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"abstract": "Concern remains among many that electroconvulsive therapy (ECT) causes \"brain damage.\" This ambiguous term presumably refers to lesions that could, in principle, be observed either grossly or microscopically in postmortem studies, and the assertion that it occurs appears to be based largely on old reports with dubious relevance to modern practice. Fortunately, using modern technique, ECT is so safe that mortality around the time of treatment is extraordinarily rare and as a result there has been little opportunity for postmortem examination of individuals who had recently had ECT. We report a case in which postmortem brain examination was performed roughly a month after the patient's last treatment.",
"affiliations": "From the *Departments of Psychiatry and Behavioral Neurosciences, and †Pathology, University of Chicago Pritzker School of Medicine and ‡Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL.",
"authors": "Anderson|Danielle|D|;Wollmann|Robert|R|;Dinwiddie|Stephen H|SH|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/YCT.0000000000000062",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1095-0680",
"issue": "30(3)",
"journal": "The journal of ECT",
"keywords": null,
"medline_ta": "J ECT",
"mesh_terms": "D000369:Aged, 80 and over; D002389:Catatonia; D004565:Electroconvulsive Therapy; D017809:Fatal Outcome; D006801:Humans; D008297:Male; D009460:Neurologic Examination",
"nlm_unique_id": "9808943",
"other_id": null,
"pages": "248-50",
"pmc": null,
"pmid": "24755716",
"pubdate": "2014-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Neuropathological evaluation of an 84-year-old man after 422 ECT treatments.",
"title_normalized": "neuropathological evaluation of an 84 year old man after 422 ect treatments"
} | [
{
"companynumb": "US-DRREDDYS-USA/USA/15/0049296",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "OLANZAPINE"
},
"drugadditional": null,
... |
{
"abstract": "Remdesivir is a direct-acting nucleoside RNA polymerase inhibitor with activity against the novel severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) virus used in the treatment of coronavirus disease 2019 (COVID-19) pneumonia. Here, we present two cases of suspected remdesivir-associated acute liver failure (ALF) in which the liver failure improved after continuous infusion acetylcysteine and withdrawal of remdesivir. Both patients had significant increases in transaminases between day 3 and day 10 of remdesivir therapy accompanied by coagulopathy and encephalopathy. After initiation of continuous infusion acetylcysteine, the transaminases of both patients rapidly improved. Ultimately, one patient fully recovered while the other died of suspected septic shock. Due to its novel nature and only recent widespread use, there are very little data on the risk of ALF from remdesivir. Additionally, the data for the use of acetylcysteine to manage non-acetaminophen-induced ALF are limited. It is important to consider the risk of remdesivir-associated ALF when weighing the risk versus benefits of use, and acetylcysteine may have a role in its management.",
"affiliations": "Department of Pharmacy, Orlando Regional Medical Center, Orlando, Florida, USA.;Department of Pharmacy, Orlando Regional Medical Center, Orlando, Florida, USA.;Department of Critical Care Medicine, Orlando Regional Medical Center, Orlando, Florida, USA.",
"authors": "Carothers|Chancey|C|0000-0002-1482-9640;Birrer|Kara|K|;Vo|Mai|M|",
"chemical_list": "D000998:Antiviral Agents; C000606551:remdesivir; D000249:Adenosine Monophosphate; D000409:Alanine; D000111:Acetylcysteine",
"country": "United States",
"delete": false,
"doi": "10.1002/phar.2464",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0277-0008",
"issue": "40(11)",
"journal": "Pharmacotherapy",
"keywords": "COVID-19; Remdesivir; SARS-CoV-2; acetylcysteine; acute liver failure; adverse drug reactions; coronavirus; toxicology",
"medline_ta": "Pharmacotherapy",
"mesh_terms": "D000111:Acetylcysteine; D000249:Adenosine Monophosphate; D000368:Aged; D000369:Aged, 80 and over; D000409:Alanine; D000998:Antiviral Agents; D000086382:COVID-19; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D017114:Liver Failure, Acute; D008111:Liver Function Tests; D000086402:SARS-CoV-2; D016896:Treatment Outcome",
"nlm_unique_id": "8111305",
"other_id": null,
"pages": "1166-1171",
"pmc": null,
"pmid": "33006138",
"pubdate": "2020-11",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Acetylcysteine for the Treatment of Suspected Remdesivir-Associated Acute Liver Failure in COVID-19: A Case Series.",
"title_normalized": "acetylcysteine for the treatment of suspected remdesivir associated acute liver failure in covid 19 a case series"
} | [
{
"companynumb": "US-HIKMA PHARMACEUTICALS USA INC.-US-H14001-21-01171",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "AMIODARONE"
},
"dr... |
{
"abstract": "Graves' disease is the most prevalent cause of hyperthyroidism in children. The treatment commonly involves antithyroid therapy using a thionamide. We present a case of a 13-year-old girl with the antithyroid arthritis syndrome, presenting as a migratory polyarthritis, after the initiation of thionamide treatment for Graves' disease. Antithyroid arthritis syndrome warranted immediate cessation of thionamide. Improvement of the arthritis was seen in subsequent days. As there are no other reversible treatment modalities for Graves' disease in children, definitive treatment with radioactive iodine was needed to control the hyperthyroidism in this child. Antithyroid arthritis syndrome presenting as a migratory polyarthritis is a severe adverse effect of a common pediatric disease and should therefore be recognized by pediatricians.",
"affiliations": null,
"authors": "Janson|Jo-Anne|JA|;de Laat|Paul|P|;Draaisma|Jos M T|JM|",
"chemical_list": "D013956:Antithyroid Agents; D008713:Methimazole",
"country": "Germany",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0334-018X",
"issue": "28(9-10)",
"journal": "Journal of pediatric endocrinology & metabolism : JPEM",
"keywords": null,
"medline_ta": "J Pediatr Endocrinol Metab",
"mesh_terms": "D000293:Adolescent; D013956:Antithyroid Agents; D001168:Arthritis; D005260:Female; D006111:Graves Disease; D006801:Humans; D008713:Methimazole",
"nlm_unique_id": "9508900",
"other_id": null,
"pages": "1169-71",
"pmc": null,
"pmid": "25968432",
"pubdate": "2015-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Migratory polyarthritis as an adverse effect of thiamazole use in a 13-year-old girl with Graves' disease.",
"title_normalized": "migratory polyarthritis as an adverse effect of thiamazole use in a 13 year old girl with graves disease"
} | [
{
"companynumb": "NL-SUN PHARMACEUTICAL INDUSTRIES LTD-2015R1-103848",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "METHIMAZOLE"
},
"dru... |
{
"abstract": "In this report, transmission of malaria via a liver, a kidney, and possibly a heart allograft from a single donor is described. The donor had immigrated from Cameroon to Germany 18 months before, but had no clinical signs of active malaria infection. The liver transplant recipient and one of the two kidney transplant patients developed febrile illness with the appearance of Plasmodium vivax in blood smears 5 and 6 wk after transplantation, respectively. In the heart transplant recipient, a subclinical malaria infection was suspected based on a rise of malaria antibodies late after transplantation, whereas the recipient of the second kidney allograft had no clinical or laboratory evidence of malaria. Both liver and kidney recipients with active malaria responded to medical treatment. However, the liver transplant patient developed progressive cholestasis and died 5 months after transplantation from liver failure possibly due to side effects of the malaria medication. Other cases of malaria in solid organ recipients are briefly reviewed.",
"affiliations": "Department of Hepatobiliary Surgery, University Hospital Eppendorf, Hamburg, Germany. lfisher@uke.uni-hamburg.de",
"authors": "Fischer|L|L|;Sterneck|M|M|;Claus|M|M|;Costard-Jäckle|A|A|;Fleischer|B|B|;Herbst|H|H|;Rogiers|X|X|;Broelsch|C E|CE|",
"chemical_list": null,
"country": "Denmark",
"delete": false,
"doi": "10.1034/j.1399-0012.1999.130609.x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0902-0063",
"issue": "13(6)",
"journal": "Clinical transplantation",
"keywords": null,
"medline_ta": "Clin Transplant",
"mesh_terms": "D000328:Adult; D005260:Female; D016027:Heart Transplantation; D006801:Humans; D016030:Kidney Transplantation; D016031:Liver Transplantation; D008288:Malaria; D008297:Male; D008875:Middle Aged",
"nlm_unique_id": "8710240",
"other_id": null,
"pages": "491-5",
"pmc": null,
"pmid": "10617239",
"pubdate": "1999-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Transmission of malaria tertiana by multi-organ donation.",
"title_normalized": "transmission of malaria tertiana by multi organ donation"
} | [
{
"companynumb": "DE-SA-2017SA246897",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nDrug-induced autoimmune hepatitis is an acute and potentially severe side effect, particularly often reported after the long-term use of minocycline. The condition's characteristic biochemical findings are highly elevated transaminase levels, only mildly increased markers of cholestasis and bilirubin levels, an elevated IgG concentration and a high antinuclear antibody (ANA) titre.\n\n\nMETHODS\nA 14-year-old girl developed autoimmune hepatitis due to the long-term use of minocycline for acne vulgaris. She presented with icterus and very high transaminase levels. The patient made a full recovery after the medication was discontinued.\n\n\nCONCLUSIONS\nThis type of autoimmune hepatitis can be differentiated from 'classic' autoimmune hepatitis by the patient's quick recovery after stopping the inducing drug and no relapse of the condition after the discontinuation of glucocorticoid therapy.",
"affiliations": "Ziekenhuis Gelderse Vallei, afd. Kindergeneeskunde, Ede, the Netherlands. aldenhovenm@zgv.nl",
"authors": "Aldenhoven|Mieke|M|;van Enk|J Gert|JG|;Avis|Wim A|WA|",
"chemical_list": "D000900:Anti-Bacterial Agents; D000974:Antibodies, Antinuclear; D007074:Immunoglobulin G; D008911:Minocycline",
"country": "Netherlands",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0028-2162",
"issue": "157(3)",
"journal": "Nederlands tijdschrift voor geneeskunde",
"keywords": null,
"medline_ta": "Ned Tijdschr Geneeskd",
"mesh_terms": "D000152:Acne Vulgaris; D000293:Adolescent; D000900:Anti-Bacterial Agents; D000974:Antibodies, Antinuclear; D056486:Chemical and Drug Induced Liver Injury; D005260:Female; D019693:Hepatitis, Autoimmune; D006801:Humans; D007074:Immunoglobulin G; D008911:Minocycline",
"nlm_unique_id": "0400770",
"other_id": null,
"pages": "A5465",
"pmc": null,
"pmid": "23328022",
"pubdate": "2013",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Minocycline-induced autoimmune hepatitis.",
"title_normalized": "minocycline induced autoimmune hepatitis"
} | [
{
"companynumb": "NL-RANBAXY-2013R1-67880",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "MINOCYCLINE\\MINOCYCLINE HYDROCHLORIDE"
},
"dru... |
{
"abstract": "In lymphangioleiomyomatosis patients receiving sirolimus treatment, transient leukopenia in the morning may be due to circadian rhythm, with leukocyte counts recovering later in the day, indicating that a decrease in drug dose may not be warranted http://ow.ly/jPFz30iysgV.",
"affiliations": "Pulmonary Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.;Pulmonary Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.;Pulmonary Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.;Pulmonary Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.;Critical Care Medicine Dept, NIH Clinical Center, Bethesda, MD, USA.;Division of Pulmonary, Critical Care and Sleep Medicine, National Jewish Health, Denver, CO, USA.;Division of Respiratory, Critical Care and Occupational Pulmonary Medicine, Dept of Internal Medicine, University of Utah Health Sciences Center, Salt Lake City, UT, USA.;Dept of Laboratory Medicine, NIH Clinical Center, Bethesda, MD, USA.;Pulmonary Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.",
"authors": "Gopalakrishnan|Vissagan|V|;Jones|Amanda M|AM|;Julien-Williams|Patricia|P|;Machado|Tania|T|;Danner|Robert L|RL|https://orcid.org/0000-0001-5715-3823;Swigris|Jeffrey J|JJ|;Paine|Robert|R|;Lozier|Jay N|JN|;Moss|Joel|J|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1183/23120541.00121-2017",
"fulltext": "\n==== Front\nERJ Open ResERJ Open ResERJORerjorERJ Open Research2312-0541European Respiratory Society 10.1183/23120541.00121-201700121-2017Original Research Letter13Pseudoneutropenia in lymphangioleiomyomatosis (LAM) patients receiving sirolimus: evaluation in a 100 patient cohort Pseudoneutropenia in LAM patients receiving sirolimusGopalakrishnan Vissagan 12Jones Amanda M. 1Julien-Williams Patricia 1Machado Tania 1https://orcid.org/0000-0001-5715-3823Danner Robert L. 3Swigris Jeffrey J. 4Paine Robert III5Lozier Jay N. 6Moss Joel 11 Pulmonary Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA2 Rush Medical College, Rush University Medical Center, Chicago, IL, USA3 Critical Care Medicine Dept, NIH Clinical Center, Bethesda, MD, USA4 Division of Pulmonary, Critical Care and Sleep Medicine, National Jewish Health, Denver, CO, USA5 Division of Respiratory, Critical Care and Occupational Pulmonary Medicine, Dept of Internal Medicine, University of Utah Health Sciences Center, Salt Lake City, UT, USA6 Dept of Laboratory Medicine, NIH Clinical Center, Bethesda, MD, USAJoel Moss, Pulmonary Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Room 6D05, Building 10, 9000 Rockville Pike Bethesda, MD, USA, 20892-1590. E-mail: mossj@nhlbi.nih.gov1 2018 20 3 2018 4 1 00121-201702 10 2017 02 2 2018 The content of this work is not subject to copyright. Design and branding are copyright ©ERS 20182018This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial Licence 4.0.Diurnal variation in white blood cells (WBC), particularly neutrophils, is well-described [1]. WBC levels are lower in the morning and increase through the day [1, 2]. Drugs with immunosuppressive effects, such as sirolimus, may further lower WBC counts. This phenomenon has been observed in clozapine and related atypical antipsychotic medications, drugs with known immunosuppressive effects [3, 4]. For patients receiving these drugs, blood counts measured in the early morning may lead to a false impression of low WBC/neutrophil counts (“pseudoleukopenia/pseudoneutropenia”) [4–8] that may result in discontinuation or a reduction in dose and suboptimal treatment. Of importance, isolated morning neutropenia is not known to increase the risk of infection [6, 9].\n\nIn lymphangioleiomyomatosis patients receiving sirolimus treatment, transient leukopenia in the morning may be due to circadian rhythm, with leukocyte counts recovering later in the day, indicating that a decrease in drug dose may not be warranted\nhttp://ow.ly/jPFz30iysgV\n\nNational Heart, Lung, and Blood Institutehttp://doi.org/10.13039/10000005095-H-0186\n==== Body\nTo the Editor:\n\nDiurnal variation in white blood cells (WBC), particularly neutrophils, is well-described [1]. WBC levels are lower in the morning and increase through the day [1, 2]. Drugs with immunosuppressive effects, such as sirolimus, may further lower WBC counts. This phenomenon has been observed in clozapine and related atypical antipsychotic medications, drugs with known immunosuppressive effects [3, 4]. For patients receiving these drugs, blood counts measured in the early morning may lead to a false impression of low WBC/neutrophil counts (“pseudoleukopenia/pseudoneutropenia”) [4–8] that may result in discontinuation or a reduction in dose and suboptimal treatment. Of importance, isolated morning neutropenia is not known to increase the risk of infection [6, 9].\n\nLymphangioleiomyomatosis (LAM) is a rare, multisystem disease, characterised by cystic lung destruction, lymphatic infiltration and renal angiomyolipomas. It may occur sporadically or in association with tuberous sclerosis complex, an autosomal dominant, neurocutaneous disorder [10, 11]. The disease is treated with inhibitors of mechanistic target of rapamycin (mTOR), such as sirolimus (rapamycin) or everolimus [10–14]. Sirolimus is an immunosuppressive agent that inhibits activation and proliferation of T-cells and B-cells by reducing interleukin-2 production, and has been approved by the Food and Drug Administration for use in transplant recipients for over 17 years [15, 16]. Sirolimus has been recently approved for use in LAM [17]. In a prior study evaluating the sustained effects of sirolimus in LAM, neutropenia/leukopenia was reported in 40% of patients, and upper respiratory tract infections were reported in 66% [12]. To avoid increased risk of infection while on the drug, systemic immunity is monitored in part by obtaining a complete blood count (CBC) with differential. Diurnal variation may not be appreciated in the interpretation of low WBC counts.\n\nWe report here a patient with LAM (female, age 53 years) receiving sirolimus who presented in the morning (06:00 h) with low WBC and neutrophil counts (3.18×103 µL−1 and 1.54×103 µL−1, respectively). Previously, neutropenia caused the primary physician to decrease the dose of sirolimus. Repeat of the cell counts later in the day showed an increase in WBC and neutrophil counts by 42% (4.53×103 µL−1) and 88% (2.91×103 µL−1), respectively. These WBC and neutrophil levels would not warrant modification of the sirolimus dose.\n\nThe objective of this study was to determine if LAM patients experience pseudoleukopenia and/or pseudoneutropenia, particularly when they are on sirolimus treatment, and whether this phenomenon is associated with increased incidence or severity of infection. To test this hypothesis, we examined a cohort of 100 LAM patients either treated or not treated with sirolimus. All patients participated in NHLBI Protocol 95-H-0186, and gave written informed consent before enrolment. We compared leukocyte counts at three time-points throughout the day. Since diurnal effects are also affected by food intake, particularly lipids, we measured leukocyte counts prior to meals and following breakfast and lunch [18]. In patients that experienced pseudoleukopenia and/or pseudoneutropenia, incidence and severity of infection was collected up to 1 year prior to the study date and up to 1 year after the study date.\n\n100 female patients with LAM (mean age 50.8±10.4 years) were provided a breakfast and lunch of their choosing after a fasting period of ∼7 h. Blood samples were taken at three times: morning (06:00 h ±1.5 h) prior to breakfast, mid-day (11:00 h ±1.5 h) about 2 h after breakfast, and afternoon (15:00 h ±1.5 h) about 1 h after lunch. A CBC with differential and lipid panel was obtained at each measurement. ANOVA was used to analyse results within and between patients and, in addition, based on sirolimus use (55 patients receiving sirolimus, 45 patients not receiving sirolimus). The National Institutes of Health Clinical Center indicates the normal range of WBC counts and neutrophil counts as 3.98–10.04×103 µL−1 and 1.56–6.13×103 µL−1, respectively. As such, pseudoleukopenia was defined as a change in WBC count from <3.98×103 µL−1 in the morning to >3.98×103 µL−1 at mid-day or in the afternoon. Likewise, pseudoneutropenia was defined as a change in neutrophil count from <1.56×103 µL−1 in the morning to >1.56×103 µL−1 at mid-day or in the afternoon.\n\nAmong patients receiving sirolimus, 16.4% (nine out of 55 patients) presented with pseudoleukopenia, while 2.2% of patients not receiving sirolimus (one out of 45 patients) presented with pseudoleukopenia. 7.3% of patients receiving sirolimus (four out of 55 patients) presented with pseudoneutropenia, while 8.89% of patients not recieiving sirolimus (four out of 45 patients) presented with pseudoneutropenia. However, neutrophil counts were 35% lower in the morning (p=0.041) in patients on sirolimus experiencing pseudoneutropenia compared to patients off treatment experiencing pseudoneutropenia (figure 1b). Notably, multivariate analysis showed that treatment status significantly affected variation in WBC and neutrophil count between the morning and mid-day/afternoon (p≤0.0087) (figure 1).\n\nFIGURE 1 a) White blood cell (WBC) counts for 10 lymphangioleiomyomatosis (LAM) patients (nine on sirolimus, one off sirolimus) experiencing pseudoneutropenia in the morning and during mid-day or afternoon. The dotted line is the lower threshold of the normal range for WBC counts (3.98×103μL−1). b) Neutrophil counts for eight LAM patients (four on sirolimus, four off sirolimus) experiencing pseudoneutropenia in the morning and during mid-day or afternoon. The dotted line is the lower threshold of the normal range for neutrophil counts (1.56×103 μL−1). Comparisons between morning and mid-day/afternoon values were conducted with an unpaired t-test and assessment of treatment interaction was conducted with two-way repeated measures ANOVA.\n\nAmong the 14 patients who experienced pseudoneutropenia/pseudoleukopenia, incidence of infection was evaluated 8.9±3.0 months prior to the study date (n=11 patients) and 7.7±2.4 months after the study date (n=10 patients). The severity of all reported infections was mild based on the Common Terminology Criteria for Adverse Events (supplementary material) [19]. Rates of infection between patients receiving sirolimus and not treated with sirolimus were similar (25% in patients off sirolimus and 20% in patients on sirolimus) (supplementary material).\n\nIn the larger patient cohort (n=100 patients), absolute counts for WBC, neutrophils and monocytes were lowest in the morning, and increased later in the day (p<0.0001) (figure 2). Eosinophil counts decreased from the morning to the early afternoon (p<0.0001). Significant changes in monocyte count throughout the day were only observed in patients on sirolimus (p<0.0001). Lymphocyte, basophil and immature granulocyte counts did not show significant variation throughout the study period. Triglyceride levels increased throughout the day; however, total cholesterol levels were not statistically different.\n\nFIGURE 2 Comparison of absolute counts for a, b) white blood cells (WBC), c, d) neutrophils, e, f) monocytes, and g, h) eosinophils for 100 patients with lymphangioleiomyomatosis (LAM) (44 not receiving sirolimus treatment (a, c, e and g), 55 receiving sirolimus treatment (b, d, f and h)) at three time-points during the day. Box-and-whisker plots show median values, upper and lower quartiles, and highest and lowest values. ANOVA was used to analyse results within and between patients. *: p≤0.05; **: p≤0.01; ***: p≤0.001; ****: p≤0.0001; ns: p>0.05.\n\nOur results show that some LAM patients on sirolimus experience pseudoleukopenia and pseudoneutropenia. Given the transient nature of this event and the importance of sirolimus therapy in stabilising lung function, distinguishing between pseudoleukopenia and persistent sirolimus-induced leukopenia is critical. In patients experiencing pseudoleukopenia or pseudoneutropenia, infection rates were low and similar in patients both on and off treatment. Furthermore, all infections reported about 9 months prior to the study date and 8 months after the study date were mild. As such, we confirm that isolated morning neutropenia or leukopenia did not increase risk of infection. If morning WBC or neutrophil counts are less than the normal range, we suggest repeating CBCs later in the day and using those results as a better metric of sirolimus toxicity.\n\nDiurnal variation in WBC counts is well documented, and is linked with cyclic changes in adrenocorticotropic hormone and cortisol levels, which peak in the morning [1]. This hormonal variation probably promotes redistribution of leukocytes within a 24-h period. While this variation was generally observed in all patients, our results further show that sirolimus treatment may enhance cyclic changes in WBC and neutrophil count. This is indicated by significant treatment interactions in WBC and neutrophil counts between morning and mid-day/afternoon values in patients experiencing pseudoleukopenia or pseudneutropenia (figure 1). These results suggest an effect of sirolimus on circadian pathways. There is known involvement of mTOR signalling in the suprachiasmatic nuclei (SCN) of the hypothalamus, the source of the mammalian circadian clock [20]. mTOR is a downstream target of the p42/44 mitogen-activated protein kinase (MAPK) signalling pathway, and light triggers coordinate cyclic AMP-response element binding protein (CREB) and mTOR activation in SCN neurons [20]. The data suggest that inducible translation, mediated by a light-responsive mTOR cascade in the SCN, contributes to the circadian clock entrainment process. Thus, modification of this mTOR signalling through sustained sirolimus treatment could modify diurinal variation in WBC counts.\n\nThe observed decrease in eosinophil count from morning to early afternoon supports previous studies exploring the role of the circadian clock in eosinophils and mast cells, and could explain why allergic diseases are frequently exacerbated when eosinophil counts peak between midnight and early morning [21].\n\nIn conclusion, although WBC counts must be monitored when treating patients with immunosuppressive drugs, transient leukopenia in the morning may be a result of circadian rhythm, and leukocyte counts may recover later in the day. This may not necessarily warrant a decrease in drug dose. Diurnal variation should be considered when morning WBC counts are used as the basis for decreasing treatment dose. Currently, morning pseudoneutropenia has only been reported with antipsychotic medications; however, our findings show that this phenomenon is present with sirolimus as well [5, 9].\n\nSupplementary material\n10.1183/23120541.00121-2017.Supp1Please note: supplementary material is not edited by the Editorial Office, and is uploaded as it has been supplied by the author.\n\n00121-2017_Supplementarymaterial\n\n Acknowledgements\nWe thank the LAM Foundation and the Tuberous Sclerosis Alliance for their assistance in recruiting patients for our studies. We thank Henry Masur of the Critical Care Medicine Department at the NIH Clinical Center (Bethesda, MD, USA) for his advice and support.\n\nThis article has supplementary material available from openres.ersjournals.com\n\nSupport statement: This study was funded by the Intramural Research Program, NIH, National Heart, Lung, and Blood Institute (95-H-0186), and the NIH Medical Research Scholars Program, a public–private partnership supported jointly by the NIH and generous contributions to the Foundation for the NIH from the Doris Duke Charitable Foundation, the American Association for Dental Research, the Colgate-Palmolive Company, Genentech, and other private donors. For a complete list, visit the Foundation website at http://www.fnih.org. Funding information for this article has been deposited with the Crossref Funder Registry.\n\nConflict of interest: None declared.\n==== Refs\nReferences\n1 Scheiermann C , Kunisaki Y , Frenette PS \nCircadian control of the immune system . Nat Rev Immunol \n2013 ; 13 : 190 –198 .23391992 \n2 Suzuki S , Toyabe S , Moroda T , et al. \nCircadian rhythm of leucocytes and lymphocytes subsets and its possible correlation with the function of the autonomic nervous system . Clin Exp Immunol \n1997 ; 110 : 500 –508 .9409657 \n3 Rettenbacher MA , Hofer A , Kemmler G , et al. \nNeutropenia induced by second generation antipsychotics: a prospective investigation . Pharmacopsychiatry \n2010 ; 43 : 41 –44 .20175050 \n4 Porter R , Mohamed A \nDiurnal variation of neutropenia during clozapine treatment . Int J Neuropsychopharmacol \n2006 ; 9 : 373 –374 .16191205 \n5 Pinnaka S , Roberto AJ , Giordano A , et al. \nAripiprazole-induced transient morning pseudoneutropenia in an 11-year-old male . J Child Adolesc Psychopharmacol \n2016 ; 26 : 858 –859 .26397725 \n6 Esposito D , Corruble E , Hardy P , et al. \nRisperidone-induced morning pseudoneutropenia . Am J Psychiatry \n2005 ; 162 : 397 .\n7 Esposito D , Aouille J , Rouillon F , et al. \nMorning pseudoneutropenia during clozapine treatment . World J Biol Psychiatry \n2003 ; 4 : 192 –194 .14608591 \n8 Singh G , Kodela S \nMorning pseudoneutropenia during risperidone treatment . BMJ Case Rep \n2009 ; https://doi.org/10.1136/bcr.06.2008.0288 .\n9 Esposito D , Aouille J , Rouillon F , et al. \nTwo-year follow-up of a patient with successful continuation of clozapine treatment despite morning pseudoneutropenia . J Clin Psychiatry \n2004 ; 65 : 1281 .\n10 McCormack FX , Gupta N , Finlay GR , et al. \nOfficial American Thoracic Society/Japanese Respiratory Society clinical practice guidelines: lymphangioleiomyomatosis diagnosis and management . Am J Respir Crit Care Med \n2016 ; 194 : 748 –761 .27628078 \n11 Harari S , Torre O , Cassandro R , et al. \nThe changing face of a rare disease: lymphangioleiomyomatosis . Eur Respir J \n2015 ; 46 : 1471 –1485 .26405290 \n12 Yao J , Taveira-DaSilva AM , Jones AM , et al. \nSustained effects of sirolimus on lung function and cystic lung lesions in lymphangioleiomyomatosis . Am J Respir Crit Care Med \n2014 ; 190 : 1273 –1282 .25329516 \n13 Cottin V \nTreatment of lymphangioleiomyomatosis: building evidence in orphan diseases . Eur Respir J \n2014 ; 43 : 966 –969 .24687668 \n14 Goldberg HJ , Harari S , Cottin V , et al. \nEverolimus for the treatment of lymphangioleiomyomatosis: a phase II study . Eur Respir J \n2015 ; 46 : 783 –794 .26113676 \n15 Napoli KL , Taylor PJ \nFrom beach to bedside: history of the development of sirolimus . Ther Drug Monit \n2001 ; 23 : 559 –586 .11591905 \n16 Gomez C , Taillé C , Lazor R , et al. \nProlonged sirolimus therapy in advanced pulmonary lymphangioleiomyomatosis; a multicenter French experience . Eur Respir J \n2012 ; 40 : Suppl. 56, P1776 .\n17 Singla A , Gupta N , Apewokin S , et al. \nSirolimus for the treatment of lymphangioleiomyomatosis . Expert Opin Orphan Drugs \n2017 ; 5 : 907 –921 .\n18 Morimoto Y , Arisue K , Yamamura Y \nRelationship between circadian rhythm of food intake and that of plasma corticosterone and effect of food restriction on circadian adrenocortical rhythm in the rat . Neuroendocrinology \n1977 ; 23 : 212 –222 .909626 \n19 National Cancer Institute (U.S.) \nCommon Terminology Criteria for Adverse Events (CTCAE) . Revised Edn \nBethesda , U.S. Dept. of Health and Human Services, National Institutes of Health, National Cancer Institute , 2009 .\n20 Cao R , Lee B , Cho HY , et al. \nPhotic regulation of the mTOR signaling pathway in the suprachiasmatic circadian clock . Mol Cell Neurosci \n2008 ; 38 : 312 –324 .18468454 \n21 Baumann A , Gonnenwein S , Bischoff SC , et al. \nThe circadian clock is functional in eosinophils and mast cells . Immunology \n2013 ; 140 : 465 –474 .23876110\n\n",
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"title": "Pseudoneutropenia in lymphangioleiomyomatosis (LAM) patients receiving sirolimus: evaluation in a 100 patient cohort.",
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"abstract": "A 69-year-old man renal transplant recipient for 4 years, presented with 4-day history of cough and dyspnoea. He was diagnosed with community-acquired pneumonia and treated accordingly. He deteriorated requiring intensive care unit admission and intubation. Mycobacterial culture from bronchoalveolar lavage grew colonies within 7 days of incubation while Mycobacterium tuberculosis PCR was negative. The antibiotic regimen was adjusted to cover for rapidly growing mycobacteria with imipenem, amikacin and clarithromycin. The final culture reported Mycobacterium cosmeticum He improved on the antibiotic regimen given which the organism turned to be sensitive to. We reported the second case with M. cosmeticum that fulfilled the diagnostic criteria for non-tuberculous mycobacterial lung infection. Improvement of patient's lung infection on appropriate antibiotics points to a causal relationship.",
"affiliations": "Department of Medicine, King Fahad Specialist Hospital, Dammam, Saudi Arabia ahmed.jishi1@gmail.com.;Department of Medicine, King Fahd Hospital of the University, Imam Abdulrahman Bin Faisal University, Al Khobar, Saudi Arabia.;Department of Medicine, King Fahad Specialist Hospital, Dammam, Saudi Arabia.",
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"fulltext": "\n==== Front\nBMJ Case Rep\nBMJ Case Rep\nbmjcr\nbmjcasereports\nBMJ Case Reports\n1757-790X\nBMJ Publishing Group BMA House, Tavistock Square, London, WC1H 9JR\n\nbcr-2020-234800\n10.1136/bcr-2020-234800\nCase Report\n1506\n495\n505\n508\n523\nPneumonia due to Mycobacterium cosmeticum in a renal transplant recipient\nhttp://orcid.org/0000-0002-2193-8618\nAljishi Ahmed 1\nAlwazzeh Marwan Jabr 2\nKristjansson Mar 1\n1 Department of Medicine, King Fahad Specialist Hospital, Dammam, Saudi Arabia\n2 Department of Medicine, King Fahd Hospital of the University, Imam Abdulrahman Bin Faisal University, Al Khobar, Saudi Arabia\nCorrespondence to Dr Ahmed Aljishi; ahmed.jishi1@gmail.com\n2021\n2 3 2021\n2 3 2021\n14 3 e23480027 1 2021\n© BMJ Publishing Group Limited 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.\n2021\nhttp://creativecommons.org/licenses/by-nc/4.0/ This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.\n\nA 69-year-old man renal transplant recipient for 4 years, presented with 4-day history of cough and dyspnoea. He was diagnosed with community-acquired pneumonia and treated accordingly. He deteriorated requiring intensive care unit admission and intubation. Mycobacterial culture from bronchoalveolar lavage grew colonies within 7 days of incubation while Mycobacterium tuberculosis PCR was negative. The antibiotic regimen was adjusted to cover for rapidly growing mycobacteria with imipenem, amikacin and clarithromycin. The final culture reported Mycobacterium cosmeticum. He improved on the antibiotic regimen given which the organism turned to be sensitive to. We reported the second case with M. cosmeticum that fulfilled the diagnostic criteria for non-tuberculous mycobacterial lung infection. Improvement of patient’s lung infection on appropriate antibiotics points to a causal relationship.\n\nrenal transplantation\npneumonia (respiratory medicine)\nspecial-featureunlocked\n==== Body\nBackground\n\nAlthough relatively rare, non-tuberculous mycobacterial (NTM) infections remain clinically relevant, especially in immunosuppressed patients. Among solid organ transplant recipients, they are most prevalent among lung transplant recipients with lung and pleura being the most common sites of infection.1 2 Identification is associated with a significantly increased mortality rate in transplant recipients.3 Timely identification and diagnosis will help direct appropriate management of these patients. As NTM are ubiquitous in the environment, diagnostic criteria were developed to help differentiate true infection from contamination or colonisation.\n\nMycobacterium cosmeticum is a rapidly growing NTM. It has been rarely reported in the literature as a cause of different infections mostly in immunocompromised patients. Its role as a cause of lung infection has been reported only once. We report herein a case of a renal transplant recipient who developed pneumonia secondary to M. cosmeticum. This adds to the growing literature about this rarely reported organism.\n\nCase presentation\n\nA 69-year-old man presented to the emergency department with 4-day history of dry cough, progressive shortness of breath, fever with chills and progressive fatigue. The patient had a history of urinary schistosomiasis complicated with reflux nephropathy and end-stage renal failure. He was on haemodialysis for 6 years before he underwent a successful living-related renal transplant 4 years before presentation with good graft function. The patient was hypertensive and also had a history of empyema secondary to parapneumonic effusion and right lung decortication 3 years ago.\n\nHe was on nifedipine 120 mg once daily, lisinopril 10 mg once daily, mycophenolate 750 mg two times per day, prednisolone 5 mg once daily and tacrolimus 0.5 mg two times per day (all orally).\n\nOn admission, he was pale, tachypneic (22 breaths/min), had O2 saturation of 92% on room air and had bilateral fine crackles, more in the right lower zone.\n\nHis initial investigations showed leucopenia with white cell count of 3.31×109/L, neutrophils 45.1%, lymphocytes 38.2%, monocytes 7.1% and eosinophils 8.4%, anaemia with haemoglobin of 93 g/L, hyponatremia of 130 mEq/L and an erythrocyte sedimentation rate of 51 mm/hour. Screening of viral pathogens and sputum culture were negative. HIV serology was negative. Our patient was presented before the COVID-19 pandemic. Chest X-ray (CXR) revealed diffuse reticulonodular infiltrates with opacity in the right lower zone (figure 1).\n\nFigure 1 Chest X-ray on admission showed diffuse reticulo-nodular infiltrates with irregular opacity in the right lower zone.\n\nThe patient was treated for community-acquired pneumonia with levofloxacin. Over the next few days, the patient’s condition worsened. Repeated CXR showed worsening bilateral infiltrates (figure 2). Chest CT showed a diffuse bilateral airspace consolidation, reticulation and ground glass appearance with lower lobes predominance (figure 3). Piperacillin/tazobactam was added, and the patient was shifted to the intensive care unit (ICU), intubated and ventilated.\n\nFigure 2 Chest X-ray on fourth day of admission showed increase of bilateral pulmonary infiltrates.\n\nFigure 3 CT chest showed a diffuse bilateral air space consolidation, reticulation and ground glass appearance with lower lobes predominance.\n\nBronchoalveolar lavage (BAL) and new microbiological investigations were performed. The results for gram stain, bacterial and fungal cultures, cytology for Pneumocystis jiroveci, acid-fast bacilli (AFB) staining, respiratory viruses and Mycobacterium tuberculosis PCR were negative. However, on the seventh day of incubation, AFB were noted in BAL mycobacterial culture. Assuming rapid growing NTM infection, he was started on imipenem, amikacin and clarithromycin. Cultures were sent for species identification (at Mayo Clinic Laboratories, Rochester, Minnesota, USA). M. cosmeticum was identified. It was sensitive to clarithromycin and amikacin.\n\nOutcome and follow-up\n\nThe patient improved markedly (figure 4), extubated and shifted from ICU after 26 days. He was treated with this antibiotic regimen for 4 weeks and discharged home on oral antibiotics and home oxygen after 36 days of hospitalisation. Repeated mycobacterial culture from BAL 6 weeks after starting treatment was negative which suggests a good response.\n\nFigure 4 Chest X-ray after treatment showed improvement of bilateral pulmonary infiltrates.\n\nDiscussion\n\nNTM comprise more than 150 different species and are distributed worldwide.4 Many of these bacteria can lead to opportunistic infections with different clinical manifestations. According to Runyon classification, NTM are divided into slowly growing mycobacteria and rapidly growing mycobacteria.5 Rapidly growing mycobacteria form colonies within 7 days of inoculation in solid culture media.\n\nAs NTMs are ubiquitous environmental organisms, diagnostic criteria were developed to distinguish true infection from contamination or colonisation. The American Thoracic Society and Infectious Disease Society of America (ATS/IDSA) definition of NTM pulmonary disease require clinical and microbiological criteria to be fulfilled. Clinical criteria include pulmonary symptoms, nodular or cavitary opacities on chest radiograph, or a high-resolution CT scan that shows multifocal bronchiectasis with multiple small nodules and appropriate exclusion of other diagnoses. Microbiological criteria include at least two positive sputum cultures, at least one bronchial wash/lavage or biopsy with compatible histopathological features and positive culture.6\n\nTransplanted patients are more susceptible to opportunistic and atypical infections as they are immunosuppressed. NTM infections are relatively rare among solid organ transplant patients and most commonly affect lung transplant recipients.1 2 The incidence of NTM in renal transplant recipients is between 0.16% and 0.38%.7 A retrospective study of solid organ transplant patients by Longworth et al2 found that Mycobacterium avium complex and Mycobacterium abscessus to be the most prevalent NTM infections with lung and pleura to be the most common site of infection.\n\nIn case of non-resolving or atypical infections, NTM infections have to be suspected and investigated in transplant recipients as they are associated with significantly increased mortality, 50% at 3 years versus 13% in solid organ transplant recipients without NTM infection.3 Patients with NTM infections typically need a prolonged course of antibiotics which differ depending on the organism and site of infection.\n\nM. cosmeticum is a rapidly growing mycobacterium that was first isolated from a sink in a nail salon in the USA,8 then from monument sandstones9 and household potable water.10 Its role as a human pathogen was first described in 2004 after the isolation from a granulomatous subdermal lesion of a female patient in Venezuela.8 Similar cases were later reported in the literature.11 12\n\nM. cosmeticum has been described to cause other infections as catheter-related bloodstream infection,13 granulomatous colitis,14 ascites,15 16 and was described to cause bacteremia in a preterm patient.17\n\nThe role of M. cosmeticum as a respiratory pathogen is not well established. It was isolated first from the sputum of an HIV patient in addition to Mycobacterium scrofulaceum. It was not mentioned in the report by Cooksey et al13 if the patient had evidence of lung infection or not. More recently, M. cosmeticum was reported in sputum of two patients from Saudi Arabia.18 One of them was post lung transplant and fulfilled the criteria of NTM lung disease according to the ATS/IDSA diagnostic criteria.6\n\nWe report the second case of M. cosmeticum pneumonia that has fulfilled the diagnostic criteria. First, the patient had symptoms and signs of pulmonary infection. Second, all routine tests for common pathogens were negative and the patient did not respond to initial broad-spectrum empiric antimicrobial therapy. Third, the culture of BAL was positive for M. cosmeticum. The combination of being a transplant recipient on immunosuppressive medications and possibly previous lung decortication surgery have contributed to his lung NTM lung infection.\n\nIn our patient, M. cosmeticum was the only organism that was isolated, and the improvement following appropriate antibiotic therapy points to a causal relationship. Differential diagnosis includes infection with a resistant unidentified organism that was covered with increasing the spectrum of antibiotic coverage. Use of culture-independent techniques as sequencing could have detected a potentially pathogenic microorganism as they are associated with increased sensitivity.19 20\n\nLearning points\n\nMycobacterium cosmeticum, a rapidly growing non-tuberculous mycobacterium (NTM), that was initially described to cause skin and soft tissue infection, can be a cause of lung infection.\n\nAlthough relatively rare, NTM lung infection should be suspected and investigated in immunocompromised patients who do not improve on initial empiric therapy.\n\nRapidly growing mycobacteria form colonies within 7 days of incubation in solid culture media.\n\nClinical and microbiologic diagnostic criteria have to be fulfilled to diagnose NTM lung disease.\n\nMore research is needed regarding the clinical use of culture-independent techniques in respiratory infections to improve the diagnostic yield, especially in critically ill patients.\n\nImproved basic science understanding is needed to better identify factors that cause NTM infections to be pathogenic in some patients.\n\nContributors: AA contributed to planing, reviewing and reporting. MK contributed to planning and review of the article. MA contributed to review and reporting of case.\n\nFunding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.\n\nCompeting interests: None declared.\n\nPatient consent for publication: Next of kin consent obtained.\n\nProvenance and peer review: Not commissioned; externally peer reviewed.\n==== Refs\nReferences\n\n1 George IA, Santos CAQ, Olsen MA, et al . Epidemiology and outcomes of nontuberculous mycobacterial infections in solid organ transplant recipients at a midwestern center. Transplantation 2016;100 :1073–8. 10.1097/TP.0000000000001123 26950719\n2 Longworth SA, Vinnard C, Lee I, et al . Risk factors for nontuberculous mycobacterial infections in solid organ transplant recipients: a case-control study. Transpl Infect Dis 2014;16 :76–83. 10.1111/tid.12170 24350627\n3 Longworth SA, Blumberg EA, Barton TD, et al . Non-tuberculous mycobacterial infections after solid organ transplantation: a survival analysis. Clin Microbiol Infect 2015;21 :43–7. 10.1016/j.cmi.2014.07.001 25636926\n4 van der Werf MJ, Ködmön C, Katalinić-Janković V, et al . Inventory study of non-tuberculous mycobacteria in the European Union. BMC Infect Dis 2014;14 :62. 10.1186/1471-2334-14-62 24502462\n5 Runyon EH. Anonymous mycobacteria in pulmonary disease. Med Clin North Am 1959;43 :273–90. 10.1016/S0025-7125(16)34193-1 13612432\n6 Griffith DE, Aksamit T, Brown-Elliott BA, et al . An official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases. Am J Respir Crit Care Med 2007;175 :367–416. 10.1164/rccm.200604-571ST 17277290\n7 Doucette K, Fishman JA. Nontuberculous mycobacterial infection in hematopoietic stem cell and solid organ transplant recipients. Clin Infect Dis 2004;38 :1428–39. 10.1086/420746 15156482\n8 Cooksey RC, de Waard JH, Yakrus MA, et al . Mycobacterium cosmeticum sp. nov., a novel rapidly growing species isolated from a cosmetic infection and from a nail salon. Int J Syst Evol Microbiol 2004;54 :2385–91. 10.1099/ijs.0.63238-0 15545488\n9 Kusumi A, Li XS, Katayama Y. Mycobacteria isolated from angkor monument sandstones grow chemolithoautotrophically by oxidizing elemental sulfur. Front Microbiol 2011;2 :104. 10.3389/fmicb.2011.00104 21747806\n10 Perez-Martinez I, Aguilar-Ayala DA, Fernandez-Rendon E. Occurrence of potentially pathogenic nontuberculous mycobacteria in Mexican house hold potable water: a pilot study. BMCRes 2013;6 :531.\n11 Rivera-Olivero IA, Guevara A, Escalona A, et al . [Soft-tissue infections due to non-tuberculous mycobacteria following mesotherapy. What is the price of beauty]. Enferm Infecc Microbiol Clin 2006;24 :302–6. 10.1157/13089664 16762255\n12 Beer K, Waibel J. Disfiguring scarring following mesotherapy-associated Mycobacterium cosmeticum infection. J Drugs Dermatol 2009;8 :391–3.19363858\n13 Cooksey RC, de Waard JH, Yakrus MA, et al . Mycobacterium cosmeticum, Ohio and Venezuela. Emerg Infect Dis 2007;13 :1267–9. 10.3201/eid1308.061061 17953114\n14 Boschetti G, Cotte E, Moussata D, et al . Identification of Mycobacterium cosmeticum sp. as a novel colitogenic infectious agent in a nonimmunocompromised patient. Inflamm Bowel Dis 2011;17 :E128–30. 10.1002/ibd.21804 21739530\n15 Addley J, McKeagney P, Turner G, et al . Mycobacterium cosmeticum as an unusual cause of ascites. BMJ Case Rep 2010;2010 :bcr0420091733. 10.1136/bcr.04.2009.1733\n16 Anand AS, Kuriakose VG, Govindan K. Multicentric Castleman’s disease with Mycobacterium cosmeticum infection. Arch Surg Oncol 2017;3 :1.\n17 Koay WLA, Aigbivbalu L, Patel J. A neonate born with Mycobacterium cosmeticum bacteraemia. BMJ Case Rep 2015;2015 :bcr2015213452. 10.1136/bcr-2015-213452\n18 Varghese B, Enani M, Shoukri M, et al . Emergence of rare species of nontuberculous mycobacteria as potential pathogens in Saudi Arabian clinical setting. PLoS Negl Trop Dis 2017;11 :e0005288. 10.1371/journal.pntd.0005288 28076350\n19 Dickson RP, Erb-Downward JR, Prescott HC, et al . Analysis of culture-dependent versus culture-independent techniques for identification of bacteria in clinically obtained bronchoalveolar lavage fluid. J Clin Microbiol 2014;52 :3605–13. 10.1128/JCM.01028-14 25078910\n20 Mancini N, Carletti S, Ghidoli N, et al . The era of molecular and other non-culture-based methods in diagnosis of sepsis. Clin Microbiol Rev 2010;23 :235–51. 10.1128/CMR.00043-09 20065332\n\n",
