sulfamethoxazole (TMP-SMX) as a prophylaxis for Pneumocystis pneumonia (PCP) (Fig. 1).\n\nShe suffered from diarrhea, skin rash, and itching sense on POD 99. There was a fever over 39°C. From POD 105, piperacillin/tazoperan was administered for ten days as an empirical antibiotic for cholangitis after liver transplantation. Skin biopsy was performed on POD 106 for erythematous maculopapular rash in the arms, legs, and torso. Acute GVHD was confirmed in the biopsy (Fig. 2A). She stopped taking Tacrolimus from POD 109. Steroid dosage was increased on POD 108 as we could not rule out Tacrolimus as the cause of skin problems. Concerning that piperacillin/tazoperan might lead to eosinophilia, drug rash, and drug fever, we changed Piperacillin/Tazoperan into Levofloxacin after ten days.\n\nA liver biopsy was performed. There was no evidence of GVHD. However, acute hepatitis with reactive hemophagocytosis due to acute viral infection and drug/toxin-induced liver injury were observed (Fig. 2B). The rash and itching sense of the trunk were exacerbated from POD 117. The rash was a generalized maculopapular rash that started from the neck and spread from the center to the peripheral. Oral mucositis and multiple ulcerative lesions in the oral cavity appeared. There were tingling, tearing, swelling around the eyes, hyperemia, blepharitis, and dry eyes. We suspected ocular GVHD Grade 1. Thus, steroid pulse therapy was done from POD 119. We retrospectively reviewed the clinical course of this patient and suspected DRESS syndrome due to several medications. TMP-SMX was discontinued on POD 119 and tenofovir was discontinued on POD 121. Skin biopsy was retaken on POD 121 due to itching sense, multiple bullae on both dorsum of the hand, both sole, and bullous pemphigoid. The biopsy result was drug eruption with superficial perivascular lymphocytic infiltration.\n\nAfterward, most skin lesions in the torso (Fig. 3A) and limbs improved (Fig. 3B). However, skin detachment of the abdomen and hands progressed further and onycholysis of nails appeared (Fig. 3C). Multiple ulcerative lesions appeared over the near-total palate, lip, and buccal mucosa (Fig. 3A, 3D, 3E). There were erosions of the vulva and perianal areas (Fig. 3F). On POD 224, we suspected PCP pneumonia because of fever and diffuse ground-glass opacity pattern on chest computed tomography. Clindamycin and primaquine were administered for three weeks. On POD 242, tenofovir was resumed as she was a hepatitis B virus carrier. After three days, urticaria, severe pruritus, erythema, and edema occurred. These symptoms disappeared after drug cessation. There was no further occurrence after follow-up for four months.\n\nDISCUSSION\n\nThere is no specific test method for SCAR. Its diagnosis is mainly based on clinical features. Differential diagnosis of DRESS from other drug eruptions depends on skin involvement and specific symptoms such as organ involvement, lymphadenopathy, and eosinophilia [5]. In order to diagnose DRESS, the RegiSCAR group and the Japanese consensus group have proposed some criteria. Although there are only a few differences in these criteria, the criteria porposed by the Japanese consensus group are more strict overall than those proposed by the RegiSCAR group. In the criteria proposed by the Japanese consensus group, DRESS corresponds to drug-induced hypersensitivity syndrome (DiHS). The RegiSCAR group has suggested a scoring system to validate DRESS. The list is composed of major clinical characteristics of DRESS. By scoring each criterion from -1 point to +2 points, we calculate the total score. Diagnosis of DRESS is made based on the total score: < 2, no case; 2–3 points, possible case; 4–5 points, probable case; > 5 points, definite case [6].\n\nIn our patient, on postoperative 34 days, the first symptom appeared. According to the RegiSCAR scoring system, the total score was 4, satisfying a probable case of DRESS. However, our case only met three of seven criteria of the Japanese consensus group, not satisfying DiHS.\n\nOn postoperative 117 days, our patient suffered from a relapse of symptoms, including ocular involvement. According to the RegiSCAR scoring system, the total score was 5, following the probable case of DRESS. In addition, five of seven criteria of the Japanese consensus group criteria were met, satisfying DiHS.\n\nA recent pharmacogenomic study has reported a high association between human leukocyte antigen (HLA) genotype and specific drugs. This association is not prevalent worldwide. It shows a racial difference. Currently, well-known SCAR related HLA genotypes are: abacavir and HLA-B*57:01 in White, allopurinol and HLA-B*58:01 in Han Chinese, carbamazepine/oxcarbamazepine and HLA-B*15:02 in Han Chinese, carbamazepine/oxcarbamazepine and HLA-A*31:01 in European, lamotrigine and HLA-B*15:02 in Han Chinese, dapsone and HLA-B*13:01 in Han Chinese, phenytoin and HLA-B*15:02 in Han Chinese, and nevirapine and HLA-B*35:03 in Asian [7]. HLA-B*15:02 allele was reported in 100% of patients who developed SJS and TEN caused by carbamazepine in Taiwan. The risk of developing SJS and TEN after carbamazepine administration was one thousand times higher in allele positive than that in allele negative. As the high correlation was reported in Han Chinese, Taiwan, and United States, the U.S. Food and Drug Administration (FDA) recommended administering carbamazepine after pre-analyzing the HLA genotype in Asians in 2007 [8]. However, this strong association was not found in White, Korean, or Japanese [9,10]. These differences among races ere due to distribution of HLA-B*15:02. The frequency of HLA-B*15:02 is positive in 15% of the population in Hong Kong, Thailand, Malaysia, about 10% in Taiwan, 2%–4% in South Asia, and 1% in Korean and Japanese [11].\n\nIn this case, the patient has an HLA-B*15:02 positive allele, corresponding to the association mentioned above with carbamazepine. Multiple drugs were administered in this patient. However, the possibility of carbamazepine as the cause was high relative to other medications. We had a lot of difficulties in the diagnosis. Initially, her clinical features were similar to those of acute GVHD and eosinophilia was considered a secondary finding based on antibiotics. However, despite an appropriate treatment, her skin lesions became more severe and her clinical features were inconsistent with biopsy findings. We were finally able to diagnose and treat DRESS syndrome through a detailed retrospective review of the carbamazepine use history, HLA type favorable for DRESS syndrome, eosinophilia, and the patient’s clinical course. Eosinophilia was not confirmed at the time of the initial skin lesion occurrence. It showed increasing findings upon continuous follow-up. If we initially suspected that eosinophilia was a symptom of SCAR rather than a secondary result of antibiotic treatment, it would have been easier to diagnose and treat her DRESS syndrome.\n\nDRESS syndrome is mainly managed by symptomatic treatment. Above all, it is imperative to stop suspected medications based on detailed medical history immediately. In comparison with SJS and TEN, organ involvement is the main problem of DRESS syndrome. Therefore, systemic steroid administration is imperative and effective. IVIG is not recommended routinely [12]. However, IVIG is known to be effective in lowering the hyperactive inflammatory response [13]. In our patient, skin rash and various symptoms due to persistently hyperstimulated immune reactions appeared. The effect was insignificant even when high-dose steroids were used. We used IVIG in an attempt to reduce non-specific inflammatory reactions. Our experience of this case suggests that early diagnosis of DRESS followed by timely management can lead to favorable outcomes.\n\nIn conclusion, we report a rare case of DRESS in a liver transplantation recipient. Suspicion of DRESS syndrome through signs and symptoms is essential. Early diagnosis can lead to successful treatment, thus preventing further infection and multi-organ failure.\n\nFig. 1 Relationships of the disease progression course with eosinophil count and medication history. LDLT, living donor liver transplantation; POD, postoperative day; GVHD, graft-versus-host disease; CMV, cytomegalovirus; IVIG, intravenous immunoglobulin.\n\nFig. 2 (A) Skin biopsy showing superficial perivascular lymphocytic infiltration, suggestive of acute graft-versus-host disease (H&E, ×400). (B) Liver biopsy showing acute hepatitis and reactive hemophagocytosis due to drug/toxin-induced liver injury (Masson’s Trichrome stain, ×800).\n\nFig. 3 (A) Skin lesion of torso including neck. (B) Right forearm. (C) Onycholysis of nails. (D) Ulcerative lesions on total palate. (E) Lip and tongue. (F) Vulva and perianal area.\n\nCONFLICT OF INTEREST\n\nNo potential conflict of interest relevant to this article was reported.\n\nAUTHOR CONTRIBUTIONS\n\nConceptualization: JML. Data curation: AC. Methodology: JML. Visualization: KH, ESH. Writing - original draft: AC, JML. Writing - review & editing: SKH, YRC, NJY, KWL, KSS.\n==== Refs\nREFERENCES\n\n1 Harr T French LE 2012 Stevens-Johnson syndrome and toxic epidermal necrolysis Chem Immunol Allergy 97 149 166 10.1159/000335627 22613860\n2 Pichler WJ Adam J Daubner B Gentinetta T Keller M Yerly D 2010 Drug hypersensitivity reactions: pathomechanism and clinical symptoms Med Clin North Am 94 645 664 xv 10.1016/j.mcna.2010.04.003 20609855\n3 Camous X Calbo S Picard D Musette P 2012 Drug Reaction with Eosinophilia and Systemic Symptoms: an update on pathogenesis Curr Opin Immunol 24 730 735 10.1016/j.coi.2012.07.010 23062470\n4 Husain Z Reddy BY Schwartz RA 2013 DRESS syndrome: Part I. Clinical perspectives J Am Acad Dermatol 68 693.e1 693.e14 quiz 706 708 10.1016/j.jaad.2013.01.033 23602182\n5 Kim DH Koh YI 2014 Comparison of diagnostic criteria and determination of prognostic factors for drug reaction with eosinophilia and systemic symptoms syndrome Allergy Asthma Immunol Res 6 216 221 10.4168/aair.2014.6.3.216 24843796\n6 Cho YT Yang CW Chu CY 2017 Drug reaction with eosinophilia and systemic symptoms (DRESS): an interplay among drugs, viruses, and immune system Int J Mol Sci 18 1243 10.3390/ijms18061243 28598363\n7 Phillips EJ Chung WH Mockenhaupt M Roujeau JC Mallal SA 2011 Drug hypersensitivity: pharmacogenetics and clinical syndromes J Allergy Clin Immunol 127 3 Suppl S60 S66 10.1016/j.jaci.2010.11.046 21354501\n8 Chen P Lin JJ Lu CS Ong CT Hsieh PF Yang CC 2011 Carbamazepine-induced toxic effects and HLA-B*1502 screening in Taiwan N Engl J Med 364 1126 1133 10.1056/NEJMoa1009717 21428768\n9 Kim SH Lee KW Song WJ Kim SH Jee YK Lee SM 2011 Carbamazepine-induced severe cutaneous adverse reactions and HLA genotypes in Koreans Epilepsy Res 97 190 197 10.1016/j.eplepsyres.2011.08.010 21917426\n10 McCormack M Alfirevic A Bourgeois S Farrell JJ Kasperavičiūtė D Carrington M 2011 HLA-A*3101 and carbamazepine-induced hypersensitivity reactions in Europeans N Engl J Med 364 1134 1143 10.1056/NEJMoa1013297 21428769\n11 Yip VL Marson AG Jorgensen AL Pirmohamed M Alfirevic A 2012 HLA genotype and carbamazepine-induced cutaneous adverse drug reactions: a systematic review Clin Pharmacol Ther 92 757 765 10.1038/clpt.2012.189 23132554\n12 Husain Z Reddy BY Schwartz RA 2013 DRESS syndrome: Part II. Management and therapeutics J Am Acad Dermatol 68 709.e1 709.e9 quiz 718 720 10.1016/j.jaad.2013.01.032 23602183\n13 Jordan SC Toyoda M Vo AA 2009 Intravenous immunoglobulin a natural regulator of immunity and inflammation Transplantation 88 1 6 10.1097/TP.0b013e3181a9e89a 19584672\n\n",
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"abstract": "Background. Non-AIDS-defining cancers represent a rising health issue among HIV-infected patients. Nevertheless, HIV testing is not systematic during the initial cancer staging. Here, we report a case of HIV infection diagnosed three years after chemotherapy initiation for multiple myeloma. Results. A 57-year-old woman diagnosed with multiple myeloma underwent a first round of chemotherapy by bortezomib/lenalidomide and then with bortezomib/liposomal-doxorubicine/dexamethasone, with partial remission, poor hematological tolerance, and multiple episodes of pneumococcal infection. Allogenic stem cell transplantation was proposed leading to HIV testing, which revealed seropositivity, with an HIV viral load of 5.5 Log10/mL and severe CD4 T cell depletion (24 cells/mm(3)). Chemotherapy by bendamustin was initiated. Multidisciplinary staff decided the initiation of antiretroviral therapy with tenofovir/emtricitabin/efavirenz and prophylaxis against opportunistic infections. After 34 months, patient achieved complete remission, sustained HIV suppression, and significant CD4 recovery (450 cells/mm(3)), allowing effective pneumococcal immunization without relapse. Conclusion. Our case illustrates the drawback that ignored HIV infection is still causing to cancer patients receiving chemotherapy and highlights the importance of early HIV testing in oncology. A multidisciplinary approach including oncologists/hematologists, virologists, and pharmacists is recommended in order to avoid drug interactions between chemotherapy and antiretroviral drugs. Moreover, prophylactic medication is recommended in these patients regardless of CD4+ cell count at the initiation of chemotherapy.",
"affiliations": "Aix Marseille Université, APHM Hôpital Sainte-Marguerite, Service d'Immuno-Hématologie Clinique, 270 boulevard de Sainte Marguerite, 13274 Marseille Cedex 09, France; INSERM U912 (SESSTIM), 13006 Marseille, France.;Aix Marseille Université, APHM Hôpital Sainte-Marguerite, Service d'Immuno-Hématologie Clinique, 270 boulevard de Sainte Marguerite, 13274 Marseille Cedex 09, France.;Fondation Institut Hospitalo-Universitaire Méditerranée Infection, Pôle des Maladies Infectieuses et Tropicales Clinique et Biologique, Fédération de Bactériologie-Hygiène-Virologie, CHU Timone, 264 rue Saint-Pierre, 13385 Marseille Cedex 05, France.;Département d'Hématologie, Institut Paoli Calmettes, 232 boulevard de Sainte Marguerite, 13273 Marseille Cedex 09, France.;Aix Marseille Université, APHM Hôpital Sainte-Marguerite, Service d'Immuno-Hématologie Clinique, 270 boulevard de Sainte Marguerite, 13274 Marseille Cedex 09, France.;Aix Marseille Université, APHM Hôpital Sainte-Marguerite, Service d'Immuno-Hématologie Clinique, 270 boulevard de Sainte Marguerite, 13274 Marseille Cedex 09, France.;Aix Marseille Université, APHM Hôpital Sainte-Marguerite, Service d'Immuno-Hématologie Clinique, 270 boulevard de Sainte Marguerite, 13274 Marseille Cedex 09, France.;Aix Marseille Université, APHM Hôpital Sainte-Marguerite, Service d'Immuno-Hématologie Clinique, 270 boulevard de Sainte Marguerite, 13274 Marseille Cedex 09, France.;Aix Marseille Université, AP-HM Hôpital de la Timone, Service de Pharmacocinétique et Toxicologie, CRO2 INSERM U911, 13385 Marseille Cedex 05, France.",
"authors": "Poizot-Martin|I|I|0000-0002-5676-5411;Brégigeon|S|S|;Tamalet|C|C|;Bouabdallah|R|R|;Zaegel-Faucher|O|O|;Obry-Roguet|V|V|;Ivanova|A|A|;Cano|C E|CE|;Solas|C|C|",
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"fulltext": "\n==== Front\nCase Rep Oncol MedCase Rep Oncol MedCRIONMCase Reports in Oncological Medicine2090-67062090-6714Hindawi Publishing Corporation 10.1155/2016/8515218Case ReportA Case of Undiagnosed HIV Infection in a 57-Year-Old Woman with Multiple Myeloma: Consequences on Chemotherapy Efficiency and Safety http://orcid.org/0000-0002-5676-5411Poizot-Martin I. \n1\n\n2\n\n*\nBrégigeon S. \n1\nTamalet C. \n3\nBouabdallah R. \n4\nZaegel-Faucher O. \n1\nObry-Roguet V. \n1\nIvanova A. \n1\nCano C. E. \n1\nSolas C. \n5\n1Aix Marseille Université, APHM Hôpital Sainte-Marguerite, Service d'Immuno-Hématologie Clinique, 270 boulevard de Sainte Marguerite, 13274 Marseille Cedex 09, France2INSERM U912 (SESSTIM), 13006 Marseille, France3Fondation Institut Hospitalo-Universitaire Méditerranée Infection, Pôle des Maladies Infectieuses et Tropicales Clinique et Biologique, Fédération de Bactériologie-Hygiène-Virologie, CHU Timone, 264 rue Saint-Pierre, 13385 Marseille Cedex 05, France4Département d'Hématologie, Institut Paoli Calmettes, 232 boulevard de Sainte Marguerite, 13273 Marseille Cedex 09, France5Aix Marseille Université, AP-HM Hôpital de la Timone, Service de Pharmacocinétique et Toxicologie, CRO2 INSERM U911, 13385 Marseille Cedex 05, France*I. Poizot-Martin: isabelle.poizot@ap-hm.frAcademic Editor: Josep M. Ribera\n\n2016 20 7 2016 2016 851521826 4 2016 20 6 2016 21 6 2016 Copyright © 2016 I. Poizot-Martin 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.\nBackground. Non-AIDS-defining cancers represent a rising health issue among HIV-infected patients. Nevertheless, HIV testing is not systematic during the initial cancer staging. Here, we report a case of HIV infection diagnosed three years after chemotherapy initiation for multiple myeloma. Results. A 57-year-old woman diagnosed with multiple myeloma underwent a first round of chemotherapy by bortezomib/lenalidomide and then with bortezomib/liposomal-doxorubicine/dexamethasone, with partial remission, poor hematological tolerance, and multiple episodes of pneumococcal infection. Allogenic stem cell transplantation was proposed leading to HIV testing, which revealed seropositivity, with an HIV viral load of 5.5 Log10/mL and severe CD4 T cell depletion (24 cells/mm3). Chemotherapy by bendamustin was initiated. Multidisciplinary staff decided the initiation of antiretroviral therapy with tenofovir/emtricitabin/efavirenz and prophylaxis against opportunistic infections. After 34 months, patient achieved complete remission, sustained HIV suppression, and significant CD4 recovery (450 cells/mm3), allowing effective pneumococcal immunization without relapse. Conclusion. Our case illustrates the drawback that ignored HIV infection is still causing to cancer patients receiving chemotherapy and highlights the importance of early HIV testing in oncology. A multidisciplinary approach including oncologists/hematologists, virologists, and pharmacists is recommended in order to avoid drug interactions between chemotherapy and antiretroviral drugs. Moreover, prophylactic medication is recommended in these patients regardless of CD4+ cell count at the initiation of chemotherapy.