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"mesh_terms": "D000368:Aged; D000583:Amikacin; D017291:Clarithromycin; D006801:Humans; D016030:Kidney Transplantation; D008297:Male; D009159:Mycobacteriaceae; D009165:Mycobacterium Infections, Nontuberculous",
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"title": "Pneumonia due to Mycobacterium cosmeticum in a renal transplant recipient.",
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"abstract": "Potassium is an extracellular ion that plays an important role in the electrophysiological function of the heart. Any change in the extracellular concentration of potassium can have a marked impression upon cardiac electrophysiology. Underlying kidney disease, certain medical conditions, dietary indiscretions, and medications can precipitate hyperkalemia. Drug-induced hyperkalemia is one of the most important causes of increased serum potassium in everyday clinical practice. Hyperkalemia can lead to various life-threatening dysrhythmias and if left untreated, it will ultimately cause ventricular arrhythmias and asystole. This case report describes an end-stage renal disease (ESRD) patient taking atenolol who presented with hyperkalemia and type II second degree atrioventricular (AV) block. He presented with hyperkalemia when atenolol was introduced and normalized when atenolol was discontinued. The heart block completely resolved after treatment of hyperkalemia.",
"affiliations": "Internal Medicine, Interfaith Medical Center, Brooklyn, USA.;Internal Medicine, Interfaith Medical Center, Brooklyn, USA.",
"authors": "Oo|Kay Thi|KT|;Yee|Hnin Wut|HW|",
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"fulltext": "\n==== Front\nCureus\nCureus\n2168-8184\nCureus\n2168-8184\nCureus Palo Alto (CA)\n\n10.7759/cureus.13151\nCardiology\nEmergency Medicine\nNephrology\nA Case of Reversible Atrioventricular Block Potentially Associated with Atenolol-Induced Hyperkalemia\nMuacevic Alexander\nAdler John R\nOo Kay Thi 1\nYee Hnin Wut 1\n1 Internal Medicine, Interfaith Medical Center, Brooklyn, USA\nKay Thi Oo drkaythioo@gmail.com\n5 2 2021\n2 2021\n13 2 e131515 2 2021\nCopyright © 2021, Oo et al.\n2021\nOo et al.\nThis is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.\nThis article is available from https://www.cureus.com/articles/51732-a-case-of-reversible-atrioventricular-block-potentially-associated-with-atenolol-induced-hyperkalemia\nPotassium is an extracellular ion that plays an important role in the electrophysiological function of the heart. Any change in the extracellular concentration of potassium can have a marked impression upon cardiac electrophysiology. Underlying kidney disease, certain medical conditions, dietary indiscretions, and medications can precipitate hyperkalemia. Drug-induced hyperkalemia is one of the most important causes of increased serum potassium in everyday clinical practice. Hyperkalemia can lead to various life-threatening dysrhythmias and if left untreated, it will ultimately cause ventricular arrhythmias and asystole. This case report describes an end-stage renal disease (ESRD) patient taking atenolol who presented with hyperkalemia and type II second degree atrioventricular (AV) block. He presented with hyperkalemia when atenolol was introduced and normalized when atenolol was discontinued. The heart block completely resolved after treatment of hyperkalemia.\n\nhyperkalemia\nbeta-blocker\nend stage renal disease (esrd)\nsecond degree heart block\nreversible heart block\nThe content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus.\n==== Body\nIntroduction\n\nHyperkalemia is a potentially life-threatening condition that is defined as a serum potassium level above a reference range, usually greater than 5.0 mEq/L; severe hyperkalemia is often defined as a level greater than 6.0 mEq/L. Prescribed medications, over-the-counter drugs, and nutritional supplements that can affect the potassium levels are used by many patients. Although most of these products are well tolerated, drug-induced hyperkalemia may develop in patients with underlying renal impairment or other abnormalities in potassium handling [1]. In hospitalized patients, the incidence of hyperkalemia ranges from 1.3% to 10%, with a mortality rate of 1 per 1,000 patients [2]. Drug-induced hyperkalemia is one of the most important causes in everyday clinical practice and has been identified as a primary contributing factor of hyperkalemia in 35%-75% of hospitalized patients [2]. Beta-blockers are postulated to induce hyperkalemia by suppressing catecholamine stimulated renin release, decrease aldosterone levels and impair cellular uptake of potassium [3]. Beta-blocker can increase serum potassium level by 1 mmol/L or more in end-stage renal disease (ESRD) [2]. Hyperkalemia is more commonly seen with nonselective rather than with cardio-selective beta-blockers [2]. However, there is one reported case of atenolol-induced hyperkalemia in the medical literature [4]. The duration of hyperkalemia can be fairly prolonged with advanced chronic kidney disease, particularly when renally cleared beta-blockers such as atenolol, are administered [2].\n\nThere is one reported case of complete heart block induced by hyperkalemia in an ESRD patient that completely resolved to normal with hyperkalemia treatment but months later developed permanent right bundle branch block (RBBB) and left anterior fascicular block [5]. The uniqueness of our case is that although there can be various ranges of heart block induced by hyperkalemia, there is no reported case so far presenting with reversible atrioventricular (AV) block potentially associated with atenolol-induced hyperkalemia in a patient without documented heart disease.\n\nCase presentation\n\nA 64-year-old Asian male with a past medical history of hypertension, type 2 diabetes mellitus, anemia, and ESRD on hemodialysis was referred by the dialysis center for evaluation after the patient was found to have a heart rate in the 30s and was brought to the emergency department (ED) by ambulance. He receives hemodialysis at an outpatient dialysis center three days a week, reported to be compliant, and did not miss any session. However, when he went to the dialysis center, he was found to have low blood pressure (BP) of 88/47 mmHg and a heart rate (HR) of 45 bpm. Leg elevation and inhalational oxygen via nasal cannula were provided but vitals rechecked after 30 minutes revealed BP 145/68 mmHg and HR 36/min. Therefore, emergency medical services (EMS) was activated, and the patient was brought to the ED. \n\nVitals on triage in the ED were notable for BP 108/54 mmHg, HR 33 bpm, oxygen saturation 100% on 2 liters nasal cannula (NC). He was alert, awake, and answered questions appropriately. He was not aware of his slow heart rate, but he complained of feeling dizzy on and off over the past two days. He denied chest pain, palpitation, shortness of breath, and spells of blackout. Stat EKG was done which showed ventricular rate of 37 bpm, PR interval 284 ms, QRS duration of 154 ms, QTc 466 ms. Fingerstick blood glucose was 195 mg/dl. Further interpretation of EKG revealed second degree 2:1 AV conduction with wide QRS suggestive of type II second degree AV heart block and peaked T wake (Figure 1). This is not his first-time presentation with a similar picture. His past medical records showed that he was admitted three times over the past two years with a similar presentation of hyperkalemia and heart block, one time with first degree AV block, another two times with type I second degree AV block, all resolved to normal sinus rhythm after potassium was normalized. His medications list was significant for atenolol which was discontinued in his previous admissions but was again prescribed a few days before his presentation to the ED. \n\nFigure 1 EKG changes before treatment\n\nHis physical examination was unremarkable except for severe bradycardia and cool and clammy extremities. On the cardiac monitor, his heart rate was ranging between 30 bpm to 35 bpm. In view of his previous presentations and EKG findings, he was given calcium gluconate 1 gram slow intravenous (IV) stat, 10 units of IV regular insulin, 25 grams of dextrose 50%, and 12 milliliters of albuterol nebulizer while waiting for blood tests results. \n\nWhile receiving treatment, basic labs including plasma potassium were sent. The results came back with serum potassium of 8.7 mmol/L, plasma potassium of 8.6 mmol/L. Other chemistries were sodium 135 mmol/L, chloride 96 mmol/L, bicarbonate 23 mmol/L, blood urea nitrogen (BUN) 78 mg/dl, creatinine 14.54 mg/dl, glucose 192 mg/dl, magnesium 2.6 mg/dl, and phosphorous 7.3 mg/dl.\n\nHis heart rate showed slight improvement after receiving treatment. Nephrology team recommended emergency hemodialysis. He was also given 30 grams of Kayexylate orally, an additional 2 grams of calcium gluconate slow IV while awaiting hemodialysis set up. He received a total of four hours of hemodialysis with 1K bath for the first 2.5 hours followed by 2K bath for the remaining treatment. Two hours post-dialysis, potassium came back 3.3 mmol/L. \n\nThe patient was admitted to the telemetry unit with nephrology on board. His hyperkalemia was thought to be secondary to atenolol considering his multiple presentations provoked by the reintroduction of atenolol. His cardiac enzyme was not elevated. Continuous cardiac monitoring was uneventful. At the time of discharge, his potassium level was 4.6 mmol/L. Beta-blocker was held throughout his hospital stay and also not continued upon discharge. His EKG on the day of his discharge demonstrated complete resolution of the previously seen type II second degree AV block pattern. EKG showed a rate of 72 bpm, PR interval 156 ms, normal sinus rhythm, and slightly prolonged QTc 462 ms (Figure 2).\n\nFigure 2 Normal sinus rhythm after treatment\n\nDiscussion\n\nThis case depicts an unusual presentation of atenolol-induced hyperkalemia causing type II second degree heart block that resolves completely to normal after correction of hyperkalemia, and discontinuation of atenolol. In this patient, who is reported to have started taking atenolol a few days before presentation, it is reasonable to believe that his hyperkalemia could be induced by atenolol, and heart block could be contributed by atenolol-induced hyperkalemia. For some reason, even though atenolol was discontinued upon previous discharges because of similar presentation, it was again prescribed by different doctors. Contributing factors could be lost to follow up upon discharge, no dedicated primary doctor, language barrier to some extent even though language line was properly used, and lack of health knowledge. In view of his recurrent presentation of hyperkalemia-induced heart block, electrophysiologic studies would be warranted to rule out any underlying pathology. However, the disappearance of hyperkalemia-induced heart block with hyperkalemia treatment and discontinuation of atenolol, the absence of any other acute causes of AV block make it seem unlikely. The resolution of type II second degree heart block to sinus rhythm after treatment of hyperkalemia and hemodialysis also suggest that atenolol-induced hyperkalemia is responsible for this high-grade AV block. \n\nHyperkalemia can lower cell-resting action potential and causes abnormal heart muscle function resulting in EKG findings initially with tall and tented T wave, loss of P wave, prolong PR interval, widened QRS complex, and eventually sine wave before the heart stops [6]. Varying degrees of heart block can also happen with this electrolyte disturbance but advanced heart blocks such as second- and third-degree AV blocks are generally found only in patients with underlying heart disease, heart failures, or preexisting conduction abnormalities. It was reasoned that underlying coronary artery or diffuse cardiac disease have already destroyed the AV node and His-Purkinje system to a certain extent that hyperkalemia can aggravate pre-existing diagnosed or undiagnosed conduction defects [7].\n\nBeta-blocker can increase serum potassium level by 1 mmol/L or more in ESRD [2]. Hyperkalemia was mainly seen with nonselective rather than with cardio-selective beta-blockers [2]. However, there is one reported case of atenolol-induced hyperkalemia in the medical literature [4]. Severe hyperkalemia as a complication of timolol, a topically applied beta-blocker, has also been reported [2]. The duration of hyperkalemia can be fairly prolonged with advanced chronic kidney disease, particularly when renally cleared beta-blockers such as atenolol, are administered [2].\n\nIn addition to discontinuing medications that can increase potassium and removal of dietary sources of potassium intake, available treatments for hyperkalemia include intravenous calcium to ameliorate cardiac toxicity if present, intravenous insulin, glucose, nebulized beta-adrenergic agonist, oral gastrointestinal cation exchangers, loop diuretics, and emergency hemodialysis as a last resort for patients with severe renal impairment or for patients with potentially lethal hyperkalemia not responding to conservative measures [8].\n\nThis patient is reported to be compliant with hemodialysis. There was no significant modification of his diet over the past years as per the patient. This is his fourth presentation with hyperkalemia, the last two times also assumed to be provoked by the reintroduction of atenolol when studied retrospectively. Every time upon discharge, he was always lost to follow up and presented with a similar problem. Upon looking back into his past records, atenolol was discontinued every time, and he was explained the reason, but it was again prescribed by different doctors a few days before his presentation to the ED. Upon discharge this time, his dedicated primary care physician was contacted and explained the situation, and the patient was also counseled to follow up with a particular primary care physician for comprehensive care.\n\nBecause of the absence of any documented underlying cardiac disease and the correlation of recent reintroduction of beta-blocker, we would like to propose that type II second degree heart block was caused by atenolol-induced hyperkalemia. Albeit atenolol can cause heart block as well; AV block is commonly related to drugs but rarely caused by drugs [9].\n\nConclusions\n\nEven though ESRD patients are already very susceptible to hyperkalemia, in our patient who is compliant to hemodialysis, we should also look into other possible causes of this electrolyte disturbance. Beta-blockers are commonly used for the treatment of hypertension. Physicians should be aware of the medications that can precipitate hyperkalemia, patient characteristics with a higher risk of hyperkalemia, the range of dysrhythmias attributed to hyperkalemia, and implementing treatments without waiting for lab results if necessary.\n\nHuman Ethics\n\nThe authors have declared that no competing interests exist.\n\nConsent was obtained or waived by all participants in this study\n==== Refs\nReferences\n\n1 Drug-induced hyperkalemia: old culprits and new offenders Am J Med Perazella MA 307 314 109 2000 10996582\n2 Drug-induced hyperkalemia Drug Saf Ben Salem C Badreddine A Fathallah N Slim R Hmouda H 677 692 37 2014 25047526\n3 Mild hyperkalemia and low eGFR a tedious recipe for cardiac disaster in the elderly: an unusual reversible cause of syncope and heart block Heart Int Aziz EF Javed F Korniyenko A Pratap B Cordova JP Alviar CL Herzog E 0 6 2011 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3205785/\n4 Hyperkaliemia induced by atenolol [Article in English, French] Rev Med Interne Kassem H Hajjar C El Gharbi T Turner L 714 716 30 2009 19019496\n5 Disorders of impulse conduction and impulse formation caused by hyperkalemia in man Am Heart J Cohen HC Rosen KM Pick A 501 509 89 1975 1114983\n6 Electrocardiographic manifestations of hyperkalemia Am J Emerg Med Mattu A Brady WJ Robinson DA 721 729 18 2000 11043630\n7 Wenckebach block due to hyperkalemia: a case report Emerg Med Int Sohoni A Perez B Singh A 879751 2010 22046534\n8 Medscape: hyperkalemia treatment & management 12021 2020 https://emedicine.medscape.com/article/240903-treatment\n9 Drug-induced atrioventricular block: prognosis after discontinuation of the culprit drug J Am Coll Cardiol Zeltser D Justo D Halkin A Rosso R Ish-Shalom M Hochenberg M Viskin S 105 108 44 2004 15234417\n\n",
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"issue": "13(2)",
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"keywords": "beta-blocker; end stage renal disease (esrd); hyperkalemia; reversible heart block; second degree heart block",
"medline_ta": "Cureus",
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"nlm_unique_id": "101596737",
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"pages": "e13151",
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"pubdate": "2021-02-05",
"publication_types": "D002363:Case Reports",
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"title": "A Case of Reversible Atrioventricular Block Potentially Associated with Atenolol-Induced Hyperkalemia.",
"title_normalized": "a case of reversible atrioventricular block potentially associated with atenolol induced hyperkalemia"
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"abstract": "BACKGROUND\nRecently, middle meningeal artery (MMA) embolization has emerged as a potential alternative treatment option for chronic subdural hematomas (SDH). Imaging following MMA embolization often shows high density material in the subdural space, usually representing contrast leakage through the dura or, less commonly, hemorrhage. These cannot be reliably differentiated on conventional CT. Dual energy CT (DECT) provides the ability to differentiate materials that otherwise appear similar on conventional CT such as blood and iodine.\n\n\nMETHODS\nA retrospective review was conducted to evaluate patients who underwent MMA embolization for SDH between May 2019 and April 2020. Post-procedural head CT performed on an IQon Elite Spectral CT detector-based DECT scanner enabled two-material decomposition to separate iodine from blood. The dual energy reconstructions used included the virtual non-contrast and iodine no-water images.\n\n\nRESULTS\nFour representative illustrative cases were selected to highlight the ability of DECT to characterize new hyperdensity on head CT following MMA embolization as blood, contrast or a combination.\n\n\nCONCLUSIONS\nDECT allows objective differentiation of contrast leakage from blood following MMA embolization. This technology can obviate the need for additional follow-up scanning and prolonged patient observation, which in turn can result in reduced costs and radiation exposure to patients.",
"affiliations": "Interventional Radiology, Albert Einstein Medical Center, Philadelphia, Pennsylvania, USA.;Diagnostic Radiology, Albert Einstein Medical Center, Philadelphia, Pennsylvania, USA.;Diagnostic Radiology, Albert Einstein Medical Center, Philadelphia, Pennsylvania, USA.;Interventional Radiology, Albert Einstein Medical Center, Philadelphia, Pennsylvania, USA.;Interventional Radiology, Albert Einstein Medical Center, Philadelphia, Pennsylvania, USA BradyP@einstein.edu.",
"authors": "Naveed|Mujtaba Zaki|MZ|;Wang|Peter|P|;Lee|Ryan|R|;Taghipour|Mehdi|M|;Brady|Paul|P|",
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"doi": "10.1136/neurintsurg-2020-016953",
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"issue": "13(10)",
"journal": "Journal of neurointerventional surgery",
"keywords": "Artery; CT; Hemorrhage; Subdural; Technology",
"medline_ta": "J Neurointerv Surg",
"mesh_terms": "D004621:Embolization, Therapeutic; D020200:Hematoma, Subdural, Chronic; D006801:Humans; D008576:Meningeal Arteries; D012189:Retrospective Studies; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "101517079",
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"pages": "964-967",
"pmc": null,
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"pubdate": "2021-10",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Utilizing dual energy CT to distinguish blood from contrast leakage following middle meningeal artery embolization for chronic subdural hematomas.",
"title_normalized": "utilizing dual energy ct to distinguish blood from contrast leakage following middle meningeal artery embolization for chronic subdural hematomas"
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"abstract": "Diarrhea is a common complication in kidney transplant recipients. Common causes of diarrhea include infection, side effect from medication, rejection, and malignancy. A less common but important cause of diarrhea is de novo inflammatory bowel disease (IBD). This is unexpected, as these patients are already immunosuppressed. Herein, we present the case of a 45-year-old man with end-stage kidney disease because of focal segmental glomerulosclerosis who underwent preemptive kidney transplantation, with his mother as donor. His immunosuppressive regimen included methylprednisolone, mycophenolate mofetil, and tacrolimus. He had no episodes of graft dysfunction, rejection, or infectious events. Two and a half years post-transplantation, he developed bloody diarrhea. After excluding infections, colonoscopy was performed and revealed edematous mucosa and erythema with pigmentation, which are typical findings in ulcerative colitis. Despite therapy with 5-aminosalicylate and granulocyte monocyte apheresis, he presented with massive bloody diarrhea. We initiated infliximab, an anti-tumor necrosis factor-α (TNF-α) agent. He responded very well and achieved remission within 6 months after initiation of infliximab, while administration of the other immunosuppressants was maintained. His course was uneventful and no complications developed. Management of immunosuppressants for de novo IBD after organ transplantation is complicated, because treatment of IBD, graft function protection, and prevention of infection must be considered. Therefore, cooperation between transplantation physicians and gastroenterologists is essential during therapy.",
"affiliations": "Kidney Disease and Transplant Center, Shonan Kamakura General Hospital, 1370-1 Okamoto, Kamakura, Kanagawa, 247-0072, Japan. oki.rikako@gmail.com.;Kidney Disease and Transplant Center, Shonan Kamakura General Hospital, 1370-1 Okamoto, Kamakura, Kanagawa, 247-0072, Japan.;Shonan Gastroenterology Medicine Center, Shonan Kamakura General Hospital, Kamakura, Japan.;Department of Pathology, Shonan Kamakura General Hospital, Kamakura, Japan.;Kidney Disease and Transplant Center, Shonan Kamakura General Hospital, 1370-1 Okamoto, Kamakura, Kanagawa, 247-0072, Japan.;Kidney Disease and Transplant Center, Shonan Kamakura General Hospital, 1370-1 Okamoto, Kamakura, Kanagawa, 247-0072, Japan.;Kidney Disease and Transplant Center, Shonan Kamakura General Hospital, 1370-1 Okamoto, Kamakura, Kanagawa, 247-0072, Japan.;Kidney Disease and Transplant Center, Shonan Kamakura General Hospital, 1370-1 Okamoto, Kamakura, Kanagawa, 247-0072, Japan.;Kidney Disease and Transplant Center, Shonan Kamakura General Hospital, 1370-1 Okamoto, Kamakura, Kanagawa, 247-0072, Japan.;Kidney Disease and Transplant Center, Shonan Kamakura General Hospital, 1370-1 Okamoto, Kamakura, Kanagawa, 247-0072, Japan.",
"authors": "Oki|Rikako|R|0000-0002-9713-8625;Hidaka|Sumi|S|;Sasaki|Akiko|A|;Teshima|Shinichi|S|;Mochida|Yasuhiro|Y|;Miyake|Katsunori|K|;Ishioka|Kunihiro|K|;Moriya|Hidekazu|H|;Ohtake|Takayasu|T|;Kobayashi|Shuzo|S|",
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"fulltext": "\n==== Front\nCEN Case Rep\nCEN Case Rep\nCEN Case Reports\n2192-4449\nSpringer Singapore Singapore\n\n33829404\n599\n10.1007/s13730-021-00599-6\nCase Report\nDe novo ulcerative colitis after kidney transplantation treated with infliximab\nhttp://orcid.org/0000-0002-9713-8625\nOki Rikako oki.rikako@gmail.com\n\n12\nHidaka Sumi 1\nSasaki Akiko 3\nTeshima Shinichi 4\nMochida Yasuhiro 1\nMiyake Katsunori 1\nIshioka Kunihiro 1\nMoriya Hidekazu 1\nOhtake Takayasu 1\nKobayashi Shuzo 1\n1 grid.415816.f 0000 0004 0377 3017 Kidney Disease and Transplant Center, Shonan Kamakura General Hospital, 1370-1 Okamoto, Kamakura, Kanagawa 247-0072 Japan\n2 grid.26999.3d 0000 0001 2151 536X Division of Nephrology and Endocrinology, The University of Tokyo, Tokyo, Japan\n3 grid.415816.f 0000 0004 0377 3017 Shonan Gastroenterology Medicine Center, Shonan Kamakura General Hospital, Kamakura, Japan\n4 grid.415816.f 0000 0004 0377 3017 Department of Pathology, Shonan Kamakura General Hospital, Kamakura, Japan\n7 4 2021\n7 4 2021\n11 2021\n10 4 500505\n24 11 2020\n27 3 2021\n© The Author(s) 2021\nhttps://creativecommons.org/licenses/by/4.0/ Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.\nDiarrhea is a common complication in kidney transplant recipients. Common causes of diarrhea include infection, side effect from medication, rejection, and malignancy. A less common but important cause of diarrhea is de novo inflammatory bowel disease (IBD). This is unexpected, as these patients are already immunosuppressed. Herein, we present the case of a 45-year-old man with end-stage kidney disease because of focal segmental glomerulosclerosis who underwent preemptive kidney transplantation, with his mother as donor. His immunosuppressive regimen included methylprednisolone, mycophenolate mofetil, and tacrolimus. He had no episodes of graft dysfunction, rejection, or infectious events. Two and a half years post-transplantation, he developed bloody diarrhea. After excluding infections, colonoscopy was performed and revealed edematous mucosa and erythema with pigmentation, which are typical findings in ulcerative colitis. Despite therapy with 5-aminosalicylate and granulocyte monocyte apheresis, he presented with massive bloody diarrhea. We initiated infliximab, an anti-tumor necrosis factor-α (TNF-α) agent. He responded very well and achieved remission within 6 months after initiation of infliximab, while administration of the other immunosuppressants was maintained. His course was uneventful and no complications developed. Management of immunosuppressants for de novo IBD after organ transplantation is complicated, because treatment of IBD, graft function protection, and prevention of infection must be considered. Therefore, cooperation between transplantation physicians and gastroenterologists is essential during therapy.\n\nKeywords\n\nKidney transplantation\nDe novo inflammatory bowel disease\nUlcerative colitis\nDiarrhea\nInfliximab\nissue-copyright-statement© Japanese Society of Nephrology 2021\n==== Body\npmcIntroduction\n\nWidespread use of immunosuppressive agents has dramatically improved patient and organ survival rates after kidney transplantation [1]. With the increase in number of kidney transplantations (KT), various complications have emerged in clinical practice that must be managed and investigated. Gastrointestinal (GI) adverse events are common after KT, with incidence of 20–50% in KT recipients [2]. Diarrhea is a common GI adverse event with various degrees of severity, from mild to fatal. Diarrhea can affect quality of life and drug absorption, and cause great physical burden to patients. Causes of diarrhea include infection, side effect from medication, rejection, and malignancy [2]. Although less common than other causes, de novo inflammatory bowel disease (IBD) was found to be an important cause of diarrhea [2]. Despite already being immunosuppressed, several recent reports demonstrated patients who developed de novo IBD following KT [2, 3]. However, the mechanism, treatment, and management of de novo IBD after solid organ transplantation remain under evaluation, with no standard criteria. An anti-tumor necrosis factor-α (TNF-α) therapy is known to one of options for a corticosteroid-dependent course of UC [4]. To date, there are only limited clinical experience regarding the use of anti TNF-α therapy in UC in KT recipients. Herein, we present the case of a 45-year-old man who developed refractory new-onset ulcerative colitis (UC) under various immunosuppressive agents, 2.5 years after KT. He did not respond to 5-aminosalicylate, standard therapy for UC and had successfully achieved clinical remission with infliximab, an anti TNF-α therapy.\n\nCase report\n\nA 45-year-old man with end-stage kidney disease because of focal segmental glomerulosclerosis successfully underwent preemptive kidney transplantation 5 years ago, with his mother as donor. His serum creatinine level remained within 1.3–1.4 mg/dL, and no urinary abnormalities were detected while taking tacrolimus (4.0 mg), methylprednisolone (2.0 mg), and mycophenolate mofetil (MMF, 750 mg). Trough level of tacrolimus was monitored once per month, and maintained at less than 5.0 ng/ml from 3 months after KT. Prior to the current presentation, pre-transplantation colonoscopy did not reveal evidence of malignancy or IBD. Following KT, he experienced no complications such as graft dysfunction, rejection episodes, or infectious events.\n\nTwo and a half years post-transplantation, he exhibited diarrhea with bloody stool over 10 times per day. Laboratory findings upon initial presentation of diarrhea did not reveal elevated white blood cell count (4.9 × 103/μl) or serum C-reactive protein (CRP, 0.1 mg/dL) (normal range, < 0.3 mg/dL). His serum creatinine level was 1.36 mg/dL without abnormal urinary findings, which was consistent with the baseline level. Hemoglobin and platelet count were normal (12.0 g/dL and 260 × 103/μl, respectively). Stool cultures were negative for routine bacteriological examination (Shigella, Escherichia coli, and Campylobacter). Stool specimens were also negative for Clostridium difficile toxin. Cytomegalovirus (CMV) infection was ruled out by histological examination of colonic biopsy specimens and negative result from antigenemia assay. Colonoscopy revealed edematous mucosa and erythema with pigmentation, which are typical findings in UC (Fig. 1a). Light microscopic examination of colonic mucosa samples revealed severe inflammation with decreased goblet cells, and crypt abscesses, diffuse stromal lymphoplasmacytic infiltration, and irregular glands, which are also consistent with UC (Fig. 1b). Regarding histological findings, an IBD-like pattern can be observed in MMF colitis [5]. Considering most cases of MMF colitis develop within the first 6 months after onset of treatment [5], in our patient, diarrhea was believed to have resulted from UC, rather than as a side effect of MMF. Therefore, he was started on 3,000 mg of 5-aminosalicylate (5-ASA) and underwent 10 sessions of granulocyte monocyte apheresis. However, he presented with massive bloody diarrhea and serum CRP levels elevated to 2.8–3.0 mg/dL 8 months after starting treatment with 5-ASA and apheresis. Follow-up colonoscopy showed significant deterioration, as there was mucosal erosion and spontaneous bleeding, which were not observed on prior colonoscopy (Fig. 2). CMV infection was excluded by histopathological examination of specimens obtained from colon biopsy. Therefore, he was administered infliximab, anti TNF-α therapy (5.0 mg/kg). Considering the risk of infection from use of multiple immunosuppressants, administration of methylprednisolone was suspended for 2 months and later resumed. He responded very well to the new regimen and achieved remission 6 months after initiation of infliximab. Infliximab has been administered every other month on a continuing basis. Outpatient management of UC has been carefully continued with uneventful clinical course. Follow-up colonoscopy 2 years after starting treatment with infliximab showed significant improvement, based on there being no mucosal erosion or spontaneous bleeding (Fig. 3).Fig. 1 Initial colonoscopy and colon biopsy findings. a Colonoscopy revealed edematous mucosa and erythema with pigmentation. b Light microscopic examination of colonic mucosa revealed severe inflammation with decreased goblet cells, and crypt abscesses, diffuse stromal lymphoplasmacytic infiltration, and irregular glands, which are consistent with UC (hematoxylin and eosin staining × 200)\n\nFig. 2 Colonoscopy finding 8 months after starting treatment with 5-ASA and apheresis. Colonoscopy showed mucosal erosion and spontaneous bleeding\n\nFig. 3 Follow-up colonoscopy 2 years after starting treatment with infliximab. Colonoscopy showed significant improvement of inflammation\n\nDiscussion\n\nWe report the detailed clinical course of a case of de novo UC after KT in the setting of multiple immunosuppressants. The patient achieved remission following initiation of anti TNF-α therapy (infliximab) without any complications, while the doses of other immunosuppressants were maintained. This case supports that anti TNF-α therapy has a potential to be safe treatment option in refractory de novo UC in KT patients.\n\nAlthough diarrhea is well recognized as a frequent complication following KT, there are no formal guidelines or criteria for its treatment [6]. The Diarrhea Diagnosis Aid and Clinical Treatment (DIDACT) study recommended stopping nonimmunosuppressive drugs associated with diarrhea, and performing microbiological stool examination and viral screening prior to adopting an immunosuppressive regimen [6]. Excluding infectious diseases is an important first step for diagnosis of diarrhea. In a study of 7,103 cases of post-transplant diarrhea, the 3-year cumulative incidence of diarrhea was 22%, over 80% of which were diagnosed with noninfectious diarrhea with unspecified cause [7]. Differentiating MMF-related colitis, CMV infection and post-transplant IBD is particularly challenging because of similar clinical and histological findings. Table 1 showed the endoscopic and histopathological characteristics of above differential diagnosis. The definitive diagnosis of CMV-colitis requires formalin-fixed tissue with immunochemistry and tissue polymerase chain reaction (PCR) [8]. MMF-related colitis is suspected by endoscopic and histological features shown in Table 1, and confirmed when improved only by discontinuation of MMF or a 50% reduction in the initial dose of MMF [8]. It seems essential to judge comprehensively for post-KT diarrhea by clinical symptoms, endoscopic findings, histopathological examination and therapeutic diagnosis. New onset of UC accounted for 13% of all incidences of diarrhea, and was associated with increased risk of graft failure (hazard ratio: 1.31, confidence interval: 1.13–1.52, p < 0.05) [7]. According to another report, the incidence of de novo IBD after solid organ transplantation is 10 times higher than that in the overall population (20/100,000 patient-years vs. 206/100,000 patient-years) [9]. Table 2 demonstrated the previously published cases of de novo IBD after kidney transplantation.Table1 Clinical and histological characteristics of diarrhea in KT recipients\n\n\tEndoscopic findings\tHistological findings\t\nMMF related colitis [5, 8]\tErosions, hyperemia, erythema,\tEosinophils and plasma cells infiltrate, withered crypts, apoptotic bodies\t\nCMV infection [8]\tPatchy erythema, exudates, microerosions\tEnterocyte apoptosis, inclusion bodies\t\nde novo UC [4, 16]\tErythema, loss of normal vascular pattern, granularity, erosions, friability, bleeding, and ulcerations\tChronic active colitis limited to the rectum\t\nDe novo Crohn [8]\tIleitis with multiple ulcers\tExpansion of the lamina propria, crypt architectural distortion\t\n\nTable2 previously published cases of de novo IBD after kidney transplantation\n\nAuthor\tAge, sex\tOriginal disease of kidney dysfunction\tPresentation of IBD\tMaintenance immunosuppressant\tRejection\tDuration from kt to uc onset\tTreatment for uc\tPatient outcome\t\nP. Azevedo [17]\t52/M\tIgA nephropathy\tUC\tTAC, MMF\tNone\t5 months\tSteroid, 5-ASA\tClinical remission\t\nP. Azevedo [17]\t42/F\tFamilial nephropathy\tCD\tTAC, MMF, steroid\tNone\t5 years\t5-ASA, steroid\tClinical remission\t\nP. Azevedo [17]\t40/F\tAnti-GBM disease\tCD\tTAC, MMF, steroid\tNone\t10 years\t5-ASA, steroid, AZA\tClinical remission\t\nJ. Passfall [18]\t60/M\tUnknown origin\tUC\tCyA\tNone\t6 years\tSulfasalazine, steroid, 5-ASA\tClinical remission\t\nA. Hibbs [19]\t4/M\tGood pasture disease\tUC\tCyA, steroid,AZA\tNone\t4 years\tSurgery\tClinical remission\t\nO. Gheith [20]\t26/M\tIgA nephropathy\tUC\tCyA, MMF,steroid\tNone\t5 years\tSulfasalazine\tClinical remission\t\nM. Fernandes* [21]\t6/M\tMesangial sclerosis\tIBD\tTAC,MMF,steroid\t–\t3 years\t5-ASA, steroid, AZA\tClinical remission\t\nM. Fernandesa [21]\t13/M\tPosterior urethral valves\tIBD\tTAC,MMF,steroid\t–\t11 years\tSteroid, AZA\tClinical remission\t\nR. Riley [22]\t36/M\tObstructive uropathy\tIBD\tCyA,steroid\t–\t–\tSulfasalazine\tClinical remission\t\nR. Riley [22]\t39/F\tPolycystic kidney disease\tIBD\tCyA,steroid\t–\t–\tSteroid\tIntermittent flares\t\nM male, F female, UC ulcerative colitis, CD Crohn disease, GBM glomerular basement membrane, TAC tacrolimus, MMF Mycophenolate Mofetil, AZA azathioprine, CyA Cyclosporine A,5-ASA 5-aminosalicylic acid\n\naThese cases are reported as IBD-like chronic intestinal inflammation\n\nAlthough the pathogenesis of de novo IBD after solid organ transplantation remains unclear, some potential mechanisms have been suggested. It was suggested that tacrolimus increases the risk of post-transplant IBD [9]. Haagsma et al. reported that IBD-free survival was significantly higher in patients not receiving tacrolimus, compared with those receiving tacrolimus [10]. Tacrolimus suppresses interleukin-2 production, which reduces generation of regulatory T cells, which in turn are necessary for immunological homeostasis in the intestine [11]. Additionally, mice deficient in interleukin-2 were shown to develop IBD [12]. In our case, long-term use of tacrolimus may have triggered de novo UC. Given the risk of rejection, we did not decrease the dose of tacrolimus. It is well known that MMF is associated with GI side effects, with incidence of approximately 45% in patients receiving the drug [5]. However, whether MMF is related to development of de novo IBD remains controversial [9]. Pretransplant IBD was also reported to be an independent predictor associated with IBD after transplantation [9]. This fact was not applicable in our case because the patient had no history of GI complaints and there were no abnormal findings on colonoscopy pretransplantation.