\n==== Body\n1. Introduction\nThe incidence of non-AIDS-defining cancers in HIV-infected patients appears to be higher than the general population [1]. However, HIV infection is frequently undiagnosed in cancer patients and HIV testing is not systematic. In Europe, the fraction of HIV-infected people that ignore their HIV status has been estimated to 20 to 40% [2, 3]. Plasma cell neoplasms, of which multiple myeloma (MM) is the most common, represent 20% of all lymphoid malignancies in Europe [4] and stem cell transplantation (SCT) after systemic chemotherapy is currently the standard of care for this malignancy. Although practice is progressively evolving, HIV infection has historically been an exclusion criterion for SCT, while approved chemotherapy for multiple myeloma is frequently associated with hematological toxicity. Nevertheless, recent observations indicate that well-adapted antiretroviral treatment (cART) may improve the outcome of chemotherapy and even of SCT [5, 6]. Here, we report a case of HIV infection diagnosed three years after the initiation of systemic chemotherapy for MM in a female patient, which illustrates the consequences of ignored HIV infection on patient's outcome.\n\n2. Case Presentation\nPatient is a 57-year-old woman that presented with an inflammatory syndrome in February 2008. Clinicians diagnosed her with multiple myeloma on the basis of a positive myelography, a monoclonal IgG-κ gammopathy (M-protein: IgG 40 g/L; Kappa: 373 mg/L; Lambda: 195 mg/L), a β2-microglobulin 2 × ULN, and a diffuse infiltration of the spine detected by MRI. From March 2008 until December 2009, gammopathy was treated with bortezomib followed by lenalidomide, achieving partial remission. In June 2009, spinal MRI was normal and IgG was 30 g/L with no other abnormalities of the blood count and without renal failure. In May and December 2009, this patient received antimicrobial therapy for two episodes of pneumococcal pneumoniae. In November 2010, spinal MRI was normal. In January 2011, a combination of bortezomib, liposomal doxorubicine, and dexamethasone was initiated following worsening of gammopathy (IgG: 53 g/L), with IgA 1.74 g/L, IgM 11.03 g/L, normocytic anemia (107 g/L), platelet count 208 × 109/L, creatinine 45 μmol/L, normal calcemia, LDH 2 × ULN with anicteric cholestasis, β2-microglobuline 5 × ULN. Karyotype was normal. After 4 chemotherapy cycles with poor hematological tolerance, IgG was 25 g/L, and allogenic SCT was proposed. Of note, the patient presented with a new episode of pneumococcal pneumonia in March 2011. In August 2011, the patient underwent HIV testing before SCT; she tested positive for HIV with severe immune depression (CD4+ cell count: 24 cells/mm3; normal value: 600–1200) and HIV viral load 316228 copies/mL (5.5 Log10/mL). SCT was cancelled, and chemotherapy with bendamustin was proposed. An antiretroviral regimen combining tenofovir/emtricitabin/efavirenz and opportunistic prophylaxis (against pneumocystis jiroveci, toxoplasma gondii, and cytomegalovirus) was proposed by multidisciplinary staff, including a pharmacologist and virologist, to limit the risk of drug-drug interactions. After 34 months of followup, complete and sustained remission of gammopathy (IgG: 15 g/L; Kappa: 21 mg/L; Lambda: 21 mg/L; ratio 1.22) was achieved, associated with sustained HIV suppression and significant immune restoration (CD4+ T cell count: 450/mm3; 15%; Figure 1), which allowed for effective pneumococcal immunization without relapse.\n\n3. Discussion\nHere, we present a case of ignored HIV infection that severely affected the management and outcome of MM. The most likely HIV transmission route for this patient was a blood transfusion that occurred in 1978, which is 30 years prior to the diagnosis of MM and 33 years before diagnosis of HIV. Although monoclonal gammopathies of undetermined significance (MGUS) are frequent in HIV-infected patients [7, 8], our patient presented with plasma M-protein >30 g/L at diagnosis, which classifies for MM according to the International Myeloma Working Group [9]. Nevertheless, a long-term followup of MGUS patients at the Mayo Clinic revealed that around 16% of MGUS cases evolved towards a MM, with a median time of progression of 10.6 years [10]. Thus, we cannot exclude that our patient might have developed an HIV-related MGUS prior to MM.\n\nSeveral studies in industrialized countries have shown that HIV-infected patients have 2 to 5 times increased risk of developing multiple myeloma compared to the general population [11–17]. Moreover, male HIV-infected patients die three times more frequently of MM compared to uninfected age-matched individuals [18]. Recently, a case-control study including 10 HIV-infected and 28 uninfected patients treated for MM showed that HIV-infected patients receiving highly active antiretroviral therapy (HAART) had longer overall and disease-free survival than uninfected controls [19]. Hence, the awareness of HIV infection and antiretroviral treatment have a proven benefit for MM patients in terms of survival.\n\nBecause invasive pneumococcal disease is a frequent complication of HIV infection, the recurrent episodes observed in this patient should have alerted physicians to the need for HIV testing. Unfortunately, missed opportunities for HIV testing are not rare [20], stressing the need to improve HIV-related recognition in all healthcare facilities and this is particularly relevant for oncologists. Indeed, systematic HIV-testing at the initial diagnosis of cancer would allow for cautious initiation of treatment with an immunosuppressive regimen for a potentially immune-compromised patient, as in this case study. Strikingly, more than 30 years after the beginning of the AIDS epidemic, patients with AIDS-defining cancers are not always tested for HIV [21]. Because antiretroviral treatment seems to have a positive impact on survival, HIV-infected patients who also have cancer should keep or initiate a cART while undergoing treatment for malignant disease [6]. However, many chemotherapeutic and antiretroviral drugs are metabolized through the cytochrome P450 (CYP) enzyme system of the liver, increasing the chemotherapy-associated toxicity or decreasing the treatment efficacy. Hence, a multidisciplinary approach to HIV-cancer care that includes physicians, hematologist/oncologists, virologists, and pharmacists is recommended to prevent the risk of drug-drug interactions and optimize clinical management [22]. In our case, the association of the antiretroviral ritonavir, a CYP450-1A2 inducer, with bendamustin, a substrate/inhibitor of CYP450-1A2, could potentially reduce the efficacy of chemotherapy. Therefore, a ritonavir-boosted protease inhibitor-based regimen was contraindicated. Interactions with other medications that are used to treat or to prevent opportunistic infections or chemotherapy side effects should also be evaluated. Indeed, prophylactic medications are recommended in these patients regardless of their CD4+ cell count at the start of chemotherapy.\n\nCurrently, scarce data are available on the prevalence of undiagnosed HIV infection among patients who present with non-AIDS-defining cancer [23]. Nevertheless, our case highlights the importance of HIV testing during the initial cancer staging. A multidisciplinary approach to HIV-cancer care that includes physicians, hematologist/oncologists, virologists, and pharmacists is particularly relevant considering the high risk of drug-drug interactions between systemic chemotherapy and antiretroviral drugs. Furthermore, prophylactic medications are recommended in these patients regardless of their CD4+ cell count at the start of chemotherapy.\n\nAcknowledgments\nThe authors would like to thank the patient for giving consent to publish her case.\n\nAbbreviations\nSCT:Stem cell transplantation\n\nAIDS:Acquired immune deficiency\n\ncART:Combined antiretroviral therapy.\n\nConsent\nWritten informed consent was obtained from the patient for publication of this case report.\n\nCompeting Interests\nThe authors declare that they have no competing interests.\n\nFigure 1 Evolution of CD4+ T cell count during and after bendamustine chemotherapy. Graph shows longitudinal evolution of CD4+ cell counts during and after bendamustine chemotherapy (from September 19, 2011, to February 29, 2012). y-axis = CD4 cells/mm3; x-axis = date. (Top) orange box show plasma protein quantitation (g/L).\n==== Refs\n1 Shiels M. S. Cole S. R. Kirk G. D. Poole C. A meta-analysis of the incidence of non-AIDS cancers in HIV-infected individuals Journal of Acquired Immune Deficiency Syndromes 2009 52 5 611 622 10.1097/qai.0b013e3181b327ca 2-s2.0-73349120643 19770804 \n2 Hamers F. F. Phillips A. N. Diagnosed and undiagnosed HIV-infected populations in Europe HIV Medicine 2008 9 supplement 2 6 12 10.1111/j.1468-1293.2008.00584.x 2-s2.0-44949262979 18557863 \n3 Van Veen M. G. Presanis A. M. Conti S. National estimate of HIV prevalence in the Netherlands: comparison and applicability of different estimation tools AIDS 2011 25 2 229 237 10.1097/qad.0b013e32834171bc 2-s2.0-78650921515 21150562 \n4 De Angelis R. Minicozzi P. Sant M. Survival variations by country and age for lymphoid and myeloid malignancies in Europe 2000–2007: results of EUROCARE-5 population-based study European Journal of Cancer 2015 51 15 2254 2268 10.1016/j.ejca.2015.08.003 2-s2.0-84942475012 \n5 Díez-Martín J. L. Balsalobre P. Re A. Comparable survival between HIV+ and HIV- non-Hodgkin and Hodgkin lymphoma patients undergoing autologous peripheral blood stem cell transplantation Blood 2009 113 23 6011 6014 10.1182/blood-2008-12-195388 2-s2.0-67651125052 19307667 \n6 Makinson A. Tenon J.-C. Eymard-Duvernay S. Human immunodeficiency virus infection and non-small cell lung cancer: survival and toxicity of antineoplastic chemotherapy in a cohort study Journal of Thoracic Oncology 2011 6 6 1022 1029 10.1097/jto.0b013e318217b6e0 2-s2.0-79958095514 21512403 \n7 Fiorino A. S. Atac B. Paraproteinemia, plasmacytoma, myeloma and HIV infection Leukemia 1997 11 12 2150 2156 10.1038/sj.leu.2400875 2-s2.0-0031453236 9447834 \n8 Genet P. Sutton L. Chaoui D. Prevalence of monoclonal gammopathy in HIV patients in 2014 Journal of the International AIDS Society 2014 17 4, supplement 3 19649 10.7448/ias.17.4.19649 \n9 Kyle R. A. Rajkumar S. V. Criteria for diagnosis, staging, risk stratification and response assessment of multiple myeloma Leukemia 2009 23 1 3 9 10.1038/leu.2008.291 2-s2.0-58249097191 18971951 \n10 Kyle R. A. Rajkumar S. V. Monoclonal gammopathy of undetermined significance British Journal of Haematology 2006 134 6 573 589 10.1111/j.1365-2141.2006.06235.x 2-s2.0-33747480248 16938117 \n11 Clifford G. M. Polesel J. Rickenbach M. Cancer risk in the Swiss HIV cohort study: associations with immunodeficiency, smoking, and highly active antiretroviral therapy Journal of the National Cancer Institute 2005 97 6 425 432 10.1093/jnci/dji072 2-s2.0-20144381973 15770006 \n12 Dal Maso L. Franceschi S. Polesel J. Risk of cancer in persons with AIDS in Italy, 1985–1998 British Journal of Cancer 2003 89 1 94 100 10.1038/sj.bjc.6601017 2-s2.0-0042846005 12838307 \n13 Engels E. A. Pfeiffer R. M. Goedert J. J. Trends in cancer risk among people with AIDS in the United States 1980–2002 AIDS 2006 20 12 1645 1654 10.1097/01.aids.0000238411.75324.59 2-s2.0-33746773667 16868446 \n14 Grulich A. E. Li Y. McDonald A. Correll P. K. L. Law M. G. Kaldor J. M. Rates of non-AIDS-defining cancers in people with HIV infection before and after AIDS diagnosis AIDS 2002 16 8 1155 1161 10.1097/00002030-200205240-00009 2-s2.0-0037165879 12004274 \n15 Grulich A. E. van Leeuwen M. T. Falster M. O. Vajdic C. M. Incidence of cancers in people with HIV/AIDS compared with immunosuppressed transplant recipients: a meta-analysis The Lancet 2007 370 9581 59 67 10.1016/s0140-6736(07)61050-2 2-s2.0-34347323902 \n16 Newnham A. Harris J. Evans H. S. Evans B. G. Møller H. The risk of cancer in HIV-infected people in southeast England: A Cohort Study British Journal of Cancer 2005 92 1 194 200 10.1038/sj.bjc.6602273 2-s2.0-13244277996 15583689 \n17 Frisch M. Biggar R. J. Engels E. A. Goedert J. J. Association of cancer with AIDS-related immunosuppression in adults The Journal of the American Medical Association 2001 285 13 1736 1745 10.1001/jama.285.13.1736 2-s2.0-0035804852 11277828 \n18 Selik R. M. Rabkin C. S. Cancer death rates associated with human immunodeficiency virus infection in the United States Journal of the National Cancer Institute 1998 90 17 1300 1302 10.1093/jnci/90.17.1300 2-s2.0-0032475406 9731737 \n19 Li G. Lewis R. D. Mishra N. Axiotis C. A. A retrospective analysis of ten symptomatic multiple myeloma patients with HIV infection: a potential therapeutic effect of HAART in multiple myeloma Leukemia Research 2014 38 9 1079 1084 10.1016/j.leukres.2014.07.001 2-s2.0-84906936486 25064217 \n20 Champenois K. Cousien A. Cuzin L. Missed opportunities for HIV testing in newly-HIV-diagnosed patients, a cross sectional study BMC Infectious Diseases 2013 13 1, article 200 10.1186/1471-2334-13-200 2-s2.0-84876862710 \n21 Mosimann V. Cavassini M. Hugli O. Patients with AIDS-defining cancers are not universally screened for HIV: a 10-year retrospective analysis of HIV-testing practices in a Swiss university hospital HIV Medicine 2014 15 10 631 634 10.1111/hiv.12181 2-s2.0-84911091016 25102762 \n22 Rubinstein P. G. Aboulafia D. M. Zloza A. Malignancies in HIV/AIDS: from epidemiology to therapeutic challenges AIDS 2014 28 4 453 465 10.1097/qad.0000000000000071 2-s2.0-84895070106 24401642 \n23 Shrestha S. Johnson D. C. Porter D. C. Short communication: lack of occult HIV infection among non-AIDS-defining cancer patients in three academic oncology clinics in the United States AIDS Research and Human Retroviruses 2013 29 6 887 891 10.1089/aid.2012.0344 2-s2.0-84877868943 23351216\n\n",
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"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BORTEZOMIB"
},
"drug... |
{
"abstract": "We present a unique case of radiation necrosis in a child with brain stem low-grade glioma (LGG) presenting with trigeminal neuralgia. Despite extensive therapies, severe pain persisted. She received proton beam radiation with significant improvement. However, she developed radiation necrosis and hydrocephalus. Despite surgical correction of hydrocephalus, the patient remained critically ill. She was treated with dexamethasone and bevacizumab with rapid clinical improvement. Subsequent MRIs revealed almost complete resolution of the necrosis. This case illustrates the successful treatment of trigeminal neuralgia with radiation and a rare case of radiation necrosis in an LGG successfully treated with bevacizumab and dexamethasone.",
"affiliations": "Department of Hematology, Oncology and Stem Cell Transplant, Ann and Robert H. Lurie Children's Hospital of Chicago, Northwestern Feinberg School of Medicine, Chicago, Illinois.;Department of Neurosurgery, Ann and Robert H. Lurie Children's Hospital of Chicago, Northwestern Feinberg School of Medicine, Chicago, Illinois.;Proton Center of Northwestern Memorial Hospital, Warrenville, Illinois.;Department of Hematology, Oncology and Stem Cell Transplant, Ann and Robert H. Lurie Children's Hospital of Chicago, Northwestern Feinberg School of Medicine, Chicago, Illinois.",
"authors": "Pillay Smiley|Natasha|N|;Alden|Tord|T|;Hartsell|William|W|;Fangusaro|Jason|J|",
"chemical_list": "D000068258:Bevacizumab",
"country": "United States",
"delete": false,
"doi": "10.1002/pbc.26055",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1545-5009",
"issue": "63(9)",
"journal": "Pediatric blood & cancer",
"keywords": "facial tics; infant low-grade glioma; pain; pilomyxoid astrocytoma; proton beam radiation",
"medline_ta": "Pediatr Blood Cancer",
"mesh_terms": "D000068258:Bevacizumab; D001932:Brain Neoplasms; D005260:Female; D005910:Glioma; D006801:Humans; D006849:Hydrocephalus; D007223:Infant; D009336:Necrosis; D061766:Proton Therapy; D011832:Radiation Injuries; D014277:Trigeminal Neuralgia",
"nlm_unique_id": "101186624",
"other_id": null,
"pages": "1671-3",
"pmc": null,
"pmid": "27187113",
"pubdate": "2016-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Severe Radiation Necrosis Successfully Treated With Bevacizumab in an Infant with Low-Grade Glioma and Tumor-Associated Intractable Trigeminal Neuralgia.",
"title_normalized": "severe radiation necrosis successfully treated with bevacizumab in an infant with low grade glioma and tumor associated intractable trigeminal neuralgia"
} | [
{
"companynumb": "US-JNJFOC-20170809156",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHADONE HYDROCHLORIDE"
},
"drugadditional": "3"... |
{
"abstract": "A fatal case of pulmonary edema is reported after prolonged treatment with beta-mimetics during pregnancy for threatened premature labor. The mother had received betamethasone in order to enhance fetal lung maturity. Myocardial failure occurred 5 days after discontinuation of betamimetics. The potential toxic effects of beta-adrenergic agents and their association with corticosteroids are discussed. Caution is recommended when high doses of betamimetics are to be delivered to prevent premature labor. No patient should be treated unless her cardiac condition is normal. Cardiovascular evaluation should be regularly performed during the course of treatment. No patient should be discharged after treatment without a normal cardiovascular check-up.",
"affiliations": null,
"authors": "Milliez|J|J|;Blot|P|P|;Sureau|C|C|",
"chemical_list": "D000318:Adrenergic beta-Agonists; D001623:Betamethasone; D012312:Ritodrine; D000420:Albuterol",
"country": "Ireland",
"delete": false,
"doi": "10.1016/0028-2243(80)90014-3",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0301-2115",
"issue": "11(2)",
"journal": "European journal of obstetrics, gynecology, and reproductive biology",
"keywords": null,
"medline_ta": "Eur J Obstet Gynecol Reprod Biol",
"mesh_terms": "D000318:Adrenergic beta-Agonists; D000328:Adult; D000420:Albuterol; D001623:Betamethasone; D005260:Female; D006333:Heart Failure; D006801:Humans; D006819:Hyaline Membrane Disease; D007231:Infant, Newborn; D008431:Maternal-Fetal Exchange; D007752:Obstetric Labor, Premature; D011247:Pregnancy; D012312:Ritodrine",
"nlm_unique_id": "0375672",
"other_id": null,
"pages": "95-100",
"pmc": null,
"pmid": "6108879",
"pubdate": "1980-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A case report of maternal death associated with betamimetics and betamethasone administration in premature labor.",
"title_normalized": "a case report of maternal death associated with betamimetics and betamethasone administration in premature labor"
} | [
{
"companynumb": "FR-009507513-2006FRA004169",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "RITODRINE"
},
"drugadditional": null,
... |
{
"abstract": "Invasive pulmonary mucormycosis is a potentially fatal infection that can occur in immunosuppressed patients such as those who have undergone orthotopic heart transplant (OHT). High-dose intravenous antifungal agents, including amphotericin B, are generally accepted as the first-line medical treatment, with prompt surgical resection of lesions if feasible. The body of evidence guiding treatment decisions, however, is sparse, particularly regarding adjustment of immunosuppression during acute infection and long-term recovery. We present 2 cases of patients with pulmonary mucormycosis occurring within the first 6 months after OHT, both of whom successfully recovered after appropriate medical and surgical treatment, and we highlight differences in immunosuppression management strategies for this life-threatening condition.",
"affiliations": "Division of Cardiology, Department of Medicine, University of Illinois at Chicago College of Medicine, Chicago, Illinois.;Section of Cardiology, Department of Medicine.;Department of Pathology, University of Chicago Medical Center, Chicago, Illinois.;Division of Cardiology, Department of Medicine, University of Illinois at Chicago College of Medicine, Chicago, Illinois; Division of Cardiology.;Division of Cardiology, Department of Medicine, University of Illinois at Chicago College of Medicine, Chicago, Illinois; Division of Cardiology.;Division of Infectious Disease.;Department of Cardiovascular & Thoracic Surgery, Advocate Christ Medical Center, Oak Lawn, Illinois.;Department of Cardiovascular & Thoracic Surgery, Advocate Christ Medical Center, Oak Lawn, Illinois.;Division of Cardiology, Department of Medicine, University of Illinois at Chicago College of Medicine, Chicago, Illinois; Division of Cardiology.;Division of Cardiology, Department of Medicine, University of Illinois at Chicago College of Medicine, Chicago, Illinois; Division of Cardiology.;Section of Cardiology, Department of Medicine.;Division of Cardiology, Department of Medicine, University of Illinois at Chicago College of Medicine, Chicago, Illinois; Division of Cardiology. Electronic address: nikhil.narang@aah.org.",
"authors": "Hill|Michael C|MC|;Belkin|Mark N|MN|;McMullen|Phillip|P|;Pillarella|Jessica J|JJ|;Macaluso|Greg P|GP|;Treitman|Adam N|AN|;Pappas|Pat S|PS|;Tatooles|Antone J|AJ|;Cotts|William G|WG|;Andrade|Ambar A|AA|;Kim|Gene|G|;Narang|Nikhil|N|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.transproceed.2021.09.034",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1345",
"issue": null,
"journal": "Transplantation proceedings",
"keywords": null,
"medline_ta": "Transplant Proc",
"mesh_terms": null,
"nlm_unique_id": "0243532",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34772489",
"pubdate": "2021-11-09",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Management of Pulmonary Mucormycosis After Orthotopic Heart Transplant: A Case Series.",
"title_normalized": "management of pulmonary mucormycosis after orthotopic heart transplant a case series"
} | [
{
"companynumb": "US-TEVA-2022-US-2005143",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
"drugadditional": "1"... |
{
"abstract": "A 33-day-old female with an ulcerated infantile hemangioma (IH) undergoing oral therapy with propranolol 2 mg/kg per day developed hyperkalemia and hyperphosphatemia 24 h after starting medication. No electrocardiographic or clinical abnormalities secondary to the electrolyte changes were noticed. A laboratory tumor lysis syndrome (TLS) was diagnosed after excluding other causes of electrolyte imbalance in the diagnostic workup. No treatment was required to reverse the TLS condition, and the propranolol therapy was continued as the electrolyte alterations were only mild. One month later, the IH was remarkably reduced in size and no longer ulcerated. Maintenance of propranolol was extended for a total of 6 months. Parallel to the gradual involution of the IH, serum potassium and phosphorus levels returned within normal levels. We suggest that TLS may be a rare complication of ulcerated IH treated with propranolol. Clinicians must be aware and order appropriate screening tests for TLS in patients at risk.",
"affiliations": "U.O. Dermatologia Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico di Milano, Milano, Italy. rcricdoc89@gmail.com",
"authors": "Cavalli|R|R|;Buffon|R B|RB|;de Souza|M|M|;Colli|A M|AM|;Gelmetti|C|C|",
"chemical_list": "D000970:Antineoplastic Agents; D011433:Propranolol",
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000337553",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1018-8665",
"issue": "224(2)",
"journal": "Dermatology (Basel, Switzerland)",
"keywords": null,
"medline_ta": "Dermatology",
"mesh_terms": "D000970:Antineoplastic Agents; D005260:Female; D018324:Hemangioma, Capillary; D006801:Humans; D006947:Hyperkalemia; D054559:Hyperphosphatemia; D007223:Infant; D009386:Neoplastic Syndromes, Hereditary; D011433:Propranolol; D012720:Severity of Illness Index; D012878:Skin Neoplasms; D012883:Skin Ulcer; D016896:Treatment Outcome; D015275:Tumor Lysis Syndrome",
"nlm_unique_id": "9203244",
"other_id": null,
"pages": "106-9",
"pmc": null,
"pmid": "22516868",
"pubdate": "2012",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Tumor lysis syndrome after propranolol therapy in ulcerative infantile hemangioma: rare complication or incidental finding?",
"title_normalized": "tumor lysis syndrome after propranolol therapy in ulcerative infantile hemangioma rare complication or incidental finding"
} | [
{
"companynumb": "IT-AMNEAL PHARMACEUTICALS-2020-AMRX-01125",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "PROPRANOLOL HYDROCHLORIDE"
},
... |
{
"abstract": "Heparin is the only well-established anticoagulant medication for cardiopulmonary bypass making selecting an alternative anticoagulant challenging in patients with heparin-induced thrombocytopenia. Other anticoagulant medications can cause significant postoperative bleeding, especially in patients with end-stage renal disease. We present a case of a 63-year-old woman requiring aortic valve replacement with a history of heparin-induced thrombocytopenia and end-stage renal disease. Cangrelor and heparin were successfully used during cardiopulmonary bypass, offering an option for anticoagulation management for a uniquely challenging patient population.",
"affiliations": "From the Departments of Anesthesiology.;Cardiothoracic Surgery, Sulpizio Cardiovascular Center, University of California, San Diego, La Jolla, California.;Department of Pharmacy, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, California.;From the Departments of Anesthesiology.",
"authors": "Girgis|Alexander M|AM|;Golts|Eugene|E|;Humber|Doug|D|;Banks|Dalia A|DA|",
"chemical_list": "D000249:Adenosine Monophosphate; C117446:cangrelor; D006493:Heparin",
"country": "United States",
"delete": false,
"doi": "10.1213/XAA.0000000000000969",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2575-3126",
"issue": "13(1)",
"journal": "A&A practice",
"keywords": null,
"medline_ta": "A A Pract",
"mesh_terms": "D000249:Adenosine Monophosphate; D002315:Cardiopulmonary Bypass; D005260:Female; D019918:Heart Valve Prosthesis Implantation; D006493:Heparin; D006801:Humans; D007430:Intraoperative Care; D007676:Kidney Failure, Chronic; D008875:Middle Aged; D013921:Thrombocytopenia; D016896:Treatment Outcome",
"nlm_unique_id": "101714112",
"other_id": null,
"pages": "10-12",
"pmc": null,
"pmid": "30688681",
"pubdate": "2019-07-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Successful Use of Cangrelor and Heparin for Cardiopulmonary Bypass in a Patient With Heparin-Induced Thrombocytopenia and End-Stage Renal Disease: A Case Report.",
"title_normalized": "successful use of cangrelor and heparin for cardiopulmonary bypass in a patient with heparin induced thrombocytopenia and end stage renal disease a case report"
} | [
{
"companynumb": "US-DRREDDYS-USA/USA/19/0112821",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "HEPARIN SODIUM"
},
"drugadditional": "1"... |
{
"abstract": "Transfusion-related alloimmunization is a potent barrier to the engraftment of allogeneic hematopoietic stem cells in patients with nonmalignant diseases (NMDs). Memory T cells, which drive alloimmunization, are relatively resistant to commonly used conditioning agents. Alefacept, a recombinant leukocyte function antigen-3/IgG1 fusion protein, targets CD2 and selectively depletes memory versus naive T cells. Three multiply transfused pediatric patients with NMD received a short course of high-dose i.v. alefacept (.25 mg/kg/dose on days -40 and -9 and .5 mg/kg/dose on days -33, -26, -19, and -12) before undergoing unrelated allogeneic transplant in the setting of reduced-intensity pretransplant conditioning and calcineurin inhibitor-based post-transplant graft-versus-host disease (GVHD) prophylaxis. Alefacept infusions were well tolerated in all patients. Peripheral blood flow cytometry was performed at baseline and during and after alefacept treatment. As expected, after the 5 weekly alefacept doses, each patient demonstrated selective loss of CD2(hi)/CCR7(-)/CD45RA(-) effector memory (Tem) and CD2(hi)/CCR7(+)/CD45RA(-) central memory (Tcm) CD4(+) and CD8(+) T cells with relative preservation of the CD2(lo) Tem and Tcm subpopulations. In addition, depletion of CD2(+) natural killer (NK) cells also occurred. Neutrophil recovery was rapid, and all 3 patients had 100% sorted (CD3/CD33) peripheral blood donor chimerism by day +100. Immune reconstitution (by absolute neutrophil, monocyte, and lymphocyte counts) was comparable with a cohort of historical control patients. All 3 patients developed GVHD but are all now off immune suppression and >2 years post-transplant with stable full-donor engraftment. These results suggest that alefacept at higher dosing can deplete both memory T cells and NK cells and that incorporating CD2-targeted depletion into a reduced-intensity transplant regimen is feasible and safe in heavily transfused patients.",
"affiliations": "Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Emory University, Atlanta, Georgia.;Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Emory University, Atlanta, Georgia.;Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Emory University, Atlanta, Georgia.;Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Emory University, Atlanta, Georgia.;Ben Towne Center for Childhood Cancer Research, Seattle Children's Research Institute, Fred Hutchinson Cancer Research Center, and University of Washington, Seattle, Washington.;Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Emory University, Atlanta, Georgia. Electronic address: jdgsfhoran@gmail.com.",
"authors": "Stenger|Elizabeth O|EO|;Chiang|Kuang-Yueh|KY|;Haight|Ann|A|;Qayed|Muna|M|;Kean|Leslie|L|;Horan|John|J|",
"chemical_list": "D018801:CD2 Antigens; D011993:Recombinant Fusion Proteins; D000077944:Alefacept",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1083-8791",
"issue": "21(10)",
"journal": "Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation",
"keywords": "Alefacept; Conditioning; Hematopoietic stem cell transplantation; Nonmalignant diseases; Rejection",
"medline_ta": "Biol Blood Marrow Transplant",
"mesh_terms": "D000077944:Alefacept; D000741:Anemia, Aplastic; D016913:Blood Component Transfusion; D016026:Bone Marrow Transplantation; D018801:CD2 Antigens; D002648:Child; D036101:Cord Blood Stem Cell Transplantation; D019871:Dyskeratosis Congenita; D005199:Fanconi Anemia; D005260:Female; D006085:Graft Survival; D006086:Graft vs Host Disease; D065386:Historically Controlled Study; D006801:Humans; D007156:Immunologic Memory; D016130:Immunophenotyping; D007223:Infant; D007694:Killer Cells, Natural; D008212:Lymphocyte Depletion; D008297:Male; D010865:Pilot Projects; D011993:Recombinant Fusion Proteins; D016176:T-Lymphocyte Subsets; D019172:Transplantation Conditioning; D061349:Unrelated Donors",
"nlm_unique_id": "9600628",
"other_id": null,
"pages": "1845-52",
"pmc": null,
"pmid": "26095669",
"pubdate": "2015-10",
"publication_types": "D002363:Case Reports; D016430:Clinical Trial; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "18039542;23112830;19255011;17901250;24528782;19917362;14676071;21972294;21071499;20889923;19623014;3321644;12894135;12795239;10084264;17617852;7511625;16151425;3043788;3538545;24165326;10666190;23222384;23730730;21339714;24622414;2644980;21099108;24090731;10673707;23818226;23751955;21070604;20618506;19647202;17038525;17606762;22077388;18454181;16041310;12393596;8610340;18307564;2300104;17293882;22343376;11474662;20494932;16426313;19726874;19525479;17403057;24144640;19344980;11970990;24517425",
"title": "Use of Alefacept for Preconditioning in Multiply Transfused Pediatric Patients with Nonmalignant Diseases.",
"title_normalized": "use of alefacept for preconditioning in multiply transfused pediatric patients with nonmalignant diseases"
} | [
{
"companynumb": "PHHY2015US094681",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CYCLOSPORINE"
},
"drugadditional": null,
"dr... |
{
"abstract": "BACKGROUND\nPatients suffering from drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome caused by first-line antituberculosis drugs often need to be retreated rapidly. Patch tests prior to the reintroduction of antituberculosis drugs are rarely performed.\n\n\nOBJECTIVE\nTo highlight those drugs most often involved in DRESS caused by antituberculosis drugs, illustrate the potential value of patch tests to identify these culprit(s), and provide insights into how to rapidly retreat these patients.\n\n\nMETHODS\nA detailed description of the work-up of two illustrative patients, together with a literature review of similar cases, is provided.\n\n\nRESULTS\nAll first-line antituberculosis drugs may cause DRESS syndrome, but rifampicin and isoniazid are most frequently involved. Patch tests can be performed sooner than usually advised in the context of DRESS syndrome, and potentially with lower test concentrations, but false-negative results are possible. Sequential reintroduction of patch test-negative drugs is feasible, although the dose and order of drugs to be readministered, as well as the use of concomitant systemic corticosteroids, remain a matter of debate.\n\n\nCONCLUSIONS\nPatch tests in the context of DRESS syndrome caused by antituberculosis drugs, despite their shortcomings, may potentially guide rapid retreatment of these patients.",
"affiliations": "Department of Dermatology, Cliniques universitaires Saint-Luc, Brussels, Belgium.;Department of Dermatology, University Hospital Antwerp (UZA), and University of Antwerp (UA), Antwerp, Belgium.;Department of Dermatology, Cliniques universitaires Saint-Luc, Brussels, Belgium.;Department of Anatomical Pathology, Cliniques universitaires Saint-Luc, Brussels, Belgium.;Department of Dermatology, University Hospital Antwerp (UZA), and University of Antwerp (UA), Antwerp, Belgium.;Department of Clinical Sciences, Institute of Tropical Medicine, Antwerp, and Unit of Tropical Diseases, University Hospital of Antwerp (UZA) and University of Antwerp (UA), Antwerp, Belgium.;Department of Clinical Sciences, Institute of Tropical Medicine, Antwerp, and Unit of Tropical Diseases, University Hospital of Antwerp (UZA) and University of Antwerp (UA), Antwerp, Belgium.;Department of Internal Medicine, Cliniques universitaires Saint-Luc, Brussels, Belgium.;Department of Dermatology, Cliniques universitaires Saint-Luc, Brussels, Belgium.",
"authors": "Coster|Alison|A|;Aerts|Olivier|O|https://orcid.org/0000-0002-0076-2887;Herman|Anne|A|https://orcid.org/0000-0001-7000-1672;Marot|Liliane|L|;Horst|Niels|N|;Kenyon|Chris|C|;Vlieghe|Erika|E|;Hainaut|Philippe|P|;Baeck|Marie|M|https://orcid.org/0000-0003-0499-7939",
"chemical_list": "D000995:Antitubercular Agents; D007538:Isoniazid; D012293:Rifampin",
"country": "England",
"delete": false,
"doi": "10.1111/cod.13296",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0105-1873",
"issue": "81(5)",
"journal": "Contact dermatitis",
"keywords": "DRESS syndrome; antituberculosis drugs; cross-reaction; ethambutol; isoniazid; patch tests; pyrazinamide; rechallenge; rifabutin; rifampicin",
"medline_ta": "Contact Dermatitis",
"mesh_terms": "D000995:Antitubercular Agents; D063926:Drug Hypersensitivity Syndrome; D005188:False Negative Reactions; D005260:Female; D006801:Humans; D007538:Isoniazid; D008297:Male; D008875:Middle Aged; D012293:Rifampin; D055815:Young Adult",
"nlm_unique_id": "7604950",
"other_id": null,
"pages": "325-331",
"pmc": null,
"pmid": "31021423",
"pubdate": "2019-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome caused by first-line antituberculosis drugs: Two case reports and a review of the literature.",
"title_normalized": "drug reaction with eosinophilia and systemic symptoms dress syndrome caused by first line antituberculosis drugs two case reports and a review of the literature"
} | [
{
"companynumb": "BE-JNJFOC-20191112479",
"fulfillexpeditecriteria": "1",
"occurcountry": "BE",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "GOLIMUMAB"
},
"drugadditional": null,
"... |
{
"abstract": "We report a case of lithium-induced downbeat nystagmus and horizontal gaze palsy in a 62-year-old woman who was treated for a bipolar affective disorder with lithium carbonate for one month. At presentation serum lithium was within therapeutic range. No alternative causes of the ocular motility disturbances were found, and the patient improved significantly as lithium carbonate was discontinued.",
"affiliations": "Department of Ophthalmology, Rigshospitalet-Glostrup, Copenhagen, Denmark.;Department of Neurology, Neuroscience Center, Rigshospitalet-Glostrup, Copenhagen, Denmark.;Department of Ophthalmology, Rigshospitalet-Glostrup, Copenhagen, Denmark.",
"authors": "Jørgensen|Jesper Skovlund|JS|;Landschoff Lassen|Lisbeth|L|;Wegener|Marianne|M|",
"chemical_list": null,
"country": "United Arab Emirates",
"delete": false,
"doi": "10.2174/1874364101610010126",