\n\nGenerally, 5-ASA is the preferred first-line treatment for UC and oral steroids should be considered for patients who do not respond adequately to 5-ASA [4]. Patients with steroid dependent UC should be treated with an either azathioprine, 6-mercaptopurine, TNF-inhibitor or vedolizumab [4]. Regarding treatment for de novo UC after KT, no standard protocol has been established because of complexities arising from combined use of common IBD therapy and antirejection therapy. Considering previously published data of de novo UC cases in Table 2, 5-ASA, steroid or sulfasalazine have implicated in protective control against deterioration in IBD activity. TNF-α antibody (infliximab) is an established option for refractory IBD [4], but application for KT patients is still a matter of debate. Temme et al. reported the first case reports which demonstrated the clinical remission using infliximab for KT recipients with steroid-refractory UC diagnosed before KT [13]. Garrouste et al. reported seven KT recipients with IBD (5 patients with Crohn’s disease and 2 patients with UC) who were treated with anti-TNF-α therapy. According to their report, over 80% of patients achieved clinical responses [14]. Nonetheless, several complications were observed. Two patients developed infections and developed cancer [14]. In one case with Crohn disease, both acute antibody-mediated rejection and acute T-cell-mediated rejection occurred [14]. In our case, clinical remission has been maintained without any complications such as serious infection events, cancer or rejection. For preventing serious infection and rejection, elaborating the use of multiple immunosuppressants could be a value. We decided to suspend administration of methylprednisolone for 2 months at the timing of anti TNF-α therapy initiation. Confirming that no serious infections developed, methylprednisolone was resumed to reduce the risk of rejection. Williams et al. reported that anti-TNFα therapy was not associated with an increased risk of malignancy in patients with IBD [15]. Regulating bowel inflammation by anti TNF-α therapy might rather contribute to lower the risk of colon cancer. Therefore, anti TNF-α therapy with careful attention to prevention of infection and protection of graft function, could be a therapeutic alternative during aggravation of symptoms in a refractory case.\n\nIn conclusion, we report the detailed clinical course of a case of new-onset UC after KT treated with anti TNF-α therapy. De novo IBD should be considered a differential diagnosis in patients presenting post-transplantation diarrhea. Comprehensive evaluation with prompt colonoscopy and histopathological examination is recommended. Cooperation between transplantation physicians and gastroenterologists is essential during therapy.\n\nDeclarations\n\nConflict of interests\n\nThe authors have declared that no conflict of interest exists.\n\nHuman and animal rights\n\nThis article does not contain any studies with human participants or animals performed by any of the authors.\n\nInformed consent\n\nInformed consent was obtained from all individual participants included in the study.\n\nPublisher's Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Hariharan S Johnson CP Bresnahan BA Taranto SE McIntosh MJ Stablein D Improved graft survival after renal transplantation in the United States, 1988 to 1996 N Engl J Med 2000 342 605 612 10.1056/NEJM200003023420901 10699159\n2. Kurnatowska I Banasiak M Daniel P Wągrowska-Danilewicz M Nowicki M Two cases of severe de novo colitis in kidney transplant recipients after conversion to prolonged-release tacrolimus Transpl Int 2010 23 5 553 558 10.1111/j.1432-2277.2009.01009.x 19951264\n3. Parameswaran S Singh K Nada R Rathi M Kohli H Jha V Ulcerative colitis after renal transplantation: A case report and review of literature Indian J Nephrol 2011 21 120 122 10.4103/0971-4065.78063 21769176\n4. Burri E Maillard MH Schoepfer AM Seibold F Van Assche G Rivière P Treatment algorithm for mild and moderate-to-severe ulcerative colitis: an update Digestion 2020 101 2 15 10.1159/000504092 31945767\n5. Calmet FH Yarur AJ Pukazhendhi G Ahmad J Bhamidimarri KR Endoscopic and histological features of mycophenolate mofetil colitis in patients after solid organ transplantation Ann Gastroenterol 2015 28 364 371\n6. Maes B Hadaya K De Moor B Cambier P Peeters P De Meester J Severe diarrhea in renal transplant patients: Results of the DIDACT study Am J Transplant 2006 6 1466 1472 10.1111/j.1600-6143.2006.01320.x 16686772\n7. Bunnapradist S Neri L Wong W Lentine KL Burroughs TE Pinsky BW Incidence and risk factors for diarrhea following kidney transplantation and association with graft loss and mortality Am J Kidney Dis 2008 51 478 486 10.1053/j.ajkd.2007.11.013 18295064\n8. Gioco R Corona D Ekser B Puzzo L Inserra G Pinto F Gastrointestinal complications after kidney transplantation World J Gastroenterol 2020 26 5797 5811 10.3748/wjg.v26.i38.5797 33132635\n9. Gerdner L a. World Journal of Psychiatry. World J Psychiatry. 2012;2:26–32.\n10. Haagsma EB Van Den Berg AP Kleibeuker JH Slooff MJH Dijkstra G Inflammatory bowel disease after liver transplantation: The effect of different immunosuppressive regimens Aliment Pharmacol Ther 2003 18 33 44 10.1046/j.1365-2036.2003.01613.x 12848624\n11. Verdonk RC Dijkstra G Haagsma EB Shostrom VK Van Den Berg AP Kleibeuker JH Inflammatory bowel disease after liver transplantation: Risk factors for recurrence and de novo disease Am J Transplant 2006 6 1422 1429 10.1111/j.1600-6143.2006.01333.x 16686766\n12. Sadlack B Merz H Schorle H Schimpl A Feller AC Horak I Ulcerative colitis-like disease in mice with a disrupted interleukin-2 gene Cell 1993 75 253 261 10.1016/0092-8674(93)80067-O 8402910\n13. Temme J, Koziolek M, Bramlage C, Schaefer IM, Füzesi L, Ramadori G, et al. Infliximab as therapeutic option in steroid-refractory ulcerative colitis after kidney transplantation: Case report. Transplant Proc [Internet]. Elsevier Inc.; 2010;42:3880–2. Available from: 10.1016/j.transproceed.2010.08.044\n14. Garrouste C, Anglicheau D, Kamar N, Bachelier C, Rivalan J, Pereira B, et al. Anti-TNFα therapy for chronic inflammatory disease in kidney transplant recipients Clinical outcomes. Med (United States). 2016;95.\n15. Williams CJM Peyrin-Biroulet L Ford AC Systematic review with meta-analysis: malignancies with anti-tumour necrosis factor-α therapy in inflammatory bowel disease Aliment Pharmacol Ther England 2014 39 447 458 10.1111/apt.12624\n16. Mosli MH Feagan BG Zou G Sandborn WJ D’Haens G Khanna R Development and validation of a histological index for UC Gut England 2017 66 50 58 10.1136/gutjnl-2015-310393\n17. Azevedo P Freitas C Aguiar P Silva H Santos T Farrajota P A case series of de novo inflammatory bowel disease after kidney transplantation Transplant Proc United States 2013 45 1084 1087 10.1016/j.transproceed.2013.03.008\n18. Passfall J Distler A Riecken EO Zeitz M Development of ulcerative colitis under the immunosuppressive effect of cyclosporine Clin Investig 1992 70 611 613 10.1007/BF00184805\n19. Hibbs AM Bznik-Cizman B Guttenberg M Goldberg B Meyers K Ulcerative colitis in a renal transplant patient with previous Goodpasture disease Pediatr Nephrol Germany 2001 16 543 546 10.1007/s004670100600\n20. Gheith O Al-Otaibi T Tawab KA Said T Balaha MA Halim MA Erythema nodosum in renal transplant recipients: multiple cases and review of literature Transpl Infect Dis Denmark 2010 12 164 168 10.1111/j.1399-3062.2009.00474.x\n21. Fernandes MA, Braun HJ, Evason K, Rhee S, Perito ER. De novo inflammatory bowel disease after pediatric kidney or liver transplant. Pediatr Transplant. 2017;21.\n22. Riley TR Schoen RE Lee RG Rakela J A case series of transplant recipients who despite immunosuppression developed inflammatory bowel disease Am J Gastroenterol United States 1997 92 279 282\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2192-4449",
"issue": "10(4)",
"journal": "CEN case reports",
"keywords": "De novo inflammatory bowel disease; Diarrhea; Infliximab; Kidney transplantation; Ulcerative colitis",
"medline_ta": "CEN Case Rep",
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"pubdate": "2021-11",
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"title": "De novo ulcerative colitis after kidney transplantation treated with infliximab.",
"title_normalized": "de novo ulcerative colitis after kidney transplantation treated with infliximab"
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"abstract": "There are few data on the impact of COVID-19 in pregnancy, however, analyzing these data is important to guide the clinical practice, covering the early prevention, detection, patients' isolation, epidemiological investigation, diagnosis and early treatment. This is a report of three cases of COVID-19 confirmed by real-time reverse transcription - polymerase chain reaction (RT-PCR) of nasopharyngeal secretions collected in swabs from pregnant women in the city of Vitoria, Espirito Santo State, Brazil. In the three cases, all the patients presented with fever, one had shortness of breath, one had diarrhea, two of them reported abdominal pain and two of them had cough. The three patients progressed with a severe clinical evolution of COVID-19. The permanence in the intensive care unit (ICU) was more than 10 days. Two of them recovered and one remained in the ICU with irreversible refractory shock, multiple organ failure and died. The mode of delivery was individualized and based on the obstetric indication and severity of the maternal infection, and the cesarean section was indicated in the two severe maternal COVID-19 cases that evolved favorably. These newborns were premature and tested negative for COVID-19 by RT-PCR.",
"affiliations": "Programa de Pós Graduação em Doenças Infecciosas, Universidade Federal do Espírito Santo, Vitória, Espírito Santo, Brazil.;Departamento de Ginecologia e Obstetrícia, Universidade Federal do Espírito Santo, Vitória, Espírito Santo, Brazil.;Programa de Residência Médica em Ginecologia e Obstetrícia, Universidade Federal do Espírito Santo, Vitória, Espírito Santo, Brazil.;Programa de Residência Médica em Ginecologia e Obstetrícia, UNIMED Vitória, Vitória, Espírito Santo, Brazil.;Programa de Pós Graduação em Doenças Infecciosas, Universidade Federal do Espírito Santo, Vitória, Espírito Santo, Brazil.;Programa de Pós Graduação em Doenças Infecciosas, Universidade Federal do Espírito Santo, Vitória, Espírito Santo, Brazil.",
"authors": "Reis|Helena Lucia Barroso Dos|HLBD|;Boldrini|Neide Aparecida Tosato|NAT|;Caldas|João Victor Jacomele|JVJ|;Paz|Ana Paula Calazans da|APCD|;Ferrugini|Carolina Loyola Prest|CLP|;Miranda|Angelica Espinosa|AE|",
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"doi": "10.1590/s1678-9946202062049",
"fulltext": "\n==== Front\nRev Inst Med Trop Sao Paulo\nRev. Inst. Med. Trop. Sao Paulo\nrimtsp\nRevista do Instituto de Medicina Tropical de São Paulo\n0036-4665 1678-9946 Instituto de Medicina Tropical \n\n00513\n10.1590/S1678-9946202062049\nCase Report\nSevere coronavirus infection in pregnancy: challenging cases report\nhttp://orcid.org/0000-0003-2018-2529dos Reis Helena Lucia Barroso \n1\n Boldrini Neide Aparecida Tosato \n2\n Caldas João Victor Jacomele \n3\n da Paz Ana Paula Calazans \n4\n Ferrugini Carolina Loyola Prest \n1\n Miranda Angelica Espinosa \n1\n \n1 Universidade Federal do Espírito Santo, Programa de Pós Graduação em Doenças Infecciosas, Vitória, Espírito Santo, Brazil\n\n2 Universidade Federal do Espírito Santo, Departamento de Ginecologia e Obstetrícia, Vitória, Espírito Santo, Brazil\n\n3 Universidade Federal do Espírito Santo, Programa de Residência Médica em Ginecologia e Obstetrícia, Vitória, Espírito Santo, Brazil\n\n4 UNIMED Vitória, Programa de Residência Médica em Ginecologia e Obstetrícia Vitória, Espírito Santo, Brazil.\nCorrespondence to: Helena Lucia Barroso dos Reis, Universidade Federal do Espírito Santo, Hospital Universitário Cassiano Antonio Moraes, Avenida Marechal Campos, 1468, Maruípe, CEP 29043-260 Vitória, ES, Brazil Tel: +55 27 3335-7180 E-mail:dr.hbarroso@gmail.comCONFLICT OF INTERESTS\n\nThe authors have no conflict of interests to declare.\n\n\n13 7 2020 \n2020 \n62 e4920 6 2020 01 7 2020 This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.ABSTRACT\nThere are few data on the impact of COVID-19 in pregnancy, however, analyzing these data is important to guide the clinical practice, covering the early prevention, detection, patients’ isolation, epidemiological investigation, diagnosis and early treatment. This is a report of three cases of COVID-19 confirmed by real-time reverse transcription – polymerase chain reaction (RT-PCR) of nasopharyngeal secretions collected in swabs from pregnant women in the city of Vitoria, Espirito Santo State, Brazil. In the three cases, all the patients presented with fever, one had shortness of breath, one had diarrhea, two of them reported abdominal pain and two of them had cough. The three patients progressed with a severe clinical evolution of COVID-19. The permanence in the intensive care unit (ICU) was more than 10 days. Two of them recovered and one remained in the ICU with irreversible refractory shock, multiple organ failure and died. The mode of delivery was individualized and based on the obstetric indication and severity of the maternal infection, and the cesarean section was indicated in the two severe maternal COVID-19 cases that evolved favorably. These newborns were premature and tested negative for COVID-19 by RT-PCR.\n\nKEYWORDS:\nCOVID-19SARS-CoV-2PregnancyInfectious disease transmissionSevere acute respiratory syndrome\n==== Body\nINTRODUCTION\nA new coronavirus known as the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was reported in 2019 and associated with pneumonia, causing a disease known as the coronavirus disease COVID-19. It is an emergent infectious disease that was first documented in Wuhan, China, and the World Health Organization (WHO) has declared it a global public health emergency and a pandemia \n1\n . Studies on the effects of COVID-19 during pregnancy are limited; however, owing to the high transmissibility of the virus and the possible development of severe acute respiratory symptoms, it is crucial that COVID-19 is investigated in the routine clinical practice of obstetrics.\n\nPregnant women represent an important challenge in the course of the pandemic. These patients need to attend to at least monthly medical consultations throughout the course of their prenatal care visits and for the delivery \n2\n . These appointments place them at a higher risk of contracting COVID-19 at the hospital environment or in outpatient clinics, although at this moment, the impact of COVID-19 on pregnancy and on newborn infants remains unclear. A Chinese study which tested amniotic fluid, cord blood, neonatal throat swabs, and breast milk samples from COVID-19-infected mothers found that all the samples tested negative for the virus, and another study determined that three placentas of pregnant women infected by COVID-19 tested negative for the virus \n3\n\n,\n\n4\n . However, the transmission rates from mothers to the newborns remain unknown. Assessment of clinical data to better understand the effects of COVID-19 in obstetrics will provide an opportunity to protect pregnant women, their offspring and the healthcare teams involved in their care.\n\nThis study reports three cases of COVID-19 comprising pregnant women with severe respiratory failure and evaluates the clinical management of COVID-19 infection in obstetric clinics in Vitoria, Espirito Santo State, Brazil.\n\nCASE REPORTS\nCase 1\nA 28-year-old pregnant woman who worked as a nursing assistant, was a primigravida with 31 weeks of gestation age who sought the emergency unit with fever and hyperemic lesions in the right lower limb, suggestive of a bacterial skin infection. The patient did not smoke or report a prior history of asthma, tuberculosis or pneumonia. Treatment was initiated with intravenous ceftriaxone (2 g) associated with 40 IU per day of heparin, though after two days, the patient began to exhibit acute dyspnea. The room oxygen saturation was found to be 95%, and symptoms were accompanied by tachypnea and hypotension. Fifteen liters of oxygen per minute were provided by mask, and the patient was transferred to the intensive care unit (ICU) of another public institution. She was admitted in critical conditions requiring urgent intubation and mechanical ventilation. The lactate dehydrogenase (LDH) was 268 U/L, D-dimer less than 300 ng/mL (normal values below 500 ng/mL) and 3,900 white blood cells (WBC). Computed tomography (CT) scans revealed bilateral patchy ground glass opacities, and the patient was considered as a suspicious case of SARS-CoV-2 infection. Considering the CT findings and the severe evolution in the third trimester of gestation, she was medicated with 500 mg azithromycin per day, 75 mg oseltamivir phosphate twice a day and 400 mg hydroxychloroquine twice a day for five days, in addition to the ventilation support. Pulmonary embolism was excluded by using specific diagnostic tests.\n\nShe tested negative for coronavirus by the real-time reverse transcription polymerase chain reaction (RT-PCR) testing nasopharyngeal secretions swabs during the initial hospitalization. Owing to the severe clinical conditions, a cesarean section (C-section) was performed. A healthy 31-week gestational age infant, weighting 2,380 g, was delivered and transferred to the neonatal care unit because of the prematurity, the Apgar score was 8 on the 1st minute of life and 9 on the 5th minute and the preterm newborn was adequate for gestation age. The puerperal woman remained hospitalized for 18 days in the intensive care unit (ICU) due to her respiratory conditions, receiving supportive care. The patient tested positive for COVID-19 by RT-PCR on the 12th day after hospitalization. The newborn tested negative for COVID-19 by RT-PCR and was released after 5 days. The puerperal woman evolved favorably and was discharged without sequelae after 23 days.\n\nCase 2\nA 34-year-old puerperal woman who was a housewife in her second pregnancy, with one previous delivery, sought the emergency unit on the fifth day after delivery owing to an acute respiratory insufficiency. She did not report abnormalities during the antenatal care or during hospitalization for delivery. Her medical record showed that she gave birth by C-section at 40 weeks of gestational age and gave birth to a female newborn, weighing 3,875 g, with an Apgar score of 8 and 9 in the 1st and 5th minutes, respectively. The mother reported severe dry cough and acute dyspnea associated with lower back pain and mild fever occurring 24 hours before the hospitalization. The chest CT scan was suggestive of viral pneumonia with an acute inflammatory feature compromising 25 to 40% of the pulmonary parenchyma, but the findings were not suggestive of COVID-19. The angiotomograpy of the thorax was negative for pulmonary embolism and the oxygen saturation was 91%. The LDH was 328 U/L, D-dimer less than 300 ng/mL and the initial leukogram showed 5,000 WBC.\n\nThe patient was medicated with ceftriaxone (2 g/day), azithromycin (500 mg/day), oseltamivir (75 mg twice a day), and enoxaparin (initially with 40 mg daily, with increments up to 80 mg/day). The RT-PCR for SARS-CoV-2 was positive three days after the delivery, and hydroxychloroquine (400 mg twice a day) was administered initially, followed by 400 mg daily for five subsequent days along with meropenem (500 mg three times a day) and vancomycin (1 g twice a day). Ceftriaxone was discontinued.\n\nAfterwards, the patient's respiratory condition worsened, she remained in the ICU in critical conditions with a persistent high fever that last 13 days, receiving supportive care covering oxygenation, ventilation, and vasoactive drugs. The patient no longer needed the ICU hospitalization following this period and was transferred to the rehabilitation ward. Her husband and the newborn tested negative for COVID-19.\n\nCase 3\nA 25-year-old pregnant woman, who was a housewife in her third pregnancy and two previous deliveries, was referred to the hospital at 28 weeks and six days of gestational age with upper respiratory symptoms, fever, myalgia, and diarrhea for five days. Thereafter, the patient's clinical condition worsened to a non-productive cough and intense fatigue. She did not report comorbidities, but her husband presented with fever in the previous 24 hours and reported contact with two coworkers that had positive tests for COVID-19. She was transferred to the ICU. Corticosteroid therapy with 2 g hydrocortisone was initiated to accelerate the fetal lung maturation along with oseltamivir, azithromycin, ceftriaxone, and enoxaparin in standardized doses. The patient also needed mechanical ventilation. D-dimer levels were normal (308 ng/mL), and pulmonary embolism was excluded using specific diagnostic tests. The oxygen saturation was 94% and the initial leukogram showed 4,000 WBC and 11% of lymphocytes.\n\nThe COVID-19 serological tests resulted negative twice, while the RT-PCR on nasopharyngeal swab secretions was positive for SARS-CoV-2. Hydroxychloroquine was initiated (400 mg twice a day), followed by 400 mg daily for five subsequent days. A C-section was performed owing to the critical conditions of the mother, as well as severe oligohydramnios.\n\nA female infant weighing 1,255 g, adequate for gestational age was delivered. The Apgar score was 6 on the 1st minute and 7 on the 5th minute. The newborn tested negative for COVID-19 by RT-PCR, but was referred to the neonatal ICU because of the extreme prematurity, where she underwent a systemic antibiotic therapy owing to a right hemi thorax atelectasis. The neonate was released after 30 days in good conditions.\n\nThe mother remained in the ICU for 22 days, where she was treated with meropenem (500 mg three times a day) associated with vancomycin (1 g twice a day) and polymyxin-B, requiring intubation and mechanical ventilation. The LDH result went from 226 U/L to 524 U/L during the hospitalization. . Despite the ICU stay and a continuous epinephrine drip, the patient's blood pressure decreased to 60/40 mmHg and her condition evolved to irreversible refractory shock, multiple organ failure and death. The blood cultures were all negative.\n\nDISCUSSION\nThere is not yet unequivocal scientific evidence of mother-to-child transmission (MTCT) of COVID-19; whether a cesarean section could prevent transmission, whether vaginal delivery is free of additional risks, or whether the time of delivery should be anticipated \n2\n\n,\n\n3\n .\n\nCurrent recommendations are that cases should be individualized according to the instruction of the obstetrician and the degree of severity of the maternal conditions \n2\n . However, it is consensual that infection by the SARS-CoV-2 virus during pregnancy may increase the risk of maternal and fetal health deterioration because COVID-19 is an infectious disease that can evolve to severe pneumonia and admissions to the ICU, potentially resulting in the anticipation of deliveries before the pregnancy full term \n4\n . This situation occurred in two of the three cases reported, in all the cases, the patients presented with fever and the patients’ clinical conditions worsen quickly.\n\nThe patients’ ICU hospitalization were all more than 10 days. Two of them recovered, and one remained in the ICU and developed refractory shock, progressing to death.\n\nThe newborns were premature in two of the three cases due to the need to perform the C-section, but none of the newborns presented symptoms of infection, and all three tested negative for COVID-19 using RT-PCR that tested nasopharyngeal secretions. Two of the newborns were only admitted to the ICU because of their prematurity. Table 1 summarizes the findings in the three cases.\n\nTable 1 Summary of data from the three pregnant women diagnosed with COVID-19 and their initial diagnoses.\nVariables\tPatient 1\tPatient 2\tPatient 3\t\nAge (years)\t28\t34\t25\t\nGravida (parity)\t1 (0)\t1 (1)\t3 (2)\t\nGestational age at admission in weeks\t31\t1 day after delivery\t28 and 6 days\t\nFever (days)\tYes (3)\tYes (4)\tYes (14)\t\nCough\tNo\tYes\tYes\t\nShortness of breath\tNo\tYes\tYes\t\nDiarrhoea\tNo\tNo\tYes\t\nAbdominal pain\tYes\tNo\tYes\t\nPrevious comorbidities\tNo\tNo\tNo\t\nDelivery mode *\n\tC-section\tC-section\tC-section\t\nBirth outcome\tPreterm\tTerm\tPreterm\t\nApgar Score on the 1st and 5th minutes\t8:9\t8:9\t6:7\t\nFetal Growth\tAGA\tAGA\tAGA\t\nInfants’ COVID-19 RT-PCR\tNegative\tNegative\tNegative\t\nPregnancy complications\tNo\tNo\tNo\t\nInitial leukogram\t3,900/mm3\n\t5,000/ mm3\n\t4,000/mm3 Lymphocytes 11 %\t\nSPO2 - ARDS\t95-70%\t91-60%\t94-60%\t\nSerial C-reactive protein (mg/L):\t8 → 36.5\t70 → 78.6\t55.1 → 163.4\t\nLDH (U/L)\t268\t328\t540\t\nD-dimer (ng/mL)\t< 300\t<300\t308\t\nSerial blood cultures\tNA\tNA\tNegative\t\n* C-section was indicated because of the severity of the infection in two cases.\n\nAGA = Adequate for gestational age; Elevated C-reactive protein (mg/L) was considered ≥10 mg/L; Normal D-dimer value up to 500 ng/mL; O2 values are as reported at the time of diagnosis of ARDS and intubation; ARDS = Acute respiratory distress syndrome; RT-PCR = Real-time reverse transcription – polymerase chain reaction; NA = Not available; LDH = Lactate dehydrogenase.\n\nIn Brazil, there are other suggested cases of maternal mortality due to COVID-19 \n5\n . It can also be noted that the conditions of the women infected with SARS-CoV-2 during pregnancy progressed within a short period from the infection transmission and incubation period. Case 1 was admitted with a suggested bacterial skin infection, and her condition progressed to pneumonia in a few days. A previous study in China described 12.6% cases of COVID-19 presymptomatic patients; they have also reported a mean interval of 3.96 days between pre-symptoms and the diagnosis \n6\n . It is important to be attentive and perform a good anamnesis and physical examination to identify these situations.\n\nAccording to another Chinese study, the characteristics of pneumonia in pregnant women with COVID-19 do not differ from pneumonia in non-pregnant women. In a small group of nine infected pregnant women, there was no evidence of vertical transmission of COVID-19 in those who acquired the virus and developed pneumonia at the end of the pregnancy. All the patients underwent a cesarean section and all the newborns were tested for the virus and had negative results \n3\n . Another study including 43 confirmed COVID-19 pregnant women in New York city reported a 4.7% rate of critical illness; these data were similar to the ones described for non-pregnant adults with COVID-19 infections \n7\n . Similar findings were also observed in a study of pregnant Chinese women infected with COVID-19 in which there were no maternal deaths or confirmed cases of intrauterine transmission of the infection to the fetuses \n8\n\n,\n\n9\n . In the three cases examined here, all the patients initially presented with fever; one had shortness of breath, one had diarrhea, two reported abdominal pain, and two had cough. All three patients’ clinical conditions progressed rapidly.\n\nThere are still gaps regarding the MTCT and newborn infection; a case report of a pregnant woman with coronavirus infection and a newborn infected with SARS-CoV-2 36 hours after delivery was identified; however, confirmation of MTCT was not established \n10\n . A possible case of MTCT was also described elsewhere, but the newborn's RT-PCR result was negative \n11\n . Children with COVID-19 seem not to be frequently recognized, and most of those identified had only mild symptoms \n12\n .\n\nIn addition, a morphological placental study of a series of three neonatal cases of mothers infected with COVID-19 found no changes related to the infection \n4\n . Unfortunately, amniotic fluid and placenta were not tested by RT-PCR in our cases. In the patients examined here, two of the newborns were premature because of the urgency of the C-section, but they did not present symptoms of the SARS-CoV-2 infection, indicating there was no MTCT. It is also uncertain whether our institution's empiric administration of hydroxychloroquine enabled the patients’ recovery (cases 1 and 2). Currently, there is no official recommendation of chloroquine or hydroxychloroquine for COVID-19 treatment. The use of these drugs in pregnant women should only be considered if their benefits outweight the adverse effects \n13\n .\n\nAn interesting finding in this study was that case 1 was a health professional; this highlights the extra concern about the security measures regarding the protection of front-line workers from contamination. In Brazil, the only study on COVID-19 during pregnancy to date has been a review of initial data on pregnancy and the implications for assisted reproductive treatments; this study recommended postponing pregnancies \n14\n . As COVID-19 is a new challenge for health professionals and its impact on mothers and children is unknown, new studies are needed to understand the impact on pregnant women to generate evidence for improving its clinical management, treatment, and prevention.\n\nCONCLUSION\nThere is still no clinical evidence regarding the timing of delivery, vertical transmission, or the safety of vaginal delivery in pregnant women with COVID-19. The mode of delivery must be individualized, based on the obstetric indication, the severity of the maternal infection, and cesarean sections should be indicated in severe cases. To our knowledge, this is one of the first published reports on the death of a Brazilian pregnant women with confirmed COVID-19 infection.\n\nETHICS\n\nThe women had not identified their identity compromised. The ethical review board of the university hospital approved the study.\n\nFUNDING\n\nThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\n==== Refs\nREFERENCES\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 382 727 733 31978945 \n2 Chen D Yang H Cao Y Cheng W Duan T Fan C Expert consensus for managing pregnant women and neonates born to mothers with suspected or confirmed novel coronavirus (COVID-19) infection Int J Gynaecol Obstet 2020 149 130 136 32196655 \n3 Chen H Guo J Wang C Luo F Yu X Zhang W Clinical characteristics and intrauterine vertical transmission potential of COVID-19 infection in nine pregnant women: a retrospective review of medical records Lancet 2020 395 809 815 32151335 \n4 Chen S Huang B Luo DJ Li X Yang F Zhao Y Pregnant women with new coronavirus infection: a clinical characteristics and placental pathological analysis of three cases Zhonghua Bing Li Xue Za Zhi 2020 49 418 423 32114744 \n5 Amorim MM Soligo Takemoto ML Fonseca EB Maternal deaths with coronavirus disease 2019: a different outcome from low- to middle-resource countries? Am J Obstet Gynecol 2020 In Press \n6 Du Z Xu X Wu Y Wang L Cowling BJ Meyers LA Serial interval of COVID-19 among publicly reported confirmed cases Emerg Infect Dis 2020 26 1341 1343 32191173 \n7 Breslin N Baptiste C Gyamfi-Bannerman C Miller R Martinez R Bernstein K COVID-19 infection among asymptomatic and symptomatic pregnant women: Two weeks of confirmed presentations to an affiliated pair of New York City hospitals Am J Obstet Gynecol MFM 2020 2 100118 100118 \n8 Schwartz DA An analysis of 38 Pregnant women with COVID-19, their newborn infants, and maternal-fetal transmission of SARS-CoV-2: maternal coronavirus infections and pregnancy outcomes Arch Pathol Lab Med 2020 In Press \n9 Zhu H Wang L Fang C Peng S Zhang L Chang G Clinical analysis of 10 neonates born to mothers with 2019-nCoV pneumonia Transl Pediatr 2020 9 51 60 32154135 \n10 Wang S Guo L Chen L Liu W Cao Y Zhang J Feng L A case report of neonatal COVID-19 infection in China Clin Infect Dis 2020 ciaa225 In Press \n11 Dong L Tian J He S Zhu C Wang J Liu C Yang J Possible vertical transmission of SARS-CoV-2 from an infected mother to her newborn JAMA 2020 323 1846 1848 \n12 Shen KL Yang YH Diagnosis and treatment of 2019 novel coronavirus infection in children: a pressing issue World J Pediatr 2020 16 219 221 32026147 \n13 Lacroix I Bénévent J Damase-Michel C Chloroquine and hydroxychloroquine during pregnancy: what do we know? Therapie 2020 In Press \n14 Monteleone PA Nakano M Lazar V Gomes AP Martin H Bonetti TC A review of initial data on pregnancy during the COVID-19 outbreak: implications for assisted reproductive treatments JBRA Assist Reprod 2020 24 219 225 32301600\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "0036-4665",
"issue": "62()",
"journal": "Revista do Instituto de Medicina Tropical de Sao Paulo",
"keywords": null,
"medline_ta": "Rev Inst Med Trop Sao Paulo",
"mesh_terms": "D000328:Adult; D000073640:Betacoronavirus; D001938:Brazil; D000086382:COVID-19; D002585:Cesarean Section; D018352:Coronavirus Infections; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D007362:Intensive Care Units; D058873:Pandemics; D011024:Pneumonia, Viral; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious; D000086402:SARS-CoV-2",
"nlm_unique_id": "7507484",
"other_id": null,
"pages": "e49",
"pmc": null,
"pmid": "32667391",
"pubdate": "2020",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "31978945;32161941;32196655;32348744;32191173;32180426;32418732;32154135;32292903;32301600;32114744;32151335;32215581;32026147",
"title": "Severe coronavirus infection in pregnancy: challenging cases report.",
"title_normalized": "severe coronavirus infection in pregnancy challenging cases report"
} | [
{
"companynumb": "NVSC2020BR256384",
"fulfillexpeditecriteria": "1",
"occurcountry": "BR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CEFTRIAXONE"
},
"drugadditional": null,
"dru... |
{
"abstract": "OBJECTIVE\nTo evaluate the safety and efficacy of empagliflozin for 52 weeks as add-on to one other oral antidiabetes therapy in Japanese patients with type 2 diabetes mellitus (T2DM).\n\n\nMETHODS\nPatients on biguanide (n = 133), thiazolidinedione (n = 273), α-glucosidase inhibitor (n = 139), dipeptidyl-peptidase-4 inhibitor (n = 139) or glinide (n = 140) were randomized 1 : 1 to receive empagliflozin 10 or 25 mg double-blind as add-on therapy for 52 weeks. Patients on sulphonylurea (SU; n = 336) were randomized 2 : 2 : 1 to receive empagliflozin 10 or 25 mg double-blind or open-label metformin as add-on therapy for 52 weeks. The primary objective was to evaluate safety. Change from baseline in glycated haemoglobin (HbA1c) at week 52 was a secondary endpoint.\n\n\nRESULTS\nAdverse events (AEs) were reported in 67.6-84.6% of patients receiving empagliflozin. Confirmed hypoglycaemic AEs (plasma glucose ≤70 mg/dl and/or requiring assistance) were reported in 4.4 and 6.6%, respectively, of patients receiving empagliflozin 10 and 25 mg as add-on to SU and in 0.0 to 2.9%, respectively, of patients receiving empagliflozin 10 and 25 mg as add-on to other therapies. Baseline mean ± standard deviation HbA1c ranged from 7.51 ± 0.73 to 8.06 ± 0.76% across background therapy groups. At week 52, adjusted mean ± standard error changes from baseline in HbA1c ranged from -0.77 ± 0.06 to -1.00 ± 0.06% in patients receiving empagliflozin.\n\n\nCONCLUSIONS\nIn Japanese patients with T2DM, empagliflozin 10 and 25 mg as add-on to one other oral antidiabetes therapy for 52 weeks were well tolerated and were associated with clinically meaningful reductions in HbA1c.",
"affiliations": "Department of Metabolic Medicine, Kumamoto University, Kumamoto, Japan.;Division of Endocrinology, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan.;Nippon Boehringer Ingelheim Co., Ltd, Tokyo, Japan.;Nippon Boehringer Ingelheim Co., Ltd, Tokyo, Japan.;Nippon Boehringer Ingelheim Co., Ltd, Tokyo, Japan.;Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany.;Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, USA.;Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany.;Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany.",
"authors": "Araki|E|E|;Tanizawa|Y|Y|;Tanaka|Y|Y|;Taniguchi|A|A|;Koiwai|K|K|;Kim|G|G|;Salsali|A|A|;Woerle|H J|HJ|;Broedl|U C|UC|",
"chemical_list": "D001559:Benzhydryl Compounds; D001645:Biguanides; D001786:Blood Glucose; D054873:Dipeptidyl-Peptidase IV Inhibitors; D005960:Glucosides; D006442:Glycated Hemoglobin A; D065089:Glycoside Hydrolase Inhibitors; D007004:Hypoglycemic Agents; D013453:Sulfonylurea Compounds; D045162:Thiazolidinediones; C517652:hemoglobin A1c protein, human; D008687:Metformin; C089946:2,4-thiazolidinedione; C570240:empagliflozin",
"country": "England",
"delete": false,
"doi": "10.1111/dom.12464",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1462-8902",
"issue": "17(7)",
"journal": "Diabetes, obesity & metabolism",
"keywords": "SGLT2 inhibitor; empagliflozin; type 2 diabetes",
"medline_ta": "Diabetes Obes Metab",
"mesh_terms": "D000328:Adult; D000368:Aged; D001559:Benzhydryl Compounds; D001645:Biguanides; D001786:Blood Glucose; D003924:Diabetes Mellitus, Type 2; D054873:Dipeptidyl-Peptidase IV Inhibitors; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D005960:Glucosides; D006442:Glycated Hemoglobin A; D065089:Glycoside Hydrolase Inhibitors; D006801:Humans; D007003:Hypoglycemia; D007004:Hypoglycemic Agents; D007564:Japan; D008297:Male; D008687:Metformin; D008875:Middle Aged; D013453:Sulfonylurea Compounds; D045162:Thiazolidinediones; D016896:Treatment Outcome",
"nlm_unique_id": "100883645",
"other_id": null,
"pages": "665-74",
"pmc": null,
"pmid": "25772548",
"pubdate": "2015-07",
"publication_types": "D017428:Clinical Trial, Phase III; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Long-term treatment with empagliflozin as add-on to oral antidiabetes therapy in Japanese patients with type 2 diabetes mellitus.",
"title_normalized": "long term treatment with empagliflozin as add on to oral antidiabetes therapy in japanese patients with type 2 diabetes mellitus"
} | [
{
"companynumb": "CN-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2018-BI-015236",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "EMPAGLIFLOZIN"
},
... |
{
"abstract": "Varicella Zoster Virus (VZV) is a neurotropic virus whose reactivation can affect the central nervous system (CNS) and manifest as different neurological syndromes usually with dermatological involvement. Extraocular muscle palsies are not commonly described associated with VZV and their presence in the absence of a typical zoster rash is even rarer.\n\n\n\nCase report of a young immunocompetent patient with unilateral abducens nerve palsy, as an isolated manifestation of VZV infection.\n\n\n\nA 25-year-old healthy female presented to the emergency department with a subacute onset of painless horizontal binocular diploplia, over a month. Ophthalmological and neurological examination revealed an isolated right abducens nerve palsy, and polymerase chain reaction of the cerebrospinal fluid identified a VZV infection. There was no skin rash involvement. Other infectious, inflammatory, and autoimmune diseases were excluded. Treatment with intravenous acyclovir and dexamethasone improved but not completely resolved the diplopia and strabismus. The patient was submitted to a medial rectus recession surgery.\n\n\n\nVZV manifestations in the CNS can occur in healthy young individuals and can manifest in the absence of the typical skin rash. Isolated sixth nerve palsy is a very rare manifestation of VZV infection. Young patients with isolated ocular motor mononeuropathies, even with cardiovascular risk factors, benefit from a CNS-based approach and MRI and lumbar puncture should be considered. Reports show that extraocular muscle palsy associated with VZV is a transient condition and resolve partially or completely after few weeks.",
"affiliations": "Ophthalmology Department; Centro Hospitalar Universitário De Lisboa Central, Lisbon.;Ophthalmology Department; Centro Hospitalar Universitário De Lisboa Central, Lisbon.;Neurology Department, Hospital CUF Descobertas, Lisbon.;Ophthalmology Department, Hospital CUF Descobertas, Lisbon.",
"authors": "Luís|Maria Elisa Vares|MEV|;Hipólito-Fernandes|Carlos Diogo|CD|0000-0002-5972-4068;Lopes Moniz|José|J|;Ferreira|Joana Tavares|JT|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1080/09273972.2021.1948073",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0927-3972",
"issue": "29(3)",
"journal": "Strabismus",
"keywords": "Cranial nerves; Varicella Zoster Virus; cranial palsy; infection; neuro-opthalmology; neurology",
"medline_ta": "Strabismus",
"mesh_terms": "D020434:Abducens Nerve Diseases; D000328:Adult; D004172:Diplopia; D005076:Exanthema; D005260:Female; D006562:Herpes Zoster; D014645:Herpesvirus 3, Human; D006801:Humans",
"nlm_unique_id": "9310896",
"other_id": null,
"pages": "168-173",
"pmc": null,
"pmid": "34241572",
"pubdate": "2021-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "The Neurotropic Varicella Zoster Virus: a Case of Isolated Abducens Nerve Palsy without Skin Rash in a Young Healthy Woman.",
"title_normalized": "the neurotropic varicella zoster virus a case of isolated abducens nerve palsy without skin rash in a young healthy woman"
} | [
{
"companynumb": "US-AUROBINDO-AUR-APL-2021-031681",
"fulfillexpeditecriteria": "1",
"occurcountry": "PT",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "VALACYCLOVIR HYDROCHLORIDE"
},
"drugad... |
{
"abstract": "We report a case of a 26-year-old male who was diagnosed with metastatic desmoplastic small round cell tumor initially treated with systemic chemotherapy followed by tumor debulking and hyperthermic intra-peritoneal chemotherapy. The patient was in complete remission by clinical and imaging criteria for 11 months, until he developed bi-lobar hepatic disease, which was successfully treated with selective internal radiation therapy by Yttrium-90. The patient demonstrated liver-specific complete response on follow-up imaging obtained 18 months after the procedure.",
"affiliations": "Department of Diagnostic Radiology, University of Oklahoma HSC, Oklahoma, OK 73104, USA.;Department of Diagnostic Radiology, University of Oklahoma HSC, Oklahoma, OK 73104, USA.;Department of Pathology, University of Oklahoma HSC, Oklahoma, OK 73104, USA.;Department of Interventional Radiology, University of Oklahoma HSC, Oklahoma, OK 73104, USA.",
"authors": "Gill|Harkanwar|H|;Shahbazi|Natalie|N|;Yu|Zhongxin|Z|;Vanlandingham|William|W|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.radcr.2021.02.066",
"fulltext": "\n==== Front\nRadiol Case Rep\nRadiol Case Rep\nRadiology Case Reports\n1930-0433\nElsevier\n\nS1930-0433(21)00130-8\n10.1016/j.radcr.2021.02.066\nCase Report\nYttrium-90 radioembolization in desmoplastic small round cell tumor with recurrent hepatic metastasis following hyperthermic intraperitoneal chemotherapy\nGill Harkanwar MD hksgill9@gmail.com\na⁎\nShahbazi Natalie MD a\nYu Zhongxin MD b\nVanlandingham William MD c\na Department of Diagnostic Radiology, University of Oklahoma HSC, Oklahoma, OK 73104, USA\nb Department of Pathology, University of Oklahoma HSC, Oklahoma, OK 73104, USA\nc Department of Interventional Radiology, University of Oklahoma HSC, Oklahoma, OK 73104, USA\n⁎ Corresponding author. hksgill9@gmail.com\n27 3 2021\n6 2021\n27 3 2021\n16 6 12591263\n24 2 2021\n27 2 2021\n© 2021 The Authors. Published by Elsevier Inc. on behalf of University of Washington.\n2021\n\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).\nWe report a case of a 26-year-old male who was diagnosed with metastatic desmoplastic small round cell tumor initially treated with systemic chemotherapy followed by tumor debulking and hyperthermic intra-peritoneal chemotherapy. The patient was in complete remission by clinical and imaging criteria for 11 months, until he developed bi-lobar hepatic disease, which was successfully treated with selective internal radiation therapy by Yttrium-90. The patient demonstrated liver-specific complete response on follow-up imaging obtained 18 months after the procedure.\n\nKeywords\n\nYttrium 90\nRadioembolization\nDesmoplastic tumor\nHepatic metastasis\n==== Body\nIntroduction\n\nSoft tissue sarcomas (STS) are a rare group of tumors comprising less than 1% of adult malignancies and 15% of pediatric malignancies [1]. In 2020, an estimated 13,130 people (adult and children) will be diagnosed with soft tissue sarcoma in the United States, resulting in approximately 5,350 deaths [2]. A subgroup of these tumors, desmoplastic small round cell tumor, was identified as a separate entity in 1989 by Gerald and Rosai after recognizing a pathognomonic chromosomal translocation {t (11;22) (p13: q12)} that fuses the Ewing sarcoma gene (EWSR1) with the Wilms tumor suppressor gene (WT1) [3]. Desmoplastic small round cell tumor (DSRCT) is a highly aggressive mesenchymal tumor with median survival ranging from 17 to 32 months [3,4]. However, in patients affected with liver metastases, the prognosis is even poorer.\n\nMultimodality management of DSRCT includes aggressive treatments such as polychemotherapy, debulking surgery, and whole abdominal radiation. Among these, cytoreductive surgery remains the mainstay of therapeutic strategy with promising outcomes [4,5]. Yttrium-90 (90Y) is an effective intra-arterial-directed therapy for treatment of unresectable primary hepatic malignancy and metastatic disease to the liver. Only a few studies have reported effectiveness of selective internal radiation therapy (SIRT) for hepatic STS, primarily leiomyosarcoma [6,7]. To the best of our knowledge, only two prior case reports have described the role of radioembolotherapy with yttrium-90 microspheres on this extremely rare subtype of sarcoma [8,9].\n\nCase report\n\nA 26-year-old man with no significant past medical history presented with intermittent abdominal and groin pain for the past month. He was transferred from an outside hospital, where the initial computed tomography (CT) scan showed an abdominal mass and lymphadenopathy, which was concerning for lymphoma. As a result, positron emission tomography – computed tomography (PET/CT) was obtained for staging and interventional radiology was consulted for diagnostic CT-guided biopsy of the abdominal mass (Fig. 1). Histological and immunohistochemistry analysis of the specimen revealed a hypercellular tumor composed of primitive small round to oval cells surrounded by desmoplastic stroma (Fig. 2). The tumor cells stained positive for pan-cytokeratin, desmin; and were negative for CD99, myogenin, myoD1, calretinin, S-100, synaptophysin, chromogranin. Fluorescence in situ hybridization testing on the tumor tissue showed ESWR1-WT1 fusion transcript pathognomonic for DSRCT.Fig. 1 Axial PET/CT showing hypermetabolic abdominal mass (pointed arrow), FDG avid hepatic metastasis (arrow), hepatic surface implants (arrowhead) and porta hepatis lymphadenopathy (thick arrow).\n\nFig 1\n\nFig. 2 CT-guided biopsy of abdominal mass with histopathology. (a) Low power image (H&E): The tumor is highly cellular with cohesive nests of primitive small round to oval cells surrounded by desmoplastic stroma. (b) High power image (H&E): The tumor cells display nuclear hyperchromasia, inconspicuous nucleoli, nuclear crowding with prominent mitosis and karyorrhexis. (c, d) Immunohistochemical stain shows diffuse positive staining for desmin and Pan-Cytokeratin.\n\nFig 2\n\nThe patient received 3 cycles of neoadjuvant chemotherapy (vincristine, doxorubicin, cyclophosphamide, fosfamide, and etoposide) followed by debulking surgery and hyperthermic intraperitoneal chemotherapy (peritoneal index score: 17). After the surgery, adjuvant chemotherapy was initiated with 2 cycles of VAI (vincristine, actinomycin D, ifosfamide) and 1 cycle of VIT (vincristine, irinotecan, temozolomide). Given a high risk of tumor recurrence, the patient underwent frequent scans (every 3-4 months) while on surveillance and remained in complete remission for 11 months. Unfortunately, recurrent disease was noted in the right and left hepatic lobe requiring systemic chemotherapy. After 4 months of treatment, the patient was referred to interventional radiology for transarterial radioembolization of residual bi-lobar hepatic disease.\n\nThe pre 90Y planning angiogram revealed a replaced right hepatic artery arising from the superior mesenteric artery and supplying the majority the right hepatic lobe. The left hepatic artery had conventional anatomy and supplied a majority of the left hepatic lobe. We decided to coil the right gastric artery, which originated from the proximal left hepatic artery, thereby preventing nontargeted distribution of the radiotracer. A lung shunt fraction of 4.3% was calculated after administration of approximately 5 mCi of technetium 99m labeled macro-aggregated albumin. Given the bi-lobar distribution of liver disease, the patient proceeded with a staged SIRT (2-month interval) using 90Y resin radioactive microspheres (SIR-Spheres, Sirtex Medical Limited, North Sydney, New South Wales, Australia) (https://www.sirtex.com/media/169247/ssl-us-14-sir-spheres-microspheres-ifu-us.pdf). Using radial artery access (Barbeau B type circulation), we delivered 21 mCi of 90Y microspheres via the left hepatic artery and 34.2 mCi to the right hepatic tumor split between segments 5 and 6 (Fig. 3). Our targeted location was confirmed on the single-photon emission computed tomography scan (SPECT/CT). On follow-up CT and PET/CT scans obtained up to 18 months after SIRT, the patient remains free of disease burden in the liver (Fig. 4).Fig. 3 Contrast-enhanced CT showing segment 4 (arrow) and segment 5/6 (2 arrows) hepatic lesions on axial and coronal images (a, b). Post yttrium 90 radioembolization SPECT/CT demonstrating targeted radiotracer accumulation (arrow) within these lesions (c, d).\n\nFig 3\n\nFig. 4 PET/CT obtained 18 months post-treatment showed no evidence of hepatic disease burden on the maximum intensity image (MIP).\n\nFig 4\n\nDiscussion\n\nDesmoplastic small round cell tumor is a highly malignant mesenchymal tumor, most commonly found in adolescent and young adults, with a strong male predominance [4,5]. The presenting symptoms are usually nonspecific such as abdominal pain, mass, and weight loss. Clinically, DSRCT has been shown to have a predilection for serosal surfaces in the abdominopelvic cavity and a majority of cases present with advanced disease. The most common site of extra-peritoneal disease is the liver, followed by the spleen and lungs [6,7]. Diagnosis is based on histopathology with a molecular hallmark of ESWR1-WT1 fusion protein.\n\nThe therapeutic management is challenging due to the rarity and aggressive nature of the disease. A multidisciplinary treatment protocol is necessary for curative intent. Few studies have suggested the use of maximum debulking surgery with HIPEC can improve outcomes, prolonging survival at the cost of an increased toxicity [4,5]. Some authors have proposed whole abdominopelvic intensity-modulated radiation therapy (IMRT) as a part of aggressive multimodality therapy, for patients with metastatic and refractory disease [10]. As described earlier, the liver is the most common site of metastatic disease from DSCRT, hence, an intra-arterial liver directed therapy, such as 90Y, can improve survival by arresting the progression of metastatic disease to the liver [9,10].\n\nTranscatheter liver-directed therapy for hepatic sarcoma is not currently considered the standard of care, and no consensus guidelines exist for malignant DSRCT. 90Y is a beta emitter with an effective radiotherapy range and can induce cell injury through DNA damage for radiosensitive tumors. Hence, the radioisotope can be used preoperatively, to shrink the tumor; postoperatively, to eliminate any residual disease; or as palliative treatment for unresectable disease. In this case, since the patient had bi-lobar metastatic disease, SIRT with 90Y was an ideal option to provide local control and delay progression of disease. Good response was seen on initial post-treatment imaging with no significant adverse effects. During 18 months of imaging surveillance, the patient demonstrated a liver-specific complete response to therapy by clinical and imaging criteria.\n\nConclusion\n\nDSRCT is an extremely rare and highly aggressive disease with dismal outcomes, despite multimodal treatment. Our case highlights the role of selective internal radiation therapy in controlling liver metastases and expanding treatment considerations in these difficult-to-manage patients. 90Y radioembolization can play a role in extending survival and should be included as a treatment option in multidisciplinary management of metastatic DSRCT.\n\nPatient's consent\n\nWritten informed consent was obtained from the patient for publication of this case report and any accompanying images.\n\nAuthors’ contributions\n\nConceptualization and idea: HG; methodology: HG, NS; literature search and data analysis: HG; writing—original draft preparation: HG, NS; writing—review and editing: HG, WV, ZY; supervision: WV, ZY.\n\nEthical approval\n\nAll procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.\n\nFunding: This study was not supported by any funding.\n\nConflict of interest: The authors declare that they have no conflict of interest.\n==== Refs\nReferences\n\n1 Siegel RL Miller KD Jemal A. Cancer statistics CA Cancer J Clin 65 2015 5 29 25559415\n2 Cancer facts & figures 2020 American Cancer Society Available at: https://www.cancer.org/cancer/soft-tissue-sarcoma/about/key-statistics.html Accessed September 8, 2020\n3 Gerald W.L. Rosai J. Case 2 desmoplastic small cell tumor with divergent differentiation Pediatr Pathol 9 2 1989 177 183 2473463\n4 Hayes-Jordan A Green H Lin H Owusu-Agyemang P Mejia R Okhuysen-Cawley R Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) for children, adolescents, and young adults: the first 50 cases Ann Surg Oncol 22 2015 1726 1732 10.1245/s10434-014-4289-y 25564159\n5 Hayes-Jordan AA Coakley BA Green HL Xiao L Fournier K Herzog C Desmoplastic small round cell tumor treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy: results of a phase 2 trial Ann Surg Oncol 25 4 2018 872 877\n6 Miller MD Sze DY Padia SA Lewandowski RJ Salem R Mpofu P Response and overall survival for yttrium-90 radioembolization of hepatic sarcoma: a multicenter retrospective study J Vasc Interv Radiol 29 6 2018 867 873 29724518\n7 Pierce DB Johnson GE Monroe E Loggers ET Jones RL Pollock SM Safety and efficacy outcomes of embolization in hepatic sarcomas AJR Am J Roentgenol 210 1 2018 175 182 29090997\n8 Subbiah V Lamhamedi-Cherradi SE Cuglievan B Menegaz BA Camacho P Huh W Multimodality treatment of desmoplastic small round cell tumor: chemotherapy and complete cytoreductive surgery improve patient survival Clin Cancer Res 24 19 2018 4865 4873 29871905\n9 Cracco A Roy M Simpfendorfer CH. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy combined with two-stage hepatectomy for multiple and bilobar desmoplastic small round cell tumor liver metastases J Gastrointest Oncol 8 4 2017 E60 E64 28890830\n10 Pinnix CC Fontanilla HP Hayes-Jordan A Subbiah V Bilton SD Chang EL Whole abdominopelvic intensity-modulated radiation therapy for desmoplastic small round cell tumor after surgery Int J Radiat Oncol Biol Phys 83 1 2012 317 326 22104361\n\n",
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"title": "Yttrium-90 radioembolization in desmoplastic small round cell tumor with recurrent hepatic metastasis following hyperthermic intraperitoneal chemotherapy.",
"title_normalized": "yttrium 90 radioembolization in desmoplastic small round cell tumor with recurrent hepatic metastasis following hyperthermic intraperitoneal chemotherapy"
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"abstract": "Seven patients with paroxysmal nocturnal haemoglobinuria (PNH) were treated with antithymocyte globulin (ATG). Each patient received ATG (20 mg/kg/d) for 8 d and prednisone to prevent or control serum sickness. Three patients experienced a sustained improvement in at least one peripheral blood cytopenia, including one patient who had a complete trilineage response. Several pretreatment clinical features appeared to be associated with response to ATG. All responding patients had hypoproliferative features including depressed platelet counts (< 30 x 10(9)/l), and a minor degree of chronic haemolysis as indicated by relatively low reticulocyte counts (< 100 x 10(9)/l), lactate dehydrogenase (< 1000 U/l) and total bilirubin (< 17 mumol/l) levels. Responding patients continued to have chronic low-grade haemolysis after their response to immunosuppression that was similar to that observed prior to treatment. The non-responding patients had a classic haemolytic form of PNH characterized by elevated reticulocyte counts (> 100 x 10(9)/l), lactate dehydrogenase (> 2000 U/l) and total bilirubin (> 17 mumol/l) levels. The impaired haemopoiesis that occurs in hypoproliferative PNH may respond to ATG treatment, but the haemolytic component of the disease, and hence the PNH clone, is not altered by immunosuppressive therapy.",
"affiliations": "UCLA School of Medicine, USA.",
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"abstract": "Corticosteroids are effective for the treatment of many chronic and acute diseases but have many well-known adverse effects, which limit their use in some conditions. Steroid-induced psychosis is a rare side effect especially in the pediatric population. Although the estimated incidence of steroid-induced psychosis in adults is approximately 6%, it is rarely reported in the pediatric population. Moreover, it is poorly characterized and described in the literature. We report the case of a 4-year-old boy with no known medical or psychiatric history who presented to the emergency department with respiratory complaints. After observation and monitoring, the patient was diagnosed as having croup. A single dose of 8 mg dexamethasone was started intravenously. Within 3 h after the injection, the patient experienced psychiatric disturbances, including abnormal behaviors, anxiety, disorientation, decreased speech, and sleep disturbance. During the first 48 h of admission, the symptoms improved gradually, without using further medication during the rest of his hospital stay.",
"affiliations": "King Saud Hospital, Unaizah, Saudi Arabia.;Department of Pharmacy Practice, Unaizah College of Pharmacy, Qassim University, Qassim, Saudi Arabia.",
"authors": "Alsalamah|Abdullrahman|A|;Alsahali|Saud|S|https://orcid.org/0000-0001-6048-0702",
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"fulltext": "\n==== Front\nSAGE Open Med Case Rep\nSAGE Open Med Case Rep\nSCO\nspsco\nSAGE Open Medical Case Reports\n2050-313X\nSAGE Publications Sage UK: London, England\n\n10.1177/2050313X211053469\n10.1177_2050313X211053469\nCase Report\nSteroid-induced psychosis in a child with croup: A case report\nAlsalamah Abdullrahman 1\nhttps://orcid.org/0000-0001-6048-0702\nAlsahali Saud 2\n1 King Saud Hospital, Unaizah, Saudi Arabia\n2 Department of Pharmacy Practice, Unaizah College of Pharmacy, Qassim University, Qassim, Saudi Arabia\nSaud Alsahali, Department of Pharmacy Practice, Unaizah College of Pharmacy, Qassim University, Qassim, P.O. Box 5888 Unaizah 51911, Saudi Arabia. Email: s.alsahali@qu.edu.sa\n15 10 2021\n2021\n9 2050313X2110534697 7 2021\n28 9 2021\n© The Author(s) 2021\n2021\nSAGE Publications\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 pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).\nCorticosteroids are effective for the treatment of many chronic and acute diseases but have many well-known adverse effects, which limit their use in some conditions. Steroid-induced psychosis is a rare side effect especially in the pediatric population. Although the estimated incidence of steroid-induced psychosis in adults is approximately 6%, it is rarely reported in the pediatric population. Moreover, it is poorly characterized and described in the literature. We report the case of a 4-year-old boy with no known medical or psychiatric history who presented to the emergency department with respiratory complaints. After observation and monitoring, the patient was diagnosed as having croup. A single dose of 8 mg dexamethasone was started intravenously. Within 3 h after the injection, the patient experienced psychiatric disturbances, including abnormal behaviors, anxiety, disorientation, decreased speech, and sleep disturbance. During the first 48 h of admission, the symptoms improved gradually, without using further medication during the rest of his hospital stay.\n\nSteroid\ncorticosteroid\npsychosis\ncroup\nneuropsychiatric disturbance\nneurological symptoms\ncover-dateJanuary-December 2021\ntypesetterts1\n==== Body\npmcIntroduction\n\nCroup is a common respiratory disease in the pediatric population. Laryngotracheitis, laryngotracheobronchitis, and laryngotracheobronchopneumonitis belong to the croup spectrum.1,2 The pediatric incidence of croup is 3% between ages 6 months and 3 years and more frequent in girls than in boys.1,2 The major cause of croup is viruses, accounting for 80% of all cases, among which parainfluenza virus accounts for 75%.3,4\n\nClinical diagnosis is the standard diagnosis of croup. It includes many common symptoms accompanying the disease, such as barky cough, acute stridor, and hoarseness due to airway narrowing. The symptoms may worsen with emotional stress and in the night time, usually lasting 24–48 h. 1 Of all croup cases, <5% require hospital admission, of which only 1%–3% need intubation. The mortality rate in intubated cases is approximately 0.5%. 3 Croup is treated according to its severity, which is often classified using the Westley croup scoring system. 5 Corticosteroids could be used for croup of any severity. 6\n\nCorticosteroids belong to a class of steroid hormones secreted naturally by the adrenal cortex and involved in many important biological functions in human body. They are used in the treatment of a wide range of diseases, such as autoimmune diseases, asthma, arthritis, eye and skin disorders, and some types of cancer.6,7 Although corticosteroids are effective for several diseases, their many adverse effects limit their use. These adverse effects appear depending on the treatment dose and duration.8,9 The most common adverse effects are immunosuppression, adrenal suppression, osteoporosis, gastrointestinal complications, and neuropsychiatric disturbances. 8 Many corticosteroid-induced somatic symptoms are well recognized. 7 Some adverse effects such as neuropsychiatric disturbances were mostly described but poorly characterized in case reports. 7 Steroid-induced psychosis is used to describe a wide range of neuropsychiatric symptoms resulting from the use of corticosteroids. It is a well-recognized phenomenon in adults, with an incidence of approximately 6% but rarely reported in the pediatric population, with no reliable incidence rate.7,10 As steroid psychosis has a broad definition and mixed neuropsychiatric symptoms, its true incidence is difficult to determine. The symptoms include agitation, mood lability, insomnia, anxiety, hallucination, altered mental status, and delirium. 7 Hodgins et al. performed a systematic review of the literature for steroid-induced psychosis among pediatric and adolescent populations. The study identified 15 cases of steroid-induced psychosis in patients treated with steroids for different diseases such asthma, autoimmune diseases, and cancer. Moreover, in the reported cases, asthma was the most common indication for steroid therapy in pediatric patients. 11 Based on our literature search, we believe the present case is probably the first reported pediatric case diagnosed with croup and developed steroid-induced psychosis.\n\nCase\n\nA 4-year-old Saudi boy with a weight of 14 kg with no known medical or psychiatric history was brought to the emergency department of King Saud Hospital in Unaizah, Qassim, Saudi Arabia. He presented to the emergency department with fever associated with a dry, non-paroxysmal (barking) cough. He had no history of vomiting, diarrhea, headache, or abnormal movement. His growth and development were appropriate for his age. Moreover, in term of his family history, no one of his family members was reported to have a history of psychiatric disturbances or was on any antipsychotic medications.\n\nHis parents reported that he was well until the day before, when he developed a fever with a body temperature of 38.6°C. It was associated with dry, barking cough, which progressed with time and was associated with shortness of breath. They first observed stridor 2 h before the emergency department visit.\n\nOn physical examination, the patient looked distressed, with nasal flaring and good hydration and no cyanosis. His body temperature was 38.2°C; respiratory rate, 44 breaths per minute; heart rate, 113 beats per minute; and oxygen level, 98% at room air. He had red, swollen tonsil, and expiratory stridor with intercostal retraction. Thus, he was diagnosed as having croup.\n\nThe patient started treatment with 8 mg dexamethasone administered intravenously. Within 3 h after the injection, his mother noticed some abnormal behavior in the form of hitting one hand with the other in a strange way and some abnormal responses to questions from family members. The patient was re-examined lying in bed, without distress. Psychiatric evaluation revealed that he was agitated, irritable, confused, and he was restless with poor eye contact. Moreover, he had a fear from being away from his mother and disoriented to place and person. In addition, based on the child mother, the patient suddenly woke up with abnormal head movements, and it seemed that he was hearing voices. This suggested that the patient was experiencing auditory hallucinations. However, the hallucinations could not be firmly confirmed because of the patient’s age. The patient’s level of consciousness was 14 out of 15 using Glasgow Coma scale (GCS). 12 Consequently, he was admitted for close observation and full examination. His complete blood count, glucose level, electrolyte count, and urine examination, liver function test, kidney function test results were normal. Cerebrospinal fluid analysis and brain magnetic resonance imaging revealed no abnormalities. The electroencephalogram (EEG) showed normal study. All cultures were negative.\n\nDuring admission, the patient was hypoactive, crying, refusing to engage with clinical and nursing staff. In addition, he was unresponsive to his mother or responsive but with incomprehensible sentences and had episodes of screaming that lasted for hours. He had decreased appetite with sleep-wake disturbances. After the first 48 h of admission, the symptoms gradually improved. On the fifth day of admission, the child was discharged because he was doing well, afebrile for >48 h with good activity, and responsive and communicating properly. At 2-weeks’ follow-up in the outpatient department, he was alert, cooperative, and interacting well with parents.\n\nDiscussion\n\nThe pathophysiology of steroid-induced psychosis is unclear, but synthetic steroids are known to activate glucocorticoid receptors that interfere with the cortical pathway of the hypothalamic-pituitary-adrenal axis, causing mood disorders. 13 This phenomenon is classified by the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) as medication-induced psychosis. 14 The glucocorticoids could cause alteration in production and concentration of some neurotransmitter (e.g. dopamine and serotonin) which may contribute to psychiatric symptoms. 7\n\nIt is dose-dependent phenomenon which means the psychiatric symptoms are more likely to happen with high dose of steroids. However, high steroid doses may not predict the severity and type of these symptoms and how long the symptoms last.11,14 Neuropsychiatric adverse effects may appear with very low dose equivalent to 2.5-mg prednisolone. 7 Also, it may occur with any type of steroids. Some evidence in the literature suggested that oral dexamethasone have a higher risk to develop neurosynaptic symptoms over other corticosteroids, but this need further validation. 7\n\nTo meet the diagnosis criteria for steroid-induced psychosis, the symptoms should cause clinically significant distress, functional impairment, or the patient have at least hallucination or delusion after the steroids were given. Moreover, other factors that could cause neuropsychiatric symptoms, such as electrolyte imbalance, infection, and hypoglycemia must be ruled out.11,14\n\nIn this case, the patient was examined and observed closely to exclude any suspected diseases and was found to have no specific underlying disease, including psychiatric disorders. Steroid-induced psychosis manifest mild to severe symptoms, ranging from anxiety, insomnia, and irritability to mania, psychosis, delirium, and depression, among others. 15\n\nAs the patient in this case experienced mixed symptoms of neuropsychiatric disturbances such as anxiety, disorientation, restlessness, agitation, and sleep disturbance, the pediatric team obtained psychiatric evaluation for the child, which revealed that the symptoms were more likely due to the use of steroids. Many studies have shown that symptoms may develop at the beginning or late during steroid therapy and, in some cases, after treatment completion. Moreover, the duration of the symptoms varies.14,15 In most cases, the symptoms present within the first 5 days after treatment. 15 Interestingly, in this case, the symptoms started to manifest shortly after administration of a single dose of dexamethasone. The psychotic symptoms persisted for almost 5 days thereafter. Several studies reported that in most cases, the psychiatric symptoms disappear on steroid therapy cessation or dose tapering.16–18 Psychopharmacological treatment using antipsychotic agents (e.g. olanzapine and risperidone) could be used when symptoms are too severe or when treatment discontinuation or dose tapering is insufficient to alleviate the psychiatric symptoms. 15 Some studies suggested that lithium therapy could be used as prophylactic therapy to prevent steroid-induced psychiatric disturbances. Lithium therapy could be given to patients who previously developed psychiatric symptoms after steroid doses. 15 Owing to the possible adverse effects of antipsychotic agents, we preferred full examination and close observation for the patient over the use of antipsychotics. The patient’s psychiatric symptoms improved without using further medications.\n\nConclusion\n\nOnly few studies have reported cases of psychiatric disturbance resulting from steroid treatment in the pediatric population. Our patient experienced psychiatric disturbance symptoms including abnormal behaviors, anxiety, disorientation, decreased speech, and sleep disturbance after receiving a single dose of dexamethasone. The symptoms gradually improved without any further intervention. This case report along with more evidence may help clinicians identify and manage the symptoms of this iatrogenic phenomenon.\n\nDeclaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.\n\nEthical approval: The ethical approval was obtained from Regional Research Ethics Committee at Qassim Province, Saudi Arabia (reference number 1442-1428615)\n\nFunding: The author(s) received no financial support for the research, authorship, and/or publication of this article.\n\nInformed consent: Written informed consent was obtained from a legally authorized representative(s) for anonymized patient information to be published in this article.\n\nORCID iD: Saud Alsahali https://orcid.org/0000-0001-6048-0702\n==== Refs\nReferences\n\n1 Smith DK Mcdermott AJ Sullivan JF. Croup: diagnosis and management. Am Fam Physician 2018; 97 (9 ): 575–580.29763253\n2 Ernest S Khandhar PB. Laryngotracheobronchitis [Internet]. StatPearls Publishing, 2021, http://www.ncbi.nlm.Nih.gov/pubmed/30137816 (accessed 13 June 2021).\n3 Johnson DW . Croup. BMJ Clin Evid 2014; 2014 : 0321.\n4 Moraa I Sturman N Mcguire TM , et al . Heliox for croup in children. Cochrane Database of Syst Rev 2018; 10 : CD006822.\n5 Westley CR Cotton EK Brooks JG. Nebulized racemic epinephrine by IPPB for the Treatment of Croup: a double-blind study. Am J Dis Child 1978; 132 (5 ): 484–487.347921\n6 Hodgens A Sharman T. Corticosteroids [Internet]. StatPearls Publishing, 2021, http://www.ncbi.nlm.Nih.gov/pubmed/32119499 (accessed 13 June 2021).\n7 Dubovsky AN Arvikar S Stern TA , et al . The neuropsychiatric complications of glucocorticoid use: steroid psychosis revisited. Psychosomatics 2012; 53 (2 ): 103–115.22424158\n8 Liu D Ahmet A Ward L , et al . A practical guide to the monitoring and management of the complications of systemic corticosteroid therapy. All Asth Clin Immun 2013; 9 (1 ): 1–25.\n9 Da Silva JA Jacobs JW Kirwan JR , et al . Safety of low dose glucocorticoid treatment in rheumatoid arthritis: published evidence and prospective trial data. Ann Rheum Dis 2006; 65 (3 ): 285–293.16107513\n10 Bag O Erdoǧan I Sivis Onder Z , et al . Steroid-induced psychosis in a child: treatment with risperidone. Gen Hosp Psychiatry 2012; 34 (1 ): 103.e5–106.e5.\n11 Hodgins GE Saltz SB Gibbs EP , et al . Steroid-induced psychosis in the pediatric population: a new case and review of the literature. J Child Adolesc Psychopharmacol 2018; 28 (5 ): 354–359.29638141\n12 Jain S Iverson LM. Glasgow Coma Scale. StatPearls Publishing, 2021, https://www.ncbi.nlm.Nih.gov/books/NBK513298/ (accessed 13 June 2021).\n13 Janes M Kuster S Goldson TM , et al . Steroid-induced psychosis. Baylor Univ Med Cent Proc 2019; 32 (4 ): 614–615.\n14 American Psychiatric Association. Diagnostic and statistical manual of mental disorders [Internet]. American Psychiatric Association, 2013, https://psychiatryonline.org/doi/book/10.1176/appi.Books.9780890425596 (accessed 13 June 2021).\n15 Parasher A Bez J. Steroid induced psychiatric adverse effects: an overview of risk factors, clinical features and management. Int J Res Med Sci 2020; 8 (6 ): 2365–2370.\n16 Lewis DA Smith RE. Steroid-induced psychiatric syndromes: a report of 14 cases and a review of the literature. J Affect Disord 1983; 5 (4 ): 319–332.6319464\n17 Wada K Yamada N Sato T , et al . Corticosteroid-induced psychotic and mood disorders diagnosis defined by DSM-IV and clinical pictures. Psychosomatics 2001; 42 (6 ): 461–466.11815680\n18 Bender Lerner JA Kollasch E . Mood and memory changes in asthmatic children receiving corticosteroids. J Am Acad Child Adolesc Psychiatry 1988; 27 (6 ): 720–725.3198559\n\n",
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"title": "Steroid-induced psychosis in a child with croup: A case report.",
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"abstract": "OBJECTIVE\nHigh-dose methotrexate based chemotherapy is the standard treatment for patients with newly diagnosed primary central nervous system lymphoma (PCNSL). The role of rituximab is controversial because of its large size, which limits its penetration of the blood-brain barrier. In this study, we investigated the efficacy and tolerability of adding rituximab to methotrexate-cytarabine-dexamethasone combination therapy (RMAD regimen).\n\n\nRESULTS\nThe patients treated with RMAD had a complete remission rate of 66.7% after induction chemotherapy; this rate was only 33.3% in patients treated with MAD alone (p = .011). The most common grade 1-3 adverse events were similar and included hematologic toxicity, increased aminotransferase levels, and gastrointestinal reactions. Multivariate analysis revealed that rituximab treatment was associated with longer progression-free survival (PFS, p = .005) but not overall survival (OS). Additionally, we observed that elevated serum lactate dehydrogenase was associated with shorter OS and PFS.\n\n\nMETHODS\nWe retrospectively analyzed 60 immunocompetent patients with newly diagnosed PCNSL at Beijing Tiantan Hospital, Capital Medical University from January 2010 to June 2016. Twenty-four patients received 3-6 courses of 3.5 g/m2 methotrexate on day 1; 0.5-1 g/m2 cytarabine on day 2; and 5-10 mg dexamethasone on days 1, 2 and 3. Thirty-six patients received the same combination plus rituximab 375 mg/m2 on day 0. All patients repeated the treatment every 3 weeks.\n\n\nCONCLUSIONS\nHigh-dose methotrexate based chemotherapy with rituximab yields a higher complete remission rate and does not increase serious toxicities. PFS benefits from the addition of rituximab. OS has an increasing trend in patients treated with rituximab without statistical significance.",
"affiliations": "Department of Hematology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.;Department of Hematology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.;Department of Neurosurgery, Navy General Hospital, Beijing, China.;Department of Hematology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.;Department of Hematology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.;Department of Hematology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.;Department of Hematology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.;Beijing Neurosurgical Institute, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.;Department of Radiation Therapy, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.;Neuroimaging Center, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.;Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.;Department of Hematology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.",
"authors": "Sun|Xuefei|X|;Liu|Jing|J|;Wang|Yaming|Y|;Bai|Xueyan|X|;Chen|Yuedan|Y|;Qian|Jun|J|;Zhu|Hong|H|;Liu|Fusheng|F|;Qiu|Xiaoguang|X|;Sun|Shengjun|S|;Ji|Nan|N|;Liu|Yuanbo|Y|",
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"doi": "10.18632/oncotarget.17101",
"fulltext": "\n==== Front\nOncotargetOncotargetOncotargetImpactJOncotarget1949-2553Impact Journals LLC 284677821710110.18632/oncotarget.17101Research PaperMethotrexate-cytarabine-dexamethasone combination chemotherapy with or without rituximab in patients with primary central nervous system lymphoma Sun Xuefei 1Liu Jing 1Wang Yaming 2Bai Xueyan 1Chen Yuedan 1Qian Jun 1Zhu Hong 1Liu Fusheng 3Qiu Xiaoguang 4Sun Shengjun 5Ji Nan 6Liu Yuanbo 11 Department of Hematology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China2 Department of Neurosurgery, Navy General Hospital, Beijing, China3 Beijing Neurosurgical Institute, Beijing Tiantan Hospital, Capital Medical University, Beijing, China4 Department of Radiation Therapy, Beijing Tiantan Hospital, Capital Medical University, Beijing, China5 Neuroimaging Center, Beijing Tiantan Hospital, Capital Medical University, Beijing, China6 Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, ChinaCorrespondence to: Yuanbo Liu, yuanbol@ccmu.edu.cn25 7 2017 13 4 2017 8 30 49156 49164 21 12 2016 2 4 2017 Copyright: © 2017 Sun et al.2017This article is distributed under the terms of the Creative Commons Attribution License (CC-BY), which permits unrestricted use and redistribution provided that the original author and source are credited.Purpose\nHigh-dose methotrexate based chemotherapy is the standard treatment for patients with newly diagnosed primary central nervous system lymphoma (PCNSL). The role of rituximab is controversial because of its large size, which limits its penetration of the blood-brain barrier. In this study, we investigated the efficacy and tolerability of adding rituximab to methotrexate-cytarabine-dexamethasone combination therapy (RMAD regimen).\n\nResults\nThe patients treated with RMAD had a complete remission rate of 66.7% after induction chemotherapy; this rate was only 33.3% in patients treated with MAD alone (p = .011). The most common grade 1–3 adverse events were similar and included hematologic toxicity, increased aminotransferase levels, and gastrointestinal reactions. Multivariate analysis revealed that rituximab treatment was associated with longer progression-free survival (PFS, p = .005) but not overall survival (OS). Additionally, we observed that elevated serum lactate dehydrogenase was associated with shorter OS and PFS.\n\nMaterials and Methods\nWe retrospectively analyzed 60 immunocompetent patients with newly diagnosed PCNSL at Beijing Tiantan Hospital, Capital Medical University from January 2010 to June 2016. Twenty-four patients received 3–6 courses of 3.5 g/m2 methotrexate on day 1; 0.5–1 g/m2 cytarabine on day 2; and 5–10 mg dexamethasone on days 1, 2 and 3. Thirty-six patients received the same combination plus rituximab 375 mg/m2 on day 0. All patients repeated the treatment every 3 weeks.\n\nConclusions\nHigh-dose methotrexate based chemotherapy with rituximab yields a higher complete remission rate and does not increase serious toxicities. PFS benefits from the addition of rituximab. OS has an increasing trend in patients treated with rituximab without statistical significance.\n\nprimary central nervous system lymphomarituximabhigh-dose methotrexatecytarabinesurvival\n==== Body\nINTRODUCTION\nPrimary central nervous system lymphoma (PCNSL) is an aggressive non-Hodgkin lymphoma located in the brain, leptomeninges, spinal cord, cerebrospinal fluid (CSF) and intraocular structures [1, 2]. The tumor is usually diffuse large B cell lymphoma (DLBCL) and is associated with worse prognosis than systemic lymphomas of the same type. Although high-dose methotrexate (HD-MTX) is the most effective drug for PCNSL, usually with recommended dose of 3.5 g/m2 every 2–3 weeks, the median overall survival (OS) is 10–20 months, and progression-free survival (PFS) is 12–13 months [3–6]. Thus, the ability of the addition of other drugs to HD-MTX to improve the outcome of HD-MTX treatment has been examined [7–9].\n\nCytarabine (Ara-C) kills proliferating cells in the S-phase of the cell cycle. The administration of HD-Ara-C after HD-MTX (MA) increases cytotoxicity. A randomized phase II trial comparing HD-MTX alone with HD-MTX combined with HD-Ara-C showed that the addition of Ara-C increased the response rate and extended OS [10]. Rituximab is an anti-CD20 hybrid monoclonal antibody that is active against various types of B-cell lymphoma. The addition of rituximab to the cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) regimen has become a cornerstone of therapy for systemic DLBCL [11]. However, there are many concerns regarding the ability of this antibody to cross the blood-brain barrier (BBB). Preliminary evidence has demonstrated that R-CHOP may not significantly prevent central nervous system (CNS) dissemination of systemic DLBCL compared with CHOP alone [12–14]. However, in CNS lymphoma patients, the use of intravenous rituximab can induce responses in contrast-enhancement lesions, likely in lesions in which there is substantial disruption of the BBB [15]. The precise role of rituximab in PCNSL remains controversial [16–19] and has not been defined.\n\nIn this study, we retrospectively analyzed the characteristics of 60 patients with newly diagnosed PCNSL and evaluated the role of adding rituximab to the methotrexate-cytarabine-dexamethasone (MAD) regimen as a first-line chemotherapy for PCNSL.\n\nRESULTS\nPatient characteristics and treatment\nThe characteristics of the PCNSL patients are described in Table 1. The diagnosis was obtained by stereotactic biopsy (81.7%), surgery (15.0%), or CSF (3.3%). All PCNSLs were proven to be DLBCL. The male-female ratio was 1.5:1 for the 60 patients. The median patient age was 57 years (range 11 to 83 years, 27 were ≥ 60 and 33 were < 60 years old). Ten patients (16.7%) had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. The remaining 50 patients (83.3%) had an ECOG performance status of 2–4. Multiple brain lesions were observed in 35 patients (58.3%), and deep brain structures were compromised in 50 patients (83.3%). Serum lactate dehydrogenase (LDH) levels were elevated in 20 (33.3%) of the 60 patients. The patients were treated according to their will and financial conditions. In total, 24 patients received MAD induction chemotherapy, and 36 received the RMAD regimen. A total of 25 (41.7%) patients received consolidation treatment. Eighteen (30.0%) patients received WBRT as salvage therapy, and 17 (28.3%) did not pursue further treatment.\n\nTable 1 Clinical characteristics of PCNSL patients\n\t\tTotal(n = 60, %)\tRMAD(n = 36, 60%)\tMAD(n = 24, 40%)\tP value\t\nAge\t≥ 60\t27 (45.0)\t17 (47.2)\t10 (41.7)\t0.672\t\n\t< 60\t33 (55.0)\t19 (52.8)\t14 (58.3)\t\t\nGender\tMale\t36 (60.0)\t22 (61.1)\t14 (58.3)\t0.830\t\n\tFemale\t24 (40.0)\t14 (38.9)\t10 (41.7)\t\t\nLDH\tElevated\t20 (33.3)\t11 (30.6)\t8 (33.3)\t0.821\t\n\tNormal\t40 (66.7)\t25 (69.4)\t16 (66.7)\t\t\nNumber of lesions\t1\t26 (43.3)\t15 (41.7)\t11 (45.8)\t0.750\t\n\tAt least 2\t34 (56.7)\t21 (58.3)\t13 (54.2)\t\t\nECOG performance status\t0 to 1\t10 (16.7)\t6 (16.7)\t4 (16.7)\t1.000\t\n\tAt least 2\t50 (83.3)\t30 (83.3)\t20 (83.3)\t\t\nDeep structure involvement\tPresence\t50 (83.3)\t32 (88.9)\t18 (75.0)\t0.178\t\n\tAbsence\t10 (16.7)\t4 (11.1)\t6 (25.0)\t\t\nDiagnosis\tStereotactic biopsy\t49 (81.7)\t30 (83.3)\t19 (79.2)\t0.321\t\n\tSurgery\t9 (15.0)\t4 (11.1)\t5 (20.8)\t\t\n\tCSF\t2 (3.3)\t2 (5.6)\t0 (0)\t\t\nInduction treatment response\tCR\t32 (53.3)\t24 (66.7)\t8 (33.3)\t0.011\t\n\tWithout CR\t28 (46.7)\t12 (33.3)\t16 (66.7)\t\t\nFurther treatment\tConsolidation\t25 (41.7)\t17 (47.2)\t8 (33.3)\t0.267\t\n\tSalvage\t18 (30.0)\t8 (22.2)\t10 (41.7)\t\t\n\tnot proceed\t17 ((28.3)\t11 (30.6)\t6 (25.0)\t\t\nPathology\tDLBCL\t60 (100.0)\t36 (100.0)\t24 (100.0)\t0.992\t\n\tGCB\t5 (8.3)\t3 (8.3)\t2 (8.3)\t\t\n\tABC\t42 (70.0)\t25 (69.4)\t17 (70.8)\t\t\n\tUnclassified\t13 (21.7)\t8 (22.2)\t5 (20.8)\t\t\nAbbreviations: LDH, lactate dehydrogenase; ECOG, Eastern Cooperative Oncology Group; DLBCL, diffuse large B-cell lymphoma; GCB, germinal center B-cell-like; ABC, activated B-cell-like; RMAD, rituximab-methotrexate-cytarabine-dexamethasone; MAD, methotrexate-cytarabine-dexamethasone.