"fulltext": "\n==== Front\nOpen Ophthalmol JOpen Ophthalmol JTOOPHTJThe Open Ophthalmology Journal1874-3641Bentham Open TOOPHTJ-10-12610.2174/1874364101610010126ArticleLithium-Induced Downbeat Nystagmus and Horizontal Gaze Palsy Jørgensen Jesper Skovlund 1*Landschoff Lassen Lisbeth 2Wegener Marianne 11 Department of Ophthalmology, Rigshospitalet-Glostrup, Copenhagen, Denmark2 Department of Neurology, Neuroscience Center, Rigshospitalet-Glostrup, Copenhagen, Denmark* Address correspondence to this author at the Department of Ophthalmology Rigshospitalet-Glostrup Nordre Ringvej 57 2600 Glostrup; Denmark; Tel: +455133788; E-mail: jskovlund@hotmail.com29 4 2016 2016 10 126 128 3 11 2015 17 1 2016 25 1 2016 © Jørgensen et al.; Licensee Bentham Open.2016JørgensenThis is an open access article licensed under the terms of the Creative Commons Attribution-Non-Commercial 4.0 International Public License (CC BY-NC 4.0) (https://creativecommons.org/licenses/by-nc/4.0/legalcode), which permits unrestricted, non-commercial use, distribution and reproduction in any medium, provided the work is properly cited.We report a case of lithium-induced downbeat nystagmus and horizontal gaze palsy in a 62-year-old woman who was treated for a bipolar affective disorder with lithium carbonate for one month. At presentation serum lithium was within therapeutic range. No alternative causes of the ocular motility disturbances were found, and the patient improved significantly as lithium carbonate was discontinued.\n\nKeywords\nAdverse effectsDownbeat nystagmusGaze palsyLithium\n==== Body\nINTRODUCTION\nDownbeat nystagmus (DBN) is a well-known neurotoxic side effect of lithium treatment [1]. We report a rare case of lithium-induced DBN combined with horizontal gaze palsy. To our knowledge, this observation was only reported once previously [2].\n\nLithium salts are commonly prescribed for bipolar affective disorders and depression. The therapeutic range is narrow and neurological side effects are well described, and might occur despite serum-lithium levels within the therapeutic range [1, 3].\n\nCase Report\nA 62-year-old woman was admitted at the Department of Neurology, Rigshospitalet-Glostrup, with generalized weakness, extremity tremor and recurrent falls. Past medical history included epilepsy and depressions treated with lamotrigine 75 mg/day, valproate 1500 mg/day and venlafaxin 375 mg/day. Four weeks before presentation lithium carbonate 600 mg/day was added. The patient had no history of alcohol abuse.\n\nNeurological examination revealed a normal mental status, gross extremity tremor, unsteady gait and saccadic eye movements. Serum lithium level was 0.78 mmol/L (0.5 - 0.8 mmol/L), serum magnesium level was 0.87 mmol/L (0.71 - 0.94 mmol/L), and serum vitamin B12 level was 688 pmol/L (> 200 pmol/L). Magnetic resonance imaging of the brain, cerebrospinal fluid analysis as well as electroencephalography were normal. Paraneoplastic autoantibodies in serum were negative for Anti-amphiphysin, anti-CV2, anti-PMNA2, anti-Ri, anti-Yo, anti-ANNA1. In the following 3 weeks of hospitalization the patient deteriorated with progressive ataxia, tremor, cognitive impairment, and complaints of diplopia. Neuro-ophthalmic examination revealed upward gaze deviation, DBN and horizontal gaze palsy (Fig. 1). The patient was only shortly able to bring her eyes in the primary position of gaze, which elicited DBN, and was unable to bring her eyes below the horizontal plane. No voluntary horizontal saccades or pursuit movements could be elicited, and the gaze palsies were not overcome by activation of the vestibulo-ocular reflexes by doll’s head manoeuvre. Pupils were equal and light reflexes normal. The patient was unable to cooperate to formal visual acuity assessment. \n\nLithium intoxication was suspected. Repeated testing of serum lithium revealed an increase to 1.0 mmol/L, and lithium carbonate was discontinued. Within one week serum lithium level decreased to 0.2 mmol/L and symptoms and signs improved significantly. Serum lamotrigine and valproate levels were only analysed one week after lithium discontinuation when clinical signs and symptoms had improved significantly. At this point lamotrigine and valproate levels were slightly over therapeutic range, serum lamotrigine 66 µmol/L (4-50 µmol/L) and serum valproate 714 µmol/L (300-700 µmol/L). Due to the marked clinical improvement after lithium discontinuation, the slightly elevated levels of valproate and lamotrigine were not considered causative, and therefore both drugs were continued. Seven weeks after initial presentation at the Neurological Department, vertical and horizontal eye movements had normalized apart from a residual low-amplitude DBN and oscillopsia on down gaze to the right and left. Best corrected visual acuity was 20/16 in each eye. Tremor and cognitive functions had normalized though some degree of retrograde amnesia persisted.\n\nDISCUSSION\nWe strongly suspect the clinical findings to be caused by lithium carbonate intoxication. Alternative causes of DBN i.e. structural lesions of the craniocervical junction or cerebellum, encephalitis or hypomagnesemia were ruled out, and symptoms improved significantly as lithium carbonate was discontinued.\n\nVitamin B12 deficiency is known to cause eye movement disorders like DBN and internuclear ophthalmoplegia, as well as gait ataxia [4, 5]. However, in our patient serum B12 level was normal, and B12 deficiency was therefore not considered the cause of DBN. Differential diagnostic considerations in patients with ataxia and affection of the ocular motility includes Wernicke`s encephalopathy as well as paraneoplastic neurological syndromes (PNS). Wernicke`s encephalopathy is due to nutritional deficiencies especially thiamine deficiency, and vertical nystagmus has been reported in patients with this condition [6]. Our patient had no history of alcohol abuse or malnutrition making this diagnosis less likely. PNS is an extensive group of disorders that may affect any part of the nervous system and in rare cases can cause vertical nystagmus [7]. However, we do not consider this diagnosis probable due to the fast clinical restitution after lithium discontinuation, and test for paraneoplastic autoantibodies was negative.\n\nLamotrigine toxicity is recently reported to be a rare cause of DBN, and lamotrigine´s half-life is extended when used with valproate [8]. Our patient was treated uneventfully with both for a long time and DBN presented only as lithium was added. As levels of valproate and lamotrigine were slightly above therapeutic levels, we cannot rule out an additive toxic effect of lamotrigine, though. \n\nIn the presented case did symptoms and signs improve as lithium was discontinued, but this is not always the case. Halmagyi et al. reported four patients with lithium-induced DBN with persisting nystagmus despite lithium dis-continuation or reduction [3].\n\nThe pathophysiology of lithium-induced DBN is not well understood. Corbett et al. reported a case of lithium-induced DBN and horizontal gaze palsy very similar to ours, though fatal. Postmortem examination disclosed cell loss in the nuclei prepositus hypoglossi and both medial vestibular nuclei in the lower brainstem [2]. These nuclei are supposed to be a neural integrator of conjungated horizontal eye movements, and are assumed to interconnect with brain structures responsible for vertical eye movements [9]. Experimental damage in the region of the nuclei prepositus hypoglossi and medial vestibular nuclei has produced similar eye motility disorders in rhesus monkies, and the authors therefore suggests that lithium-induced DBN is due to focal neuronal damage to these brainstem structures [2].\n\nCONCLUSION\nDBN with horizontal gaze palsy is a rare condition, and lithium side effects should be considered in lithium-treated patients presenting with DBN, especially if no other metabolic or structural lesion of the brain is identified.\n\nACKNOWLEDGEMENT\nDeclared none.\n\nCONFLICT OF INTEREST\nThe authors confirm that this article content has no conflict of interest.\n\nFig. (1) Spontaneous up gaze in a 62-year-old woman with lithium intoxication. Attempts to look straight ahead elicited downbeat nystagmus.\n==== Refs\nREFERENCES\n1 Bourgeois J.A. Ocular side effects of lithium-a review. J. Am. Optom. Assoc. 1991 62 7 548 551 1813560 \n2 Corbett J.J. Jacobson D.M. Thompson H.S. Hart M.N. Albert D.W. Downbeating nystagmus and other ocular motor defects caused by lithium toxicity. Neurology 1989 39 4 481 487 10.1212/WNL.39.4.481 2648186 \n3 Halmagyi G.M. Lessell I. Curthoys I.S. Lessell S. Hoyt W.F. Lithium-induced downbeat nystagmus. Am. J. Ophthalmol. 1989 107 6 664 670 10.1016/0002-9394(89)90265-1 2499196 \n4 Akdal G. Yener G.G. Ada E. Halmagyi G.M. Eye movement disorders in vitamin B12 deficiency: two new cases and a review of the literature. Eur. J. Neurol. 2007 14 10 1170 1172 10.1111/j.1468-1331.2007.01824.x 17880572 \n5 Mayfrank L. Thoden U. Downbeat nystagmus indicates cerebellar or brain-stem lesions in vitamin B12 deficiency. J. Neurol. 1986 233 3 145 148 10.1007/BF00314420 3487624 \n6 Suzuki Y. Matsuda T. Washio N. Ohtsuka K. Transition from upbeat to downbeat nystagmus observed in a patient with Wernicke’s encephalopathy. Jpn. J. Ophthalmol. 2005 49 3 220 222 10.1007/s10384-004-0182-8 15944827 \n7 Barata P.C. Morgado J. Sousa A.P. de Oliveira S.D. Custódio M.P. da Costa L.B. Pena J.E. Breast cancer presents with a paraneoplastic neurologic syndrome. Case Rep. Oncol. 2012 5 3 616 621 10.1159/000345692 23275775 \n8 Alkawi A. Kattah J.C. Wyman K. Downbeat nystagmus as a result of lamotrigine toxicity. Epilepsy Res. 2005 63 2-3 85 88 10.1016/j.eplepsyres.2004.11.004 15716057 \n9 Leight R.J. Zee D.S. The neurology of eye movements. 2006 4th ed New York Oxford University Press\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1874-3641",
"issue": "10()",
"journal": "The open ophthalmology journal",
"keywords": "Adverse effects; Downbeat nystagmus; Gaze palsy; Lithium",
"medline_ta": "Open Ophthalmol J",
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"nlm_unique_id": "101480505",
"other_id": null,
"pages": "126-8",
"pmc": null,
"pmid": "27347248",
"pubdate": "2016",
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"title": "Lithium-Induced Downbeat Nystagmus and Horizontal Gaze Palsy.",
"title_normalized": "lithium induced downbeat nystagmus and horizontal gaze palsy"
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"companynumb": "DK-ALEMBIC PHARMACUETICALS LIMITED-2016SCAL000559",
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"activesubstancename": "VENLAFAXINE HYDROCHLORIDE"
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... |
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"abstract": "Children with Down syndrome (DS) have a 20-fold increased risk of developing leukemia compared with the general population. The aim of the study was to analyze the outcome of patients diagnosed with Down syndrome and acute lymphoblastic leukemia (ALL) in Poland between the years 2003 and 2010. A total of 1848 children were diagnosed with ALL (810 females and 1038 males). Of those, 41 (2.2%) had DS. The children were classified into three risk groups: a standard-risk group-14 patients, an intermediate-risk group-24, a high-risk group-3. All patients were treated according to ALLIC 2002 protocol. The median observation time of all patients was 6.1 years, and in patients with DS 5.3 years. Five-year overall survival (OS) was the same in all patients (86% vs 86%, long-rank test, p = .9). The relapse-free survival (RFS) was calculated as 73% in patients with DS and 81% in patients without DS during a median observation time (long-rank test, p = .3). No statistically significant differences were found in the incidence of nonrelapse mortality between those two groups of patients (p = .72). The study was based on children with ALL and Down syndrome who were treated with an identical therapy schedule as ALL patients without DS, according to risk group. This fact can increase the value of the presented results.",
"affiliations": "a Department of Pediatric Hematology, Oncology and Transplantology , Medical University , Lublin , Poland.;a Department of Pediatric Hematology, Oncology and Transplantology , Medical University , Lublin , Poland.;a Department of Pediatric Hematology, Oncology and Transplantology , Medical University , Lublin , Poland.;a Department of Pediatric Hematology, Oncology and Transplantology , Medical University , Lublin , Poland.;a Department of Pediatric Hematology, Oncology and Transplantology , Medical University , Lublin , Poland.;b Department of Hematology and Pediatrics , Children's Hospital , Warsaw , Poland.;b Department of Hematology and Pediatrics , Children's Hospital , Warsaw , Poland.;c Department of Pediatric Oncology and Hematology , Children's University Hospital , Kraków , Poland.;c Department of Pediatric Oncology and Hematology , Children's University Hospital , Kraków , Poland.;c Department of Pediatric Oncology and Hematology , Children's University Hospital , Kraków , Poland.;d Department of Pediatric Transplantology, Oncology, Hematology , Medical University , Wrocław , Poland.;e Department of Pediatric Oncology, Hematology and Transplantology , Medical University , Poznań , Poland.;e Department of Pediatric Oncology, Hematology and Transplantology , Medical University , Poznań , Poland.;f Department of Pediatrics, Hematology , Oncology and Endocrinology, Medical University , Gdańsk , Poland.;f Department of Pediatrics, Hematology , Oncology and Endocrinology, Medical University , Gdańsk , Poland.;g Department of Pediatrics, Oncology , Hematology and Diabetology, Medical University , Łódź , Poland.;g Department of Pediatrics, Oncology , Hematology and Diabetology, Medical University , Łódź , Poland.;h Department of Pediatrics , Hematology and Oncology, Collegium Medicum , Bydgoszcz , Poland.;h Department of Pediatrics , Hematology and Oncology, Collegium Medicum , Bydgoszcz , Poland.;i Department of Pediatrics , Hematology and Oncology, Medical University , Zabrze , Poland.;i Department of Pediatrics , Hematology and Oncology, Medical University , Zabrze , Poland.;j Department of Pediatric Oncology , Hematology, Medical University , Białystok , Poland.;j Department of Pediatric Oncology , Hematology, Medical University , Białystok , Poland.;k Department of Pediatrics , Hematology and Oncology, Medical University , Szczecin , Poland.;k Department of Pediatrics , Hematology and Oncology, Medical University , Szczecin , Poland.;l Department of Pediatric Oncology , Hematology and Chemotherapy, Medical University , Katowice , Poland.;l Department of Pediatric Oncology , Hematology and Chemotherapy, Medical University , Katowice , Poland.;m Department of Pediatric Oncology and Hematology , Children's Hospital , Kielce , Poland.;a Department of Pediatric Hematology, Oncology and Transplantology , Medical University , Lublin , Poland.",
"authors": "Zawitkowska|Joanna|J|;Odój|Teresa|T|;Drabko|Katarzyna|K|;Zaucha-Prażmo|Agnieszka|A|;Rudnicka|Julia|J|;Romiszewski|Michał|M|;Matysiak|Michał|M|;Kwiecińska|Kinga|K|;Ćwiklińska|Magdalena|M|;Balwierz|Walentyna|W|;Owoc-Lempach|Joanna|J|;Derwich|Katarzyna|K|;Wachowiak|Jacek|J|;Niedźwiecki|Maciej|M|;Adamkiewicz-Drożyńska|Elżbieta|E|;Trelińska|Joanna|J|;Młynarski|Wojciech|W|;Kołtan|Andrzej|A|;Wysocki|Mariusz|M|;Tomaszewska|Renata|R|;Szczepański|Tomasz|T|;Płonowski|Marcin|M|;Krawczuk-Rybak|Maryna|M|;Ociepa|Tomasz|T|;Urasiński|Tomasz|T|;Mizia-Malarz|Agnieszka|A|;Sobol-Milejska|Grażyna|G|;Karolczyk|Grażyna|G|;Kowalczyk|Jerzy|J|",
"chemical_list": null,
"country": "England",
"delete": false,
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"issn_linking": "0888-0018",
"issue": "34(4)",
"journal": "Pediatric hematology and oncology",
"keywords": "ALL; Down syndrome; chemotherapy; children",
"medline_ta": "Pediatr Hematol Oncol",
"mesh_terms": "D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols; D002648:Child; D002675:Child, Preschool; D018572:Disease-Free Survival; D004314:Down Syndrome; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007223:Infant; D008297:Male; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D015996:Survival Rate",
"nlm_unique_id": "8700164",
"other_id": null,
"pages": "199-205",
"pmc": null,
"pmid": "29040012",
"pubdate": "2017-05",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D016449:Randomized Controlled Trial",
"references": null,
"title": "Outcome of acute lymphoblastic leukemia in children with down syndrome-Polish pediatric leukemia and lymphoma study group report.",
"title_normalized": "outcome of acute lymphoblastic leukemia in children with down syndrome polish pediatric leukemia and lymphoma study group report"
} | [
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"companynumb": "PL-JAZZ-2017-PL-017025",
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"activesubstancename": "VINCRISTINE"
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"abstract": "A combination chemotherapy of paclitaxel plus carboplatin (TC) is the most frequently used regimen for gynecological malignancies. As long as it is effective, a carboplatin-containing combination chemotherapy is used for every relapse. This implies that the number of platinum administrations and the frequency of hypersensitivity reaction (HSR) increase as the prognosis improves. When a patient develops HSR to carboplatin, we have three options: 1) desensitizing and continuing to use carboplatin, 2) switching to other platinum drugs, or 3) changing to a non-platinum drug. Here we report an experience of an HSR to carboplatin in a patient with recurrent uterine carcinosarcoma. The patient was treated by surgery and TC therapy initially, resulting in no residual disease. The patient relapsed 18 months after the completion of the first-line chemotherapy and was treated with TC therapy again as second-line. An HSR to carboplatin occurred at the 10th cycle of TC in total. We replaced the carboplatin with cisplatin. A chemotherapy including cisplatin and adriamycin was repeated without further HSR. We reviewed the literature regarding HSR to carboplatin and in this paper we summarize the management for dealing with it.",
"affiliations": "Department of Obstetrics and Gynecology, School of Medicine, University of Occupational and Environmental Health, Japan.;Department of Obstetrics and Gynecology, School of Medicine, University of Occupational and Environmental Health, Japan.;Department of Obstetrics and Gynecology, School of Medicine, University of Occupational and Environmental Health, Japan.;Department of Obstetrics and Gynecology, School of Medicine, University of Occupational and Environmental Health, Japan.;Department of Obstetrics and Gynecology, School of Medicine, University of Occupational and Environmental Health, Japan.;Department of Obstetrics and Gynecology, School of Medicine, University of Occupational and Environmental Health, Japan.;Department of Obstetrics and Gynecology, School of Medicine, University of Occupational and Environmental Health, Japan.;Department of Obstetrics and Gynecology, School of Medicine, University of Occupational and Environmental Health, Japan.;Department of Obstetrics and Gynecology, School of Medicine, University of Occupational and Environmental Health, Japan.",
"authors": "Aoyama|Yoko|Y|;Ueda|Taeko|T|;Kuradome|Yohei|Y|;Hoshino|Kaori|K|;Harada|Hiroshi|H|;Kinjo|Yasuyuki|Y|;Murakami|Midori|M|;Kagami|Seiji|S|;Yoshino|Kiyoshi|K|",