\n\nResponse and survival\nAll 60 patients received at least 3 cycles of induction chemotherapy, and 46 patients completed 6 cycles. The response rates for chemotherapy are shown in Table 2. A total of 32 patients achieved CR (53.3%) after 3 cycles of induction chemotherapy. There were also 11 PR (18.3%), 11 SD (18.3%), and 6 PD (10%) patients. The 24 patients treated with MAD had the following outcomes: 8 CR (33.3%), 9 PR (37.5%), 4 SD (16.7%), and 3 PD (12.5%). The 36 patients treated with RMAD had the following outcomes: 24 CR (66.7%), 2 PR (5.6%), 7 SD (19.4%), and 3 PD (8.3%). The patient characteristics (age, sex, ECOG, LDH, number of lesions, involvement of deep structures) did not differ between patients treated with RMAD and MAD, except for the response rate. The induction chemotherapy regimen was significantly associated with the CR rate (RMAD: 66.7% vs. MAD: 33.3%, p = .011) (Table 1).\n\nTable 2 Response to induction chemotherapy\nResponse\tAll patients (n = 60)\tPatients with RMAD (n = 36)\tPatients with MAD (n = 24)\t\nComplete remission\t32 (53.3%)\t24 (66.7%)\t8 (33.3%)\t\nPartial remission\t11 (18.3%)\t2 (5.6%)\t9 (37.5%)\t\nStable disease\t11 (18.3%)\t7 (19.4%)\t4 (16.7%)\t\nProgression disease\t6 (10.0%)\t3 (8.3%)\t3 (12.5%)\t\nDied during therapy\t0 (0)\t0 (0)\t0 (0)\t\nFollow-up data were available for 54 patients. The 2-year PFS rate was 0.34, and the median PFS was 20.0 months (95% CI 15.22–24.78). The median OS for the 54 patients has not been reached. The estimated probability of OS at 4 years was 0.58 (range 0.31–0.85). The median OS in patients treated with RMAD has not been reached. However, in patients treated with MAD, the median OS was 28.0 months (95% CI 19.69–36.31). The median PFS in patients treated with RMAD was 31.0 months (95% CI 20.77–41.24). The median PFS in patients treated with MAD was 14.0 months (95% CI 4.93–23.07) (Table 3). Univariate analysis indicated that treatment with RMAD was associated with longer PFS (p = .015) but not OS (p = .176) (Figure 1). We also observed that elevated LDH was associated with shorter OS (p = .030) and PFS (p = .006) (Figure 2). Multivariate analysis revealed that the induction chemotherapy regimen and LDH level were independent risk factors for PFS. Multivariate analysis of OS identified only LDH as a prognostic indicator (Table 4).\n\nTable 3 Overall survival and progression-free survival\n\tAll patients (n = 54)\tPatients with RMAD (n = 34)\tPatients with MAD (n = 20)\t\nSurvival\t\t\t\t\nMedian OS (months, 95% CI)\tNR\tNR\t28.0 (19.69–36.31)\t\nMedian PFS (months, 95% CI)\t20.0 (15.22–24.78)\t31.0 (20.77–41.24)\t14.0 (4.93–23.07)\t\nAbbreviations: NR, not reached.\n\nFigure 1 Kaplan-Meier analysis of OS and PFS in PCNSL patients and comparison of OS and PFS between groups with or without rituximab by the log-rank test\nFigure 2 Comparison of OS and PFS between elevated LDH and normal LDH levels\nTable 4 Univariate and multivariate analyses of OS and PFS for patients (Cox test)\n\tOS\tPFS\t\nVariable\tUnivariate analysis\tMultivariate analysis\tUnivariate analysis\tMultivariate analysis\t\n\tHR\t95% CI\tP\tHR\t95% CI\tP\tHR\t95% CI\tP\tHR\t95% CI\tP\t\nAge\t0.16\t0.02–1.30\t0.086\t0.28\t0.02–3.61\t0.330\t085\t0.33–2.19\t0.737\t1.88\t0.59–5.98\t0.283\t\nGender\t1.05\t0.23–4.75\t0.949\t-\t-\t-\t0.65\t0.24–1.72\t0.385\t-\t-\t-\t\nECOG\t0.39\t0.04–3.54\t0.404\t0.72\t0.03–19.03\t0.843\t2.12\t0.28–16.03\t0.469\t2.27\t0.28–18.41\t0.444\t\nLDH\t0.15\t0.03–0.83\t0.030\t0.06\t0.00–0.97\t0.048\t0.25\t0.09–0.66\t0.006\t0.10\t0.03–0.37\t0.001\t\nNumber of lesions\t0.46\t0.10–2.17\t0.323\t0.44\t0.07–2.83\t0.389\t0.93\t0.35–2.42\t0.875\t0.89\t0.27–2.93\t0.846\t\nDeep structure involvement\t2.65\t0.27–25.94\t0.403\t4.99\t0.16–160.88\t0.365\t1.07\t0.24–4.79\t0.932\t1.11\t0.22–5.63\t0.897\t\nInduction therapeutic regimen\t3.12\t0.60–16.19\t0.176\t10.42\t0.83–131.27\t0.070\t3.25\t1.25–8.44\t0.015\t5.23\t1.64–16.70\t0.005\t\nAge, ≥ 60 y vs. < 60 y; Gender, male vs. female; ECOG, 0–1 vs. 2–4; LDH, elevated vs. normal; number of lesions, 1 vs. ≥ 2 lesions; deep structure involvement, presence vs. absence; induction therapeutic regimen, RMAD vs. MAD.\n\nToxicity\nThe toxicities are summarized in Table 5. The most frequent toxicities after induction chemotherapy were hematologic toxicity (76.7%), elevated aminotransferase levels (48.3%), and gastrointestinal reactions (46.7%). The observed neurotoxicity was predominantly leukoencephalopathy (18.3%) and appeared in patients receiving at least 6 cycles of induction chemotherapy. There were no grade 4 toxicities or treatment-related deaths. The most common grade 1–3 adverse events were similar in both treatment groups. Patients treated with rituximab experienced more frequent anaphylaxis. There were 2 cases of skin allergy, 4 cases of fever, 1 case of respiratory tract allergy, and 1 case of interstitial pneumonitis among the 36 patients treated with rituximab.\n\nTable 5 Toxicity graded according to the national cancer institute common toxicity criteria\nToxicity\tAll patients (n = 60)\tPatients with RMAD (n = 36)\tPatients with MAD (n = 24)\t\nHematological toxicity\t\t\t\t\nNeutropenia\t42 (70.0%)\t27 (75.0%)\t15 (62.5%)\t\nInfection\t18 (30.0%)\t10 (33.3)\t8 (33.3%)\t\nAnemia\t7 (11.7%)\t3 (8.3%)\t4 (16.7%)\t\nThrombocytopenia\t14 (23.3%)\t9 (25.0%)\t5 (20.8%)\t\nLiver toxicity\t\t\t\t\nAminotransferases elevated\t29 (48.3%)\t18 (50.0%)\t11 (45.8%)\t\nBilirubin elevated\t0\t0\t0\t\nNephrotoxicity\t\t\t\t\nCreatinine elevated\t6 (10%)\t4 (11.1%)\t2 (8.3%)\t\nProteinuria\t0\t0\t0\t\nHematuresis\t0\t0\t0\t\nGastrointestinal reaction\t\t\t\t\nMucositis/stomatitis\t8 (13.3%)\t5 (13.9%)\t3 (12.5%)\t\nNausea\t6 (10.0%)\t3 (8.3%)\t3 (12.5%)\t\nVomiting\t1 (1.7%)\t1 (2.8%)\t0\t\nDiarrhea\t1 (1.7%)\t1 (2.8%)\t0\t\nConstipation\t9 (15.0%)\t6 (16.7%)\t3 (12.5%)\t\nInappetence\t7 (11.7)\t4 (11.1%)\t3 (12.5%)\t\nNeurotoxicity\t\t\t\t\nLeukoencephalopathy\t11 (18.3%)\t6 (16.7%)\t5 (20.8%)\t\nAnaphylaxis\t7 (11.7%)\t7 (19.4)\t0\t\nInterstitial pneumonitis\t1\t1 (2.8%)\t0\t\nDISCUSSION\nRituximab is used in PCNSL patients due to its positive effect in non-CNS DLBCL. As a large protein, it poorly penetrates CNS. Following intravenous administration, the CSF levels of rituximab are approximately 0.1% of serum levels in patients with CNS lymphoma [20]. Although several studies have indicated that the addition of rituximab to MTX-based chemotherapy improves the survival of patients with PCNSL [16, 21, 22], the efficacy of rituximab in PCNSL need to be demonstrated further.\n\nWe retrospectively analyzed 60 PCNSL patients treated with RMAD or MAD in our single center. Comparing to MAD group, the high CR rate (67.7% vs 33.3%) and longer PFS (31 months vs 14 months) in RMAD group showed rituximab had active effect in PCNSL patients, consistent with prior analyses [18, 19, 23–27]. Comparisons of the median OS of patients treated with or without rituximab yielded different results: Madle et al. reported that rituximab treatment was an independent prognostic factor for OS in first-line treatment of PCNSL [28], whereas Mocikova et al. [18] and Kansara et al. [29] reported that the addition of rituximab to HD-MTX-based induction chemotherapy in PCNSL did not prolong median OS. Our result showed OS had an increasing trend in patients treated with rituximab, but the difference was not statistically significant (p = 0.176). The conflicting results need to be clarified by international randomized trials.\n\nThe backbone of chemotherapy regimen includes MTX and Ara-c. Previous studies have demonstrated that a reduced dose of systemic chemotherapy combined with rituximab can decrease the toxicity of systemic chemotherapy without altering efficacy [30–32]. In our study, we modified the chemotherapy regimens (MA) by reducing Ara-C to 0.5–1 g/m2 (1 dose), in contrast to the dose of 2 g/m2 (total of 4 doses) used by Ferreri et al. [10]. The result in RMAD group was a CR rate of 66.7% and no treatment-related mortalities, in contrast to the 46% CR rate and 8% treatment-related mortalities observed in patients treated with Ara-C 2 g/m2 (total of 4 doses). The result may benefit that we also delivered rituximab intravenously and used short-term treatment with small doses of dexamethasone. Meanwhile, the CR rate in MAD group was only 33.3% lower than Ferreri's result [10], it may be caused by the reduced Ara-c dose. Therefore, it is necessary to carry out prospective trial and stratified study to define the preferable dose of Ara-c.\n\nThe addition of rituximab to induction chemotherapy did not increase toxicity. The most common grade 1–3 adverse events were similar in the two groups and included neutropenia, anemia, thrombocytopenia, elevated aminotransferase levels, and gastrointestinal reactions. Rituximab is a biological agent and often causes allergic reactions, including skin allergy, fever, and respiratory tract allergy. Thus, dexamethasone and/or phenergan should be administered intravenously before administration of rituximab to prevent allergic reactions. In our study, one patient treated with rituximab developed interstitial pneumonitis. A chest CT revealed that the lesions resolved after administration of methylprednisolone 80 mg qd × 5d.\n\nOur study has several limitations that have to be regarded. This study was limited by its small sample size and shorter follow-up time. The results of this present study was preliminary conclusions of single-center study, further prospective studies with cooperation of multi-center are necessary to confirm our results.\n\nIn conclusion, we compared the response rate to induction therapy, long-term outcomes, and toxicity between the two group of PCNSL patients with RMAD and MAD regimens to assess the role of rituximab. Our data indicated that adding rituximab to first-line induction chemotherapy can increase CR rate and significantly prolong PFS. OS showed an increasing trend in patients treated with rituximab, but the difference was not statistically significant. Therefore, this observation must be validated in prospective studies with a longer follow-up period.\n\nMATERIALS AND METHODS\nPatients\nThe clinical data of 60 immunocompetent patients with PCNSL from January 2010 to June 2016 were analyzed retrospectively. PCNSL was diagnosed by stereotactic biopsy, surgery or cerebrospinal fluid (CSF) analysis according to the Revised European-American Lymphoma and WHO classifications [33]. All patients in this study provided informed consent. This study was approved by the Beijing Tiantan Hospital Ethics Committee, Capital Medical University.\n\nTreatment\nInduction chemotherapy consisted of HD-MTX, Ara-C, and dexamethasone (MAD). HD-MTX was administered intravenously at a dose of 3.5 g/m2 over 3 hours on day 1. Leucovorin rescue was initiated 24 hours after HD-MTX administration and administered every 6 hours until the methotrexate level was less than 0.10 μmol/L. Ara-C was administered intravenously at (0.5–1) g/m2 on day 2. The dose of Ara-C depended on the patient age and Eastern Cooperative Oncology Group (ECOG) performance status. Dexamethasone was administered at 5–10 mg on days 1, 2, and 3. The induction treatment consisted of 6 cycles of chemotherapy at 3-week intervals between cycles. Rituximab was administered at 375 mg/m2 on day 0 of every chemotherapy cycle.\n\nThe consolidation chemotherapy consisted of pemetrexed 900 mg/m2 administered on day 1 every 2 months for the first year and then every 6 months for year 2. Oral folic acid was administered at 400 μg daily 1 week before pemetrexed administration and continued for 3 weeks after the last dose. The patients also received intramuscular injections of 1000 μg vitamin B12 no less than 7 days before the administration of pemetrexed, and the injections were repeated every 9 weeks. The patients received two doses of 4 mg of oral dexamethasone daily for 3 days (day 0, day 1, and day 2).\n\nRescue WBRT was administered at a total dose of 45 Gy in 30 daily fractions of 1.5 Gy.\n\nEvaluation of response\nThe patient response was determined every 3 induction chemotherapy courses by contrast-enhanced Magnetic Resonance Imaging (MRI) of the brain. The responses were classified as complete remission (CR), partial remission (PR), stable disease (SD), and progression disease (PD), as described previously [30]. The patients who obtained CR after 6 cycles of induction chemotherapy received consolidation chemotherapy. The patients with PR, SD, PD, or relapse within one year received rescue WBRT. The patients with relapse after 1 year received the original induction chemotherapy. After completing induction therapy, the patients were evaluated by repeat contrast-enhanced MRI of the brain every 2 months for the first year and then every 4 months in years 2 and 3. The MRI was repeated every 6 months in years 4, 5 and 6.\n\nOS was calculated from the date of diagnosis to the time of death from any cause. PFS was calculated from the start of treatment to the time of disease progression or death due to PCNSL.\n\nEvaluation of toxicity\nThe treatment toxicity was graded using the National Cancer Institute Common Toxicity Criteria version 3.0 [34].\n\nStatistics\nThe distribution of patient characteristics was evaluated using the chi-square test. The relationships between the induction chemotherapy regimen (MAD or RMAD) and clinicopathological variables were evaluated by Fisher's exact test and the χ2 test. Kaplan-Meier survival curves were obtained, and differences in OS or PFS were calculated using the log-rank test. The multivariate analysis for OS and PFS was conducted using Cox proportional hazards regression models. All statistical analyses were performed using the SPSS 17.0 software package, and p < 0.05 was considered statistically significant.\n\nAuthors' contributions\n\nLYB designed the study and performed the experiments; LJ, SXF and LYB analyzed the data and wrote the manuscript; SXF, QJ, ZH and QXG performed the experiments; BXY and CYD collected and assembled data; WYM, JN and SSJ provided the study materials and patients.\n\nPart of this work was presented at the 58th American Society Hematology (ASH) Annual Meeting held at the San Diego Convention Center in San Diego, CA, December 3-6, 2016, and published as abstract form in Blood 2016, 128 (22): 4218.\n\nCONFLICTS OF INTEREST\n\nThe authors declare no conflicts of interest.\n\nFUNDING\n\nBeijing Natural Science Foundation (Grant No. 7172071) and National Natural Science Foundation of China General Program (Grant No. 81272842).\n==== Refs\nREFERENCES\n1 Batchelor T Loeffler JS Primary CNS lymphoma J Clin Oncol 2006 24 1281 1288 16525183 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Herbrecht R Tilly H Bouabdallah R Morel P Van Den Neste E Salles G Gaulard P Reyes F Lederlin P Gisselbrecht C CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma N Engl J Med 2002 346 235 242 11807147 \n12 Feugier P Virion JM Tilly H Haioun C Marit G Macro M Bordessoule D Recher C Blanc M Molina T Lederlin P Coiffier B Incidence and risk factors for central nervous system occurrence in elderly patients with diffuse large-B-cell lymphoma: influence of rituximab Ann Oncol 2004 15 129 133 14679132 \n13 Yamamoto W Tomita N Watanabe R Hattori Y Nakajima Y Hyo R Hashimoto C Motomura S Ishigatsubo Y Central nervous system involvement in diffuse large B-cell lymphoma Eur J Haematol 2010 85 6 10 20236301 \n14 Tai WM Chung J Tang PL Koo YX Hou X Tay KW Quek R Tao M Lim ST Central nervous system (CNS) relapse in diffuse large B cell lymphoma (DLBCL): pre- and post-rituximab Ann Hematol 2011 90 809 818 21229246 \n15 Batchelor TT Grossman SA Mikkelsen T Ye X Desideri S Lesser GJ Rituximab monotherapy for patients with recurrent primary CNS lymphoma Neurology 2011 76 929 930 21383331 \n16 Shah GD Yahalom J Correa DD Lai RK Raizer JJ Schiff D LaRocca R Grant B DeAngelis LM Abrey LE Combined immunochemotherapy with reduced whole-brain radiotherapy for newly diagnosed primary CNS lymphoma J Clin Oncol 2007 25 4730 4735 17947720 \n17 Siegal T Primary central nervous system lymphoma: current state of anti-CD20 therapy and appraisal of reported response criteria J Clin Neurosci 2014 21 709 715 24725453 \n18 Mocikova H Pytlik R Sykorova A Janikova A Prochazka V Vokurka S Berkova A Belada D Campr V Buresova L Trneny M Role of rituximab in treatment of patients with primary central nervous system lymphoma: a retrospective analysis of the Czech lymphoma study group registry Leuk Lymphoma 2016 57 2777 2783 27087066 \n19 Ly KI Crew LL Graham CA Mrugala MM Primary central nervous system lymphoma treated with high-dose methotrexate and rituximab: A single-institution experience Oncol Lett 2016 11 3471 3476 27123138 \n20 Rubenstein JL Combs D Rosenberg J Levy A McDermott M Damon L Ignoffo R Aldape K Shen A Lee D Grillo-Lopez A Shuman MA Rituximab therapy for CNS lymphomas: targeting the leptomeningeal compartment Blood 2003 101 466 468 12393404 \n21 Birnbaum T Stadler EA von Baumgarten L Straube A Rituximab significantly improves complete response rate in patients with primary CNS lymphoma J Neurooncol 2012 109 285 291 22570142 \n22 Ott RJ Brada M Flower MA Babich JW Cherry SR Deehan BJ Measurements of blood-brain barrier permeability in patients undergoing radiotherapy and chemotherapy for primary cerebral lymphoma Eur J Cancer 1991 27 1356 1361 1835848 \n23 Fritsch K Kasenda B Hader C Nikkhah G Prinz M Haug V Haug S Ihorst G Finke J Illerhaus G Immunochemotherapy with rituximab, methotrexate, procarbazine, and lomustine for primary CNS lymphoma (PCNSL) in the elderly Ann Oncol 2011 22 2080 2085 21303800 \n24 Holdhoff M Ambady P Abdelaziz A Sarai G Bonekamp D Blakeley J Grossman SA Ye X High-dose methotrexate with or without rituximab in newly diagnosed primary CNS lymphoma Neurology 2014 83 235 239 24928128 \n25 Rubenstein JL Hsi ED Johnson JL Jung SH Nakashima MO Grant B Cheson BD Kaplan LD Intensive chemotherapy and immunotherapy in patients with newly diagnosed primary CNS lymphoma: CALGB 50202 (Alliance 50202) J Clin Oncol 2013 31 3061 3068 23569323 \n26 Chamberlain MC Johnston SK High-dose methotrexate and rituximab with deferred radiotherapy for newly diagnosed primary B-cell CNS lymphoma Neuro Oncol 2010 12 736 744 20511181 \n27 Ferreri AJ Cwynarski K Pulczynski E Ponzoni M Deckert M Politi LS Torri V Fox CP Rosee PL Schorb E Ambrosetti A Roth A Hemmaway C Chemoimmunotherapy with methotrexate, cytarabine, thiotepa, and rituximab (MATRix regimen) in patients with primary CNS lymphoma: results of the first randomisation of the International Extranodal Lymphoma Study Group-32 (IELSG32) phase 2 trial Lancet Haematol 2016 3 e217 227 27132696 \n28 Madle M Kramer I Lehners N Schwarzbich M Wuchter P Herfarth K Egerer G Ho AD Witzens-Harig M The influence of rituximab, high-dose therapy followed by autologous stem cell transplantation, and age in patients with primary CNS lymphoma Ann Hematol 2015 94 1853 1857 26268792 \n29 Kansara R Shenkier TN Connors JM Sehn LH Savage KJ Gerrie AS Villa D Rituximab with high-dose methotrexate in primary central nervous system lymphoma Am J Hematol 2015 90 1149 1154 26414492 \n30 Liu J Sun XF Qian J Bai XY Zhu H Cui QU Li XY Chen YD Wang YM Liu YB Immunochemotherapy for primary central nervous system lymphoma with rituximab, methotrexate, cytarabine and dexamethasone: Retrospective analysis of 18 cases Mol Clin Oncol 2015 3 949 953 26171213 \n31 Rubenstein JL Fridlyand J Abrey L Shen A Karch J Wang E Issa S Damon L Prados M McDermott M O'Brien J Haqq C Shuman M Phase I study of intraventricular administration of rituximab in patients with recurrent CNS and intraocular lymphoma J Clin Oncol 2007 25 1350 1356 17312328 \n32 Rubenstein JL Li J Chen L Advani R Drappatz J Gerstner E Batchelor T Krouwer H Hwang J Auerback G Kadoch C Lowell C Munster P Multicenter phase 1 trial of intraventricular immunochemotherapy in recurrent CNS lymphoma Blood 2013 121 745 751 23197589 \n33 Harris NL Jaffe ES Stein H Banks PM Chan JK Cleary ML Delsol G De Wolf-Peeters C Falini B Gatter KC A revised European-American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group Blood 1994 84 1361 1392 8068936 \n34 Trotti A Colevas AD Setser A Rusch V Jaques D Budach V Langer C Murphy B Cumberlin R Coleman CN Rubin P CTCAE v3.0: development of a comprehensive grading system for the adverse effects of cancer treatment Semin Radiat Oncol 2003 13 176 181 12903007\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1949-2553",
"issue": "8(30)",
"journal": "Oncotarget",
"keywords": "cytarabine; high-dose methotrexate; primary central nervous system lymphoma; rituximab; survival",
"medline_ta": "Oncotarget",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D016543:Central Nervous System Neoplasms; D002648:Child; D003561:Cytarabine; D003907:Dexamethasone; D018450:Disease Progression; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008223:Lymphoma; D008297:Male; D008727:Methotrexate; D008875:Middle Aged; D016016:Proportional Hazards Models; D012074:Remission Induction; D000069283:Rituximab; D016019:Survival Analysis; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "101532965",
"other_id": null,
"pages": "49156-49164",
"pmc": null,
"pmid": "28467782",
"pubdate": "2017-07-25",
"publication_types": "D016428:Journal Article",
"references": "19831839;1835848;20236301;23569323;17580007;1548527;26414492;26268792;24725453;24928128;8068936;24837460;17312328;27132696;27123138;21229246;26171213;23197589;11835382;12488408;19767089;14679132;12903007;12637469;16198065;16525183;12393404;21383331;27087066;20511181;11807147;22570142;17947720;21303800",
"title": "Methotrexate-cytarabine-dexamethasone combination chemotherapy with or without rituximab in patients with primary central nervous system lymphoma.",
"title_normalized": "methotrexate cytarabine dexamethasone combination chemotherapy with or without rituximab in patients with primary central nervous system lymphoma"
} | [
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{
"abstract": "A nine-yr-old boy with EPP suffered from severe skin burns and liver failure caused by progressive cholestasis and fibrosis. OLT was performed without major complications. Four months following liver transplantation he underwent parental haploidentical HSCT. The myeloablative conditioning regimen was relatively well tolerated and hematological engraftment was rapid (on day 10). Protoporphyrin concentrations returned to normal following HSCT. However, immune recovery was significantly delayed. Varicella zoster virus reactivation resulted in impaired vision, prolonged hospitalization and eventually in multiorgan failure and death. Sequential liver and haploidentical HSCT proved feasible though a high risk procedure in this EPP patient. The management of post-IST after these combined transplantations remains a challenge and needs to be further established.",
"affiliations": "Division of Immunology, Hematology, Oncology, Bone marrow transplantation and Auto-immune disease, Department of Pediatrics, Leiden University Medical Center, Leiden, The Netherlands. f.j.smiers@lumc.nl",
"authors": "Smiers|Frans J|FJ|;Van de Vijver|Els|E|;Delsing|Bas J P|BJ|;Lankester|Arjan C|AC|;Ball|Lynne M|LM|;Rings|Edmund H H M|EH|;van Rheenen|Patrick F|PF|;Bredius|Robbert G M|RG|",
"chemical_list": null,
"country": "Denmark",
"delete": false,
"doi": "10.1111/j.1399-3046.2009.01233.x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1397-3142",
"issue": "14(4)",
"journal": "Pediatric transplantation",
"keywords": null,
"medline_ta": "Pediatr Transplant",
"mesh_terms": "D002648:Child; D017809:Fatal Outcome; D018380:Hematopoietic Stem Cell Transplantation; D006648:Histocompatibility; D006801:Humans; D016031:Liver Transplantation; D008297:Male; D046351:Protoporphyria, Erythropoietic; D019172:Transplantation Conditioning",
"nlm_unique_id": "9802574",
"other_id": null,
"pages": "471-5",
"pmc": null,
"pmid": "19735434",
"pubdate": "2010-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Delayed immune recovery following sequential orthotopic liver transplantation and haploidentical stem cell transplantation in erythropoietic protoporphyria.",
"title_normalized": "delayed immune recovery following sequential orthotopic liver transplantation and haploidentical stem cell transplantation in erythropoietic protoporphyria"
} | [
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"companynumb": "NL-SA-2017SA025658",
"fulfillexpeditecriteria": "1",
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"activesubstancename": "MYCOPHENOLATE MOFETIL"
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... |
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"abstract": "Hair loss and thinning are possible complications in those undergoing endocrine therapies with aromatase inhibitors. Alopecia in pediatric patients undergoing endocrine therapy has not been previously reported. We describe two adolescents, 14 and 16 years of age, who developed androgenetic alopecia following treatment with anastrozole for idiopathic short stature. Accordingly, the possible adverse event of alopecia should be considered in the pediatric population undergoing treatment with aromatase inhibitors.",
"affiliations": "Department of Dermatology and Cutaneous Surgery, University of Miami Hospital, Miami, Florida, USA.;Department of Dermatology and Cutaneous Surgery, University of Miami Hospital, Miami, Florida, USA.;Department of Dermatology and Cutaneous Surgery, University of Miami Hospital, Miami, Florida, USA.",
"authors": "Perper|Marina|M|https://orcid.org/0000-0003-4916-6434;Herskovitz|Ingrid|I|;Tosti|Antonella|A|",
"chemical_list": "D047072:Aromatase Inhibitors",
"country": "United States",
"delete": false,
"doi": "10.1111/pde.14339",
"fulltext": null,
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"issn_linking": "0736-8046",
"issue": "37(6)",
"journal": "Pediatric dermatology",
"keywords": "alopecia; hair disorders; pharmacology; quality of life",
"medline_ta": "Pediatr Dermatol",
"mesh_terms": "D000293:Adolescent; D000505:Alopecia; D047072:Aromatase Inhibitors; D002648:Child; D006801:Humans",
"nlm_unique_id": "8406799",
"other_id": null,
"pages": "1125-1127",
"pmc": null,
"pmid": "32869880",
"pubdate": "2020-11",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Aromatase inhibitor-induced hair loss in two adolescents.",
"title_normalized": "aromatase inhibitor induced hair loss in two adolescents"
} | [
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"companynumb": "US-APOTEX-2020AP019918",
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"occurcountry": "US",
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"activesubstance": {
"activesubstancename": "ANASTROZOLE"
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"drugadditional": null,
... |
{
"abstract": "Children with multiple relapsed or refractory leukemia have dismal survival. Research has identified engagement of immune checkpoint receptors (e.g., PD-1, PD-L1 and CTLA-4) as a mechanism for treatment resistance. For adult cancer, inhibitors of PD-1 (nivolumab) and CTLA-4 (ipilimumab) have shown promise with response rates ranging from 7 to 40%. In vitro studies using acute myeloid leukemia cell lines have shown that acute myeloid leukemia blasts may similarly utilize the PD-1/PD-L1 axis to evade an anticancer immune response. We report the first case of a pediatric patient with multiple relapsed/refractory leukemia treated with nivolumab, ipilimumab and 5-azacytidine who tolerated therapy with brief improvement of symptoms.",
"affiliations": "Department of Pediatrics, Division of Hematology/Oncology & Blood & Marrow Transplantation, Medical College of Wisconsin, Milwaukee, WI, 53226, USA.;Department of Pediatrics, Division of Hematology/Oncology & Blood & Marrow Transplantation, Medical College of Wisconsin, Milwaukee, WI, 53226, USA.;Department of Pediatrics, Division of Hematology/Oncology & Blood & Marrow Transplantation, Medical College of Wisconsin, Milwaukee, WI, 53226, USA.",
"authors": "Broglie|Larisa|L|;Gershan|Jill|J|;Burke|Michael J|MJ|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.2217/ijh-2018-0009",
"fulltext": "\n==== Front\nInt J Hematol OncolInt J Hematol OncolIJHInternational Journal of Hematologic Oncology2045-13932045-1407Future Medicine Ltd London, UK 3086352710.2217/ijh-2018-0009Case ReportCheckpoint inhibition of PD-L1 and CTLA-4 in a child with refractory acute leukemia Broglie, Gershan & BurkeCheckpoint inhibition of PD-L1 & CTLA-4 in a child with refractory acute leukemiaBroglie Larisa \n1\n\n2\nGershan Jill \n1\nBurke Michael J *\n1\n\n1 Department of Pediatrics, Division of Hematology/Oncology & Blood & Marrow Transplantation, Medical College of Wisconsin, Milwaukee, WI, 53226, USA\n2 Department of Pediatric, Division of Hematology/Oncology & Blood & Marrow Transplantation, Columbia University Medical Center, New York, NY, 10027, USA*Author for correspondence: Tel.: +1 414 955 4170; Fax: +1 414 955 6543; mmburke@mcw.edu2 2019 16 1 2019 16 1 2019 8 1 IJH1017 9 2018 11 12 2018 16 1 2019 © 2019 Michael J. Burke2019This work is licensed under a Creative Commons Attribution-NonCommercial NonDerivative 4.0 Unported License\nChildren with multiple relapsed or refractory leukemia have dismal survival. Research has identified engagement of immune checkpoint receptors (e.g., PD-1, PD-L1 and CTLA-4) as a mechanism for treatment resistance. For adult cancer, inhibitors of PD-1 (nivolumab) and CTLA-4 (ipilimumab) have shown promise with response rates ranging from 7 to 40%. In vitro studies using acute myeloid leukemia cell lines have shown that acute myeloid leukemia blasts may similarly utilize the PD-1/PD-L1 axis to evade an anticancer immune response. We report the first case of a pediatric patient with multiple relapsed/refractory leukemia treated with nivolumab, ipilimumab and 5-azacytidine who tolerated therapy with brief improvement of symptoms.\n\nKeywords: \nacute leukemiaazacytidinecheckpoint inhibitorepigeneticipilimumabnivolumabrefractoryrelapse\n==== Body\nPractice points\nRelapsed mixed lineage leukemia can be difficult to treat with standard therapies.\n\nCheckpoint blockade with nivolumab and ipilimumab has shown promise in treatment of lymphoma and melanoma with growing evidence in other malignancies, such as acute myeloid leukemia (AML).\n\nLimited data on the efficacy and tolerability of these agents has been reported in pediatrics, although current studies are ongoing.\n\nWe report a patient who tolerated combined therapy with 5-azacitidine, nivolumab and later ipilimumab. The patient was able to focus on her quality of life at home with her family during the 6 weeks of epigenetic and checkpoint inhibitor therapy. However, the patient ultimately died from disease progression.\n\nCytokine evaluation after 5-azacytidine and nivolumab therapy may help identify response to therapy. In this patient, the mixed cytokine response may reflect both activated innate immunity against the AML as well as ongoing AML proliferation.\n\nFurther studies are needed to evaluate the efficacy of checkpoint blockade in pediatric AML. Further studies are also needed to determine if cytokine assessment can help determine early response to these therapies.\n\nOutcomes for children with leukemia have improved; however, patients with multiple relapsed or refractory disease continue to have dismal survival [1,2]. In recent years, research has identified engagement of immune checkpoint receptors as a mechanism of tumor evasion [3]. T-cell checkpoint receptors such as CTLA-4 and PD-1 relay inhibitory signals that modulate T-cell activation. Blocking signaling through checkpoint receptors results in increased T-cell activation, with effector T-cell proliferation and increased cytotoxicity toward cancer cells [4]. Inhibitors of PD-1 (nivolumab) and CTLA-4 (ipilimumab) have shown promise for the treatment of advanced melanoma and relapsed Hodgkin's lymphoma with response rates ranging from 7 to 40% [4–6]. In vitro studies have shown that acute myeloid leukemia (AML) may utilize the PD-1/PD-L1 axis to evade an anticancer immune response [7–10]. These findings have prompted development of clinical trials utilizing checkpoint inhibitors for adult malignancies. However, established efficacy in pediatric hematological malignancies remains limited.\n\nHere, we report a case of a pediatric patient with multiple relapsed and refractory acute leukemia who tolerated palliative treatment with 5-azacytidine and two checkpoint inhibitors, nivolumab and ipilimumab, allowing her and her family to focus on her quality of life.\n\nCase presentation\nA 4-year-old female presented with persistent fevers and a superficial thigh abscess, unresponsive to outpatient antibiotic treatment. Evaluation revealed an elevated white blood cell count of 84,000 with 74% peripheral blasts and a mediastinal mass. Flow cytometric analysis reported a single blast immunophenotype (CD34+, CD117+, CD38+ and MPO+) with the presence of both T-lymphoid (cytoplasmic CD3+, HLA-DR-) and myelomonocytic (CD7+, CD56+, CD33+ and membrane CD3-) cell markers consistent with mixed phenotype acute leukemia. Based on this phenotype, T-cell acute lymphoblastic leukemia therapy was initially given according to the Children's Oncology Group (COG) protocol AALL0434, but, after 2 days, therapy changed to an AML-directed induction due to concern over a rising white blood cell count of >100,000 (Table 1). At the end of induction with cytarabine, daunorubicin and etoposide, a bone marrow evaluation showed complete remission (<5% blasts) with minimal residual disease (MRD) present (flow cytometry MRD = 0.5%). The patient was switched back to T-ALL therapy to complete a second induction phase (according to COG AALL0434) followed by AALL0434 consolidation with nelarabine and interim maintenance (high-dose methotrexate); however, her MRD persisted, prompting further intensification with cyclophosphamide, etoposide and nelarabine (Table 1). The decision was ultimately made to proceed to allogeneic hematopoietic cell transplantation (HCT), given the inability in achieving an MRD-negative remission (pre-HCT MRD was 0.007%). The patient proceeded to a myeloablative umbilical cord blood HCT with total body irradiation (13.2 Gy), fludarabine (75 mg/m2) and cyclophosphamide (120 mg/kg). Her post-transplant course was complicated by steroid-responsive grade IV gastrointestinal acute graft-versus-host disease, idiopathic pneumonitis and chronic graft-versus-host disease serositis.\n\nTable 1. \nChemotherapy course, complications, and disease response after each treatment.\n\nTherapy\tComplications\tResponse\t\nDiagnosis\t\n\t\nInduction per COG AALL0434 for T-ALL\n–Dexamethasone, Vincristine, PEG-asparaginase and Daunorubicin\tRising WBC >100,000\tSwitched to AAML1031 therapy on Day × 2\t\n\t\nInduction I per AAML1031\n–Etoposide, Daunorubicin, Cytarabine\t \tEnd of Induction I MRD 0.5%.\t\n\t\nInduction following AALL0434\n–Dexamethasone, Vincristine, and Daunorubicin, PEG- asparaginase\tAnaphylaxis to peg-asparaginase and Erwinia\tEnd of Induction MRD 0.065%\t\n\t\nConsolidation following AALL0434\n–Nelarabine, Cyclophosphamide, Cytarabine, steroids\t \tEnd of Consolidation MRD 0.025%\t\n\t\nInterim Maintenance 1\n–High-dose Methotrexate, Vincristine and 6-mercaptopurine (3 of 5 doses of Methotrexate received)\t \tEnd of Interim Maintenance 1 MRD 0.03%\t\n\t\n–Cyclophosphamide, Etoposide, Nelarabine\t \tEnd of Cycle MRD 0.025%.\t\n\t\nHematopoietic stem cell transplant\t \tPre-HCT MRD\n0.007%\t\n\t\nUmbilical Cord Blood HCT\nMyeloablative conditioning:\n–TBI (13.2Gy), Fludarabine (75 mg/m2), and Cyclophosphamide (120 mg/kg)\tGrade IV gut aGVHD\nCMV reactivation, BK viuria and viremia, Seizures, transplant associated microangiopathy, Pneumonitis, cGVHD (serositis with pleural pericardial effusions)\tMRD <0.001%\t\n\t\nRelapse: extramedullary disease and later bone marrow and CNS relapse\t\n\t\n–Cyclophosphamide, Etoposide, and Bortezomib\t \tEnd of Cycle MRD 0.17%\t\n\t\n–Nelarabine, skin radiation (scalp - 26Gy, perineum - 21Gy, total skin - 14Gy) with steroids\tDisease progression\t28% blasts,\nCNS blasts present\nPET - Many diffuse lesions\t\n\t\n–Gemtuzumab, Low-dose Cytarabine, and intrathecal Cytarabine\tRadiation recall with burns in her perineum\nSeizure\tEnd of Cycle MRD 0.09%, CNS negative PET single lung nodule\t\n\t\n–Venetoclax (120 mg daily for 28-day cycle)\tARF from bilateral ureteral obstruction requiring ureteral stents\tEnd of Cycle\n7% blasts,\nCNS positive\nPET lesions in mediastinum, and pelvis\t\n\t\n–Mitoxantrone, High-dose Cytarabine, Gemtuzumab\tPseudomonas Infections\nCheek cellulitis\nGastritis\nProlonged Count Recovery\tEnd of Cycle 19% blasts\nPET negative\nPeripheral blood blasts present\t\n\t\n–Nivolumab (3 mg/kg iv. on days 1 and 14),\n–Azacytidine (75 mg/m2 iv. daily × 5 days)\tStaph epi sepsis\nHSV reactivation\nLeft leg pain secondary to marrow infiltration\tEnd of Cycle Persistent disease\t\n\t\n–Nivolumab (3 mg/kg iv. on day 1)\n–Azacytidine (75 mg/m2 iv. daily × 5 days)\n–Ipilimumab (1 mg/kg iv. on day 3)\tPseudomonas sepsis\tProgressive disease\t\nARF: Acute renal failure; CMV: Cytomegalovirus; CNS: Central nervous system; COG: Children's Oncology Group; GVHD: Graft-versus-host disease; HCT: Hematopoietic cell transplantation; MRD: Minimal residue disease; PET: Positron emission tomography; WBC: White blood cell count.\n\nIn 320 days post-HCT, the patient developed an isolated submental nodule that was diagnosed histologically as leukemia cutis (expressing the same myeloid phenotype without CD3 expression from her original diagnosis). Bone marrow aspirate, spinal tap and CT evaluations showed no additional evidence of leukemia. The isolated relapse was completely resected and her parents chose close monitoring without further treatment, instead of reinduction chemotherapy, which was the recommendation of the oncology team. However, over the next few months additional subcutaneous nodules were identified. A PET/CT scan revealed disseminated chloromas. Given this relapse and the known difficulty of cure with traditional chemotherapy, next-generation-sequencing was performed on her original diagnostic bone marrow to identify any potentially targetable mutations. A lone NOTCH mutation was the only lesion identified with a potential therapeutic target. At the time of this relapse, there were no pediatric early phase clinical trials available for her to enroll in. Thus, the patient received multiple reinduction attempts with a variety of chemotherapy salvage combinations, but remission could not be achieved (Table 1).\n\nGiven the refractory nature of her disease, which at this time remained as AML without any T-ALL features, and the parent's strong interest in pursuing some form of immunotherapy, we discussed the option of combining checkpoint inhibition (nivolumab) with a DNA methyltransferase inhibitor (5-azacytidine) as was recently reported in adults with refractory AML [11]. After discussion of the potential risks and benefits of this proposed treatment, the family consented to this experimental therapy recommendation as palliative therapy, outside of the context of a clinical trial. Additionally, the parents consented to further research testing performed on their daughter's peripheral blood and bone marrow samples collected during this experimental treatment.\n\nThe patient was experiencing significant bone pain at the time prior to starting this palliative therapy for which required hospitalization for aggressive pain management with intravenous narcotics, oral methadone, gabapentin and anxiolytics (lorazepam). The patient thus received her first course of 5-azacytidine (75 mg/m2 iv. daily, days 1–5) and nivolumab (3 mg/kg iv. on days 1 and 14) while in the hospital and tolerated it well without any adverse event (AE). While receiving the combination of 5-azacytidine and nivolumab, her bone pain significantly improved to the point that she was able to be discharged home 5 days later (completing her 5 days of 5-azacytidine) on oral dilaudid, methadone and gabapentin. The patient remained home with her family, coming to the oncology clinic for twice weekly visits, including for her second dose of nivolumab on day 14 of this treatment cycle, and her pain remained well controlled with oral medications alone. At the start of the 5-azacytidine/nivolumab therapy, the patient's peripheral blood had 1% blasts present which slowly increased to 10% by day 14. Unfortunately, she continued to have persistent and rising disease as her peripheral blood blast percentage increased to 34% at day 28 of treatment.\n\nTo assess for any response to checkpoint inhibitor therapy, serum obtained 28 days after starting 5-azacytidine/nivolumab was analyzed using the human cytokine/chemokine 65-plex array (Eve Technologies, AB, Canada) that included analysis of the following cytokines/chemokines: CXCL1, CCL1, IFNα2, IFN-γ, IL-1α, IL-1β, IL-1rα, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12 (p40), IL-12 (p70), IL-13, IL-15, IL-16, IL-17A, IL-18, IL-20, IL-21, IL-23, IL-28a, IL-33, IP-10, LIF, MCP-1, MCP-2, MCP-3, MCP-4, MDC, MIP-1α, MIP-1β, MIP-1δ, PDGF-AA, PDGF-AB/BB, RANTES, SDF-1 α+β, sCD40L, SCF, TARC, TGFα, TNFα, TNFβ, TPO, TRAIL, TSLP and VEGF. The patient's serum sample was compared with normal adult controls, as no pediatric controls were available. We identified a significant increase (as determined by two-way ANOVA) in the concentration of IL-18, FLT3L, G-CSF, CXCL10 and CCL24 in the patient's serum (Figure 1). While not significant, there was also an elevation in proinflammatory cytokines, IL-6 and TNF-a. Of note, a bone marrow sample was not available for immune phenotyping or assessment of PD-1 or CTLA-4 secondary to poor sample quality.\n\nFigure 1. \nPost-treatment serum cytokines.\n\nSerum was obtained after 28 days of treatment with 5-azacytidine and nivolumab. Cytokine concentrations were analyzed by Eve Technologies (AB, Canada) using a Luminex-based platform. Control serum was obtained from normal adult donors.\n\n****p < 0.0001; ***p < 0.001; **p < 0.01 and *p < 0.05.\n\nDespite maintaining good pain control and quality of life, given the patient's persistent disease and the family's desire to continue palliative therapy, a second cycle of 5-azacytidine (75 mg/m2 iv. daily, days 1–5) and nivolumab (3 mg/kg iv. on day 1) was started with the addition of ipilimumab (1 mg/kg iv. on day 3) in hopes of improving the disease response. The combination of nivolumab and ipilimumab was according to the COG Phase I study (ADVL1412, NCT02304458) which reported safety and tolerability combining the CTLA-4 and PD-1 inhibitor (Table 1). The patient tolerated the addition of the CTLA-4 inhibitor (ipilimumab) to 5-azacytidine and nivolumab well without any AEs, including no reports of further bone pain while continuing her oral pain medications (twice daily methadone, gabapentin three-times a day and Dilaudid as needed). During the two cycles of epigenetic/checkpoint inhibitor therapy, she did not have any elevation of liver transaminases (ALT: 28–47 iU/l; AST: 16–40 iU/l) nor significant anemia (range: 7.6–12.0 g/dl) requiring red blood cell transfusions but did require a single platelet transfusion for a platelet count of 10 × 109 per liter (platelet range, 10–110 × 109/l). However, 45 days after starting the first cycle of 5-azacytidine and nivolumab and 11 days after receiving ipilimumab, the patient developed an overwhelming pseudomonas aeruginosa sepsis in the setting of increasing leukemia burden (>65% peripheral blasts; Figure 2) and succumbed to her leukemia.\n\nFigure 2. \nPercent peripheral blasts.\n\nThe percent of peripheral blasts present during the 6 weeks of epigenetic and checkpoint inhibitor therapy are reported over time (days of therapy).\n\nDiscussion\nWe report a pediatric patient with relapsed and refractory mixed phenotype acute leukemia treated with a DNA methyltransferase inhibitor (5-azacytidine) and checkpoint inhibitors (nivolumab and ipilimumab). The patient tolerated the palliative regimen very well for 6 weeks while maintaining a reasonably good quality of life, remaining outside of the hospital and with improved pain control. Importantly, there were no AEs attributed to the epigenetic/checkpoint inhibitor therapy. Unfortunately, our patient continued with persistent leukemia despite this regimen. In an attempt to evaluate the response to checkpoint blockade, we analyzed serum cytokine expression, as we were unable to evaluate PD-1 expression on either peripheral blood or bone marrow blasts.\n\nStudies have shown that checkpoint blockade is associated with a proinflammatory immune response with an increased expression of TNF-α, IFN-γ, IL-2, IL-6 and IL-17 and can precipitate autoimmunity [12,13]. After 28 days of treatment with 5-azacytidine and nivolumab, our patient had elevated concentrations of proinflammatory cytokines IL-18, CXCL10, FLT3L and CCL24 compared with normal adult control samples. IL-18 is produced upon activation of intracellular innate immune sensors and is considered tumor-suppressive [14]. CXCL10 is released by human AML cells and promotes T-cell chemotaxis [15]. Recombinant CXCL10 has also been shown to inhibit the proliferation of AML precursors [16]. Both IL-18 and CXCL10, induced by checkpoint blockade, suggest an ongoing anti-AML immune response. Unfortunately, our patient also showed evidence of elevated FLT3L and CCL24. FLT3L acts as a mitogenic growth factor for AML cells [17]. CCL24 regulates a Type-2 CD4 T-cell differentiation [18], which is associated with protumor immunity. Thus, the elevation of FLT3L and CCL24 may also be reflective of pro-AML growth and progressive disease. Although a baseline (prenivolumab treatment) serum sample was unavailable for comparison, it is possible that the elevation of these cytokines is a reflection of both activated innate immunity [14] against the AML as well as ongoing AML proliferation, although this is difficult to determine given the lack of pediatric controls.\n\nIn summary, this case demonstrates feasibility of combining 5-azacytidine with a PD-L1 and CTLA-4 antibody in a child with refractory leukemia. There were no AEs associated with this therapy over the 6 weeks of treatment and the treatment allowed for improved symptom control at home, limiting the patient's hospital visits and allowed for an improved quality of life. While the cytokine profile is interesting, the anti-AML efficacy of combined epigenetic and checkpoint blockade cannot be determined from this case. Further research is needed to determine if this strategy can be successful for treating pediatric hematologic malignancies such as AML.\n\n\nFinancial & competing interests disclosure\n\n\nThis publication was supported by the National Center for Advancing Translational Sciences, National Institutes of Health, through Grant Numbers UL1TR001436 and 1TL1TR001437 to L Broglie. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.\n\nNo writing assistance was utilized in the production of this manuscript.\n\n\nEthical conduct of research and informed consent disclosure\n\n\nThe authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.\n\nThe authors state that they have obtained verbal and written informed consent from the patient/patients for the inclusion of their medical and treatment history within this case report.\n\n\nOpen access\n\n\nThis work is licensed under the Attribution-NonCommercial-NoDerivatives 4.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/\n==== Refs\nReferences\nPapers of special note have been highlighted as: • of interest; •• of considerable interest\n\n1 Gorman MF Ji L Ko RH Outcome for children treated for relapsed or refractory acute myelogenous leukemia (rAML): a therapeutic advances in childhood leukemia (TACL) consortium study Pediatr. Blood Cancer 55 3 421 429 2010 20658611 \n2 Ko RH Ji L Barnette P Outcome of patients treated for relapsed or refractory acute lymphoblastic leukemia: a therapeutic advances in childhood leukemia consortium study J. Clin. Oncol. 28 4 648 654 2010 19841326 \n3 Armand P Immune checkpoint blockade in hematologic malignancies Blood 125 22 3393 3400 2015 25833961 \n4 Prieto PA Yang JC Sherry RM CTLA-4 blockade with ipilimumab: long-term follow-up of 177 patients with metastatic melanoma Clin. Cancer Res. 18 7 2039 2047 2012 22271879 \n5 Ansell SM Lesokhin AM Borrello I PD-1 blockade with nivolumab in relapsed or refractory Hodgkin's lymphoma N. Engl. J. Med. 372 4 311 319 2015 25482239 • Nivolumab for treatment of relapsed or refractory Hodgkin's lymphoma was able to induce a response rate of 87%, with 17% of patients achieving a complete response.\n\n\n6 Berman DM Wolchok J Weber J Hamid O O'Day S Chasalow SD Association of peripheral blood absolute lymphocyte count (ALC) and clinical activity in patients (pts) with advanced melanoma treated with ipilimumab J. Clin. Oncol. 27 15 3020 2009 19470921 \n7 Esendagli G A co-stimulatory trap set by myeloid leukemia cells Oncoimmunology 2 6 e24524 2013 23894714 •• Myeloid leukemia cells were shown to evade immune response by upregulation of PD-L1.\n\n\n8 Laurent S Palmisano GL Martelli AM CTLA-4 expressed by chemoresistant, as well as untreated, myeloid leukaemia cells can be targeted with ligands to induce apoptosis Br. J. Haematol. 136 4 597 608 2007 17367412 •• CTLA4 is expressed on acute myeloid leukemia blasts in some patients and CTLA4 blockade was able to induce apoptosis of myeloid leukemia cells.\n\n\n9 Das R Verma R Sznol M Combination therapy with anti-CTLA-4 and anti-PD-1 leads to distinct immunologic changes in vivo J. Immunol. 194 3 950 959 2015 25539810 \n10 Davids MS Kim HT Bachireddy P Ipilimumab for patients with relapse after allogeneic transplantation N. Engl. J. Med. 375 2 143 153 2016 27410923 \n11 Daver N Basu S Garcia-Manero G Phase IB/II study of nivolumab in combination with azacytidine (AZA) in patients (pts) with relapsed acute myeloid leukemia (AML) Blood Conference: 58th annual meeting of the American Society of Hematology, ASH 2016. United States;128:763 •• Nivolumab given in combination with azacytidine was well tolerated in adult patients.\n\n\n12 Hirahara K Nakayama T CD4+ T-cell subsets in inflammatory diseases: beyond the Th1/Th2 paradigm Int. Immunol. 28 4 163 171 2016 26874355 \n13 Dulos J Carven GJ van Boxtel SJ PD-1 blockade augments Th1 and Th17 and suppresses Th2 responses in peripheral blood from patients with prostate and advanced melanoma cancer J. Immunother. 35 2 169 178 2012 22306905 • PD-1 inhibition results in a shift to a proinflammatory state with an increase in proinflammatory cytokine expression.\n\n\n14 Poleganov MA Bachmann M Pfeilschifter J Muhl H Genome-wide analysis displays marked induction of EBI3/IL-27B in IL-18-activated AML-derived KG1 cells: critical role of two kappaB binding sites in the human EBI3 promotor Mol. Immunol. 45 10 2869 2880 2008 18336908 \n15 Olsnes AM Motorin D Ryningen A Zaritskey AY Bruserud O T lymphocyte chemotactic chemokines in acute myelogenous leukemia (AML): local release by native human AML blasts and systemic levels of CXCL10 (IP-10), CCL5 (RANTES) and CCL17 (TARC) Cancer Immunol. Immunother. 55 7 830 840 2006 16267679 \n16 Sarris AH Talpaz M Deisseroth AB Estrov Z Human recombinant interferon-inducible protein-10 inhibits the proliferation of normal and acute myelogenous leukemia progenitors Leukemia 10 5 757 765 1996 8656668 \n17 Dehmel U Quentmeier H Drexler HG Effects of FLT3 ligand on human leukemia cells. II. Agonistic and antgonistic effects of other cytokines Leukemia 10 2 271 278 1996 8637236 \n18 Miyagaki T Sugaya M Fujita H Eotaxins and CCR3 interaction regulates the Th2 environment of cutaneous T-cell lymphoma J. Investig. Dermatol. 130 9 2304 2311 2010 20505746\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2045-1393",
"issue": "8(1)",
"journal": "International journal of hematologic oncology",
"keywords": "acute leukemia; azacytidine; checkpoint inhibitor; epigenetic; ipilimumab; nivolumab; refractory; relapse",
"medline_ta": "Int J Hematol Oncol",
"mesh_terms": null,
"nlm_unique_id": "101600758",
"other_id": null,
"pages": "IJH10",
"pmc": null,
"pmid": "30863527",
"pubdate": "2019-02",
"publication_types": "D002363:Case Reports",
"references": "16267679;17367412;18336908;19841326;20505746;20658611;22271879;22306905;23894714;25482239;25539810;25833961;26874355;27410923;8637236;8656668",
"title": "Checkpoint inhibition of PD-L1 and CTLA-4 in a child with refractory acute leukemia.",
"title_normalized": "checkpoint inhibition of pd l1 and ctla 4 in a child with refractory acute leukemia"
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"abstract": "Case reports, case series and cohort studies have been published describing the clinical course and outcomes of people living with human immunodeficiency virus (PLWH) who contract coronavirus disease 2019 (COVID-19) pneumonia. However, the majority of the published work focuses on patients with well-controlled human immunodeficiency virus (HIV) on antiretroviral therapy (ART).\nWe present a case of a new diagnosis of HIV with Acquired Immune Deficiency Syndrome (AIDS) made simultaneously to diagnosis of COVID-19, with co-infection with pneumocystis jirovecii pneumonia (PJP) and possible cytomegalovirus (CMV) pneumonitis. The patient decompensated following initiation of ART, suggestive of possible immune reconstitution inflammatory syndrome (IRIS).\nThis case illustrates the importance of maintaining a high suspicion for HIV/AIDS in patients with risk factors. Additionally, this case raises the possibility that IRIS may develop in the setting of ART initiation in patients with COVID-19.",
"affiliations": "Division of Infectious Diseases, Beth Israel Deaconess Medical Center, Harvard Medical School, 110 Francis Street, Suite GB, Boston, MA, 02215, USA.;Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA, 02215, USA.;Division of Infectious Diseases, Beth Israel Deaconess Medical Center, Harvard Medical School, 110 Francis Street, Suite GB, Boston, MA, 02215, USA.;Division of Infectious Diseases, Beth Israel Deaconess Medical Center, Harvard Medical School, 110 Francis Street, Suite GB, Boston, MA, 02215, USA.",
"authors": "Merchant|Elisabeth A|EA|;Flint|Kristen|K|;Barouch|Dan H|DH|;Blair|Barbra M|BM|",
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"doi": "10.1016/j.idcr.2021.e01153",
"fulltext": "\n==== Front\nIDCases\nIDCases\nIDCases\n2214-2509\nElsevier\n\nS2214-2509(21)00109-8\n10.1016/j.idcr.2021.e01153\ne01153\nCase Report\nCo-infection with coronavirus disease 2019, previously undiagnosed human immunodeficiency virus, Pneumocystis jirovecii pneumonia and cytomegalovirus pneumonitis, with possible immune reconstitution inflammatory syndrome\nMerchant Elisabeth A. emerchan@bidmc.harvard.edu\nelisabeth.merchant.md@gmail.com\na1⁎\nFlint Kristen b1\nBarouch Dan H. ac\nBlair Barbra M. a\na Division of Infectious Diseases, Beth Israel Deaconess Medical Center, Harvard Medical School, 110 Francis Street, Suite GB, Boston, MA, 02215, USA\nb Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA, 02215, USA\nc Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, 3 Blackfan Circle, Boston, MA, 02115, USA\n⁎ Corresponding author. emerchan@bidmc.harvard.eduelisabeth.merchant.md@gmail.com\n1 Co-equal first authors.\n\n07 5 2021\n2021\n07 5 2021\n24 e011532 3 2021\n4 5 2021\n4 5 2021\n© 2021 The Authors. Published by Elsevier Ltd.\n2021\n\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).\nHighlights\n\n• Co-infection with COVID-19 and HIV should be considered in people with risk factors.\n\n• People with AIDS can have both COVID-19 and opportunistic infections.\n\n• People with AIDS and COVID-19 may be at risk for immune reconstitution syndrome.\n\n• Further study of COVID-19 in people with AIDS is needed.\n\nBackground\n\nCase reports, case series and cohort studies have been published describing the clinical course and outcomes of people living with human immunodeficiency virus (PLWH) who contract coronavirus disease 2019 (COVID-19) pneumonia. However, the majority of the published work focuses on patients with well-controlled human immunodeficiency virus (HIV) on antiretroviral therapy (ART).\n\nCase presentation\n\nWe present a case of a new diagnosis of HIV with Acquired Immune Deficiency Syndrome (AIDS) made simultaneously to diagnosis of COVID-19, with co-infection with pneumocystis jirovecii pneumonia (PJP) and possible cytomegalovirus (CMV) pneumonitis. The patient decompensated following initiation of ART, suggestive of possible immune reconstitution inflammatory syndrome (IRIS).\n\nConclusions\n\nThis case illustrates the importance of maintaining a high suspicion for HIV/AIDS in patients with risk factors. Additionally, this case raises the possibility that IRIS may develop in the setting of ART initiation in patients with COVID-19.\n\nKeywords\n\nCOVID-19\nHIV\nAIDS\nPJP\nIRIS\n==== Body\nBackground\n\nCo-infection with human immunodeficiency virus (HIV) and coronavirus disease 2019 (COVID-19) remains incompletely understood [1,2]. Poorly controlled HIV or acquired immune deficiency syndrome (AIDS) is a risk factor for many opportunistic infections, however it is unclear if AIDS increases risk of COVID-19 acquisition or severity. Alternatively, over-exuberant immune response can be a feature of severe COVID-19 infections, against which HIV-associated immune dysfunction has been hypothesized to be protective, and it has been suggested that some antiretroviral therapy (ART) may have activity against SARS-COV-2 [3].\n\nThe majority of published data is in patients with well-controlled HIV although the literature is growing around persons living with HIV (PLWH) complicated by AIDS and COVID-19 [1,2]. There have also been reports of opportunistic infections in the subset of PLWH who have AIDS and COVID-19, including prior reports of COVID-19 and pneumocystis jirovecii pneumonia (PJP) [4]. We present a patient simultaneously diagnosed with COVID-19 and HIV/AIDS complicated by both PJP and possible CMV pneumonitis, who decompensated after initiation of ART, suggestive of immune reconstitution inflammatory syndrome (IRIS).\n\nCase presentation\n\nA 38-year-old previously healthy cis-gender man who has sex with men presented with two weeks of exertional dyspnea and dry cough. He noted significant weight loss and anorexia over the preceding 6 months, however denied additional symptoms. He had no known exposures to persons with COVID-19 or HIV.\n\nOn presentation, he was febrile to 101.3 °F, tachycardic with heart rate 121 beats/min, tachypneic with respiratory rate of 26 breaths/min and hypoxic (oxygen saturation 93 % on room air). Exam was notable for fine pulmonary rales. Labs are summarized in Table 1. Additionally, his COVID-19 nasopharyngeal polymerase chain reaction (PCR) swab was positive, as was HIV testing. Computed tomography (CT) of the chest showed bilateral diffuse ground glass opacification (GGO) with areas of crazy paving in the lower lobes and subpleural reticular opacities.Table 1 Laboratory values at admission and on hospital day 13.\n\nTable 1Laboratory\t\n\tAdmission\tHospital day 13\tNormal Range\t\n\tHematology\t\nWhite blood cell count (K/μL)\t4.9\t10.2\t4.0–10.0\t\nHemoglobin (g/dL)\t10.3\t11.4\t13.7–17.5\t\nHematocrit (%)\t31.1\t33.2\t40–51\t\nPlatelet count (K/μL)\t271\t262\t150–400\t\nAbsolute neutrophil count (K/μL)\t3.7\t9.56\t1.6–6.1\t\nAbsolute lymphocyte count (K/μL)\t0.86\t0.50\t1.2–3.7\t\nAbsolute CD4 lymphocyte count (cells/μL)\t51\t--\t350−1100\t\nCD4 Cells, Percent\t6%\t--\t\t\nAbsolute CD8 lymphocyte count (cells/μL)\t568\t--\t193–685\t\nCD8 Cells, Percent\t68 %\t--\t\t\nCD4/CD8 ratio\t0.09\t--\t0.84–3.0\t\n\n\n\t\n\tChemistry\t\nSodium (mEq/L)\t137\t128\t135–147\t\nPotassium (mEq/L)\t3.9\t4.7\t3.5–5.4\t\nChloride (mEq/L)\t105\t98\t96–108\t\nBicarbonate (mEq/L)\t18\t18\t22–32\t\nUrea Nitrogen (mg/dL)\t10\t30\t6–20\t\nCreatinine (mg/dL)\t0.8\t1.0\t0.5–1.2\t\nGlucose (mg/dL)\t107\t103\t70–100\t\nAspartate Aminotransferase (IU/L)\t34\t63\t0–40\t\nAlanine Aminotransferase (IU/L)\t21\t99\t0–40\t\nAlkaline Phosphatase (IU/L)\t70\t89\t40–130\t\nTotal Bilirubin (mg/dL)\t1.1\t0.3\t0–1.5\t\nLactate Dehydrogenase (IU/dL)\t522\t349 (on 7/1/20)\t94–250\t\nTroponin T (ng/mL)\t<0.01\t<0.01 (on 7/1/20)\t0–0.01\t\n\n\n\t\nViral Load\t\t\t\t\nHIV-1 Viral load (log10 copies/mL)\t5.6\t3.1\t\t\n\n\n\t\nInflammatory Markers\t\nC-Reactive Protein (mg/L)\t8.2\t119.1 (on 7/7/20)\t0–5.0\t\nFerritin (ng/mL)\t864\t924\t30–400\t\nFibrinogen (mg/dL)\t--\t693\t180−400\t\nD-Dimer (ng/mL)\t3695\t887\t0–500\t\n\nOn hospital day (HD) 1, he was noted to have worsening hypoxemia, with oxygen saturation 77 % on room air, which improved with nasal cannula oxygen. He received remdesivir on HD 2 through 6, and was started on empiric oral trimethoprim/sulfamethoxazole (TMP/SMX) and prednisone 40 mg every 12 h for presumed PJP. On HD 2, he had improving clinical status with resolution of fevers and hypoxemia. He was initiated on ART (bictegravir, emtricitabine, and tenofovir alafenamide). On HD 6 he re-developed an oxygen requirement. On HD 9 steroids were tapered to 40 mg daily, and further decreased to 20 mg daily on HD 11. On HD 13 had a fever of 101.8 °F with laboratory changes as summarized in Table 1. Repeat chest CT showed worsening diffuse bilateral GGO (Fig. 1). Prednisone dose was increased to 60 mg daily on HD 13. He required intubation for hypoxemia on HD 15. He was found to have positive serum CMV PCR (4.06 log IU/mL) and was started on IV ganciclovir. After intubation, a bronchoalveolar lavage (BAL) was positive for PJP by immunofluorescence (IF) and for CMV by PCR (4.7 log IU/mL). He was noted to have increasing inflammatory markers, so was given pulse-dose methylprednisolone 500 mg daily for possible IRIS on HD 17 through HD 19, with temporary improvement in inflammatory markers and ventilator requirements. ART was continued throughout hospitalization. On HD 20 his steroids were transitioned to prednisone 60 mg daily. He worsened again, requiring extracorporal membrane oxygenation (ECMO) initiation on HD 22. He had refractory hypoxemia despite ECMO, and was ultimately transitioned to comfort measures and passed away.Fig. 1 CT chest with diffuse bilateral ground glass opacification with areas of crazy paving and subpleural reticular opacities.\n\nFig. 1\n\nDiscussion\n\nThe majority of the descriptions of HIV and COVID-19 co-infection to date are in persons with well-controlled HIV on ART [1,2]. In these studies, additional risk factors for COVID-19 infection (eg. hypertension, hyperlipidemia, diabetes, etc) were frequently reported, similar to the general population [1,2]. The described clinical presentation of PLWH with COVID-19 has also been similar to the general population, with the majority presenting with cough, fevers, arthralgias/myalgias, headache, or sore throat [1,2].\n\nA recent systematic review of the literature through October 2020 included 82 studies and a total of 643,018 PLWH, including 19 patients not on ART. COVID-19 outcomes in PLWH with well-controlled HIV were similar to those in the general population with a similar distribution of patients fully recovering, requiring ICU levels of care, or dying. No difference was detected in clinical features, laboratory findings or severity of illness between those on ART and those not on ART, although this number was too small to provide definite conclusions. The systematic review also identified patients with co-diagnoses of new HIV and COVID-19, which together with the case we present, highlights the importance of maintaining a high suspicion for HIV infection in patients who are not improving as expected [2].\n\nWhile there is increasing data surrounding poorly-controlled HIV and opportunistic infections in patients with COVID-19, there have not yet been reports of immune reconstitution inflammatory syndrome (IRIS) in PLWH with COVID-19. There is one case report of a patient who did not have HIV but who had pancytopenia from chemotherapy and presented with COVID-19 pneumonia, who had an IRIS-like reaction after receiving G-CSF [5]. IRIS can either present as unmasking IRIS, in which an underlying undiagnosed opportunistic infection is unmasked, or as paradoxical IRIS, in which symptoms from an infection appear to worsen after starting ART [6]. The opportunistic infections most commonly associated with IRIS include CMV retinitis, cryptococcal meningitis, and tuberculosis [7]. Other diseases associated with IRIS include Kaposi’s sarcoma, Mycobacterium avium complex, Herpes Simplex Virus, Varicella Zoster Virus, Hepatitis B and C, and Toxoplasma gondii [6,7]. IRIS is relatively rare in PJP, seen in only 4 % of patients with HIV-associated PJP who are initiated on ART [8]. IRIS with CMV pneumonia is even more rare, with one case report in the literature [9]. Despite the risk of IRIS, current guidelines recommend initiation of treatment within two weeks of diagnosis of HIV even in the presence of opportunistic infections, with the exception of acute cryptococcal meningitis, because of the benefits associated with early initiation of ART [10].\n\nGiven the multiple, co-occurring infections, it is difficult to know exactly which diagnosis (or combination of diagnoses) drove our patient's clinical course. A diagnosis of IRIS is supported by worsening hypoxia four days after starting ART, while on the appropriate steroid dose for PJP (prednisone 40 mg every 12 h), a higher dose than is recommended for COVID-19 pneumonia (40 mg prednisone daily, equivalent to 6 mg dexamethasone daily) [11,12]. He developed fevers, rising inflammatory markers and worsening radiographic findings two days after this prednisone dose was decreased to 40 mg daily, with subsequent improvement on pulse dose methylprednisolone. This correlation between clinical status and steroid dose could be consistent with IRIS possibly related to COVID-19 given the rarity of IRIS with PJP or CMV pneumonitis. However, as steroids are also mainstays of treatment in both PJP and COVID-19 pneumonia, either of these etiologies could have contributed to this correlation. Additionally, COVID-19 pneumonia alone can present with a delayed pro-inflammatory respiratory decompensation, although this has been described typically between days 4 and 10 of illness, while our patient decompensated at HD 13 (approximately one month after symptom onset) [13,14]. It is also possible that more than one of his pro-inflammatory diagnoses contributed to his respiratory failure and ultimate demise.\n\nConclusions\n\nThis case report demonstrates the potential for multiple concurrent infections in patients with either COVID-19 or HIV. It highlights the importance of considering HIV in patients with risk factors and consistent presentations. Despite social isolation measures, new cases of both acute and chronic HIV continue to be diagnosed, in patients with COVID-19 and those undergoing routine screening [15]. Furthermore, this case raises the concern that in patients with AIDS and COVID-19, initiation of ART could cause IRIS and lead to worsened outcomes. More data is needed to investigate this possibility, and the potential risks of ART initiation in similar clinical scenarios.\n\nMost current evidence suggests PLWH with well-controlled HIV have similar outcomes to the general population. However, of the few described cases of PLWH with AIDS or poorly controlled HIV, there have been multiple cases with poor outcomes, including our patient. This supports the possibility that poorly-controlled HIV increases risk of severe COVID-19. These findings are significantly limited by the paucity of data, highlighting the need for further investigation into the effects of COVID-19 among PLWH, particularly those with poorly-controlled disease.\n\nFunding\n\nThis work was not supported by external funding.\n\nConsent\n\nVerbal consent was obtained from the patient shortly before he was intubated. However, we were unable to obtain written consent prior to intubation and subsequent expiration of the patient. Consent not obtained from next-of-kin as it was unknown if he had disclosed his diagnosis of HIV to his next-of-kin.\n\nEthical approval\n\nNone.\n\nAuthor statement\n\nElisabeth Merchant, MD and Kristin Flint, MD: Writing – Original Draft, Review and Editing.\n\nBarbra Blair, MD and Dan Barouch, MD: Writing – Review and editing; Supervision.\n\nDeclaration of Competing Interest\n\nThe authors report no declarations of interest.\n==== Refs\nReferences\n\n1 Costenaro P. Minotti C. Barbieri E. Giaquinto C. Donà D. SARS-CoV-2 infection in people living with HIV: a systematic review Rev Med Virol 2020 10.1002/rmv.2155\n2 Lee K.W. Yap S.F. Ngeow Y.F. Lye M.S. COVID-19 in people living with HIV: a systematic review and meta-analysis Int J Environ Res Public Health 18 2021 3554 10.3390/ijerph18073554 33808066\n3 Fung M. Babik J.M. COVID-19 in immunocompromised hosts: what we know so far Clin Infect Dis 2020 Oxford Academic. Clinical Infectious Disease\n4 Broadhurst A.G.B. Lalla U. Taljaard J.J. Louw E.H. Koegelenberg C.F.N. Allwood B.W. The diagnostic challenge of pneumocystis pneumonia and COVID-19 co-infection in HIV Respirol Case Rep 9 2021 10.1002/rcr2.725\n5 Mertens J. Laghrib Y. Kenyon C. A case of steroid-responsive, COVID-19 immune reconstitution inflammatory syndrome following the use of granulocyte colony-stimulating factor Open Forum Infect Dis 7 2020 10.1093/ofid/ofaa326\n6 Huis in’ t Veld D. Sun H.Y. Hung C.C. Colebunders R. The immune reconstitution inflammatory syndrome related to HIV co-infections: a review Eur J Clin Microbiol Infect Dis 31 2012 919 927 10.1007/s10096-011-1413-9 21964588\n7 Müller M. Wandel S. Colebunders R. Attia S. Furrer H. Egger M. Immune reconstitution inflammatory syndrome in patients starting antiretroviral therapy for HIV infection: a systematic review and meta-analysis Lancet Infect Dis 10 2010 251 261 10.1016/S1473-3099(10)70026-8 20334848\n8 Achenbach C.J. Harrington R.D. Dhanireddy S. Crane H.M. Casper C. Kitahata M.M. Paradoxical immune reconstitution inflammatory syndrome in HIV-infected patients treated with combination antiretroviral therapy after AIDS-defining opportunistic infection Clin Infect Dis 54 2012 424 433 10.1093/cid/cir802 22095568\n9 Petarra-Del Río S. Rodriguez-Hernandez A. Anguiano-Landa L. Aguilar-Portillo G. Zavala-Trujillo I. Nava-Zavala A.H. Immune reconstitution inflammatory syndrome and cytomegalovirus pneumonia case report: highlights and missing links in classification criteria and standardized treatment Case Rep Infect Dis 2017 2017 1 7 10.1155/2017/9314580\n10 Günthard H.F. Saag M.S. Benson C.A. del Rio C. Eron J.J. Gallant J.E. Antiretroviral drugs for treatment and prevention of HIV infection in Adults: 2016 recommendations of the international antiviral society-USA Panel JAMA - J Am Med Assoc 316 2016 191 210 10.1001/jama.2016.8900\n11 Panel on Opportunistic Infections in Adults and Adolescents with HIV Guidelines for the prevention and treatment of opportunistic infections in adults and adolescents with HIV: recommendations from the Centers for Disease Control and Prevention, the National Institutes of Health and the HIV Medicine Association of the Infectious Diseases Society of America 2021 Available at http://aidsinfo.nih.gov/contentfiles/lvguidelines/adult_oi.pdf. [Accessed 4/21/2021 [W4-W8]]\n12 COVID-19 Treatment Guidelines Panel Coronavirus disease 2019 (COVID-19) treatment guidelines 2021 National Institutes of Health Available at https://www.covid19treatmentguidelines.nih.gov/. [Accessed 4/21/2021]\n13 Wang F. Qu M. Zhou X. Zhao K. Lai C. Tang Q. The timeline and risk factors of clinical progression of COVID-19 in Shenzhen, China J Transl Med 18 2020 270 10.1186/s12967-020-02423-8 32620125\n14 Cohen P.A. Hall L.E. John J.N. Rapoport A.B. The early natural history of SARS-CoV-2 infection: clinical observations from an urban, ambulatory COVID-19 clinic Mayo Clin Proc 95 2020 1124 1126 10.1016/j.mayocp.2020.04.010 32451119\n15 Stanford K.A. Friedman E.E. Schmitt J. Spiegel T. Ridgway J.P. Moore M. Routine screening for HIV in an urban emergency department during the COVID-19 pandemic AIDS Behav 1 2020 3 10.1007/s10461-020-02899-x\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2214-2509",
"issue": "24()",
"journal": "IDCases",
"keywords": "AIDS; COVID-19; HIV; IRIS; PJP",
"medline_ta": "IDCases",
"mesh_terms": null,
"nlm_unique_id": "101634540",
"other_id": null,
"pages": "e01153",
"pmc": null,
"pmid": "33977081",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "32855992;29075540;32620125;33501974;27404187;20334848;21964588;32361800;32875716;33664959;22095568;32451119;33808066",
"title": "Co-infection with coronavirus disease 2019, previously undiagnosed human immunodeficiency virus, Pneumocystis jirovecii pneumonia and cytomegalovirus pneumonitis, with possible immune reconstitution inflammatory syndrome.",
"title_normalized": "co infection with coronavirus disease 2019 previously undiagnosed human immunodeficiency virus pneumocystis jirovecii pneumonia and cytomegalovirus pneumonitis with possible immune reconstitution inflammatory syndrome"
} | [
{
"companynumb": "US-CHEPLA-C20212702",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
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"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": null,
"... |
{
"abstract": "BACKGROUND\nHypoglycemia is a potential side effect of beta-blockers; however, no cases have been reported in children with long QT syndrome (LQTS).\n\n\nOBJECTIVE\nThe purpose of this study was to determine the frequency and severity of hypoglycemia among children with beta-blocker-treated LQTS.\n\n\nMETHODS\nA retrospective study was performed to identify children with LQTS evaluated from 2000 to 2014 who developed symptomatic hypoglycemia while being treated with a beta-blocker.\n\n\nRESULTS\nNine children (3%; 7 boys; average corrected QT interval 486 ± 35 ms) developed 13 episodes (0.005 events per 100 treatment years) of beta-blocker-associated hypoglycemia (mean initial glucose 21 ± 7 mg/dL), including 3 of 157 patients with LQTS type 1 (LQT1; 1.9%) and 6 of 105 with LQTS type 2 (LQT2; 5.7%). The mean age at hypoglycemic event was 3.5 ± 2 years (range 7 months to 9 years), involving nadolol in 6 cases (mean dose 1.4 ± 0.2 mg/kg/d) and propranolol in 3 (mean dose 2.7±1 mg/kg/d). Hypoglycemic events were more frequent in patients with LQT2 than in those with LQT1 (10 vs. 3 events; P = .02). Hypoglycemia-triggered seizures were observed in 6 patients, fasting ketoacidosis in 5, and 7 patients required hospitalization (mean of 3 ± 2 days). Decreased caloric intake before the event was identified in all patients and a concomitant viral infection in 3.\n\n\nCONCLUSIONS\nThis is the largest single-center case series of beta-blocker-induced hypoglycemia. Clinicians should be cognizant of hypoglycemia symptoms in younger children during periods of poor appetite and during viral illness, and parents of these children should be educated about the signs and symptoms of hypoglycemia. A potential LQT2-hypoglycemia genotype-phenotype relationship warrants further investigation.",
"affiliations": "Division of Pediatric Cardiology, Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, Minnesota.;Division of Pediatric Cardiology, Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, Minnesota; Department of Molecular Pharmacology and Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Rochester, Minnesota.;Division of Pediatric Cardiology, Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, Minnesota.;Division of Pediatric Cardiology, Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, Minnesota; Department of Molecular Pharmacology and Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Rochester, Minnesota; Division of Cardiovascular Diseases, Department of Medicine, Mayo Clinic, Rochester, Minnesota. Electronic address: ackerman.michael@mayo.edu.",
"authors": "Poterucha|Joseph T|JT|;Bos|J Martijn|JM|;Cannon|Bryan C|BC|;Ackerman|Michael J|MJ|",
"chemical_list": "D000319:Adrenergic beta-Antagonists; D001786:Blood Glucose; D009248:Nadolol; D011433:Propranolol",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1547-5271",
"issue": "12(8)",
"journal": "Heart rhythm",
"keywords": "Beta-blockers; Hypoglycemia; Long QT syndrome; Pediatrics",
"medline_ta": "Heart Rhythm",
"mesh_terms": "D000319:Adrenergic beta-Antagonists; D001786:Blood Glucose; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007003:Hypoglycemia; D007223:Infant; D007662:Ketosis; D008133:Long QT Syndrome; D008297:Male; D009248:Nadolol; D011433:Propranolol; D012189:Retrospective Studies; D016896:Treatment Outcome",
"nlm_unique_id": "101200317",
"other_id": null,
"pages": "1815-9",
"pmc": null,
"pmid": "25929701",
"pubdate": "2015-08",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Frequency and severity of hypoglycemia in children with beta-blocker-treated long QT syndrome.",
"title_normalized": "frequency and severity of hypoglycemia in children with beta blocker treated long qt syndrome"
} | [
{
"companynumb": "US-TEVA-587791USA",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "NADOLOL"
},
"drugadditional": null,
"drugad... |
{
"abstract": "A 44-year-old woman who had end-stage kidney disease from diabetes and hypertension underwent a deceased donor kidney transplantation. Eighteen months after the transplantation she developed an abrupt increase in her creatinine level and a kidney biopsy specimen showed the presence of a plasma cell-rich infiltrate. A vast majority of the plasma cells were kappa (κ) light chain restricted on in situ hybridization. κ and lambda (λ) free light chain were elevated in her serum and so was the κ/λ ratio. A bone marrow biopsy specimen showed no evidence of clonal plasmacytosis. A positron emission tomography (PET) scan showed hypermetabolic activity confined to the kidney. Prior to transplantation she was Epstein-Barr virus (EBV) immunoglobulin (Ig)G-negative but had detectable EBV based on polymerase chain reaction (PCR) in her blood during this episode. Despite reduction in immunosuppression there was no change in the κ/λ ratio and her renal function worsened. She underwent a transplant nephrectomy and her κ/λ ratio became normal. Twenty-one months later she is lymphoma-free and doing well on dialysis. Plasmacytoma-like post-transplantation lymphoproliferative disorder (PTLD) is rare and even more is the localization of the malignancy to the allograft. When reduction of immunosuppression is unsuccessful in treatment, removal of the organ may be necessary as is demonstrated in our case.",
"affiliations": "Department of Medicine, Division of Nephrology, University of Iowa, Iowa City, Iowa. Electronic address: sarat-kuppachi@uiowa.edu.",
"authors": "Kuppachi|S|S|;Naina|H V|HV|;Self|S|S|;Fenning|R|R|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1345",
"issue": "45(7)",
"journal": "Transplantation proceedings",
"keywords": null,
"medline_ta": "Transplant Proc",
"mesh_terms": "D000328:Adult; D064591:Allografts; D001706:Biopsy; D005260:Female; D006801:Humans; D007676:Kidney Failure, Chronic; D016030:Kidney Transplantation; D010954:Plasmacytoma",
"nlm_unique_id": "0243532",
"other_id": null,
"pages": "2791-4",
"pmc": null,
"pmid": "24034051",
"pubdate": "2013-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Plasmacytoma-like post-transplantation lymphoproliferative disorder confined to the renal allograft: a case report.",
"title_normalized": "plasmacytoma like post transplantation lymphoproliferative disorder confined to the renal allograft a case report"
} | [
{
"companynumb": "US-APOTEX-2018AP008426",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": "1",
... |
{
"abstract": "Brentuximab vedotin is an antibody-drug conjugate (ADC) that selectively delivers monomethyl auristatin E (MMAE) into CD30-expressing cells. This study evaluated the CYP3A-mediated drug-drug interaction potential of brentuximab vedotin and the excretion of MMAE. Two 21-day cycles of brentuximab vedotin (1.2 or 1.8 mg/kg intravenously) were administered to 56 patients with CD30-positive hematologic malignancies. Each patient also received either a sensitive CYP3A substrate (midazolam), an effective inducer (rifampin), or a strong inhibitor (ketoconazole). Brentuximab vedotin did not affect midazolam exposures. ADC exposures were unaffected by concomitant rifampin or ketoconazole; however, MMAE exposures were lower with rifampin and higher with ketoconazole. The short-term safety profile of brentuximab vedotin in this study was generally consistent with historic clinical observations. The most common adverse events were nausea, fatigue, diarrhea, headache, pyrexia, and neutropenia. Over a 1-week period, ∼23.5% of intact MMAE was recovered after administration of brentuximab vedotin; all other species were below the limit of quantitation. The primary excretion route is via feces (median 72% of the recovered MMAE). These results suggest that brentuximab vedotin (1.8 mg/kg) and MMAE are neither inhibitors nor inducers of CYP3A; however, MMAE is a substrate of CYP3A.",
"affiliations": "Seattle Genetics, Inc., Bothell, WA 98021, USA. than@seagen.com",
"authors": "Han|Tae H|TH|;Gopal|Ajay K|AK|;Ramchandren|Radhakrishnan|R|;Goy|Andre|A|;Chen|Robert|R|;Matous|Jeffrey V|JV|;Cooper|Maureen|M|;Grove|Laurie E|LE|;Alley|Stephen C|SC|;Lynch|Carmel M|CM|;O'Connor|Owen A|OA|",
"chemical_list": "D000970:Antineoplastic Agents; D065692:Cytochrome P-450 CYP3A Inhibitors; D018796:Immunoconjugates; D017730:Ki-1 Antigen; D009842:Oligopeptides; D000079963:Brentuximab Vedotin; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; D008874:Midazolam; D007654:Ketoconazole; C495575:monomethyl auristatin E; D012293:Rifampin",
"country": "England",
"delete": false,
"doi": "10.1002/jcph.116",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0091-2700",
"issue": "53(8)",
"journal": "Journal of clinical pharmacology",
"keywords": "biotechnology; clinical pharmacology; clinical trials; drug metabolism; oncology; pharmacokinetics",
"medline_ta": "J Clin Pharmacol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents; D000079963:Brentuximab Vedotin; D018592:Cross-Over Studies; D051544:Cytochrome P-450 CYP3A; D065692:Cytochrome P-450 CYP3A Inhibitors; D004347:Drug Interactions; D005243:Feces; D005260:Female; D019337:Hematologic Neoplasms; D006801:Humans; D018796:Immunoconjugates; D007654:Ketoconazole; D017730:Ki-1 Antigen; D008297:Male; D008874:Midazolam; D008875:Middle Aged; D009842:Oligopeptides; D012293:Rifampin; D055815:Young Adult",
"nlm_unique_id": "0366372",
"other_id": null,
"pages": "866-77",
"pmc": null,
"pmid": "23754575",
"pubdate": "2013-08",
"publication_types": "D017426:Clinical Trial, Phase I; D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": "8453848;19769391;17766698;12714494;21047225;10080826;22614995;22271209;20086002;22267010;22080439;1310894;17962422;11697753;12535574;21519855;8181191;20643572;12097283;18079362;20200513;12778055;22454421",
"title": "CYP3A-mediated drug-drug interaction potential and excretion of brentuximab vedotin, an antibody-drug conjugate, in patients with CD30-positive hematologic malignancies.",
"title_normalized": "cyp3a mediated drug drug interaction potential and excretion of brentuximab vedotin an antibody drug conjugate in patients with cd30 positive hematologic malignancies"
} | [
{
"companynumb": "US-JNJFOC-20131015102",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "KETOCONAZOLE"
},
"drugadditional": null,
... |
{
"abstract": "A 35-year-old woman with a history of indeterminate colitis developed symptoms of multiple sclerosis after treatment with infliximab. Neurologic examination confirmed upper and lower extremity motor and sensory deficits. MRI showed multiple enhancing white matter lesions distributed throughout her brain as well as her thoracic spine. There may be a link between inflammatory demyelinating disease of the central nervous system and anti-tumor necrosis-alpha therapy. This case report describes the onset or worsening of a demyelinating process after the initiation of infliximab therapy in a patient with indeterminate colitis.",
"affiliations": "Department of Medicine, Cedars-Sinai Medical Center, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, CA 90048, USA.",
"authors": "Enayati|Pedram J|PJ|;Papadakis|Konstantinos A|KA|",
"chemical_list": "D000911:Antibodies, Monoclonal; D005765:Gastrointestinal Agents; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab",
"country": "United States",
"delete": false,
"doi": "10.1097/01.mcg.0000155126.82171.32",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0192-0790",
"issue": "39(4)",
"journal": "Journal of clinical gastroenterology",
"keywords": null,
"medline_ta": "J Clin Gastroenterol",
"mesh_terms": "D000328:Adult; D000911:Antibodies, Monoclonal; D001921:Brain; D003092:Colitis; D005260:Female; D005500:Follow-Up Studies; D005765:Gastrointestinal Agents; D006801:Humans; D000069285:Infliximab; D008279:Magnetic Resonance Imaging; D009103:Multiple Sclerosis; D013116:Spinal Cord; D013909:Thorax; D014409:Tumor Necrosis Factor-alpha",
"nlm_unique_id": "7910017",
"other_id": null,
"pages": "303-6",
"pmc": null,
"pmid": "15758624",
"pubdate": "2005-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Association of anti-tumor necrosis factor therapy with the development of multiple sclerosis.",
"title_normalized": "association of anti tumor necrosis factor therapy with the development of multiple sclerosis"
} | [
{