"chemical_list": "D016190:Carboplatin; D017239:Paclitaxel; D002945:Cisplatin",
"country": "Japan",
"delete": false,
"doi": "10.7888/juoeh.43.81",
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"issue": "43(1)",
"journal": "Journal of UOEH",
"keywords": "carboplatin; chemotherapy; cisplatin; hypersensitivity reaction; uterine carcinosarcoma",
"medline_ta": "J UOEH",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D016190:Carboplatin; D002296:Carcinosarcoma; D002945:Cisplatin; D004342:Drug Hypersensitivity; D057915:Drug Substitution; D005260:Female; D006801:Humans; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D017239:Paclitaxel; D016896:Treatment Outcome; D014594:Uterine Neoplasms",
"nlm_unique_id": "7909645",
"other_id": null,
"pages": "81-86",
"pmc": null,
"pmid": "33678789",
"pubdate": "2021",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Hypersensitivity Reaction to Carboplatin in Gynecologic Cancer: A Case Report and a Review of the Literature.",
"title_normalized": "hypersensitivity reaction to carboplatin in gynecologic cancer a case report and a review of the literature"
} | [
{
"companynumb": "JP-MLMSERVICE-20210325-2801782-1",
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"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CISPLATIN"
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"drugadditional": null,
... |
{
"abstract": "Lymphomatoid granulomatosis (LG) is an uncommon lymphoproliferative disease characterised by angiocentric and angioinvasive cellular infiltrates. The lung is the usual primary site with secondary central nervous system (CNS) involvement in 20% of cases. Primary cerebral LG is a rare but potentially treatable disease with protean manifestations. Diagnosis is problematical and may be delayed when extracerebral disease is absent or occult. Six cases of cerebral LG are presented, and the clinical features, laboratory investigations, neuroimaging and pathological findings are reviewed.",
"affiliations": "Department of Neurology and Clinical Neurophysiology, Sir Charles Gairdner Hospital, Western Australia, Australia.",
"authors": "Kermode|A G|AG|;Robbins|P D|PD|;Carroll|W M|WM|",
"chemical_list": null,
"country": "Scotland",
"delete": false,
"doi": "10.1016/s0967-5868(96)90031-4",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0967-5868",
"issue": "3(4)",
"journal": "Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia",
"keywords": null,
"medline_ta": "J Clin Neurosci",
"mesh_terms": null,
"nlm_unique_id": "9433352",
"other_id": null,
"pages": "346-53",
"pmc": null,
"pmid": "18638900",
"pubdate": "1996-10",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Cerebral lymphomatoid granulomatosis.",
"title_normalized": "cerebral lymphomatoid granulomatosis"
} | [
{
"companynumb": "NVSC2020DE160310",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "3",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditional": null,
"dr... |
{
"abstract": "OBJECTIVE\nTo present the various orbital soft-tissue changes that can result from the use of topical prostaglandin analogs.\n\n\nMETHODS\nA case series of patients seen in a referral oculoplastic practice with presumed prostaglandin orbitopathy.\n\n\nRESULTS\nThirty-five patients were found to have a variety of disorders, including deepening of the superior sulci (24/35), hypertrichosis (32/35), periocular erythema (24/35), and meibomian gland dysfunction (18/35). Marginal eyelid thinning with posterior migration of the lash line was commonly present (34/35). Increased eyelid margin tension with horizontal eyelid shortening (32/35) was often associated with lateral canthal deformity or displacement (15/35). Lower eyelid retraction (18/35) seemed to contribute to ptosis in some patients, secondary to apparent tethering at the lateral canthus. Functional conditions resulting from the above structural abnormalities included tractional ptosis (n = 4), cicatricial entropion (n = 3), cicatricial ectropion (n = 2), trichiasis (n = 2), eyelid subluxation (n = 1), and chalazia (n = 1).\n\n\nCONCLUSIONS\nWhile topical prostaglandin analogs are well-tolerated by many patients with glaucoma, some individuals using these medications develop structural changes of the orbital soft tissue resulting in a variety of cosmetic and functional eyelid disorders. The eyelid margins can thin, causing posterior migration of the lashes. Increased horizontal tension of the eyelids may result in acquired blepharophimosis and upper or lower eyelid malposition. These orbital changes may be partially reversible in some patients. When possible, it is reasonable to withhold the prostaglandin and allow a period of observation before proceeding with surgical correction.",
"affiliations": "Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, Missouri, U.S.A.",
"authors": "Custer|Philip L|PL|;Kent|Tiffany L|TL|",
"chemical_list": "D000959:Antihypertensive Agents; D009883:Ophthalmic Solutions; D011455:Prostaglandins A, Synthetic",
"country": "United States",
"delete": false,
"doi": "10.1097/IOP.0000000000000431",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0740-9303",
"issue": "32(2)",
"journal": "Ophthalmic plastic and reconstructive surgery",
"keywords": null,
"medline_ta": "Ophthalmic Plast Reconstr Surg",
"mesh_terms": "D000287:Administration, Topical; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000959:Antihypertensive Agents; D005140:Eyelashes; D005141:Eyelid Diseases; D005260:Female; D005901:Glaucoma; D006801:Humans; D006983:Hypertrichosis; D008297:Male; D008537:Meibomian Glands; D008875:Middle Aged; D009883:Ophthalmic Solutions; D009916:Orbital Diseases; D011455:Prostaglandins A, Synthetic",
"nlm_unique_id": "8508431",
"other_id": null,
"pages": "102-5",
"pmc": null,
"pmid": "25719374",
"pubdate": "2016",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Observations on Prostaglandin Orbitopathy.",
"title_normalized": "observations on prostaglandin orbitopathy"
} | [
{
"companynumb": "PHHY2017US120335",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "TRAVOPROST"
},
"drugadditional": "1",
"druga... |
{
"abstract": "BACKGROUND\nAddition of bevacizumab/targeted therapy to cores consisting of four to five previously failed cytotoxic drugs employed at low/moderate dosages has produced third- and fourth-line regression of refractory gastric and ovarian cancer. Targeted therapy added to cores of previously failed drugs has similarly produced responses of refractory pancreatic cancer.\n\n\nMETHODS\nThe aim of the present study was to evaluate the addition of targeted therapy to failed cores for patients with end-stage disease. Patients all had end-stage measurable cholangiocarcinoma and active progression during treatment with cores. Targeted therapy, bevacizumab or cetuximab, at standard dosages and schedule was added to the failed cores, which consisted of: gemcitabine, fluorouracil, leucovorin and irinotecan on day 1, and a platin with/without docetaxel on day 2, each at its prior dose and schedule. Electronic medical records facilitated identification of patients for intent-to-treat analysis.\n\n\nRESULTS\nAll 13 patients had measurable disease; all standard cytotoxins had been used and failed before the start of treatment with targeted therapy added to the cores. The response rates according to the Response Evaluation Criteria in Solid Tumors and response duration range were: bevacizumab cores: 3/6, 6 to 19 months, and cetuximab cores: 5/7, 10 to 28 months. Responses produced clinical benefit and one late neoadjuvant R0 resection. There were no limiting hematological adverse events due to the cores. Limiting adverse events were hypertension in two patients and an easily controlled duodenal ulcer in one.\n\n\nCONCLUSIONS\nBevacizumab cores and cetuximab cores both produced response rates which satisfy phase II criteria for further investigation. As cores, failed cytotoxic drugs, many at one-quarter to half of their standard doses have been found to produce synergistic benefit in combination with targeted therapy for end-stage patients in four diseases. Co-treatment with no longer active cytotoxic core drugs can demonstrate efficacy attributable to the targeted therapy. This approach is a worthy, cost-effective fast-track registration strategy and distinctly different from trials testing primary treatment.",
"affiliations": "MZB Foundation for Cancer Research, New York, NY, U.S.A. bruckneroncology@gmail.com.;Bruckner Oncology, Bronx, NY, U.S.A.;Department of Surgery, Mount Sinai School of Medicine, New York, NY, U.S.A.",
"authors": "Bruckner|Howard W|HW|;Hirschfeld|Azriel|A|;Schwartz|Myron|M|",
"chemical_list": "D000068258:Bevacizumab; D000068818:Cetuximab",
"country": "Greece",
"delete": false,
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"issn_linking": "0250-7005",
"issue": "36(1)",
"journal": "Anticancer research",
"keywords": "Bevacizumab; cetuximab; cholangiocarcinoma; drug resistance; low-dose cytotoxins",
"medline_ta": "Anticancer Res",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D000068258:Bevacizumab; D000068818:Cetuximab; D018281:Cholangiocarcinoma; D006801:Humans",
"nlm_unique_id": "8102988",
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"pages": "399-402",
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"pmid": "26722072",
"pubdate": "2016-01",
"publication_types": "D016428:Journal Article",
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"title": "Targeted Therapy for Resistant Cholangiocarcinoma with Bevacizumab or Cetuximab Added to Failed Cytotoxic Drug Cores.",
"title_normalized": "targeted therapy for resistant cholangiocarcinoma with bevacizumab or cetuximab added to failed cytotoxic drug cores"
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"abstract": "Fibrin clot properties in acute ischaemic stroke (AIS) are unfavourably altered, including faster formation of denser and poorly lysable fibre networks. We investigated clot properties in AIS patients treated with recombinant tissue plasminogen activator (rtPA) and their impact on clinical outcome. In 74 consecutive AIS patients eligible for rtPA treatment, we assessed ex vivo plasma fibrin clot formation, permeability (Ks), and rtPA-induced lysis, along with peak thrombin generation, fibrinolysis proteins and inhibitors at three time points - on admission, after 24 hours and 3 months since stroke. Clinical outcome was assessed using the NIHSS and mRS scores. Compared with the pretreatment values, fibrin networks assessed 24 hours since thrombolysis were formed more slowly (+20.5 % lag phase on turbidimetry), were less compact (+36.9 % Ks), composed of thinner fibres (-10.6 % lower maximum absorbancy [ΔAb]), which were lysed more rapidly (-20.8 % clot lysis time [CLT] and +7.1 % the rate of rtPA-induced D-dimer release from clots [D-Drate]). Thrombin generation and fibrinolysis proteins remained elevated. Lower ΔAb (<0.86 at 405 nm), shorter CLT (<105 min), and higher D-Drate (>0.072 mg/l/min) assessed at baseline predicted good outcome (mRS 0-2) at 3 months after adjustment for age and fibrinogen. Logistic regression adjusted for potential confounders showed that good outcome at 3 months was predicted by pretreatment D-Drate, while pretreatment CLT predicted excellent outcome (mRS of 0-1). In conclusion, formation of denser fibrin clots displaying impaired lysability and pattern of their changes induced by thrombolysis may affect clinical outcome in AIS patients.",
"affiliations": "Anetta Undas, Institute of Cardiology, Jagiellonian University Medical College, 80 Pradnicka St., 31-202 Krakow, Poland, Tel.: +48 12 6143004, Fax: +48 12 6142120, E-mail: mmundas@cyf-kr.edu.pl.",
"authors": "Bembenek|Jan P|JP|;Niewada|Maciej|M|;Siudut|Jakub|J|;Plens|Krzysztof|K|;Członkowska|Anna|A|;Undas|Anetta|A|",
"chemical_list": "D005337:Fibrin; D010959:Tissue Plasminogen Activator",
"country": "Germany",
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"doi": "10.1160/TH16-12-0954",
"fulltext": null,
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"issn_linking": "0340-6245",
"issue": "117(7)",
"journal": "Thrombosis and haemostasis",
"keywords": "Stroke; thrombolysis; thrombosis; tissue plasminogen activator; treatment outcome",
"medline_ta": "Thromb Haemost",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D001777:Blood Coagulation; D002545:Brain Ischemia; D005260:Female; D005337:Fibrin; D063285:Fibrin Clot Lysis Time; D005342:Fibrinolysis; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D020521:Stroke; D015912:Thrombolytic Therapy; D010959:Tissue Plasminogen Activator; D016896:Treatment Outcome",
"nlm_unique_id": "7608063",
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"pubdate": "2017-06-28",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Fibrin clot characteristics in acute ischaemic stroke patients treated with thrombolysis: the impact on clinical outcome.",
"title_normalized": "fibrin clot characteristics in acute ischaemic stroke patients treated with thrombolysis the impact on clinical outcome"
} | [
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"abstract": "BACKGROUND National guidelines and consensus statements suggest a 24-hour window for endovascular recanalization in patients presenting with acute ischemic stroke due to large-vessel occlusion. However, the safety and efficacy of extending the window for intervention remains to be definitively established. CASE REPORT A healthy 26-year-old woman presented with headache, left-sided hemiplegia, and rightward gaze palsy 2 days after a minor trauma. Time last known well was approximately 50 hours prior to presentation. Computed tomography angiography revealed dissection of the distal right internal carotid artery and occlusion of the M1 segment of the right middle cerebral artery. Magnetic resonance imaging showed a small area of acute infarct in the right basal ganglia and right insular cortex, but suggested a large ischemic penumbra; this was confirmed with cerebral perfusion analysis. In light of the patient's young age and potential for penumbral salvage, mechanical thrombectomy of an M1 thrombus and stenting of an internal carotid artery dissection were performed nearly 60 hours after the onset of symptoms. The patient demonstrated marked clinical improvement over the following days and was discharged home in excellent condition one week after presentation. Based on our clinical experience and other emerging data, we propose that extension of the 24-hour window for endovascular intervention may improve functional outcomes among select individuals. CONCLUSIONS A 24-hour window for endovascular thrombectomy is appropriate for many patients presenting with acute ischemic stroke. However, in select individuals, extension of the window to 48 hours or beyond may improve functional outcomes.",
"affiliations": "Department of Radiology, University of Southern California, Keck School of Medicine, Los Angeles, CA, USA.;Reno Radiological Associates, Reno, NV, USA.;University of Nevada, Reno School of Medicine, Reno, NV, USA.;University of Nevada, Reno School of Medicine, Reno, NV, USA.",
"authors": "Beutler|Bryce D|BD|;Rangaswamy|Rajesh|R|;King|Richard D|RD|;Tabaac|Burton J|BJ|",
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"country": "United States",
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"doi": "10.12659/AJCR.930291",
"fulltext": "\n==== Front\nAm J Case Rep\nAm J Case Rep\namjcaserep\nThe American Journal of Case Reports\n1941-5923\nInternational Scientific Literature, Inc.\n\n33840809\n10.12659/AJCR.930291\n930291\nArticles\nDelayed Endovascular Thrombectomy for Ischemic Stroke in a Young Woman with No Known Risk Factors: A Case Report\nBeutler Bryce D. DEF1\nRangaswamy Rajesh AB234\nKing Richard D. ABE45\nTabaac Burton J. ADEF467\n1 Department of Radiology, University of Southern California, Keck School of Medicine, Los Angeles, CA, U.S.A.\n2 Reno Radiological Associates, Reno, NV, U.S.A.\n3 Department of Neurointerventional Radiology, Renown Regional Medical Center, Reno, NV, U.S.A.\n4 University of Nevada, Reno School of Medicine, Reno, NV, U.S.A.\n5 Department of Critical Care, Renown Regional Medical Center, Reno, NV, U.S.A.\n6 Department of Neurology, Renown Regional Medical Center, Reno, NV, U.S.A.\n7 Renown Health, Acute Care Neurology Division, Reno, NV, USA\nCorresponding Author: Bryce D. Beutler, e-mail: brycebeutler@hotmail.com\nAuthors’ Contribution:\n\nA Study Design\n\nB Data Collection\n\nC Statistical Analysis\n\nD Data Interpretation\n\nE Manuscript Preparation\n\nF Literature Search\n\nG Funds Collection\n\nConflict of interest: None declared\n\n2021\n12 4 2021\n22 e930291-1e930291-7\n05 12 2020\n23 2 2021\n02 3 2021\n© Am J Case Rep, 2021\n2021\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)\nPatient: Female, 26-year-old\n\nFinal Diagnosis: Internal carotid artery dissection\n\nSymptoms: Dysarthria • gaze palsy • hemiplegia • sensory loss\n\nMedication: —\n\nClinical Procedure: Endovascular stenting and mechanical thrombectomy\n\nSpecialty: Neurology • Radiology\n\nObjective:\n\nUnusual clinical course\n\nBackground:\n\nNational guidelines and consensus statements suggest a 24-hour window for endovascular recanalization in patients presenting with acute ischemic stroke due to large-vessel occlusion. However, the safety and efficacy of extending the window for intervention remains to be definitively established.\n\nCase Report:\n\nA healthy 26-year-old woman presented with headache, left-sided hemiplegia, and rightward gaze palsy 2 days after a minor trauma. Time last known well was approximately 50 hours prior to presentation. Computed tomography angiography revealed dissection of the distal right internal carotid artery and occlusion of the M1 segment of the right middle cerebral artery. Magnetic resonance imaging showed a small area of acute infarct in the right basal ganglia and right insular cortex, but suggested a large ischemic penumbra; this was confirmed with cerebral perfusion analysis. In light of the patient’s young age and potential for penumbral salvage, mechanical thrombectomy of an M1 thrombus and stenting of an internal carotid artery dissection were performed nearly 60 hours after the onset of symptoms. The patient demonstrated marked clinical improvement over the following days and was discharged home in excellent condition one week after presentation. Based on our clinical experience and other emerging data, we propose that extension of the 24-hour window for endovascular intervention may improve functional outcomes among select individuals.\n\nConclusions:\n\nA 24-hour window for endovascular thrombectomy is appropriate for many patients presenting with acute ischemic stroke. However, in select individuals, extension of the window to 48 hours or beyond may improve functional outcomes.