"companynumb": "US-AMGEN-USASP2017053320",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ETANERCEPT"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nThe objective of this study was to analyze clinical patterns of visual field defects (VFDs) reported with topiramate treatment and assess possible mechanism of action (MOA) for antiepileptic drug (AED) associated VFDs.\n\n\nMETHODS\nA comprehensive topiramate database review included preclinical data, sponsor's clinical trials database, postmarketing spontaneous reports, and medical literature. All treatment-emergent adverse events (TEAEs) suggestive of retinal dysfunction/damage were summarized. Relative risk (RR) was computed from topiramate double-blind, placebo-controlled trials (DBPCTs) data.\n\n\nRESULTS\nPreclinical studies and medical literature review suggested that despite sharing gamma-aminobutyric acid (GABA)-ergic MOA with other AEDs, topiramate treatment was not associated with VFDs. TEAEs suggestive of retinal dysfunction/damage were observed in 0.3%-0.7% of adults and pediatric patients with topiramate (N=4,679) versus ≤0.1% with placebo (N=1,834) in DBPCTs for approved indications (epilepsy and migraine prophylaxis); open-label trials (OLTs) and DBPCTs for investigational indications had similar incidence. Overall, 88% TEAEs were mild or moderate in severity. Serious TEAEs were very rare (DBPCTs: 0%; OLTs: ≤0.1%), and most were not treatment limiting, and resolved. The most common visual TEAEs (approved indications) were VFD, scotoma, and optic atrophy. The incidence of TEAEs in DBPCTs (approved and investigational indications) was higher in topiramate-treated (N=9,169) versus placebo-treated patients (N=5,023; 0.36% vs 0.24%), but the RR versus placebo-treated patients was not significant (RR: 1.51 [95% confidence interval: 0.78, 2.91]).\n\n\nCONCLUSIONS\nVFDs do not appear to be a class effect for AEDs with GABA-ergic MOA. The RR for VFDs is not significantly different between topiramate and placebo treatment.",
"affiliations": "Janssen Research & Development, LLC, Titusville, NJ.;Byers Eye Institute, Stanford University, Palo Alto, CA, USA.;Janssen Research & Development, LLC, Titusville, NJ.;Janssen Research & Development, LLC, Titusville, NJ.;Janssen Research & Development, LLC, Titusville, NJ.",
"authors": "Ford|Lisa|L|;Goldberg|Jeffrey L|JL|;Selan|Fred|F|;Greenberg|Howard E|HE|;Shi|Yingqi|Y|",
"chemical_list": null,
"country": "New Zealand",
"delete": false,
"doi": "10.2147/OPTH.S125768",
"fulltext": "\n==== Front\nClin OphthalmolClin OphthalmolClinical OphthalmologyClinical Ophthalmology (Auckland, N.Z.)1177-54671177-5483Dove Medical Press 10.2147/OPTH.S125768opth-11-983ReviewComprehensive review of visual defects reported with topiramate Ford Lisa 1Goldberg Jeffrey L 2Selan Fred 1Greenberg Howard E 1Shi Yingqi 11 Janssen Research & Development, LLC, Titusville, NJ2 Byers Eye Institute, Stanford University, Palo Alto, CA, USACorrespondence: Lisa Ford, Neurosciences, Janssen Research & Development, LLC, 1125 Trenton-Harbourton Road, Titusville, NJ 08560, USA, Tel +1 609 730 2909, Fax +1 609 730 4583, Email lford1@its.jnj.com2017 23 5 2017 11 983 992 © 2017 Ford et al. This work is published and licensed by Dove Medical Press Limited2017The 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.Objective\nThe objective of this study was to analyze clinical patterns of visual field defects (VFDs) reported with topiramate treatment and assess possible mechanism of action (MOA) for antiepileptic drug (AED) associated VFDs.\n\nMethods\nA comprehensive topiramate database review included preclinical data, sponsor’s clinical trials database, postmarketing spontaneous reports, and medical literature. All treatment-emergent adverse events (TEAEs) suggestive of retinal dysfunction/damage were summarized. Relative risk (RR) was computed from topiramate double-blind, placebo-controlled trials (DBPCTs) data.\n\nResults\nPreclinical studies and medical literature review suggested that despite sharing gamma-aminobutyric acid (GABA)-ergic MOA with other AEDs, topiramate treatment was not associated with VFDs. TEAEs suggestive of retinal dysfunction/damage were observed in 0.3%–0.7% of adults and pediatric patients with topiramate (N=4,679) versus ≤0.1% with placebo (N=1,834) in DBPCTs for approved indications (epilepsy and migraine prophylaxis); open-label trials (OLTs) and DBPCTs for investigational indications had similar incidence. Overall, 88% TEAEs were mild or moderate in severity. Serious TEAEs were very rare (DBPCTs: 0%; OLTs: ≤0.1%), and most were not treatment limiting, and resolved. The most common visual TEAEs (approved indications) were VFD, scotoma, and optic atrophy. The incidence of TEAEs in DBPCTs (approved and investigational indications) was higher in topiramate-treated (N=9,169) versus placebo-treated patients (N=5,023; 0.36% vs 0.24%), but the RR versus placebo-treated patients was not significant (RR: 1.51 [95% confidence interval: 0.78, 2.91]).\n\nConclusion\nVFDs do not appear to be a class effect for AEDs with GABA-ergic MOA. The RR for VFDs is not significantly different between topiramate and placebo treatment.\n\nKeywords\ngamma-aminobutyric acidretinal dysfunctionscotomatopiramatevisual field defects\n==== Body\nIntroduction\nGlobally, topiramate is approved in children and adults for at least one indication including adjunctive and monotherapy treatment of partial onset seizures and primary generalized tonic–clonic seizures as well as adjunctive treatment of seizures associated with Lennox–Gastaut syndrome, and in adolescents and adults for migraine prophylaxis.1\n\nThe precise mechanisms by which topiramate, a sulfamate-substituted mono-saccharide, exerts its antiseizure and migraine prophylactic effects are unknown. Results from electrophysiological and biochemical studies on cultured neurons have suggested three properties that may contribute to the antiepileptic efficacy of topiramate: sodium channel blocking action, potentiation of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), and antagonism of the kainate/a-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) subtype of the excitatory amino acid glutamate receptor.2 GABA is a more potent modulator in the retina and GABA potentiation is the mechanism of action (MOA) of several antiepileptic drugs (AEDs) including vigabatrin and pregabalin.3–6\n\nVisual field defects (VFDs) can manifest as scotoma, both homonymous and heteronymous hemianopia, and peripheral vision loss or tunnel vision.7 A variety of ophthalmologic treatment-emergent adverse events (TEAEs) have been reported with topiramate use, including acute angle-closure glaucoma, maculopathy, ciliochoroidal detachment, ciliary body edema, and acute myopic shift, some of which are associated with VFDs.1,8–10 These TEAEs suggest that topiramate therapy has the potential to cause VFDs. Preclinical findings in topiramate-treated rabbits suggest that topiramate may damage the retina, similar to vigabatrin.11 In humans, ~30% of adult patients exposed to vigabatrin have reported some degree of VFDs that are irreversible.12,13 This study was aimed to determine the possible MOA for VFDs reported with topiramate treatment and to comprehensively analyze clinical patterns including type of VFDs, risk factors for their development, relationship to topiramate dose and duration of therapy, and persistence of VFDs.\n\nMethods\nLiterature search\nA search and review of the cases from the global safety database (SCEPTRE) was carried out for only spontaneous cases. No formal literature review was conducted and reviewed in this report. However, cases reported from the literature may have been included in the SCEPTRE if the Center of Excellence identified the published literature in their searches.\n\nValid, spontaneous, medically confirmed or not confirmed cases with topiramate as suspect or suspect-interacting drug (highest version in date range) received cumulatively through May 31, 2013, were included in the review. Cases that were in workflow at the time of the database search were not captured as part of this search. Also, adverse events were coded to the preferred terms (PTs) included in the Medical Dictionary for Regulatory Activities (MedDRA, version 16.0).\n\nAll cases were retrieved independent of the reporter’s relationship attribution, and all spontaneous cases were considered possibly related at the time of entry into the database. Therefore, individual assessments may not be in agreement with the causality assessment of the reporter.\n\nComparison with other GABA-ergic medications\nPregabalin and vigabatrin have a GABA-ergic MOA and are associated with VFDs. Topiramate has a similar MOA. Thus, the MOA of topiramate, pregabalin, and vigabatrin, and its association with VFDs were reviewed based on a search of the medical literature. Differences in how these three drugs inhibit GABA signaling may still account for differences in their adverse event profiles. VFDs were defined as TEAEs coded to PTs included in MedDRA (version 14.0) high level term visual field disorders (Table S1).\n\nConcern about a possible association of topiramate therapy with VFDs and its possible relationship to a significant reduction of retinal function appears to arise, at least partly, from a study by Kjellström et al.11 Other studies have further examined the effects of vigabatrin, pregabalin, and topiramate on cerebral and retinal GABA levels in animal models. A formal literature search was conducted to identify animal studies.\n\nPreclinical evidence that explored topiramate’s effects on visual function was summarized from animal studies, including topiramate’s effects on retinal function and histopathology in rabbits;11 effects of gabapentin, vigabatrin, and topiramate in rats;5 topiramate in an excitotoxin-induced neurotoxicity model that used two different retinal primary cultures, and a rat model of retinal ischemic injury.14 A clinical study (healthy volunteers) assessing the effect of topiramate, lamotrigine, and gabapentin on cerebral GABA levels was also reviewed.3\n\nA comprehensive retrospective data review included analysis of all Janssen R&D sponsored data from double-blind, placebo-controlled trials (DBPCTs) and open-label trials (OLTs) in approved and investigational indications for topiramate, and postmarketing spontaneous reports (Janssen R&D safety database). In addition, the medical literature for AEDs (cutoff date: April 2015) was reviewed.\n\nComprehensive retrospective review of clinical trial data\nAll Janssen R&D-sponsored trials for topiramate in approved and investigational indications reviewed for this analysis were approved indications: adjunctive treatment of epilepsy (DBPCTs =17, OLTs =30), monotherapy treatment of epilepsy (DBPCTs =5, OLTs =3), and migraine prophylaxis (DBPCTs =13, OLTs =8); investigational indications: bipolar disorder (DBPCTs =7, OLTs =5), essential tremor (DBPCTs =1, OLTs =1), binge eating disorder (DBPCTs =2, OLTs =1), diabetic peripheral neuropathy (DBPCTs =5, OLTs =4), obesity (DBPCTs =11, OLTs =1), alcohol dependency (DBPCTs =1), and cognitive function (observer-blinded trial =1).\n\nSpontaneous postmarketing reports from Janssen R&D safety database\nAll spontaneously reported postmarketing cases (July 1995 to April 2015) of visual symptoms possibly associated with retinal dysfunction were reviewed in topiramate-treated patients. The Global Medical Safety database, Strategic Clinical and Epidemiological Pharmacovigilance Technology for Risk Evaluation were searched for all medically confirmed and consumer reported cases, using prespecified MedDRA high level terms or system-organ class or both.\n\nData analysis\nThe search terms used for TEAEs suggestive of retinal dysfunction or damage were PTs coded using MedDRA (version 14.0). For DBPCTs, TEAEs were summarized for each indication separately and for all doses combined (for patients randomized to topiramate and placebo, but not to active controls). For studies with only flexible doses of topiramate and without fixed dose groups, all topiramate-treated patients were combined in one group and the actual administered dose range was indicated. All randomized patients who took at least one dose of topiramate or placebo were included in the summaries. For OLTs, TEAEs were summarized for all topiramate-treated patients by indication, combining all doses. Patients randomized to an active comparator medication during the double-blind (DB) phase, but who were switched to topiramate during the open-label (OL) phase, were added to the topiramate group. Relative risk (RR) was calculated for the DBPCTs using a derived dataset which included, from each study, the number of patients on topiramate and placebo, and the number of patients with retinal-related TEAEs per treatment group. All spontaneously reported postmarketing cases that included topiramate, identified as either a suspect including co-suspect, suspect-interacting, or concomitant medication were retrieved, independent of the reporter’s relationship attribution. There were too few patients per dose category to allow for stratification by dose analysis.\n\nStudies were combined by treatment group (topiramate or placebo). The proportions and RR were then calculated based on a 2×2 table that resulted from the pooled dataset. The P-value was calculated based on a chi-square test. RR, its standard error, and 95% confidence interval were calculated according to Altman.15\n\nResults\nRelationship of GABA-ergic MOA to VFDs\nHuman studies\nTopiramate, vigabatrin, and pregabalin share a GABA-ergic component in their MOA. Furthermore, other drugs (barbiturates, benzodiazepines, and tiagabine) with a GABA-ergic component in their MOA do not affect retinal function in humans.16–18 Cerebral GABA levels were elevated in healthy adults treated with topiramate, lamotrigine, or gabapentin; however, no correlation with VFDs was observed.5\n\nAnimal studies\nRetinal immunohistology revealed significant accumulation of GABA in amacrine cells in the inner nuclear layer and in the inner plexiform layer in 4 of 6 topiramate-treated rabbits, compared with controls.11 However, serum topiramate levels in these rabbits (6.4–15.8 μmol/L) were comparatively lower than in patients with refractory focal epilepsy (6–56 μmol/L), who did not demonstrate any dose-related VFDs;19 results seemed to be affected by the poor tolerability of topiramate in rabbits.\n\nIn rats (N=110) treated with vigabatrin, topiramate, or gabapentin, retinal GABA concentrations were significantly increased with vigabatrin, but not with topiramate or gabapentin treatment;5 results suggesting important differences among these drugs on retinal GABA metabolism. Topiramate decreased the excitotoxin-induced neurotoxicity of glutamate or AMPA in a concentration-dependent manner in retinal or retinal ganglion cell cultures.14 In a rat model, topiramate reduced the ischemia-induced decrease in the amplitude of the electroretinogram b-waves 3 days after ischemia and ischemia-induced retinal degenerative changes.\n\nThese data from both human and animal studies suggest that retinal toxicity is not a class-specific TEAE in GABA-ergic AEDs, but rather significant variation exists within this class. Overall, this review of AEDs associated with VFDs suggested that VFDs were not a class effect for drugs having a GABA-ergic component in their MOA.\n\nComprehensive retrospective review of clinical trial data\nTrials in approved indications\nAcross these trials, topiramate DB exposure for patients was up to 16 weeks, and OL phase median exposure was approximately 1 year.\n\nDBPCTs (NCT00231556; NCT00236639; NCT00231530; NCT00236730; NCT00236691)\nThe incidence of TEAEs suggestive of retinal dysfunction or damage was higher among topiramate-treated patients (N=4,679; ranging from 0.3% to 0.7% for all topiramate doses combined) compared with placebo-treated patients (N=1,834; ≤0.1%, retinal tear in one patient in the migraine prophylaxis indication) (Table 1). The most commonly reported TEAEs among topiramate-treated patients were VFDs (0.3% in each indication) and scotoma (<0.1% to 0.4% across indications); TEAEs occurred in the dose range, 50–1,000 mg/day. All events were mild or moderate in severity with no serious TEAEs. Treatment limiting VFDs occurred in 2 patients (migraine prophylaxis indication), which led to permanent discontinuation of the study drug in 1 patient, and dose reduction in the other (VFDs resolved in both).\n\nOLTs\nThe incidence of TEAEs suggestive of retinal dysfunction or damage ranged from 0.3% (7/2,750) in migraine studies to 0.7% in monotherapy epilepsy studies (all topiramate doses combined) (Table 1). For migraine studies, this included patients who received placebo during the DB phase, but who switched to topiramate in the OL phase. The majority of TEAEs reported in topiramate-treated patients were VFDs (all indications: 0.1%–0.4%), scotoma (migraine prophylaxis and monotherapy epilepsy: <0.1% to 0.4%), and optic atrophy (adjunctive epilepsy: 0.2%). Optic atrophy TEAEs were all reported for patients receiving adjunctive topiramate treatment for epilepsy, who were also concomitantly receiving valproate, another AED that has been associated with VFDs.18,20,21 Most of the TEAEs were mild or moder ate in severity; the majority resolved. Few TEAEs were serious: retinal hemorrhage in 1 patient in monotherapy epilepsy indication (resolved) and occlusion of retinal vein in 1 patient in migraine prophylaxis indication (persisted). In topiramate-treated patients, the study drug was discontinued in 4 patients (VFD, tunnel vision, retinal hemorrhage, and occlusion of retinal vein, N=1 in each; all 3 events except retinal vein occlusion resolved), and dose was adjusted in 1 patient (optic atrophy).\n\nTrials in investigational indications\nDBPCTs\nThe incidence of TEAEs suggestive of retinal dysfunction or damage ranged from 0% to 0.8% among topiramate-treated patients, compared with 0%–1.1% among placebo-treated patients (Table 2). This is based on TEAEs suggestive of retinal damage reported in investigational indication studies. The most commonly reported TEAE was VFD (0.1%–0.5% in all indications; none serious). These events occurred in patients treated with topiramate in a dose range of <100–600 mg/day. Three events from studies conducted for an obesity indication were treatment limiting: two patients discontinued the study drug (tunnel vision, events resolved) while one patient had a dose reduction (retinal hemorrhage). In the placebo-treated patients, the most frequent adverse event was retinal hemorrhage.\n\nOLTs\nThe incidence of TEAEs suggestive of retinal dysfunction or damage in the OLTs was <0.1% except for the diabetic peripheral neuropathy indication (1.4%) (Table 2). The most commonly reported events among topiramate-treated patients (including those receiving placebo during the DB phase who switched to topiramate during OL) were retinopathy (0.6%), retinal hemorrhage (0.3%), and retinal detachment (0.2%), all in the diabetic neuropathy indication. Only one serious event of retinal detachment (diabetic neuropathy indication) was reported. One TEAE that was treatment limiting (retinal detachment) resolved after the study drug was temporarily discontinued.\n\nRR analysis\nOnly DBPCTs in both approved and investigational indications were included in the RR analysis, for which all topiramate dose groups and events were combined due to sparse data. The incidence of events in the topiramate group (0.36%) was not significantly different from that in the placebo group (0.24%; RR of topiramate vs placebo treatment 1.51; 95% confidence interval: 0.78, 2.91) (Figure 1).\n\nSpontaneous postmarketing reports\nFrom July 1995 to April 2015, 96 spontaneous postmarketing reports of visual field disorders in topiramate-treated patients were retrieved, which included VFDs (N=89), tunnel vision (N=11), scotoma (N=6), hemianopia homonymous (N=4), and hemianopia (N=3). The largest number of cases occurred in the 36–50 age group and women. VFDs were considered serious in 68% of the overall cases (Table 3). The latency of the cases was variable, ranging from a few hours up to 10 years. Of the 96 case reports, 75 were excluded by case-level review, because of poor documentation (N=42), not confirmed medically (N=15), or confounded by concomitant disease or medication (N=18). The remaining 21 reports included 14 cases that were confirmed medically and 7 cases that were not. Of the 14 medically confirmed cases, 13 cases (2 were duplicates, hence only one was retained) reported a plausible temporal relationship between exposure to the drug and the TEAE, 9 cases reported a positive dechallenge, and 1 case reported a positive rechallenge. Based on the overall reporting rate in the Global Medical Safety worldwide safety database, VFDs occur at a rate of 1 per 118,339 person-years, and the assigned Council for International Organizations of Medical Sciences frequency category was “very rare.”\n\nCase reporting positive rechallenge\nThe patient experienced depression and visual scotoma 22 days after initiating topiramate therapy. Two months later, the dose was decreased from 50 to 25 mg daily. Due to persistence of symptoms, therapy was withdrawn 2 months later. Approximately 1 month after stopping therapy, topiramate was restarted at 25 mg daily and after some days, the patient again experienced the same symptoms.\n\nMarketing authorization holder comment\nThe close temporal relationship between initiation of therapy and onset of the adverse event, continuation of the event during therapy, and the reappearance of symptoms when the patient was readministered topiramate suggest a relationship between the therapy and events. No ophthalmologic evaluation was provided to determine the nature and extent of the scotoma and to establish the similarity of the original event and that of the rechallenge.\n\nDiscussion\nThis comprehensive review examined the relationship between topiramate therapy and VFD ophthalmologic disorders by comparing its MOA in preclinical studies and available medical literature with other AEDs associated with VFD and assessed the sponsor’s clinical database and postmarketing spontaneous reports for topiramate-related VFDs.\n\nThe similarity in MOA of topiramate to other AEDs, for example, vigabatrin and pregabalin, which are associated with increased VFDs, suggested that VFDs may be a class effect.22,23 In particular, the GABA-ergic MOA of these AEDs is responsible for elevated GABA levels in the retina, which leads to retinal damage. However, it was found that other AEDs (eg, benzodiazepines, felbamate, levetiracetam, gabapentin, tiagabine, etc) with a GABA-ergic MOA are not associated with visual disorders, which suggests that VFDs are not a class effect for drugs with this MOA.17,18,22 The VFDs linked to vigabatrin therapy are related to dysfunction of GABA-ergic cells of the inner retina, which could be the primary target for toxic injury.24 Clinically, vigabatrin has been associated with permanent VFDs characterized by concentrically constricted fields.12,13 In contrast, topiramate has shown retinal protective properties in excitotoxin-induced neurotoxicity models.14 Topiramate has been associated with acute myopia which is associated with secondary angle-closure glaucoma, primarily due to drug-induced idiosyncratic ocular syndrome in reaction to the sulfamate moiety of topiramate, similar to that seen with other sulfa containing medications such as sulfamethizole, chlorthalidone, ethoxzolamide, hydrochlorothiazide, sulfapyridine, trimethoprim, and acetazolamide.25–27 Although this phenomenon is not completely understood, it is suggested that it could be caused by ciliary body swelling resulting in anterior movement of the lens, and by lens thickening.28\n\nThis review of the product sponsor’s clinical trials database showed that while the drug exposure in OLTs was generally longer, the incidence of TEAEs suggestive of retinal dysfunction or damage with topiramate therapy in DBPCTs was similar to the OLTs for both approved and investigational indications. This suggests that increased dosing duration did not confer increased risk of VFDs. In addition, the VFDs in this study occurred following topiramate doses ranging from 50 to 1,000 mg/day, which is similar to the reports in literature, suggesting that the severity of VFDs does not correlate with higher doses.29,30 In a case report, angle-closure glaucoma was reported in a patient with topiramate plasma levels that were lower than the therapeutic level.31 A limitation of this current review is that precise information of TEAEs and a dose–response relationship could not be determined. Thus, findings from the clinical trials in this study, and literature, suggest that the idiosyncrasy (unusual or odd behavior of person) hypothesis for topiramate-induced VFDs may be a possibility. Although the authors searched databases that included literature referencing, they did not conduct a formal literature review in the Embase and Medline search engines, and may thus have missed a limited number of additional reports.\n\nFor approved indications in children and adults, there was a higher incidence among epilepsy patients compared with migraine patients. For epilepsy patients, those treated with adjunctive topiramate had a higher incidence of VFD compared to monotherapy topiramate. However, the latter were also receiving concomitant AEDs, carbamazepine, valproate, gabapentin, and vigabatrin that are associated with visual disorders.22 It should also be considered that symptoms of aura can also occur in migraine or epilepsy. It is noteworthy that, compared to the general population, patients with epilepsy or migraine have a higher incidence of visual disturbances. In adult and pediatric patients with migraine treated with topiramate (Table 1), VFDs associated with topiramate therapy could be misdiagnosed as a migraine attack, and the patient could be treated with higher doses of topiramate, which could further aggravate the problem.32\n\nIn diabetic peripheral neuropathy DBPCTs, retinal hemorrhage was reported in a higher percentage of patients treated with placebo than in topiramate-treated patients. In the OLTs for investigational indications, all but one treatment-limiting adverse event was reported in patients from diabetic peripheral neuropathy studies, a population that is more prone to developing vision complications. This reiterates the fact that the underlying disease could be a potential confounder. Diabetic retinopathy is the leading cause of vision loss in adults of working age (20–65 years) in industrialized countries, and it is estimated that >2.5 million people worldwide are affected by it.10\n\nIn addition, the statistical analysis based on several DBPCTs (approved and investigational indications) comparing the occurrence of VFDs following topiramate and placebo treatment demonstrated that the RRs of VFDs were not significantly different for both. Few events were serious and treatment limiting, and most were reversible. Resolution of VFD symptoms upon discontinuation of topiramate has been reported in the literature.8,9,33,34\n\nThe review of cumulative postmarketing reports involving TEAEs of VFDs with topiramate treatment that was conducted for this current analysis showed that the majority of patients were adults (despite inclusion of both adults and children) and women. Although women have a marginally lower incidence of epilepsy than men, topiramate’s other approved indication, migraine, occurs more frequently in women, with a ratio of 2.3:1 (women:men).35,36 In patients where latency was reported, three-fourths developed VFDs within 6 months of treatment initiation. A rechallenge in VFD was conducted to decipher the underlying mechanisms for TEAEs induced by the drug and was confirmed only in one patient. Thus, medically confirmed TEAEs of VFD that suggest a relationship between topiramate and VFDs as evaluated on the basis of temporal relationship, positive dechallenge or rechallenge, or presence of confounders were rare, and the majority were reversible.\n\nOne of the strengths of this study was that the results are based on a comprehensive and large database of patients, including randomized DBPCTs and long-term OLTs, in which safety during longer exposure periods was obtained. The occurrence of postmarketing reports of VFDs, including scotoma and maculopathy, was rare. Based on this comprehensive review of preclinical, clinical, and postmarketing information, ophthalmological TEAEs, including VFDs, do not appear to be a class effect for AEDs with similar GABA-ergic components in their MOA. A comprehensive review of topiramate data revealed a slightly increased incidence of visual TEAEs in topiramate-treated versus placebo-treated patients. However, RR assessment was found to be not significant, and thus clinical relevance of such risks cannot be ascribed to topiramate therapy. Warnings indicate that if any ophthalmologic event, symptom, or sign persists on examination during topiramate treatment, an evaluation by the prescribing physician would be required, which appears to be consistent with the level of risk identified in this study. Given topiramate’s documented effectiveness for the approved therapeutic indications,19,37–39 the overall benefit–risk balance for its use, as indicated, remains favorable.\n\nSupplementary material\nTable S1 MedDRA (version 14.0) preferred terms suggestive of retinal dysfunction or damage\n\nMacular cyst\tMacular ischemia\t\nMacular degeneration\tVenous stasis retinopathy\t\nAge-related macular degeneration\tBiopsy conjunctiva\t\nMacular opacity\tBiopsy conjunctiva abnormal\t\nMaculopathy\tBiopsy conjunctiva normal\t\nVitreous adhesions\tBiopsy cornea\t\nPars plana cyst\tBiopsy cornea abnormal\t\nRetinal cyst\tBiopsy cornea normal\t\nRetinal degeneration\tBiopsy retina\t\nRetinal depigmentation\tBiopsy retina abnormal\t\nRetinal degeneration\tBiopsy retina normal\t\nRetinal deposits\tBiopsy sclera\t\nRetinal detachment\tBiopsy sclera abnormal\t\nRetinal dystrophy\tBiopsy sclera normal\t\nRetinal pallor\tFundoscopy\t\nRetinal pigment epitheliopathy\tFundoscopy abnormal\t\nRetinal pigmentation\tFundoscopy normal\t\nRetinal scar\tGonioscopy\t\nRetinal tear\tGonioscopy abnormal\t\nRetinopathy solar\tGonioscopy normal\t\nRetinoschisis congenital\tParacentesis eye\t\nRetinal toxicity\tParacentesis eye abnormal\t\nMacular hole\tParacentesis eye normal\t\nOsteoporosis-pseudoglioma syndrome\tRetinogram\t\nDetachment of retinal pigment epithelium\tRetinogram normal\t\nRetinal pigment epithelial tear\tRetinogram abnormal\t\nAcquired pigmented retinopathy\tVisual field tests\t\nLaurence–Moon–Bardet–Biedl syndrome\tVisual field tests abnormal\t\nMacular pseudohole\tVisual field tests normal\t\nRetinoschisis\tOptic nerve disorder\t\nSubretinal fibrosis\tOptic neuropathy\t\nMacular scar\tToxic optic neuropathy\t\nRetinal infiltrates\tVisual pathway disorder\t\nChorioretinitis\tVisual evoked potentials\t\nChoroid tubercles\tVisual evoked potentials abnormal\t\nChoroiditis\tVisual evoked potentials normal\t\nDiabetic retinal edema\tBlindness\t\nMacular edema\tChorioretinal atrophy\t\nCystoid macular edema\tChorioretinal scar\t\nRetinal edema\tChorioretinopathy\t\nRetinal vasculitis\tChoroidal detachment\t\nRetinitis\tChoroidal effusion\t\nRetinitis viral\tChoroidal hematoma\t\nToxocariasis\tChoroidal hemorrhage\t\nVitreous abscess\tChoroidal infarction\t\nVitritis\tChoroidal neovascularization\t\nNecrotizing retinitis\tChoroidal sclerosis\t\nHemianopia\tExudative retinopathy\t\nHemianopia heteronymous\tOptic atrophy\t\nHemianopia homonymous\tOptic disc disorder\t\nScotoma\tOptic disc drusen\t\nTunnel vision\tOptic nerve cupping\t\nVisual field defect\tPapillophlebitis\t\nUhthoff ’s phenomenon\tRetinal artery embolism\t\nMacular vasospasm\tRetinal artery occlusion\t\nOptic ischemic neuropathy\tRetinal artery thrombosis\t\nOptic nerve infarction\tRetinal disorder\t\nRetinal artery spasm\tRetinal exudates\t\nRetinal artery stenosis\tRetinal neovascularization\t\nRetinal ischemia\tRetinal vascular disorder\t\nRetinal hemorrhage\tRetinal vascular thrombosis\t\nRetinal vein thrombosis\tRetinopathy\t\nRetinal vein occlusion\tVenous stasis retinopathy\t\nRetinal vascular occlusion\tVitreous hemorrhage\t\nRetinal infarction\t\t\n Acknowledgments\nDr Sangita P Patil and Dr Vaibhav R Deshpande (SIRO Clinpharm Pvt Ltd) provided writing assistance and Dr Wendy P Battisti (Janssen Research & Development, LLC) provided additional editorial support and reviewed this manuscript. This study was funded by Janssen Research & Development, LLC. The sponsor also provided a formal review of this manuscript.\n\nDisclosure\n\nDrs Ford, Selan, Greenberg, and Shi are employees of Janssen and hold company stocks. Dr Goldberg has received honoraria as a consultant from Janssen, Allergan, and Theravance. The authors report no other conflicts of interest in this work.\n\nFigure 1 Risk analysis for VFDs.\n\nNotes: RR for VFDs between the topiramate group (all dose groups combined) and placebo group was not significant. 95% CI (0.78, 2.91).\n\nAbbreviations: CI, confidence interval; RR, relative risk; VFDs, visual field defects.\n\nTable 1 TEAEs suggestive of retinal damage reported in approved indication studies\n\n\tPlacebo\nN (%)\tAll TPM\nN (%)\t\nAdjunctive epilepsy trials\t\t\t\nDB phase: 100–400, 600–1,000 mg/day, 5–25 mg/kg/day\t(N=570)\t(N=1,099)\t\n Patients with retinal damage TEAEs\t0\t5 (0.5)\t\n Scotoma\t0\t1 (0.1)\t\n Tunnel vision\t0\t1 (0.1)\t\n VFD\t0\t3 (0.3)\t\nOL phase\t(N=264)a\t(N=2,262)a\t\n Patients with retinal damage TEAEs\t0\t12 (0.5)\t\n Blindness\t0\t1 (<0.1)\t\n Optic atrophy\t0\t4 (0.2)\t\n Papillophlebitis\t0\t1 (<0.1)\t\n Retinal hemorrhage\t0\t1 (<0.1)\t\n Retinal vein occlusion\t0\t1 (<0.1)\t\n VFD\t0\t4 (0.2)\t\nMonotherapy epilepsy trials\t\t\t\nDB phase: 50, 100, 200, 400,\t–\t(N=1,365)\t\n500 mg/day\t\t\t\n Patients with retinal damage TEAEs\t\t10 (0.7)\t\n Retinal hemorrhage\t\t1 (0.1)\t\n Scotoma\t\t5 (0.4)\t\n VFD\t\t4 (0.3)\t\nOL phase\t–\t(N=708)b\t\n Patients with retinal damage TEAEs\t\t5 (0.7)\t\n Blindness\t\t1 (0.1)\t\n Macular degeneration\t\t1 (0.1)\t\n Retinal hemorrhage\t\t1 (0.1)d\t\n Scotoma\t\t3 (0.4)\t\n VFD\t\t1 (0.1)\t\nMigraine prophylaxis trials\t\t\t\nDB phase: 50, 100, 200 mg/day, 2–3 mg/kg/day\t(N=1,264)\t(N=2,215)\t\n Patients with retinal damage TEAEs\t1 (0.1)\t7 (0.3)\t\n Retinal tear\t1 (0.1)\t0\t\n Scotoma\t0\t1 (<0.1)\t\n VFD\t0\t6 (0.3)\t\nOL phase\t(N=492)c\t(N=2,258)c\t\n Patients with retinal damage TEAEs\t2 (0.4)\t5 (0.2)\t\n Blindness\t0\t1 (<0.1)\t\n Retinal degeneration\t0\t1 (<0.1)\t\n Retinal vein occlusion\t0\t1 (<0.1)d\t\n Scotoma\t0\t1 (<0.1)\t\n Tunnel vision\t0\t1 (<0.1)\t\n VFD\t2 (0.4)\t0\t\nNotes:\n\na Placebo group: patients who received placebo in DB phase but were switched to TPM during OL phase. TPM group: patients who received TPM during the DB phase and OL phase.\n\nb All patients received TPM during the OL phase. TPM: patients who were randomized to an active control during DB phase.\n\nc Placebo group: patients who received placebo in DB phase but were switched to TPM during OL phase. TPM group: patients who received TPM or an active comparator during the DB phase and who either remained on TPM or were switched from active control to TPM during the OL phase.\n\nd Serious TEAEs.\n\nAbbreviations: DB, double-blind; OL, open-label; TEAE, treatment-emergent adverse event; TPM, topiramate; VFD, visual field defect.\n\nTable 2 TEAEs suggestive of retinal damage reported in investigational indication studies\n\n\tPlacebo N (%)\tAll TPM N (%)\t\nBipolar disorder\t\t\t\nDB phase: ≤200, >200–400, 500–600 mg/day\t(N=630)\t(N=892)\t\n Patients with retinal damage TEAEs\t0\t2 (0.2)\t\n Retinal degeneration\t0\t1 (0.1)\t\n VFD\t0\t1 (0.1)\t\nOL phase\t(N=261)a\t(N=436)a\t\n Patients with retinal damage TEAEs\t0\t1 (0.2)\t\n Vitreous hemorrhage\t0\t1 (0.2)\t\nBinge eating disorder\t\t\t\nDB phase: 200, 400 mg/day\t(N=202)\tTPM 400 mg/day\t\n\t\t(N=202)\t\n Patients with retinal damage TEAEs\t0\t1 (0.5)\t\n VFDs\t0\t1 (0.5)\t\nDiabetic peripheral neuropathy\t\t\t\nDB phase: 100, 200, 400 mg/day\t(N=531)\t(N=1,140)\t\n Patients with retinal damage TEAEs\t6 (1.1)\t9 (0.8)\t\n Optic atrophy\t1 (0.2)\t0\t\n Optic nerve disorder\t0\t1 (0.1)\t\n Retinal detachment\t2 (0.4)\t0\t\n Retinal hemorrhage\t2 (0.4)\t1 (0.1)\t\n Retinal infarction\t0\t1 (0.1)\t\n Retinal tear\t0\t1 (0.1)\t\n Retinopathy\t0\t2 (0.2)\t\n Scotoma\t0\t1 (0.1)\t\n Vitreous adhesions\t0\t1 (0.1)\t\n Vitreous hemorrhage\t2 (0.4)\t0\t\n VFD\t0\t1 (0.1)\t\nOL phase\t(N=357)b\t(N=574)b\t\n Patients with retinal damage TEAEs\t6 (1.7)\t7 (1.2)\t\n Macular edema\t1 (0.3)\t0\t\n Retinal detachment\t1 (0.3)\t1 (0.2)c\t\n Retinal hemorrhage\t2 (0.6)\t1 (0.2)\t\n Retinopathy\t2 (0.6)\t4 (0.7)\t\n Tunnel vision\t0\t1 (0.2)\t\nObesity\t\t\t\nDB phase: <100, 100–200, >200–400 mg/day\t(N=1,373)\t(N=3,164)\t\n Patients with retinal damage TEAEs\t5 (0.4)\t9 (0.3)\t\n Macular degeneration\t1 (0.1)\t0\t\n Retinal disorder\t1 (0.1)\t0\t\n Retinal hemorrhage\t1 (0.1)\t1 (<0.1)\t\n Scotoma\t0\t1 (<0.1)\t\n Tunnel vision\t0\t3 (0.1)\t\n VFD\t2 (0.1)\t4 (0.1)\t\nNotes:\n\na Placebo group: patients who received placebo in DB phase but were switched to TPM during OL phase. TPM group: patients who received TPM or an active comparator during the DB phase and who either remained on TPM or were switched from active control to TPM during the OL phase.\n\nb Placebo group: patients who received placebo in DB phase but were switched to TPM during the OL phase. TPM group: patients who received TPM during the DB phase and OL phase.\n\nc Serious TEAE.\n\nAbbreviations: DB, double-blind; OL, open-label; TEAE, treatment-emergent adverse event; TPM, topiramate; VFDs, visual field defects.\n\nTable 3 Patient demographics, seriousness, latency, and reversibility for patients of VFD reported with topiramate treatment\n\nCharacteristics\tNumber of patients N=96\t\nSex\t\t\n Men\t25\t\n Women\t66\t\n Not reported\t5\t\nAge group (years)\t\t\n ≤17\t8\t\n 18–35\t26\t\n 36–50\t30\t\n 51–64\t13\t\n ≥65\t5\t\n Not reported\t14\t\nIndication (≥2 patients)\t\t\n Epilepsy\t24\t\n Migraine prophylaxis\t15\t\n Migraine\t12\t\n Convulsion\t5\t\n Bipolar disorder\t4\t\n Headache\t3\t\n Neuralgia\t3\t\n Convulsion prophylaxis\t2\t\n Partial seizures\t2\t\n Unknown\t11\t\nSeriousness\t\t\n Serious\t64\t\n Nonserious\t32\t\nLatencya\t\t\n <7 days\t8\t\n 1 week to 1 month\t19\t\n >1 month to 3 months\t14\t\n >3 months to 6 months\t10\t\n >6 months to 1 year\t3\t\n >1 year to 5 years\t13\t\n >5 years\t2\t\n Not reported\t27\t\nReversibility\t\t\n Reversible\t36\t\n Not reversible\t20\t\n Unknown\t40\t\nNote:\n\na Time course from the initial topiramate administration to the reported event of interest.\n\nAbbreviation: VFD, visual field defect.\n==== Refs\nReferences\n1 Topamax. Prescribing information [Internet] Available from: https://www.topamax.com/sites/default/files/topamax.pdf Accessed July 12, 2016 \n2 Shank RP Gardocki JF Streeter AJ Maryanoff BE An overview of the preclinical aspects of topiramate: pharmacology, pharmacokinetics, and mechanism of action Epilepsia 2000 41 Suppl 1 S3 S9 \n3 Kuzniecky R Ho S Pan J Modulation of cerebral GABA by topiramate, lamotrigine, and gabapentin in healthy adults Neurology 2002 58 3 368 372 11839834 \n4 Petroff OA Rothman DL Behar KL Mattson RH Human brain GABA levels rise after initiation of vigabatrin therapy but fail to rise further with increasing dose Neurology 1996 46 5 1459 1463 8628502 \n5 Sills GJ Butler E Forrest G Ratnaraj N Patsalos PN Brodie MJ Vigabatrin, but not gabapentin or topiramate, produces concentration-related effects on enzymes and intermediates of the GABA shunt in rat brain and retina Epilepsia 2003 44 7 886 892 12823570 \n6 Errante LD Petroff OAC Acute effects of gabapentin and pregabalin on rat forebrain cellular GABA, glutamate, and glutamine concentrations Seizure 2003 12 5 300 306 12810343 \n7 Schiefer U Visual field defects – essentials for neurologists J Neurol 2003 250 4 407 411 12760380 \n8 Fraunfelder FW Fraunfelder FT Keates EU Topiramate-associated acute, bilateral, secondary angle-closure glaucoma Ophthalmology 2004 111 1 109 111 14711721 \n9 Mandal A Chatterjee S Bose S Ganguly G Ocular adverse effects of topiramate: two case reports Indian J Pharmacol 2008 40 6 278 280 21279186 \n10 Quagliato LB Barella K Abreu Neto JM Quagliato EM Topiramate-associated acute, bilateral, angle-closure glaucoma: case report Arq Bras Oftalmol 2013 76 1 48 49 23812529 \n11 Kjellström S Bruun A Isaksson B Eriksson T Andréasson S Ponjavic V Retinal function and histopathology in rabbits treated with topiramate Doc Ophthalmol 2006 113 3 179 186 17111186 \n12 Kälviäinen R Nousiainen I Visual field defects with vigabatrin: epidemiology and therapeutic implications CNS Drugs 2001 15 3 217 230 11463129 \n13 Wild JM Martinez C Reinshagen G Harding GF Characteristics of a unique visual field defect attributed to vigabatrin Epilepsia 1999 40 12 1784 1794 10612345 \n14 Yoneda S Tanaka E Goto W Ota T Hara H Topiramate reduces excitotoxic and ischemic injury in the rat retina Brain Res 2003 967 1–2 257 266 12650986 \n15 Altman DG Practical Statistics for Medical Research Boca Raton, FL Chapman & Hall/CRC 1991 611 \n16 Nousiainen DI Mäntyjärvi M Kälviäinen R Visual function in patients treated with the GABAergic anticonvulsant drug tiagabine Clin Drug Investig 2012 20 6 393 400 \n17 Sills GJ Patsalos PN Butler E Forrest G Ratnaraj N Brodie MJ Visual field constriction: accumulation of vigabatrin but not tiagabine in the retina Neurology 2001 57 2 196 200 11468302 \n18 Verrotti A Lobefalo L Priolo T Color vision in epileptic adolescents treated with valproate and carbamazepine Seizure 2004 13 6 411 417 15276145 \n19 Christensen J Andreasen F Poulsen JH Dam M Randomized, concentration-controlled trial of topiramate in refractory focal epilepsy Neurology 2003 61 9 1210 1218 14610122 \n20 Arndt CF Salle M Derambure PH Defoort-Dhellemmes S Hache J-C The effect on vision of associated treatments in patients taking vigabatrin: carbamazepine versus valproate Epilepsia 2002 43 8 812 817 12180998 \n21 Paulus W Schwarz G Steinhoff BJ The effect of anti-epileptic drugs on visual perception in patients with epilepsy Brain J Neurol 1996 119 Pt 2 539 549 \n22 Verrotti A Manco R Matricardi S Franzoni E Chiarelli F Antiepileptic drugs and visual function Pediatr Neurol 2007 36 6 353 360 17560495 \n23 Zaccara G Perucca P Gangemi PF The adverse event profile of pregabalin across different disorders: a meta-analysis Eur J Clin Pharmacol 2012 68 6 903 912 22271298 \n24 Duboc A Hanoteau N Simonutti M Vigabatrin, the GABA-transaminase inhibitor, damages cone photoreceptors in rats Ann Neurol 2004 55 5 695 705 15122710 \n25 Panday VA Rhee DJ Review of sulfonamide-induced acute myopia and acute bilateral angle-closure glaucoma Compr Ophthalmol Update 2007 8 5 271 276 18201514 \n26 Thambi L Kapcala LP Chambers W Topiramate-associated secondary angle-closure glaucoma: a case series Arch Ophthalmol 2002 120 8 1108 12149075 \n27 Tripathi RC Tripathi BJ Haggerty C Drug-induced glaucomas: mechanism and management Drug Saf 2003 26 11 749 767 12908846 \n28 Ikeda N Ikeda T Nagata M Mimura O Ciliochoroidal effusion syndrome induced by sulfa derivatives Arch Ophthalmol 2002 120 12 1775 12470170 \n29 Natesh S Rajashekhara SK Rao ASD Shetty B Topiramate-induced angle closure with acute myopia, macular striae Oman J Ophthalmol 2010 3 1 26 28 20606870 \n30 Tanaka S Chuman Y Akaike K Doi W A case of topiramate-induced angle closure glaucoma Nihon Shinkei Seishin Yakurigaku Zasshi 2011 31 3 131 133 Japanese 21800704 \n31 Spaccapelo L Leschiutta S Aurea C Ferrari A Topiramate-associated acute glaucoma in a migraine patient receiving concomitant citalopram therapy: a case-report Cases J 2009 2 1 87 19171058 \n32 Willett MC Edward DP Refractory topiramate-induced angle-closure glaucoma in a man: a case report J Med Case Reports 2011 5 33 \n33 Asensio-Sánchez VM Torreblanca-Agüera B Martínez-Calvo S Calvo MJ Rodríguez R Severe ocular side effects with Topamax Arch Soc Esp Oftalmol 2006 81 6 345 348 Spanish 16804780 \n34 Foroozan R Buono LM Foggy visual field defect Surv Ophthalmol 2003 48 4 447 451 12850232 \n35 Macgregor EA Rosenberg JD Kurth T Sex-related differences in epidemiological and clinic-based headache studies Headache 2011 51 6 843 859 21631472 \n36 McHugh JC Delanty N Epidemiology and classification of epilepsy: gender comparisons Int Rev Neurobiol 2008 83 11 26 18929074 \n37 Al Ajlouni S Shorman A Daoud AS The efficacy and side effects of topiramate on refractory epilepsy in infants and young children: a multi-center clinical trial Seizure 2005 14 7 459 463 16087357 \n38 Chung SS A review of the efficacy and safety of extended-release topiramate in the adjunctive treatment for refractory partial-onset seizures Ther Adv Neurol Disord 2015 8 3 131 136 25941540 \n39 Chung SS Fakhoury TA Hogan RE Once-daily USL255 as adjunctive treatment of partial-onset seizures: randomized phase III study Epilepsia 2014 55 7 1077 1087 24902983\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1177-5467",