\n\nKeywords:\n\nNeuroimaging\nStroke\nThrombectomy\n==== Body\nBackground\n\nCurrent clinical guidelines for the early management of patients with acute ischemic stroke suggest a 24-hour window for endovascular recanalization [1–3]. However, extending the window beyond 24 hours may result in a favorable outcome; emerging evidence indicates that clinical and imaging findings, rather than time last known well (TLKW), should guide management in the setting of ischemic stroke. Indeed, in select patients, endovascular intervention may improve outcomes even when performed days after symptom onset. We describe a 26-year-old woman who presented with a two-day history of progressively worsening neurologic deficits who demonstrated marked clinical improvement following endovascular stenting and thrombectomy. Written informed consent was obtained for the publication of case details.\n\nCase Report\n\nA 26-year-old woman presented to the Emergency Department complaining of headache and weakness. The patient explained that she had suffered a minor ground-level fall without apparent injury 3 days earlier; she had returned to her usual state of health upon going to bed that evening (TLKW). Upon waking the following morning, she began to experience a constant throbbing occipital and right temporal headache (8 hours since TLKW). In addition, she described the insidious onset of predominantly left-sided weakness. Symptoms progressively worsened over the following 2 days, prompting the patient to finally seek care in the Emergency Department (50 hours since TLKW).\n\nThe patient had been healthy prior to the onset of symptoms. She took daily oral contraceptive pills, but no other prescription medications or supplements. There was no personal or family history of atherosclerotic disease or hypercoagulability syndrome, nor was there a personal history of thrombosis or miscarriage. The patient denied use of alcohol or tobacco, but did endorse weekly marijuana use.\n\nThe patient was slightly tachypneic on presentation (temperature: 36.4°C; blood pressure: 122/63 mmHg; heart rate: 60 beats per minute; respiratory rate: 18 respirations per minute; oxygen saturation: 99%). Physical examination revealed a partial right gaze palsy, left facial paresis, dysarthria, left hemisensory loss of 90% as compared to the right, and unilateral motor weakness (3/5 left upper-extremity strength and 0/5 left lower-extremity strength). National Institutes of Health Stroke Scale (NIHSS) score was 15. Initial laboratory studies for stroke risk factors were unremarkable (total cholesterol: 175 mg/dL [low-density lipoprotein: 89 mg/dL, high-density lipoprotein: 59 mg/dL], triglycerides: 135 mg/dL, hemoglobin A1c: 5.4%). Fasting blood glucose was 90 mg/dL. Hematologic studies were within normal limits (prothrombin time: 13 seconds, international normalized ratio: 0.95, hemoglobin: 12.7 g/dL, hematocrit: 37.3%). The patient tested negative for coronavirus disease-19 (Table 1).\n\nA non-contrast computed tomography (CT) scan of the head was obtained and demonstrated a region of hypodensity within the right insular ribbon; Alberta Stroke Program Early CT Score (ASPECTS) was 9. CT angiography showed occlusion of the supraclinoid segment of the right internal carotid artery (ICA) and M1 segment of the middle cerebral artery (MCA) (Figure 1). Findings were further characterized with magnetic resonance angiography (MRA), which showed a proximal right ICA occlusion with intramural thrombus (Figures 2, 3). Magnetic resonance imaging showed only a small area of acute infarct in the right basal ganglia and right insular cortex (Figure 4); this was confirmed on CT cerebral perfusion analysis, which demonstrated a completed infarct volume of 5 milliliters (mL) and mismatched volume representing ischemic brain/penumbra of 17 mL. Tmax greater than 6 seconds representing combination of completed infarct and ischemia was 22 mL (Figure 5). Correlation of the clinical presentation and imaging findings suggested a small ischemic stroke with a comparatively large penumbra. The patient was immediately started on aspirin 81 milligrams.\n\nThe case was discussed with the neurology and neurointerventional radiology teams, who concluded that, in light of the patient’s young age, large penumbra, and risk for complete infarction, the potential benefits of endovascular recanalization outweighed any potential risks. The patient and her family agreed.\n\nThe patient was transported to the angiography lab approximately 4.5 hours after presentation and nearly 55 hours since TLKW. A right cervical carotid angiogram demonstrated dissection of the right internal carotid origin with intramural hematoma (Figure 6). A right internal carotid stent was placed across the dissected segment with an embolic protection device (Figure 7). The subsequent angiogram demonstrated a right supraclinoid segment occluded by thrombus; aspiration thrombectomy was performed. After multiple aspirations, a modified treatment in cerebral ischemia (mTICI) score of 2a was achieved. Immediately after the mTICI 2a reperfusion, the patient began moving her left upper and lower extremities, suggesting significant improvement. It was therefore decided not to remove a small distal M2 segment thrombus so as to minimize the potential for adverse events. Post-thrombectomy angiography showed patency of the ICA and M1 segment (Figure 8).\n\nAntiplatelet drugs were not administered immediately following the procedure in order to reduce the risk of hemorrhagic conversion of the right basal ganglia infarct. A follow-up MRA obtained on Oct 5 was significant for non-visualization of the right common carotid artery and right ICA, indicating carotid stent occlusion. However, there was reconstitution of the supraclinoid portion of the right ICA, likely via the patent posterior communicating and anterior communicating arteries (Figure 9). A subsequent MRI demonstrated stable infarcts in the insular region and basal ganglia with a patent right supraclinoid right internal carotid artery.\n\nThe patient began participating in physical, occupational, and speech therapy on Oct 5. Aspirin 81 milligrams daily was continued and atorvastatin 40 milligrams nightly was started for secondary prevention. Dual antiplatelet therapy was not indicated, given the stent occlusion. Re-evaluation by the neurology team revealed marked improvement in function. The patient exhibited complete resolution of gaze palsy and dysarthria. Left hemisensory loss has improved from a decrease of 90% to 30%. Left upper-extremity motor strength had improved to 4+/5 (previously 3/5) and left lower-extremity motor strength had improved to 4–/5 (previously 0/5). The patient was discharged home on Oct 7 with an NIHSS score of 5. Aspirin 81 and atorvastatin were continued.\n\nA comprehensive stroke workup revealed that the patient was heterozygous for the factor V Leiden gene mutation. In addition, prothrombin G20210A (Factor II) DNA analysis was positive for a heterozygous mutation. Protein C and S, antithrombin III, beta-2 glycoprotein antibodies, and anticardiolipin antibodies were all within normal limits (Table 1). A 2D echocardiogram with bubble study showed evidence of an early right-to-left shunt suggestive of atrial septal defect or patent foramen ovale. The findings were discussed in detail with neuroradiology and neurointerventional specialists, who confirmed that the MRA and intraprocedural angiography definitively demonstrated dissection at the proximal ICA. However, it was also emphasized that the presence of a dissection did not necessarily exclude other causes of stroke. Given the patient’s thrombotic risk factors, including a right-to-left intracardiac shunt, oral contraceptive use, and factor V Leiden and prothrombin G20210A heterozygosity, it was postulated that a paradoxical embolism may have occurred prior to or in parallel with the traumatic dissection. Further history was most suggestive of the former hypothesis, as the patient noted that she had experienced transient episodes of left-sided weakness months prior to her presentation in the Emergency Department.\n\nThe patient agreed to switch to progestin-only contraceptives given her increased risk for thrombosis and continued to participate in outpatient physical and occupational therapy. Modified Rankin Scale for Neurologic Disability at 90 days was 1. No further episodes of stroke-like symptoms have been reported.\n\nDiscussion\n\nIn 2015, MR CLEAN (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands) demonstrated that patients who underwent early endovascular mechanical thrombectomy (EVT) experienced superior functional outcomes as compared to those who received standard medical therapy alone [4]. The results of several other trials subsequently established EVT as the standard of care for patients with acute ischemic stroke due to large-vessel occlusion who presented within 6 hours of symptom onset [5–7]. Three years later, the DEFUSE-3 (Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke) trial provided evidence that the six-hour window for EVT could be extended to 16 hours among individuals presenting with neurologic deficits that were out of proportion to infarct size [2]; this was later extended to 24 hours in the DAWN (DWI or CTP Assessment with Clinical Mismatch in the Triage of Wake-Up and Late Presenting Strokes Undergoing Neurointervention with Trevo) trial [3]. The 24-hour window for EVT has since been integrated into national guidelines for the management of acute ischemic stroke [1].\n\nThe DEFUSE-3 and DAWN trials marked a paradigm shift in the management of acute ischemic stroke, introducing a patient selection model predicated on perfusion and penumbra rather than time last known well (TLKW). Patients included in the DEFUSE-3 trial had a small initial infarct volume (less than 70 mL) and relatively large penumbra (15 mL or more), while the DAWN trial used clinical core mismatch to determine patient eligibility. Both studies represented a significant departure from the time window dogma and established that a physiology- and imaging-based approach to management could improve outcomes among patients in whom standard medical therapy would offer marginal benefit.\n\nEmerging evidence suggests that the EVT window can be extended well beyond 24 hours. A 2018 retrospective review by Desai et al concluded that EVT is safe and effective in patients with acute ischemic stroke due to large-vessel occlusion who present up to 156 hours after symptom onset [8]. In addition, a case report by Aguilar-Salinas et al describes remarkable improvement in a woman who underwent EVT nearly one week after TLWK [9]. A more recent study demonstrated that the window for EVT may be extended even beyond one week. In a 2020 case-control study of 150 patients with acute ischemic stroke due to internal carotid or middle cerebral artery occlusion who had salvageable brain tissue and an NIHSS score of 6 or greater, Kim et al found that EVT was associated with better outcomes than medical therapy alone, including among patients presenting up to 10 days after TLKW [10]. However, no other major studies have since examined a fundamental question of stroke management: when, if ever, does the EVT window close? The data unequivocally show that patient selection should be individualized based on clinical presentation, imaging, and perfusion analysis; thus, it is reasonable to question the value of TLKW in evaluating patient eligibility for EVT. Indeed, our 26-year-old patient was conceivably spared lifelong disability by looking outside the arbitrary 24-hour window.\n\nPatient selection in the DAWN trial was based on 3 major inclusion criteria: (1) radiologic evidence of large-vessel occlusion; (2) mismatch between the severity of the neurologic deficit and infarct volume, with a minimum NIHSS score of 10 for patients with an infarct volume of less than 31 mL and minimum NIHSS score of 20 for patients with an infarct volume of 31–51 mL; and (3) TLKW 6–24 hours prior to presentation. We advocate for a similar patient selection model based on correlation of clinical presentation and tissue perfusion. However, TLKW, beyond the 4.5-hour tissue plasminogen window, should not be used to determine eligibility. Furthermore, we believe that select individuals with an NIHSS below 10 should be considered for EVT; this decision should be based on baseline functional status, co-morbidities, patient goals, and possible outcomes.\n\nConclusion\n\nIn conclusion, there is a paucity of data pertaining to late EVT in the setting of acute ischemic stroke due to large-vessel occlusion. However, the results of the recent study by Kim et al and our experience with EVT in a patient presenting 2 days after LKTW provide further evidence supporting a clinical- and imaging-based approach to patient selection rather than relying on the current 24-hour time window guideline. Large-scale prospective studies are warranted to examine the value of the time window for EVT, if any, and identify which patients are most likely to benefit from late intervention.\n\nFigure 1. CT angiography demonstrating occlusion of the supraclinoid portion of the right internal carotid artery and M1 segment of the right middle cerebral artery (arrow).\n\nFigure 2. Magnetic resonance angiography (MRA), coronal view, demonstrating a proximal right internal carotid artery occlusion with intramural thrombus (arrow).\n\nFigure 3. Magnetic resonance angiography (MRA), axial view, demonstrating a proximal right internal carotid artery occlusion with intramural thrombus (arrow).\n\nFigure 4. Magnetic resonance imaging (MRI) showing a small area of acute infarct in the right basal ganglia and right insular cortex (arrowhead).\n\nFigure 5. CT cerebral perfusion analysis showing a small region of complete infarct with a comparatively large ischemic penumbra (5 and 17 mL, respectively).\n\nFigure 6. Right cervical carotid angiogram demonstrating dissection of the right internal carotid origin with intramural hematoma (arrowhead).\n\nFigure 7. Digital subtraction angiography (DSA) demonstrating the internal carotid artery stent with embolic protection device (arrowheads).\n\nFigure 8. Post-thrombectomy angiography showing a patent right internal carotid artery and M1 segment of the middle cerebral artery (arrowhead).\n\nFigure 9. Magnetic resonance angiography (MRA) showing a patent supraclinoid portion of the internal carotid artery and M1 segment of the middle cerebral artery through a patent anterior communicating artery (arrow).\n\nTable 1. Laboratory studies for a 26-year-old woman presenting with acute ischemic stroke.\n\nLaboratory study\tValue (reference range)\t\nHematology\t\nHemoglobin\t12.7 g/dL (12.0–15.5 g/dL)\t\nHematocrit\t37.3% (35.5–44.9%)\t\nProthrombin time (PT)\t13 seconds (10–13 seconds)\t\nInternational normalized ratio (INR) 0.95 (0.8–1.1)\t\nChemistry\t\nTotal cholesterol\t175 mg/dL (<200 mg/dL)\t\nLow-density lipoprotein\t89 mg/dL (<130 mg/dL)\t\nHigh-density lipoprotein\t59 mg/dL (>60 mg/dL)\t\nTriglycerides\t135 mg/dL (<150 mg/dL)\t\nFasting glucose\t90 mg/dL (80–100 mg/dL)\t\nHemoglobin A1c (HbA1c)\t5.4% (<5.9%)\t\nInfection\t\nCoronarvirus disease-19\tNegative\t\nAutoimmune and hypercoagulability studies\t\nFactor V Leiden\tHeterozygous\t\nProthrombin G20210A (Factor II)\tHeterozygous\t\nProtein C and S\tNormal\t\nAnticardiolipin antibodies (IgA, IgG, IgM)\tNegative\t\nBeta-2 glycoprotein antibodies (IgA, IgG, IgM)\tNegative\t\n\nConflicts of Interest\n\nNone declared.\n==== Refs\nReferences:\n\n1. Warner JJ Harrington RA Sacco RL Elkind MSV Guidelines for the early management of patients with acute ischemic stroke: 2019 update to the 2018 guidelines for the early management of acute ischemic stroke Stroke 2019 50 12 3331 32 31662117\n2. Albers GW Marks MP Kemp S Thrombectomy for stroke at 6 to 16 hours with selection by perfusion imaging N Engl J Med 2018 378 8 708 18 29364767\n3. Nogueira RG Jadhav AP Haussen DC Thrombectomy 6 to 24 hours after stroke with a mismatch between deficit and infarct N Engl J Med 2018 378 1 11 21 29129157\n4. Berkhemer OA Fransen PS Beumer D A randomized trial of intraarterial treatment for acute ischemic stroke N Engl J Med 2015 372 1 11 20 25517348\n5. Chen CJ Ding D Starke RM Endovascular vs medical management of acute ischemic stroke Neurology 2015 85 22 1980 90 26537058\n6. Jovin TG Chamorro A Cobo E Thrombectomy within 8 hours after symptom onset in ischemic stroke N Engl J Med 2015 372 24 2296 306 25882510\n7. Goyal M Menon BK van Zwam WH Endovascular thrombectomy after large-vessel ischaemic stroke: A meta-analysis of individual patient data from five randomised trials Lancet 2016 387 10029 1723 31 26898852\n8. Desai SM Haussen DC Aghaebrahim A Thrombectomy 24 hours after stroke: beyond DAWN J Neurointerv Surg 2018 10 11 1039 42 29807887\n9. Aguilar-Salinas P Santos R Granja MF Revisiting the therapeutic time window dogma: Successful thrombectomy 6 days after stroke onset BMJ Case Rep 2018 2018 bcr2018014039\n10. Kim BJ Menon BK Kim JY Endovascular treatment after stroke due to large vessel occlusion for patients presenting very late from time last known well JAMA Neurol 2020 [Online ahead of print]\n\n",
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"issn_linking": "1941-5923",
"issue": "22()",
"journal": "The American journal of case reports",
"keywords": null,
"medline_ta": "Am J Case Rep",
"mesh_terms": "D000328:Adult; D002545:Brain Ischemia; D002343:Carotid Artery, Internal; D057510:Endovascular Procedures; D005260:Female; D006801:Humans; D000083242:Ischemic Stroke; D020521:Stroke; D017131:Thrombectomy; D016896:Treatment Outcome",
"nlm_unique_id": "101489566",
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"pages": "e930291",
"pmc": null,
"pmid": "33840809",
"pubdate": "2021-04-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "29364767;29807887;25517348;31662117;26537058;29129157;25882510;32777014;26898852;30012573",
"title": "Delayed Endovascular Thrombectomy for Ischemic Stroke in a Young Woman with No Known Risk Factors: A Case Report.",
"title_normalized": "delayed endovascular thrombectomy for ischemic stroke in a young woman with no known risk factors a case report"
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"abstract": "BACKGROUND\nIn patients treated with TNF-antagonists, incident cases of tuberculosis (TB) after a negative screening have been reported, leading to the suggestion that improved TB testing is necessary.\n\n\nOBJECTIVE\nThe aim of the current study is to establish the incidence of TB and its characteristics in patients with inflammatory bowel disease (IBD) under TNF antagonists to design improved prevention strategies.\n\n\nMETHODS\nIBD patients from a single center treated with anti-TNF therapy between January 2000 and September 2011 were identified through a database that prospectively records clinical data, treatments and adverse events.\n\n\nRESULTS\nDuring the study period 423 patients received anti-TNF therapy. Screening for latent TB infection (LTBI) previous to anti-TNF treatment was positive in 30 patients (6.96%). Seven patients (1.65%) developed TB while under anti-TNF treatment. Six patients (five under immunosuppressant treatment) had a negative LTBI screening. TST was positive in one patient not receiving immunosuppressants, and was treated with isoniazid before starting anti-TNF therapy. In 4 patients TB was diagnosed within the first 16 weeks after starting anti-TNF therapy. Three cases had pulmonary TB and 4 extrapulmonary disease.\n\n\nCONCLUSIONS\nIn the IBD population under study, incidence of TB infection associated with anti-TNF therapy is higher than that reported in controlled trials and occurs early after treatment initiation. False negative results of LTBI despite appropriate measures may occur, suggesting that more effective screening strategies are needed.",
"affiliations": "Department of Gastroenterology, Hospital Clínic de Barcelona, CIBER-EHD, Barcelona, Spain.",
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"keywords": null,
"medline_ta": "J Crohns Colitis",
"mesh_terms": "D000068879:Adalimumab; D000328:Adult; D000893:Anti-Inflammatory Agents; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D005188:False Negative Reactions; D005260:Female; D006801:Humans; D015994:Incidence; D015212:Inflammatory Bowel Diseases; D000069285:Infliximab; D055985:Latent Tuberculosis; D008297:Male; D008875:Middle Aged; D012307:Risk Factors; D016896:Treatment Outcome; D014374:Tuberculin Test; D014376:Tuberculosis",
"nlm_unique_id": "101318676",
"other_id": null,
"pages": "208-12",
"pmc": null,
"pmid": "22677117",
"pubdate": "2013-04",
"publication_types": "D023362:Evaluation Study; D016428:Journal Article",
"references": null,
"title": "Risk of developing tuberculosis under anti-TNF treatment despite latent infection screening.",
"title_normalized": "risk of developing tuberculosis under anti tnf treatment despite latent infection screening"
} | [
{
"companynumb": "ES-ROXANE LABORATORIES, INC.-2015-RO-00351RO",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "INFLIXIMAB"
},
"drugadditi... |
{
"abstract": "Hemophagocytic lymphohistiocytosis (HLH) is a condition caused by a pathologic immune activation, which is responsible for its signs and symptoms. It may also appear as a secondary process caused by malignancy. Developing HLH during treatment for acute lymphoblastic leukemia (ALL) is extremely uncommon, but underdiagnosis may be fatal. Two patients with ALL on chemotherapy maintenance treatment who developed HLH triggered by infection are presented here. We emphasize the importance of being aware of this condition when a patient with ALL in complete remission presents with unexplained hepatomegaly, cytopenia, and fever. Early diagnosis and treatment may be lifesaving.",
"affiliations": "Pediatric Hematology and Oncology Unit, Madrid Montepríncipe Hospital.;Pediatric Hematology and Oncology Unit, Madrid Montepríncipe Hospital.;Pediatric Hematology and Oncology Unit, Madrid Montepríncipe Hospital.;Hemathology and Hemotherapy Department, HM Group, Boadilla del Monte, Madrid, Spain.;Pediatric Hematology and Oncology Unit, Madrid Montepríncipe Hospital.;Pediatric Hematology and Oncology Unit, Madrid Montepríncipe Hospital.",
"authors": "Martínez-Romera|Isabel|I|;Villa|Marta|M|;Areal|Pilar|P|;Rodrigo|Esther|E|;Herrero|Blanca|B|;López-Ibor|Blanca|B|",
"chemical_list": "D000970:Antineoplastic Agents",
"country": "United States",
"delete": false,
"doi": "10.1097/MPH.0000000000000932",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1077-4114",
"issue": "40(2)",
"journal": "Journal of pediatric hematology/oncology",
"keywords": null,
"medline_ta": "J Pediatr Hematol Oncol",
"mesh_terms": "D000970:Antineoplastic Agents; D002648:Child; D005260:Female; D006801:Humans; D016867:Immunocompromised Host; D007239:Infections; D051359:Lymphohistiocytosis, Hemophagocytic; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma",
"nlm_unique_id": "9505928",
"other_id": null,
"pages": "e108-e110",
"pmc": null,
"pmid": "28859036",
"pubdate": "2018-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Hemophagocytic Lymphohistiocytosis: A Dangerous Intruder in Pediatric Acute Lymphoblastic Leukemia.",
"title_normalized": "hemophagocytic lymphohistiocytosis a dangerous intruder in pediatric acute lymphoblastic leukemia"
} | [
{
"companynumb": "ES-MYLANLABS-2018M1074098",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHOTREXATE"
},
"drugadditional": "3",
... |
{
"abstract": "Resistant strains of cytomegalovirus can be difficult to treat in cases of congenital cytomegalovirus retinitis. The authors describe a case of recurrent bilateral congenital cytomegalovirus retinitis in an immunocompetent newborn with ganciclovir resistance successfully treated uniquely with dual therapy of intravenous ganciclovir and foscarnet and dual intravitreal injections with ganciclovir and foscarnet. [J Pediatr Ophthalmol Strabismus. 2016;53:e58-e60.].",
"affiliations": null,
"authors": "Boss|Joseph D|JD|;Rosenberg|Kevin|K|;Shah|Rajiv|R|",
"chemical_list": "D000998:Antiviral Agents; D017245:Foscarnet; D015774:Ganciclovir",
"country": "United States",
"delete": false,
"doi": "10.3928/01913913-20161003-02",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0191-3913",
"issue": "53()",
"journal": "Journal of pediatric ophthalmology and strabismus",
"keywords": null,
"medline_ta": "J Pediatr Ophthalmol Strabismus",
"mesh_terms": "D000998:Antiviral Agents; D003587:Cytomegalovirus; D017726:Cytomegalovirus Retinitis; D024882:Drug Resistance, Viral; D004359:Drug Therapy, Combination; D005260:Female; D017245:Foscarnet; D015774:Ganciclovir; D006801:Humans; D007223:Infant; D058449:Intravitreal Injections; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious; D012008:Recurrence; D019562:Viral Load; D014822:Vitreous Body",
"nlm_unique_id": "7901143",
"other_id": null,
"pages": "e58-e60",
"pmc": null,
"pmid": "27783090",
"pubdate": "2016-10-22",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Dual Intravitreal Injections With Foscarnet and Ganciclovir for Ganciclovir-Resistant Recurrent Cytomegalovirus Retinitis in a Congenitally Infected Infant.",
"title_normalized": "dual intravitreal injections with foscarnet and ganciclovir for ganciclovir resistant recurrent cytomegalovirus retinitis in a congenitally infected infant"
} | [
{
"companynumb": "US-ROCHE-1854085",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "FOSCARNET"
},
"drugadditional": null,
"drug... |
{
"abstract": "Carbamazepine overdose is a common, toxic ingestion, manifesting as central nervous system (CNS) and respiratory depression. Carbamazepine is highly protein bound with a large volume of distribution and, therefore, inefficiently removed by conventional hemodialysis. We describe the successful use of continuous venovenous hemodialysis (CVVHD) with 5% albumin enhanced dialysate in a 31-year-old female who developed CNS depression, hypotension and respiratory failure, requiring mechanical ventilation, after an intentional ingestion of approximately 10 g of extended release carbamazepine, Tegretol CR(®). The peak drug level was 26 mcg/ml, therapeutic range 8-12 mcg/ml, with toxicity often developing a level above 15 mcg/ml. Normal half-life of drug elimination is 35-60 h in carbamazepine naïve patients. In contrast, with albumin-enhanced dialysis, we observed a drug half-life of 18 h. She was extubated on day two and was transferred to inpatient psychiatry by day 3 without significant neurologic sequelae. In vitro studies have been done with bovine blood demonstrating significant carbamazepine removal using CVVHD with albumin-enhanced dialysate. There has been very limited experience using albumin-enhanced CVVHD in an adult patient with carbamazepine toxicity.",
"affiliations": "Clinical and Interventional Nephrology, San Antonio Kidney Disease Center, San Antonio, TX, USA, armynephrologist@yahoo.com.",
"authors": "Narayan|Rajeev|R|;Rizzo|Meagan|M|;Cole|Michael|M|",
"chemical_list": "D000418:Albumins; D018692:Antimanic Agents; D015312:Hemodialysis Solutions; D002220:Carbamazepine",
"country": "Japan",
"delete": false,
"doi": "10.1007/s10047-014-0754-4",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1434-7229",
"issue": "17(2)",
"journal": "Journal of artificial organs : the official journal of the Japanese Society for Artificial Organs",
"keywords": null,
"medline_ta": "J Artif Organs",
"mesh_terms": "D000328:Adult; D000418:Albumins; D018692:Antimanic Agents; D002220:Carbamazepine; D062787:Drug Overdose; D005260:Female; D015312:Hemodialysis Solutions; D006801:Humans; D006435:Renal Dialysis",
"nlm_unique_id": "9815648",
"other_id": null,
"pages": "206-9",
"pmc": null,
"pmid": "24449266",
"pubdate": "2014-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "14754959;16225101;10866333;8364265;11993842;12217004;3750374;17295658;11393268;17666577;18723569;6485876",
"title": "Successful treatment of severe carbamazepine toxicity with 5% albumin-enhanced continuous venovenous hemodialysis.",
"title_normalized": "successful treatment of severe carbamazepine toxicity with 5 albumin enhanced continuous venovenous hemodialysis"
} | [
{
"companynumb": "PHHY2014US083436",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CARBAMAZEPINE"
},
"drugadditional": null,
"d... |
{
"abstract": "Platinum-based combinations are efficacious in the treatment of advanced non-small cell lung cancer (NSCLC) but their toxicity makes them unsuitable for elderly and for patients with co-morbidities. We assessed the efficacy and toxicity of low-dose of paclitaxel in patients who were elderly or who had contraindications against cisplatin therapy. Seventy-one patients (median age 68; range 42-82 years) with unresectable NSCLC were treated with weekly paclitaxel (80 mg/m2) infusion (1 h) for several cycles without intervening rest periods. Thirty-seven patients had PS 1 and 34 had PS 2 status. A total of 614 courses were administered (median 9, range 2-20). There were no episodes of grade 4 toxicities and only 1 patient had grade 3 thrombopenia. Grade 3 anemia or neutropenia were not observed and severe non-hematological toxicity was uncommon: grade 1-2 fatigue in 52%; grade 1-2 motor neuropathy in 42% and grade 3 in 5.5%; grade 1-2 sensory neuropathy in 46.3% of patients. Twenty-seven of the 67 evaluable patients (40.3%) had an objective response, whereas 26 patients (38.8%) had stable disease. The median overall survival for the entire group was 8.4 months (95% CI = 5.6 to 11.2) and the 1-year and 2-year survival was 37.4% and 12.1%, respectively. The median time-to-progression was 5.4 months (95% CI = 3.3 to 7.4). Our data show that low-dose weekly paclitaxel is active and well tolerated in this group of patients with NSCLC and poor prognosis and, as such, is useful for patients in whom platinum-based combinations are not suitable.",
"affiliations": "Department of Medical Oncology, Hospital Arnau de Vilanova, 46015 Valencia, Spain. juan_osc@gva.es",
"authors": "Juan|O|O|;Albert|A|A|;Villarroya|T|T|;Sánchez|R|R|;Casan|R|R|;Caranana|V|V|;Campos|J M|JM|;Alberola|V|V|",
"chemical_list": "D000972:Antineoplastic Agents, Phytogenic; D017239:Paclitaxel; D002945:Cisplatin",
"country": "Slovakia",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0028-2685",
"issue": "50(3)",
"journal": "Neoplasma",
"keywords": null,
"medline_ta": "Neoplasma",
"mesh_terms": "D000230:Adenocarcinoma; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000972:Antineoplastic Agents, Phytogenic; D018287:Carcinoma, Large Cell; D002289:Carcinoma, Non-Small-Cell Lung; D002294:Carcinoma, Squamous Cell; D002945:Cisplatin; D005260:Female; D006801:Humans; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D017239:Paclitaxel; D011379:Prognosis; D016879:Salvage Therapy; D015996:Survival Rate; D013997:Time Factors",
"nlm_unique_id": "0377266",
"other_id": null,
"pages": "204-9",
"pmc": null,
"pmid": "12937854",
"pubdate": "2003",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Weekly paclitaxel for advanced non-small cell lung cancer patients not suitable for platinum-based therapy.",
"title_normalized": "weekly paclitaxel for advanced non small cell lung cancer patients not suitable for platinum based therapy"
} | [
{
"companynumb": "ES-PFIZER INC-2020229035",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "DEXCHLORPHENIRAMINE"
},
"drugadditional": nul... |
{
"abstract": "A 56-year-old man was admitted to our hospital with leukocytosis, anemia, and thrombocytopenia. Acute monoblastic leukemia was diagnosed. Two subsequent courses of consolidation chemotherapy consisted of conventional doses of cytarabine and intermediate-dose cytarabine. Intermediate-dose cytarabine was infused intravenously every 12 hr for 6 days. On day 15 after the final infusion of cytarabine, the patient suffered headache, and on day 21, he experienced a decrease in sensation on the sole of his left foot. Magnetic resonance imaging (MRI) of the brain revealed widespread areas of white matter edema. Cerebrospinal fluid (CSF) examination revealed an increase in the number of cells to 31 mm(-3); the majority were lymphocytes. No infiltration of leukemia cells was seen. After 2 months, brain MRI findings were normal. The clinicoradiologic features of the case were consistent with reversible posterior leukoencephalopathy syndrome (RPLS). RPLS in the present case was unlikely to have been caused by direct neurotoxicity because (1) the doses of cytarabine (500 mg/m(2); total dose 9.2 g) were much smaller than those in reported cases and were repeatedly infused until RPLS developed; (2) the RPLS developed 21 days after the final infusion of cytarabine, a much longer period than previously reported; (3) the slight leukocytosis in the CSF observed on day 33 might also have been related to the cellular immune responses evoked by the infused cytarabine. These details suggest not only that direct cerebral neurotoxicity of cytarabine but also that some type of allergic response may have been involved in the development of RPLS.",
"affiliations": "Department of Hematology, Showa University School of Medicine, Tokyo, Japan. b-saito@med.showa-u.ac.jp",
"authors": "Saito|Bungo|B|;Nakamaki|Tsuyoshi|T|;Nakashima|Hidetoshi|H|;Usui|Takako|T|;Hattori|Norimichi|N|;Kawakami|Keiichiro|K|;Tomoyasu|Shigeru|S|",
"chemical_list": "D000964:Antimetabolites, Antineoplastic; D003561:Cytarabine",
"country": "United States",
"delete": false,
"doi": "10.1002/ajh.20772",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0361-8609",
"issue": "82(4)",
"journal": "American journal of hematology",
"keywords": null,
"medline_ta": "Am J Hematol",
"mesh_terms": "D000964:Antimetabolites, Antineoplastic; D001927:Brain Diseases; D003561:Cytarabine; D004342:Drug Hypersensitivity; D006801:Humans; D007948:Leukemia, Monocytic, Acute; D008297:Male; D008875:Middle Aged; D020258:Neurotoxicity Syndromes; D013577:Syndrome",
"nlm_unique_id": "7610369",
"other_id": null,
"pages": "304-6",
"pmc": null,
"pmid": "16947320",
"pubdate": "2007-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Reversible posterior leukoencephalopathy syndrome after repeat intermediate-dose cytarabine chemotherapy in a patient with acute myeloid leukemia.",
"title_normalized": "reversible posterior leukoencephalopathy syndrome after repeat intermediate dose cytarabine chemotherapy in a patient with acute myeloid leukemia"
} | [
{
"companynumb": "JP-FRESENIUS KABI-FK201703388",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "MITOXANTRONE HYDROCHLORIDE"
},
"drugaddi... |
{
"abstract": "BACKGROUND\nExtraintestinal manifestations of nontyphoidal salmonellosis are usually seen in patients with cellular immunodeficiency. Pleural empyema caused by nontyphoidal Salmonella is very rare clinical presentation of salmonellosis and there are just a few cases described in a literature. We presented a very rare case of pleural empyema caused by Salmonella enteritidis in a patient with non-Hodgkin limphoma.\n\n\nMETHODS\nA 60-year-old male with low grade B-cell lymphoma, mucosa associated lymphoid tissue (MALT) type in IV clinical degree, manifested with infiltration of stomach, bronchus, pleura and peritoneum was admitted to the hospital. Initially the patient was presented with non-specific symptoms and signs, suggesting poor general condition. During the hospitalization his pleural fluid became purulent and changes in blood counts were registered with the increase of leukocytes, especially neutrophils. A large number of leukocytes was found by microscopic evaluation of pleural fluid and Salmonella enteritidis was isolated by its culture. There were no pathogenic bacteria in stool culture and hemoculture remained sterile. Toxins A and B of Clostridium difficile were not detected in stool. The patient was treated by ciprofloxacin and cefrtiaxone for 14 days with drainage of the purulent content, what was followed by the resolution and organization of the pleural fluid. After the stabilization of his general condition, chemotherapy with cyclophosphamide, vincristine, prednisone (COP) was introduced, with complete response.\n\n\nCONCLUSIONS\nAlthough rare, pleural empyema caused by nontyphoidal Salmonella should be considered in patients with severe immunosuppression, because appropriate antimicrobial therapy with surgical measures are very important for the outcome in these patients.",
"affiliations": null,
"authors": "Kojić|Miroslav|M|;Nozić|Darko|D|;Tarabar|Olivera|O|;Perisić|Nenad|N|",
"chemical_list": null,
"country": "Serbia",
"delete": false,
"doi": "10.2298/vsp141031004k",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0042-8450",
"issue": "73(3)",
"journal": "Vojnosanitetski pregled",
"keywords": null,
"medline_ta": "Vojnosanit Pregl",
"mesh_terms": "D001984:Bronchial Neoplasms; D016724:Empyema, Pleural; D006801:Humans; D016867:Immunocompromised Host; D018442:Lymphoma, B-Cell, Marginal Zone; D008297:Male; D008875:Middle Aged; D009378:Neoplasms, Multiple Primary; D010534:Peritoneal Neoplasms; D010997:Pleural Neoplasms; D012480:Salmonella Infections; D012477:Salmonella enteritidis; D013274:Stomach Neoplasms; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "21530700R",
"other_id": null,
"pages": "280-3",
"pmc": null,
"pmid": "27295915",
"pubdate": "2016-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Pleural empyema caused by Salmonella enteritidis in a patient with non-Hodgkin lymphoma.",
"title_normalized": "pleural empyema caused by salmonella enteritidis in a patient with non hodgkin lymphoma"
} | [
{
"companynumb": "RS-WATSON-2016-16842",
"fulfillexpeditecriteria": "1",
"occurcountry": "RS",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nBiliary tract cancer (BTC) is a rare and lethal disease with few therapeutic options. Preclinical data suggest that the epidermal growth factor receptor (EGFR) pathway could be involved in its progression.\n\n\nMETHODS\nThis open-label, randomized phase 2 trial recruited chemotherapy-naive patients with advanced BTC displaying a wild-type (WT) KRAS status. Patients were randomized to gemcitabine (1000 mg/m(2) ) and oxaliplatin (100 mg/m(2) ) with (arm A) or without (arm B) panitumumab (6 mg/kg) for up to 12 cycles. The primary endpoint was progression-free survival (PFS) analyzed in an intention-to-treat fashion.\n\n\nRESULTS\nEighty-nine patients (45 in arm A and 44 in arm B) were enrolled between June 2010 and September 2013. After a median follow-up of 10.1 months, the median PFS was 5.3 months (95% confidence interval, 3.3-7.2 months) in arm A and 4.4 months (95% confidence interval, 2.6-6.2 months) in arm B (P = .27). No survival differences were observed: the median overall survival was 9.9 months in arm A and 10.2 months in arm B (P = .42). In a subgroup analysis, no differences in PFS according to the site of the primary tumor were observed; patients with intrahepatic cholangiocarcinoma treated with panitumumab may have had a survival benefit in comparison with the control group (15.1 vs 11.8 months, P = .13). As for safety, skin toxicity was the main adverse event in arm A (80% of the patients). A higher incidence of diarrhea (55.5% vs 31.8%), mucositis (22.2% vs 13.6%), and constipation (24.4% vs 15.9%) was seen in arm A.\n\n\nCONCLUSIONS\nThese results confirm the marginal role of anti-EGFR therapy even for WT KRAS-selected BTC.",
"affiliations": "Department of Oncology, University of Turin Medical School/Piedmont Foundation for Oncology, Candiolo Cancer Institute - FPO, IRCCS, Candiolo, Italy.;Department of Oncology, University of Turin Medical School/Piedmont Foundation for Oncology, Candiolo Cancer Institute - FPO, IRCCS, Candiolo, Italy.;Department of Medical Oncology, San Raffaele Scientific Institute, IRCCS, Milan, Italy.;Department of Oncology, University of Turin Medical School/Piedmont Foundation for Oncology, Candiolo Cancer Institute - FPO, IRCCS, Candiolo, Italy.;Department of Medical Oncology, San Raffaele Scientific Institute, IRCCS, Milan, Italy.;Department of Oncology, Medical Oncology 1 Division, Città Della Salute e Della Scienza Hospital and University, Turin, Italy.;Department of Colorectal Oncology, National Cancer Institute G. Pascale Foundation, Naples, Italy.;Department of Colorectal Oncology, National Cancer Institute G. Pascale Foundation, Naples, Italy.;Niguarda Cancer Center, Niguarda Ca' Granda Hospita, Milan, Italy.;Department of Oncology, University and General Hospital, Udine, Italy.;Department of Oncology, University of Turin Medical School/Piedmont Foundation for Oncology, Candiolo Cancer Institute - FPO, IRCCS, Candiolo, Italy.;Department of Oncology, University and General Hospital, Udine, Italy.;Niguarda Cancer Center, Niguarda Ca' Granda Hospita, Milan, Italy.;Department of Oncology, Medical Oncology 1 Division, Città Della Salute e Della Scienza Hospital and University, Turin, Italy.;Department of Medical Oncology, San Raffaele Scientific Institute, IRCCS, Milan, Italy.;Department of Oncology, University of Turin Medical School/Piedmont Foundation for Oncology, Candiolo Cancer Institute - FPO, IRCCS, Candiolo, Italy.",
"authors": "Leone|Francesco|F|;Marino|Donatella|D|;Cereda|Stefano|S|;Filippi|Roberto|R|;Belli|Carmen|C|;Spadi|Rosella|R|;Nasti|Guglielmo|G|;Montano|Massimo|M|;Amatu|Alessio|A|;Aprile|Giuseppe|G|;Cagnazzo|Celeste|C|;Fasola|Gianpiero|G|;Siena|Salvatore|S|;Ciuffreda|Libero|L|;Reni|Michele|M|;Aglietta|Massimo|M|",
"chemical_list": "D000911:Antibodies, Monoclonal; C117307:KRAS protein, human; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D003841:Deoxycytidine; D000077544:Panitumumab; C056507:gemcitabine; C512478:EGFR protein, human; D066246:ErbB Receptors; D016283:Proto-Oncogene Proteins p21(ras)",
"country": "United States",
"delete": false,
"doi": "10.1002/cncr.29778",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0008-543X",
"issue": "122(4)",
"journal": "Cancer",
"keywords": "KRAS; biliary cancer; chemotherapy; cholangiocarcinoma; gemcitabine and oxaliplatin (GEMOX); panitumumab",
"medline_ta": "Cancer",
"mesh_terms": "D000230:Adenocarcinoma; D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal; D000971:Antineoplastic Combined Chemotherapy Protocols; D001650:Bile Duct Neoplasms; D017734:Bile Ducts, Extrahepatic; D001653:Bile Ducts, Intrahepatic; D001661:Biliary Tract Neoplasms; D018281:Cholangiocarcinoma; D003841:Deoxycytidine; D018572:Disease-Free Survival; D066246:ErbB Receptors; D005260:Female; D005706:Gallbladder Neoplasms; D006801:Humans; D008297:Male; D008875:Middle Aged; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D000077544:Panitumumab; D011379:Prognosis; D016283:Proto-Oncogene Proteins p21(ras); D016896:Treatment Outcome",
"nlm_unique_id": "0374236",
"other_id": null,
"pages": "574-81",
"pmc": null,
"pmid": "26540314",
"pubdate": "2016-02-15",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial",
"references": null,
"title": "Panitumumab in combination with gemcitabine and oxaliplatin does not prolong survival in wild-type KRAS advanced biliary tract cancer: A randomized phase 2 trial (Vecti-BIL study).",
"title_normalized": "panitumumab in combination with gemcitabine and oxaliplatin does not prolong survival in wild type kras advanced biliary tract cancer a randomized phase 2 trial vecti bil study"
} | [
{
"companynumb": "IT-CIPLA LTD.-2016IT01760",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "OXALIPLATIN"
},
"drugadditional": null,
... |
{
"abstract": "Objectives: This study aims to evaluate and compare the use of subcutaneous anti-TNF for RA in a Brazilian real-life setting. Methods: A prospective cohort of biological disease-modifying antirheumatic drug (bDMARD)-naïve patients treated with adalimumab, etanercept, golimumab, and certolizumab was developed. Medication persistence, disease activity by the Clinical Disease Activity Index (CDAI), functionality by the Health Assessment Questionnaire (HAQ), quality of life by the European Quality of Life 5 Dimensions (EQ-5D), and safety were evaluated at 6 and 12 months. Results: In a total of 327 individuals, 211 (64.5%) were persistent at 12 months. Patients improved after the use of anti-TNF, with a reduction in the mean of CDAI and HAQ, in addition to an increase in the mean of EQ-5D (p < 0.05). The number of patients who achieved the clinical response was 114 (34.86%) by CDAI, 212 (64.83%) by HAQ, and 215 (65.75%) by EQ-5D at 12 months. There were no statistically significant differences among the drugs (p > 0.05). The anti-TNF was well tolerated. Conclusion: Anti-TNF reduced disease activity, in addition to improving patients' functionality and quality of life. Additional pharmacotherapeutic monitoring can be essential to achieve better results.",
"affiliations": "Health Assessment, Technology, and Economy Group, Center for Exact, Natural and Health Sciences, Federal University of Espírito Santo , Alegre, Brazil.;Health Assessment, Technology, and Economy Group, Center for Exact, Natural and Health Sciences, Federal University of Espírito Santo , Alegre, Brazil.;Medicine School, Federal University of Minas Gerais , Belo Horizonte, Brazil.;Department of Social Pharmacy, College of Pharmacy, Federal University of Minas Gerais , President Antônio Carlos Avenue, 6627, Campus Pampulha, Belo Horizonte, Brazil.;Department of Social Pharmacy, College of Pharmacy, Federal University of Minas Gerais , President Antônio Carlos Avenue, 6627, Campus Pampulha, Belo Horizonte, Brazil.;Health Technology Assessment Unit, Hospital Alemão Oswaldo Cruz , São Paulo, Brazil.;Department of Social Pharmacy, College of Pharmacy, Federal University of Minas Gerais , President Antônio Carlos Avenue, 6627, Campus Pampulha, Belo Horizonte, Brazil.;Department of Social Pharmacy, College of Pharmacy, Federal University of Minas Gerais , President Antônio Carlos Avenue, 6627, Campus Pampulha, Belo Horizonte, Brazil.",
"authors": "Dos Santos|Jéssica Barreto Ribeiro|JBR|;da Silva|Michael Ruberson Ribeiro|MRR|0000-0003-2550-7249;Kakehasi|Adriana Maria|AM|;Acurcio|Franciscode Assis|FA|0000-0002-5880-5261;Almeida|Alessandra Maciel|AM|;Alves de Oliveira Junior|Haliton|H|0000-0002-0289-4947;Pimenta|Pedro Ricardo Kömel|PRK|;Alvares-Teodoro|Juliana|J|",
"chemical_list": "D000911:Antibodies, Monoclonal; D018501:Antirheumatic Agents; D000079424:Tumor Necrosis Factor Inhibitors; C529000:golimumab; D000068879:Adalimumab; D000068800:Etanercept; D000068582:Certolizumab Pegol",
"country": "England",
"delete": false,
"doi": "10.1080/1744666X.2021.1850271",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1744-666X",
"issue": "16(12)",
"journal": "Expert review of clinical immunology",
"keywords": "Adalimumab; certolizumab; etanercept; golimumab; observational study; rheumatoid arthritis",
"medline_ta": "Expert Rev Clin Immunol",
"mesh_terms": "D000068879:Adalimumab; D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal; D018501:Antirheumatic Agents; D001172:Arthritis, Rheumatoid; D000068582:Certolizumab Pegol; D000068800:Etanercept; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D011788:Quality of Life; D016896:Treatment Outcome; D000079424:Tumor Necrosis Factor Inhibitors",
"nlm_unique_id": "101271248",
"other_id": null,
"pages": "1217-1225",
"pmc": null,
"pmid": "33203248",
"pubdate": "2020-12",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "FIRST LINE OF SUBCUTANEOUS ANTI-TNF THERAPY FOR RHEUMATOID ARTHRITIS: A PROSPECTIVE COHORT STUDY.",
"title_normalized": "first line of subcutaneous anti tnf therapy for rheumatoid arthritis a prospective cohort study"
} | [
{
"companynumb": "BR-JNJFOC-20201151196",
"fulfillexpeditecriteria": "1",
"occurcountry": "BR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ETANERCEPT"
},
"drugadditional": "3",
"... |
{
"abstract": "Pancreatic adenocarcinoma has an extremely poor prognosis. With the best available treatments, the median overall survival duration is still less than 1 year. Most patients develop anorexia and major muscle mass loss that interfere with chemotherapy tolerance and survival. In this paper, we present a case in which these problems were a major concern. A multidisciplinary approach with chemotherapy and close nutritional support permitted better control of the disease and longer survival. We also review the literature on nutritional interventions that show an improvement in quality of life and survival in these patients.",
"affiliations": "Instituto Superior de Ciências da Saúde Egas Moniz, Nutrition Consultation, Campus Universitário Quinta da Granja, Monte de Caparica, Portugal.;Instituto Superior de Ciências da Saúde Egas Moniz, Nutrition Consultation, Campus Universitário Quinta da Granja, Monte de Caparica, Portugal.;Champalimaud Foundation, Champalimaud Clinic Centre - Digestive Cancer Unit. Avenida Brasília, Lisboa, Portugal.;Instituto Superior de Ciências da Saúde Egas Moniz, Nutrition Consultation, Campus Universitário Quinta da Granja, Monte de Caparica, Portugal.",
"authors": "Ramalho|R|R|;Ramalho|P|P|;Couto|N|N|;Pereira|P|P|",
"chemical_list": "D015295:Antigens, Tumor-Associated, Carbohydrate; D024682:BRCA2 Protein; C551750:BRCA2 protein, human; D001786:Blood Glucose; D002272:Carcinoembryonic Antigen; D015525:Fatty Acids, Omega-3; D012709:Serum Albumin; D002097:C-Reactive Protein; D003404:Creatinine; D005723:gamma-Glutamyltransferase; D000410:Alanine Transaminase",
"country": "England",
"delete": false,
"doi": "10.1038/ejcn.2017.47",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0954-3007",
"issue": "71(6)",
"journal": "European journal of clinical nutrition",
"keywords": null,
"medline_ta": "Eur J Clin Nutr",
"mesh_terms": "D000368:Aged; D000410:Alanine Transaminase; D000886:Anthropometry; D015295:Antigens, Tumor-Associated, Carbohydrate; D024682:BRCA2 Protein; D001786:Blood Glucose; D015992:Body Mass Index; D002097:C-Reactive Protein; D002272:Carcinoembryonic Antigen; D003404:Creatinine; D015525:Fatty Acids, Omega-3; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D018482:Muscle, Skeletal; D018529:Nutritional Support; D010190:Pancreatic Neoplasms; D011379:Prognosis; D011788:Quality of Life; D012709:Serum Albumin; D005723:gamma-Glutamyltransferase",
"nlm_unique_id": "8804070",
"other_id": null,
"pages": "795-797",
"pmc": null,
"pmid": "28378854",
"pubdate": "2017-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "27163178;24746976;26437072;26181186;25425246;25907586;23299701;21864184;26505257;27637832",
"title": "Omega-3 therapeutic supplementation in a patient with metastatic adenocarcinoma of the pancreas with muscle mass depletion.",
"title_normalized": "omega 3 therapeutic supplementation in a patient with metastatic adenocarcinoma of the pancreas with muscle mass depletion"
} | [
{
"companynumb": "PT-ACCORD-053532",
"fulfillexpeditecriteria": "1",
"occurcountry": "PT",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CAPECITABINE"
},
"drugadditional": "1",
"dru... |
{
"abstract": "Proton pump inhibitors (PPIs) are not widely recognized as a cause of drug-induced thrombocytopenia. Literature is mainly confined to case reports and has been insufficient to explore the possibility that this adverse event may be attributed to a class effect of PPI therapy. We present a case where platelet counts dropped from 177 (×10(3) per mm(3)) to 47 (×10(3) per mm(3)) within 6 days after the patient was switched from omeprazole to pantoprazole. There have been case reports of thrombocytopenia caused by PPIs; however, this is noted to be extremely rare. In our case, the patient developed thrombocytopenia on two separate occasions of exposure to pantoprazole, which resolved after stopping the medicine, thus providing definite proof of pantoprazole causing thrombocytopenia. Moreover, the patient did not have thrombocytopenia with omeprazole, thus suggesting that thrombocytopenia with PPIs might be an individual drug effect rather than a class effect. This occurrence has been reported in three other case reports as well. From the nine case reports that we have reviewed, direct causal relationship was found in a few reports only. It has been hypothesized that this adverse effect may be immune mediated, but further investigations are still needed to identify the exact pathogenesis.",
"affiliations": "Department of Internal Medicine, Creighton University Medical Center , Omaha, NE , USA and.",
"authors": "Kallam|Avyakta|A|;Singla|Abhishek|A|;Silberstein|Peter|P|",
"chemical_list": "D054328:Proton Pump Inhibitors",
"country": "England",
"delete": false,
"doi": "10.3109/09537104.2014.953045",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0953-7104",
"issue": "26(6)",
"journal": "Platelets",
"keywords": "Pantoprazole; proton pump inhibitors; proton pump inhibitors causing thrombocytopenia; thrombocytopenia",
"medline_ta": "Platelets",
"mesh_terms": "D006801:Humans; D008297:Male; D008875:Middle Aged; D010976:Platelet Count; D054328:Proton Pump Inhibitors; D013921:Thrombocytopenia",
"nlm_unique_id": "9208117",
"other_id": null,
"pages": "598-601",
"pmc": null,
"pmid": "25207666",
"pubdate": "2015",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Proton pump induced thrombocytopenia: A case report and review of literature.",
"title_normalized": "proton pump induced thrombocytopenia a case report and review of literature"
} | [
{
"companynumb": "US-APOTEX-2015AP012396",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LISINOPRIL"
},
"drugadditional": null,
... |
{
"abstract": "Mobile or migratory intradural extramedullary schwannoma have been reported many times in the lumbar levels, however only twice in cervical spine and six times in thoracic spine. Double migration was reported only once. The exact cause of the migration of a schwannoma arising from the nerve sheath of a spinal nerve root is unclear and especially mysterious in cervical and thoracic spine. We report a 49 year old male who presented with multiple sclerosis confirmed on brain MRI and CSF showing oligoclonal bands, with concomitant spinal myelopathy from a thoracic intradural extramedullary lesion. Serial MRIs showed rostral migration of lesion initially from T10 level to T6 and then caudally to T9 level on day of surgery. Intra operatively it was mobile with respirations and disconnected from any neural or vascular attachments. Histopathology confirmed a benign schwannoma with areas of necrosis. This is the rare occurrence of double migration of thoracic intradural schwannoma with possibility of tumor disconnection due to high dose steroid therapy for multiple sclerosis.",
"affiliations": "Department of Neurosurgery, Liverpool Hospital, Sydney, NSW, Australia. Electronic address: krishna.tallapragada@gmail.com.;Department of Neurosurgery, Liverpool Hospital, Sydney, NSW, Australia.;Department of Neurosurgery, Liverpool Hospital, Sydney, NSW, Australia.;Department of Neurosurgery, Liverpool Hospital, Sydney, NSW, Australia; University of NSW, Sydney, NSW, Australia.",
"authors": "Tallapragada|Krishna|K|;Nguyen|Lana|L|;Liyanage|Indika|I|;Sheridan|Mark|M|",
"chemical_list": null,
"country": "Scotland",
"delete": false,
"doi": "10.1016/j.jocn.2019.08.041",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0967-5868",
"issue": "69()",
"journal": "Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia",
"keywords": null,
"medline_ta": "J Clin Neurosci",
"mesh_terms": "D006801:Humans; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis; D009442:Neurilemmoma; D013120:Spinal Cord Neoplasms; D013904:Thoracic Vertebrae",
"nlm_unique_id": "9433352",
"other_id": null,
"pages": "272-276",
"pmc": null,
"pmid": "31439491",
"pubdate": "2019-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Rare case of double migration of thoracic intradural schwannoma.",
"title_normalized": "rare case of double migration of thoracic intradural schwannoma"
} | [
{
"companynumb": "NVSC2019AU039977",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE"
},
"drugadditional": "3",
... |
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