"issue": "11()",
"journal": "Clinical ophthalmology (Auckland, N.Z.)",
"keywords": "gamma-aminobutyric acid; retinal dysfunction; scotoma; topiramate; visual field defects",
"medline_ta": "Clin Ophthalmol",
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"pages": "983-992",
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"title": "Comprehensive review of visual defects reported with topiramate.",
"title_normalized": "comprehensive review of visual defects reported with topiramate"
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"abstract": "A man in his late 40s with sickle cell anaemia (HbSS) presented to the emergency department with 2 weeks of diffuse oedema, increased abdominal girth and dyspnoea. His anasarca was thought to be indicative of an acute decompensation of his known liver cirrhosis with transfusion-induced haemosiderosis. While his anasarca improved with diuresis, his direct hyperbilirubinaemia suddenly worsened without any signs of haemolysis, biliary disease or obstruction. He also developed an acute worsening in serum creatinine (1.17-7.0 mg/dL in 7 days) despite subsequent treatment for presumed hepatorenal syndrome (HRS). Given his clinical decline, the patient's goals of care were transitioned to comfort measures only. His clinical presentation and rapid liver and renal deterioration were most typical of sickle cell intrahepatic cholestasis (SCIC). SCIC can lead to rapid deterioration in renal function and can be mistaken for HRS. When SCIC is suspected, consideration of exchange transfusions should be made early.",
"affiliations": "Harvard Medical School, Boston, Massachusetts, USA.;Massachusetts General Hospital, Boston, Massachusetts, USA.;Massachusetts General Hospital, Boston, Massachusetts, USA.;Massachusetts General Hospital, Boston, Massachusetts, USA.",
"authors": "Im|Dana DaEun|DD|;Essien|Utibe|U|;DePasse|Jacqueline W|JW|;Chiappa|Victor|V|",
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"country": "England",
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"issue": "2015()",
"journal": "BMJ case reports",
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"medline_ta": "BMJ Case Rep",
"mesh_terms": "D065290:Acute-On-Chronic Liver Failure; D000755:Anemia, Sickle Cell; D004417:Dyspnea; D004487:Edema; D017809:Fatal Outcome; D006801:Humans; D006932:Hyperbilirubinemia; D008103:Liver Cirrhosis; D008297:Male; D008875:Middle Aged; D010166:Palliative Care; D010349:Patient Compliance; D051437:Renal Insufficiency",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "26135492",
"pubdate": "2015-07-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "24565828;11343226;870977;15747337;17394147;7446549;3918737;13402890;7485022;23888237;21445921",
"title": "Acute on chronic liver failure in a patient with sickle cell anaemia (HbSS).",
"title_normalized": "acute on chronic liver failure in a patient with sickle cell anaemia hbss"
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"companynumb": "PHHY2015US080480",
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"abstract": "Real-world data on the new anti-sclerostin antibody drug, romosozumab, remain scarce. There is a strong need to accumulate and analyze data on romosozumab treatment for such conditions as osteoporosis. The purpose of this study was to investigate the therapeutic and adverse effects of romosozumab for osteoporosis treatment in clinical practice. Of the 230 osteoporosis patients prescribed romosozumab from September 2019 in this prospective multicenter cohort study, 204 patients completed 12 months of treatment. The primary outcome of interest was the rate of change in bone mineral density (BMD) of the lumbar spine, total hip, and femoral neck as measured by dual-energy X-ray absorptiometry. Secondary outcomes included changes in bone turnover markers and serum-corrected calcium level as well as the incidence of adverse events. At 6 and 12 months of romosozumab treatment, the respective percentage change in BMD from baseline was 7.4% and 12.2% for the lumbar spine, 1.8% and 5.8% for the total hip, and 2.9% and 6.0% for the femoral neck, all of which were significantly higher (P < 0.001) than baseline values. Patients who switched from another osteoporosis regimen exhibited significantly lower lumbar spine BMD gains versus treatment-naïve patients, especially for cases switching from denosumab. P1NP was significantly increased at 6 months (58.9%; P < 0.01), while TRACP-5b was significantly decreased at 6 months (-14.7%; P < 0.001) and 12 months (-18.8%; P < 0.001) versus baseline values. The largest rate of decrease in serum-corrected calcium was 3.7% at 12 months. Sixty-four (27.8%) of 230 patients experienced an adverse event, and 7 (3.0%) new fractures were recorded. In sum, romosozumab treatment for 12 months significantly improved lumbar spine, total hip, and femoral neck BMD according to real-world data.",
"affiliations": "Kobayakawa Orthopedic and Rheumatologic Clinic, 1969 Kunou, Fukuroi, Shizuoka 437-0061, Japan.;Department of Orthopaedic Surgery, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan.;Department of Orthopaedic Surgery, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan.;Department of Clinical Support Office, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, 3-18-22 Honkagome, Bunkyou-ku, Tokyo 113-8677, Japan.;Department of Orthopaedic Surgery, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan.;Department of Orthopaedic Surgery, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan.;Department of Orthopaedic Surgery, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan.",
"authors": "Kobayakawa|Tomonori|T|;Suzuki|Takako|T|;Nakano|Masaki|M|;Saito|Makoto|M|;Miyazaki|Akiko|A|;Takahashi|Jun|J|;Nakamura|Yukio|Y|",
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"doi": "10.1016/j.bonr.2021.101068",
"fulltext": "\n==== Front\nBone Rep\nBone Rep\nBone Reports\n2352-1872\nElsevier\n\nS2352-1872(21)00323-5\n10.1016/j.bonr.2021.101068\n101068\nArticle\nReal-world effects and adverse events of romosozumab in Japanese osteoporotic patients: A prospective cohort study\nKobayakawa Tomonori a\nSuzuki Takako bc\nNakano Masaki b\nSaito Makoto d\nMiyazaki Akiko b\nTakahashi Jun b\nNakamura Yukio yxn14@shinshu-u.ac.jp\nb⁎\na Kobayakawa Orthopedic and Rheumatologic Clinic, 1969 Kunou, Fukuroi, Shizuoka 437-0061, Japan\nb Department of Orthopaedic Surgery, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan\nc Department of Human Nutrition, Faculty of Human Nutrition, Tokyo Kasei Gakuin University, 22 Sanban-cho, Chiyoda-ku, Tokyo 102-8341, Japan\nd Department of Clinical Support Office, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, 3-18-22 Honkagome, Bunkyou-ku, Tokyo 113-8677, Japan\n⁎ Corresponding author. yxn14@shinshu-u.ac.jp\n16 4 2021\n6 2021\n16 4 2021\n14 10106830 1 2021\n10 4 2021\n13 4 2021\n© 2021 The Author(s)\n2021\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).\nReal-world data on the new anti-sclerostin antibody drug, romosozumab, remain scarce. There is a strong need to accumulate and analyze data on romosozumab treatment for such conditions as osteoporosis. The purpose of this study was to investigate the therapeutic and adverse effects of romosozumab for osteoporosis treatment in clinical practice. Of the 230 osteoporosis patients prescribed romosozumab from September 2019 in this prospective multicenter cohort study, 204 patients completed 12 months of treatment. The primary outcome of interest was the rate of change in bone mineral density (BMD) of the lumbar spine, total hip, and femoral neck as measured by dual-energy X-ray absorptiometry. Secondary outcomes included changes in bone turnover markers and serum-corrected calcium level as well as the incidence of adverse events. At 6 and 12 months of romosozumab treatment, the respective percentage change in BMD from baseline was 7.4% and 12.2% for the lumbar spine, 1.8% and 5.8% for the total hip, and 2.9% and 6.0% for the femoral neck, all of which were significantly higher (P < 0.001) than baseline values. Patients who switched from another osteoporosis regimen exhibited significantly lower lumbar spine BMD gains versus treatment-naïve patients, especially for cases switching from denosumab. P1NP was significantly increased at 6 months (58.9%; P < 0.01), while TRACP-5b was significantly decreased at 6 months (−14.7%; P < 0.001) and 12 months (−18.8%; P < 0.001) versus baseline values. The largest rate of decrease in serum-corrected calcium was 3.7% at 12 months. Sixty-four (27.8%) of 230 patients experienced an adverse event, and 7 (3.0%) new fractures were recorded. In sum, romosozumab treatment for 12 months significantly improved lumbar spine, total hip, and femoral neck BMD according to real-world data.\n\nHighlights\n\n• Romosozumab for 12 months significantly improved BMD according to real-world data.\n\n• Switching from denosumab and bisphosphonate displayed lower gains in lumbar BMD.\n\n• The co-administration of a vitamin D3 analogue might prevent hypocalcemia.\n\nKeywords\n\nAdverse event\nBone mineral density\nBone turnover marker\nOsteoporosis\nRomosozumab\n==== Body\n1 Introduction\n\nBesides bisphosphonates, denosumab and teriparatide are also widely used for patients with osteoporosis. They are undoubtedly effective treatments (Cummings et al., 2009; McClung et al., 2005; Leder et al., 2015) but carry several disadvantages: denosumab is associated with multiple compression fractures after its discontinuation (Cummings et al., 2018). Similarly, teriparatide is reported to be an effective therapeutic drug to reduce the risk of hip fractures (Diez-Perez et al., 2019), however, according to the Guidelines for Prevention and Treatment of Osteoporosis (2011) in Japan, the clinical evidence of the efficacy of teriparatide on hip fracture prevention is still insufficient, and it is ranked as grade C (Orimo et al., 2012) regarding the evaluation grading in the guideline. Some patients also consider the strict daily drug administration of teriparatide inconvenient (Leder et al., 2015). In consultations with those patients, it became apparent to improve BMD as soon as possible to prevent further fractures and maintain patient care.\n\nIn March 2019, the anti-sclerostin antibody drug romosozumab first became available in clinical practice in Japan for osteoporosis for high-risk fracture cases of osteoporosis (Assessment of Fracture Risk and Its Application to screening for Postmenopausal Osteoporosis, 1994; Soen et al., 2013). Romosozumab has the dual effect of promoting bone formation and decreasing bone resorption by inhibiting the suppression of Wnt signaling (Ominsky et al., 2015; Taylor et al., 2016). However, there is little evidence on its therapeutic efficacy and adverse events in the real world due to its short history.\n\nThe viewpoint of clinical trials differs considerably from that of analyses of real-world data. Clinical trials are performed to assess drug efficacy and safety in strictly targeted populations. Thus, even if a clinical trial determines a new drug to be effective and safe, whether the drug is efficacious for each patient in the population and its risk-benefit relationship cannot be completely ascertained. The aim of studies on actual medical practice focuses on individual patients encountered by physicians. Accordingly, the purpose of this cohort investigation was to examine the real-world clinical and adverse effects of romosozumab for osteoporosis treatment.\n\n2 Materials and methods\n\n2.1 Study design and participants\n\nFrom March 2019, this prospective observational study was conducted at our clinic and 4 affiliated institutions. The subjects were primary and secondary osteoporosis patients who were administered romosozumab for 12 months. All patients were injected subcutaneously with 210 mg of romosozumab at the study onset and then monthly thereafter. Patients with lower 25OHD values were offered an active vitamin D3 analogue and, if not inclined, were recommended to take commercially available vitamin D3 and calcium supplements.\n\nRomosozumab was positively used to treat patients diagnosed as having severe osteoporosis, especially those with a high risk of fracture, regardless of the presence or absence of prior treatment for osteoporosis. The definition of severe osteoporosis by the World Health Organization is a BMD value that is 2.5 standard deviation (SD) or more below the average value for young healthy women (i.e., T-score < −2.5 SD) in the presence of 1 or more fragility fractures, or if BMD at the lumbar spine is less than −3.3 SD, or with 2 or more existing vertebral fractures (Assessment of Fracture Risk and Its Application to screening for Postmenopausal Osteoporosis, 1994; Soen et al., 2013; Marcus et al., 2003). In the present study, patients who fulfilled the criteria of severe osteoporosis were recruited as subjects. The occurrence of fracture did not have to be recent, although the age of fracture occurrence was designated as 45 years or older. Fragility fractures of the skull, facial bones, metacarpals, fingers and toes, pathologic fractures, and fractures associated with severe trauma were excluded. Also, patients were excluded if they had experienced a cardiovascular event within the previous year or exhibited hypocalcemia.\n\nThe protocol of this study was approved by the ethics committee of our institution (approval numbers: 4349 and 4351). Written informed consent was obtained from all participants prior to enrollment. This study was conducted following the tenets outlined in the Declaration of Helsinki.\n\n2.2 Primary and secondary outcomes of interest\n\nTo evaluate the effects of 12-month romosozumab therapy on BMD as the primary outcome of interest, dual-energy X-ray absorptiometry (DXA) was employed using a Prodigy Fuga (GE Healthcare, Madison, WI, USA). The minimum significant change for this model was 2% (Shepherd et al., 2006). Lumbar vertebra DXA measured the lumbar 2–4 levels and excluded any vertebral body with a T-score of 1.0 higher than the vertebral body with the lowest T-score. DXA readings were taken at baseline and at 6 and 12 months of treatment. Primary osteoporosis and secondary osteoporosis were distinguished from interviews and medication history. For a more detailed analysis, subjects were divided into groups with and without a history of osteoporosis treatment to examine the therapeutic effects of romosozumab. Among the subjects with an osteoporosis treatment history, the effects of romosozumab were further evaluated according to the type of pretreatment drug (bisphosphonate, denosumab, or teriparatide).\n\nAs secondary outcomes of interest, the serum bone turnover markers of procollagen type 1 N-terminal propeptide 1 (P1NP) and tartrate-resistant acid phosphatase isoform 5b (TRACP-5b) were measured by the enzyme immunoassay (EIA) and chemiluminescent enzyme immunoassay (CLEIA) methods for each subject at baseline and after 6 months and 12 months. A previous report demonstrated that TRACP-5b levels were useful bone resorption markers that demonstrated higher clinical sensitivity and signal-to-noise ratio as compared with serum CTX levels (Nenonen et al., 2005). Serum calcium measurements had an intra-assay coefficient of variation of <4.0% (Ca-AL Type C kit; Serotech, Chitose, Japan). Serum-corrected calcium values were determined and used in the present study (Payne et al., 1973). Measurements of serum-corrected calcium were performed at baseline and at 2 weeks, 4 weeks, 6 months, and 12 months of treatment. The changes in serum-corrected calcium were also examined according to estimated glomerular filtration rate (eGFR) in mL/min/1.73 m2, which was designated as ≧ 90 in the normal group, 60 ≦ eGFR < 89 in the mild dysfunction group, 30 ≦ eGFR < 59 in the moderate dysfunction group, and 29 > eGFR in the severe group (Coresh et al., 2003). The rate of change in serum-corrected calcium was also investigated with respect to the absence or presence of a vitamin D3 analogue, such as alfacalcidol or eldecalcitol. Lastly, the incidence of adverse events was recorded throughout the study period.\n\n2.3 Statistical analysis\n\nPatient background parameters are expressed as the mean ± SD. P1NP and TRACP-5b are expressed as the median. The changes in percentage or value from baseline to the study time points for BMD, P1NP, and TRACP-5b, as well as changes in percentage for serum-corrected calcium levels, were assessed using the Wilcoxon signed-rank test. The Wilcoxon rank-sum test was employed to evaluate the differences between each group with regards to the percentage changes from baseline for BMD, bone turnover markers, and serum-corrected calcium. Differences between study groups were determined by ANOVA or Fisher's exact test. A Kaplan–Meier curve was constructed to delineate the cumulative incidence of discontinuation during the observation period. A two-tailed P-value of <0.05 was considered statistically significant for all analyses. All statistical testing was conducted using R version 3.6.0 (R Core Team, 2019; http://www.R-project.org/).\n\n3 Results\n\n3.1 Characteristics of patients\n\nA total of 230 subjects were initially enrolled. During the study period, 26 subjects discontinued romosozumab treatment who were either lost to follow-up, citing such personal circumstances as economic reasons (16 subjects), or withdrew due to adverse events (10 subjects). The remaining 204 patients were used in subsequent analyses (Fig. 1). Discontinuation data were excluded from evaluations of romosozumab efficacy.Fig. 1 Subject flow diagram throughout the 12-month romosozumab treatment period. Subjects receiving selective estrogen receptor modulators or vitamin D3 as previous treatments were excluded from the study.\n\nFig. 1\n\nThe baseline demographics and characteristics of the subjects are shown in Table 1. The mean ± SD age was 73.6 ± 13.1 years in this predominantly female (85.3%) cohort. Mean BMD T-scores were −2.56 ± 1.24 for the lumbar spine, −2.51 ± 0.89 for the total hip, and −3.01 ± 0.96 for the femoral neck. Seventy-one (35.1%) subjects had a prevalent vertebral fracture and 52 (25.7%) patients had a history of previous non-vertebral fracture. Over half of the patients (107; 52.5%) had a history of osteoporosis treatment. Among them, 42 (20.6%) patients received bisphosphonates, 31 (15.2%) received denosumab, and 34 (16.7%) received teriparatide. S-Table 1 summarizes the patient characteristics based on primary and secondary osteoporosis. Secondary osteoporosis was defined as diminished bone mass in the presence of some factors, such as an underlying disease or medication. Although glucocorticoids were a major distinguishing factor of secondary osteoporosis in this study involving 35 patients (43%), other factors included rheumatoid arthritis (29 patients; 35.8%), systemic lupus erythematosus (4 patients; 4.9%), malignant tumor/lymphoma (21 patients; 25.9%), diabetes mellitus (7 patients; 8.6%), chronic kidney disease (6 patients; 7.4%), and others (15 patients; 18.5%). The number of patients for each factor was counted redundantly.Table 1 Demographic and Clinical Characteristics of Subjects at Baseline. Data are expressed as the mean ± standard deviation or the number (%) of all patients who completed 12 months of romosozumab treatment. P1NP and TRACP-5b are expressed as median values.\n\nTable 1\tN = 204\t\nAge (years)\t73.6 ± 13.1\t\nFemale, n (%)\t174 (85.3)\t\nBody mass index (kg/m2)a\t21.0 ± 3.3\t\nBone mineral density T-score\t\t\n Lumbar spine\t−2.56 ± 1.24\t\n Total hips\t−2.51 ± 0.89\t\n Femoral neck\t−3.01 ± 0.96\t\nDuration of previous treatment (M)\t28\t\nPrior vertebral fracture, n (%)\t71 (35.1)\t\nPrior non-vertebral fracture at >45 yrs. of age, n (%)\t52 (25.7)\t\nPrior fractures of both vertebrae and non-vertebrae, n (%)\t16 (7.9)\t\nPrior osteoporosis treatment, n (%)\t107 (52.5)\t\n Bisphosphonate\t42 (20.6)\t\n Denosumab\t31 (15.2)\t\n Teriparatide\t34 (16.7)\t\nConcomitant use of active vitamin D, n (%)\t108 (52.9)\t\nGlucocorticoid use, n (%)\t35 (17.2)\t\nMedian serum total P1NP (IQR), μg/L\t64.2 (9.5–495)\t\nMedian serum TRACP-5b (IQR), mU/dL\t457.5 (81–1500)\t\nSerum albumin, g/dL\t4.09 ± 0.35\t\nSerum-corrected calcium, mg/dL\t9.28 ± 0.44\t\nSerum phosphorus, mg/dL\t3.60 ± 0.56\t\neGFR, mL/min/1.73 m2\t67.2 ± 23.5\t\n25OHD, ng/mL\t16.0 ± 6.48\t\nucOC, ng/mL\t7.95 ± 7.76\t\nIntact PTH, μg/mL\t52.2 ± 42.2\t\nP1NP, procollagen type 1 N-terminal propeptide; IQR, inter-quartile range; TRACP-5b, tartrate-resistant acid phosphatase isoform 5b; eGFR, estimated glomerular filtration rate; 25OHD, 25-hydroxyvitamin D; ucOC, undercarboxylated osteocalcin; intact PTH, intact parathyroid hormone.\n\na Calculated as weight in kilograms divided by the square of height in meters.\n\n3.2 Primary outcomes\n\nAt 6 and 12 months of romosozumab treatment, the percentage change in BMD from baseline was 7.4% and 12.2% for the lumbar spine, 1.8% and 5.8% for the total hip, and 2.9% and 6.0% for the femoral neck in overall subjects. All increases were significant (P < 0.001) versus baseline values (Fig. 2A-C).Fig. 2 Mean percentage change from baseline to 6 and 12 months in bone mineral density (BMD) of the (A) lumbar spine, (B) total hip, and (C) femoral neck. *P < 0.05, **P < 0.01, and ***P < 0.001 versus baseline (Wilcoxon's signed-rank test). Bars indicate the mean ± standard errors. Mean percentage change in the primary and secondary osteoporosis groups from baseline to 6 months and 12 months in BMD of the (D) lumbar spine, (E) total hip, and (F) femoral neck. Bars indicate the mean ± standard errors. *P < 0.05, **P < 0.01, and ***P < 0.001 versus baseline (Wilcoxon's signed-rank test).\n\nFig. 2\n\nWe also investigated BMD at 6 months and 12 months of romosozumab treatment based on the presence of primary or secondary osteoporosis. The percentage change in BMD from baseline for primary osteoporosis was 7.9% (P < 0.001) and 12.9% (P < 0.001) for the lumbar spine, 2.0% (P < 0.001) and 5.9% (P < 0.001) for the total hip, and 3.0% (P < 0.001) and 6.2% (P < 0.001) for the femoral neck, while that for secondary osteoporosis was 6.6% (P < 0.001) and 11.1% (P < 0.001) for the lumbar spine, 1.6% (P < 0.05) and 5.7 (P < 0.001) for the total hip, and 2.8% (P < 0.001) and 5.8% (P < 0.001) for the femoral neck. There were no significant differences between the primary and secondary groups at any time point (Fig. 2D-F).\n\nTable 2 summarizes the demographic and clinical characteristics of the subjects to examine the efficacy of romosozumab according to previous treatments. Notably, lumbar spine BMD was comparably higher at baseline in patients switching from denosumab. Lumbar spine BMD respectively increased by 9.4% and 14.4% at 6 months and 12 months in the treatment-naïve group, 5.0% and 9.6% in the bisphosphonate group, 2.3% and 7.2% in the denosumab group, and 8.9% and 13.3% in the teriparatide group as compared with baseline values. All increases were significant (P < 0.001) versus baseline. We observed a significant difference in lumbar BMD gains for the bisphosphonate group (P < 0.01) and denosumab group (P < 0.001) as compared with the treatment-naïve group (Fig. 3A). Total hip BMD respectively increased by 2.4% (P < 0.001) and 5.9% (P < 0.001) at 6 months and 12 months in the treatment-naïve group, 0.2% (P = 0.78) and 4.3% (P < 0.001) in the bisphosphonate group, 0.9% (P = 0.52) and 5.6% (P < 0.001) in the denosumab group, and 2.8% (P < 0.01) and 7.5% (P < 0.001) in the teriparatide group as compared with baseline values (Fig. 3B). There were significant differences for the bisphosphonate group (P < 0.001) and denosumab group (P < 0.05) as compared with the treatment-naïve group at 6 and 12 months. Femoral neck BMD respectively increased by 3.1% (P < 0.001) and 6.3% (P < 0.001) at 6 months and 12 months in the treatment-naïve group, 2.3% (P < 0.05) and 5.3% (P < 0.001) in the bisphosphonate group, 3.1% (P = 0.06) and 6.0% (P < 0.01) in the denosumab group, and 3.0% (P < 0.05) and 5.8% (P < 0.001) in the teriparatide group as compared with baseline values. No remarkable differences from the treatment-naïve group were noted (Fig. 3C). As shown in Table 2, patient BMD levels differed among the treatment-naïve group and previously treated groups. In comparisons among the groups, the mean values of BMD at each site (S-Fig. 1A-C) and the values of gained BMD versus baseline (S-Fig. 1D-F) showed comparable findings at 6 months and 12 months of treatment.Table 2 Demographic and Clinical Characteristics of Subject Groups (treatment-naïve group, bisphosphonate group, denosumab group, and teriparatide group) at Baseline. Data are expressed as the mean ± standard deviation or the number (%) of patients. P1NP and TRACP-5b are expressed as median values.\n\nTable 2\tNaïve\nN = 97\tBisphosphonates\nN = 42\tDenosumab\nN = 31\tTeriparatide\nN = 34\tP-value\t\nAge (years)\t74.4 ± 13.1\t73.4 ± 13.9\t69.6 ± 19.1\t68.9 ± 16.0\t0.407\t\nFemale, n (%)\t82 (84.5)\t36 (85.7)\t25 (83.3)\t31 (91.2)\t0.819\t\nBody mass index (kg/m2)a\t21.3 ± 3.5\t20.6 ± 4.6\t19.8 ± 4.5\t19.5 ± 3.8\t0.088\t\nBone mineral density T-score\t\t\t\t\t\t\n Lumbar spine\t−2.85 ± 1.09\t−2.39 ± 1.25\t−1.70 ± 1.30\t−2.78 ± 1.24\tP < 0.001\t\n Total hip\t−2.66 ± 0.84\t−2.25 ± 0.98\t−2.48 ± 0.88\t−2.55 ± 1.03\t0.142\t\n Femoral neck\t−3.23 ± 0.85\t−2.75 ± 1.10\t−2.86 ± 0.95\t−2.92 ± 1.14\t0.145\t\nDuration of previous treatment (M)\t–\t29\t39\t16\tP < 0.001\t\nPrior vertebral fracture, n (%)\t35 (36.1)\t13 (31.0)\t9 (30.0)\t15 (44.1)\t0.543\t\nPrior non-vertebral fracture at >45 years of age, n (%)\t23 (23.6)\t10 (23.8)\t6 (20.0)\t12 (35.3)\t0.512\t\nPrior fractures of both vertebrae and non-vertebrae, n (%)\t7 (7.2)\t2 (4.8)\t3 (10.0)\t4 (11.8)\t0.659\t\nConcomitant active vitamin D, n (%)\t51 (52.6)\t21 (50.0)\t16 (51.6)\t20 (58.8)\t–\t\nGlucocorticoid use, n (%)\t8 (8.2)\t8 (19.0)\t11 (35.5)\t8 (23.5)\t0.004\t\nMedian serum total P1NP (IQR), μg/L\t73.3\n(18.0–495)\t25.6\n(12.2–88.9)\t23.6\n(9.5–373)\t98.9\n(39.8–363)\tP < 0.001\t\nMedian serum TRACP-5b (IQR), mU/dL\t587.0\n(222–1370)\t308.5\n(121–771)\t243.50\n(81–1020)\t531.0\n(262–1500)\tP < 0.001\t\nSerum albumin, g/dL\t4.14 ± 0.38\t4.01 ± 0.31\t4.08 ± 0.32\t4.07 ± 0.30\t0.309\t\nSerum-corrected calcium, mg/dL\t9.24 ± 0.35\t9.38 ± 0.45\t9.29 ± 0.53\t9.31 ± 0.36\t0.303\t\nSerum phosphorus, mg/dL\t3.57 ± 0.56\t3.45 ± 0.44\t3.72 ± 0.65\t3.76 ± 0.56\t0.097\t\neGFR, mL/min/1.73 m2\t67.9 ± 25.6\t64.9 ± 17.7\t64.3 ± 27.4\t70.3 ± 20.1\t0.621\t\n25OHD, ng/mL\t15.9 ± 6.21\t16.7 ± 5.92\t18.4 ± 8.81\t13.5 ± 5.09\t0.017\t\nucOC, ng/mL\t9.10 ± 8.43\t2.87 ± 2.31\t1.45 ± 1.29\t9.50 ± 6.26\tP < 0.001\t\nIntact PTH, μg/mL\t59.1 ± 52.1\t43.4 ± 19.9\t49.2 ± 44.2\t50.4 ± 32.0\t0.188\t\nP1NP, procollagen type 1 N-terminal propeptide; IQR, inter-quartile range; TRACP-5b, tartrate-resistant acid phosphatase isoform 5b; eGFR, estimated glomerular filtration rate; 25OHD, 25-hydroxyvitamin D; ucOC, undercarboxylated osteocalcin; intact PTH, intact parathyroid hormone.\n\nDifferences between the groups were determined by ANOVA or Fisher's exact test.\n\na Calculated as weight in kilograms divided by the square of height in meters.\n\nFig. 3 Mean percentage change in bone mineral density (BMD) of the (A) lumbar spine, (B) total hip, and (C) femoral neck from baseline to 6 and 12 months depending on previous therapy. Bars indicate the mean ± standard errors. *P < 0.05, **P < 0.01, and ***P < 0.001 versus baseline (Wilcoxon's signed-rank test). †P < 0.05, ††P < 0.01, and †††P < 0.001 versus treatment-naïve group (Wilcoxon's rank-sum test).\n\nFig. 3\n\n3.3 Secondary outcomes\n\nThe mean changes in P1NP and TRACP-5b levels at 6 months and 12 months from baseline in overall subjects were studied as secondary outcomes. In addition, the median values of serum P1NP and TRACP-5b and their inter-quartile range as well as the mean changes in bone turnover marker values during treatment were compared in the absence or presence of prior treatment. In the cohort, P1NP was significantly increased at 6 months (58.9%; P < 0.01) and 12 months (55.9%; P < 0.01), while TRACP-5b was significantly decreased at 6 months (−14.7%; P < 0.001) and 12 months (−18.8%; P < 0.001) versus baseline values (Fig. 4A, B).Fig. 4 Mean percentage change from baseline to 6 months and 12 months in (A) procollagen type 1 N-terminal propeptide (P1NP) and (B) tartrate-resistant acid phosphatase isoform 5b (TRACP-5b) in overall subjects. Bars indicate the mean ± standard errors.\n\nMedian value of (C) P1NP (μg/L) and (D) TRACP-5b (mU/dL) depending on the absence or presence of previous treatment at baseline, 6 months, and 12 months. Bars indicate inter-quartile range.\n\nMean value of change from baseline to 6 months and 12 months in (E) P1NP (μg/L) and (F) TRACP-5b (mU/dL) depending on the absence or presence of previous treatment. Bars indicate the mean ± standard errors. *P < 0.05, **P < 0.01, and ***P < 0.001 versus baseline (Wilcoxon's signed-rank test). †P < 0.05, ††P < 0.01, and †††P < 0.001 versus the treatment-naïve group (Wilcoxon's rank-sum test).\n\nFig. 4\n\nIn analytical studies by comparisons based on the presence or absence of previous treatment, P1NP was lower in the bisphosphonate and denosumab groups (P < 0.001) and TRACP-5b was higher in the treatment-naïve and teriparatide groups (P < 0.001) in the clinical characteristics of the patients at baseline (Table 2). Significant changes in both turnover markers during treatment were observed (Fig. 4C-D).\n\nP1NP in the treatment-naïve group was significantly increased (+11.8 μg/L; P < 0.05) at 6 months and decreased (−13.5 μg/L; P < 0.01) at 12 months as compared with baseline values. P1NP was significantly increased in the bisphosphonate group (6 months: +19.4 μg/L; P < 0.001, 12 months: +19.6 μg/L; P < 0.001) and denosumab group (6 months: +44.8 μg/L; P < 0.01, 12 months: +48.7 μg/L; P < 0.01), and significantly decreased in the teriparatide group (6 months: −34.9 μg/L; P < 0.001, 12 months: −46.1 μg/L; P < 0.01) versus baseline values. There were significant differences among treatment-naïve and switch groups (Fig. 4E).\n\nTRACP-5b was significantly decreased in the treatment-naïve group (6 months: −211.2 mU/dL; P < 0.001, 12 months: −270.6 mU/dL; P < 0.001), bisphosphonate group (6 months: −70.1 mU/dL; P < 0.01, 12 months: −72.4 mU/dL; P < 0.001), and teriparatide group (6 months: −368.5 mU/dL; P < 0.001, 12 months: −406.7 mU/dL; P < 0.01), and significantly increased in the denosumab group (6 months: +131.4 mU/dL; P < 0.05, 12 months: +58.3 mU/dL; P < 0.05) as compared with baseline values. There were significant differences among the treatment-naïve and switch groups (Fig. 4F).\n\nThe change rate of serum-corrected calcium at 2 weeks of romosozumab treatment was −2.5%, which was significantly different from baseline (P < 0.001). The largest rate of change in serum-corrected calcium was −3.7% (P < 0.001) at 12 months of romosozumab (Fig. 5A). Regarding renal function, the normal, mild dysfunction, moderate dysfunction, and severe dysfunction groups contained 31, 106, 59, and 8 cases, respectively. There were no remarkable differences in the change rate of serum-corrected calcium according to the degree of renal dysfunction (Fig. 5B). However, the change rate of serum-corrected calcium was significantly lower in subjects with vitamin D3 analogue co-administration (2 weeks: P < 0.05, 4 weeks: P < 0.05, 12 months: P < 0.01 versus subjects without a vitamin D3 analogue) (Fig. 5C). We encountered no cases of clinical hypocalcemia (i.e., CTCAE v5.0 grade 3 or higher, calcium <7.0 mg/dL, and clinical symptoms requiring hospitalization) severe enough to discontinue romosozumab therapy since we recommended patients with a vitamin D deficiency/insufficiency to take active vitamin D preparations. As the administration of active vitamin D carries some risk of hypercalcemia, we did not recommend calcium preparations. For patients not wanting additional medicine, we recommended commercially available supplements of vitamin D or calcium instead.Fig. 5 Mean percentage change from baseline to 2 weeks (W), 4 weeks, 6 months (M), and 12 months in serum-corrected calcium level of (A) all subjects, (B) subjects based on renal function, and (C) subjects with or without prescription of a vitamin D analogue. *P < 0.05, **P < 0.01, and ***P < 0.001 versus baseline (Wilcoxon's signed-rank test). †P < 0.05, ††P < 0.01, and †††P < 0.001 versus group with a vitamin D analogue (Wilcoxon's rank-sum test).\n\nFig. 5\n\nKaplan–Meier survival testing was employed to estimate the continuation rate of romosozumab treatment, which was 88.4% during 12 months (S-Fig. 4 in the supplementary materials). A total of 64 adverse events were observed (Table 3). The majority of events were temporary, mild, and did not result in drug discontinuation. The most frequent adverse event was an injection site reaction associated with pain, swelling, and redness lasting 2 days or longer. Ten (4.3%) discontinuation cases due to adverse events were recorded (S-Table2), and 4 (1.7%) serious adverse events occurred. Of note, a cardiovascular event (cerebral infarction) was observed in 1 (0.4%) case during the study period, and 1 (0.4%) case of osteonecrosis of the jaw occurred. The latter patient had been treated with an antiresorptive agent (bisphosphonate preparations) for 6 months prior to romosozumab administration. In addition, 1 (0.4%) patient experienced mild hypocalcemia of grade 2 as defined by the CTCAE v5.0 grading scale during 12 months of treatment without subjective symptoms. The patient did not require drug discontinuation. Seven (3.0%) subjects experienced new fractures during romosozumab treatment. No patient discontinued romosozumab due to a new fracture.Table 3 Adverse Events. Data are expressed as the number of patients (%) and include all patients who received at least 1 romosozumab injection (N = 230).\n\nTable 3\tTotal\n(N = 230)\t\nAll adverse events\t64 (27.8)\t\nAdverse events leading to discontinuation of trial participation\t10 (4.3)\t\nSerious adverse events\t4 (1.7)\t\nAnterior mediastinal tumor (recurrence of breast cancer)\t\t\n Cerebral infarction\t1 (0.4)\t\n Osteonecrosis of the jaw\t1 (0.4)\t\nPneumothorax\t1 (0.4)\t\nInjection site reactiona\t32 (13.9)\t\n Pain\t18 (7.8)\t\n Swelling\t13 (5.7)\t\n Redness\t1 (0.4)\t\nOther events of interest\t17 (7.4)\t\n Hypozincemia\t1 (0.4)\t\nArrhythmia\t1 (0.4)\t\n Fever\t2 (0.9)\t\n Anacatesthesia\t1 (0.4)\t\n Osteonecrosis of the leg\t1 (0.4)\t\n Numbness in limbs\t1 (0.4)\t\n Rash\t1 (0.4)\t\n Blood pressure elevation\t2 (0.9)\t\n Facial flare\t1 (0.4)\t\n Fatigue\t3 (1.3)\t\n Dysphoria\t2 (0.9)\t\n Headache\t1 (0.4)\t\n Bloody discharge\t1 (0.4)\t\n Hypocalcemiab\t1 (0.4)\t\nNew fractures during romosozumab therapy\t7 (3.0)\t\n Thoracic or/and lumbar spine\t3 (1.3)\t\n Left proximal tibial fracture\t1 (0.4)\t\n Left distal radius fracture\t1 (0.4)\t\n Left distal fibular fracture\t1 (0.4)\t\n Right proximal humeral fracture\t1 (0.4)\t\na The most frequent adverse event was injection site reaction associated with pain, swelling, and redness lasting 2 days or longer.\n\nb Hypocalcemia was judged as Grade 2 or higher on the CTCAE v5.0 grading scale.\n\n4 Discussion\n\nThe present study provides important real-world findings on the recently approved drug, romosozumab, in Japanese patients with osteoporosis. Significant gains were observed for lumbar, total hip, and femoral neck BMD following a 12-month treatment regimen along with significant changes in bone turnover markers. The drug was generally well tolerated. Patients switching from other osteoporotic drugs, especially denosumab, displayed lower gains in lumbar and total hip BMD, while co-administration of a vitamin D3 analogue might prevent hypocalcemia.\n\nClinical trials, such as the FRAME study (Cosman et al., 2016) and Ishibashi's study (Ishibashi et al., 2017) have shown the efficacy of romosozumab. However, there are key distinctions to be made between clinical trial data and real-world data. The first is the rigorous selection and exclusion criteria specific to clinical trials. In the FRAME study and Ishibashi's study, patients with a T-score of −3.5 or lower, prior osteoporosis drug use, secondary osteoporosis, 25OHD of 20 ng/mL or less, and age over 90 years were excluded. However, in actual clinical situations, many such patients consult their physician for medication. Therefore, observational research plays an important role to bridge the gap between clinical trials and the real world. For example, unlike data obtained overseas, approximately 90% of the Japanese suffer from a vitamin D deficiency or insufficiency as a complication of osteoporosis (Holick et al., 2012; Tamaki et al., 2017). In real-world practice, our approach in osteoporosis treatment is prompt therapeutic intervention without waiting for vitamin D improvement to a sufficient level. It was reported that the presence or absence of vitamin D supplementation during the use of bisphosphonates did not significantly affect a BMD increase (Nakamura et al., 2017). Furthermore, Ebina et al. found romosozumab to significantly increase BMD even in a state of vitamin D deficiency/insufficiency (Ebina et al., 2020). Therefore, the treatment of osteoporosis with vitamin D deficiency is an opportunity to produce valuable data, and accumulating evidence on the administration and follow-up of romosozumab treatment is clinically important, especially in Japan. In addition, no previous studies have shown the effectiveness of romosozumab for secondary osteoporosis. We observed that romosozumab was effective in both secondary and in primary osteoporosis. In other clinical trials under strict conditions, romosozumab was used after a washout period in the absence of treatment so as to investigate the uninfluenced benefits of romosozumab itself. However, in actual osteoporosis treatment, there are also many switch cases in which the effects of previous osteoporosis treatment are insufficient or the drug has been discontinued due to unexpected side effects; such situations may require the use of romosozumab despite residual effects from the prior treatment. Therefore, it is very meaningful to examine the clinical effect of romosozumab without setting a washout period, in line with actual clinical practice. In this study, romosozumab produced significant increases in BMD as compared with baseline at both 6 and 12 months, regardless of the pretreatment drug. However, in switch cases from such bone resorption inhibitors as bisphosphonates and denosumab, the rate of increase in BMD was significantly lower than in the treatment-naïve group. Bisphosphonates are believed to suppress bone formation by lining cells (Gasser et al., 2000), which may persist after switching to romosozumab. In fact, the baseline value of P1NP in the bisphosphonate group was lower than that in the treatment-naïve and teriparatide groups. Therefore, it was considered that the increase in BMD was hampered due to delayed action of bone formation mechanisms. In the denosumab group, the rate of BMD increase might have been smaller compared with the treatment-naïve group due to a rebound increase in remodeling following discontinuation. We presumed that the increase rate of BMD was relatively smaller than that in the naïve group because TRACP-5b, a major bone resorption marker, increased due to denosumab discontinuation, thereby leading to the activation of osteoclasts and progression of bone resorption, which sustained the effect of denosumab. This may be the reason why the bone resorption marker was increased only in the denosumab group. As was also witnessed in the STRUCTURE study, romosozumab treatment after a switch from bisphosphonates produced a significant elevation in BMD at the lumbar spine and total hip in our study (Langdahl et al., 2017). Furthermore, extension of the phase II romosozumab study has revealed successful treatment with romosozumab after denosumab (Kendler et al., 2019). According to the study by Kendler et al., treatment with denosumab followed by romosozumab produced no significant increase in BMD at the total hip, which was different from our study. It could be that the study included subjects with relatively mild symptoms (average baseline T-scores at the total hip and femoral neck were −1.48 and −1.83, respectively), younger subjects (average age was 65 years), and patients who had received romosozumab for over 2 years prior to denosumab. On the other hand, our study contained subjects with lower baseline BMD (average baseline T-scores at the total hip and femoral neck were −2.51 and −3.01, respectively). It was therefore possible that the significant improvement of BMD in our study was attributable to the lower T-scores being more susceptible to the effects of romosozumab. Moreover, the administration of romosozumab is strictly limited to 12 months or less for therapeutic use in Japan, and so the patients naïve to romosozumab were thought to be more responsive to the drug. The above factors may explain the differing outcomes in our study to other results. Overall, however, this investigation demonstrates that romosozumab remains effective regardless of the presence or type of prior osteoporosis regimen and without a specified washout time.\n\nIn the FRAME study, the change rate of serum-corrected calcium levels peaked at 2 weeks after drug administration, and the decrease rate was approximately −3.0% (Cosman et al., 2016). This rate in our study was largest at −3.7% at 12 months. We also investigated the rate of change in serum-corrected calcium after administration of romosozumab according to renal function, with no remarkable findings noted. However, the change rate was lower in subjects with co-administration of a vitamin D3 analogue than in those without. Therefore, supplementation may prevent hypocalcemia by combined use with romosozumab.\n\nRegarding serious adverse events, we witnessed a cardiovascular event of cerebellar infarction. The patient could be discharged from a rehabilitation facility with no major sequelae, and a causal relationship with romosozumab is still unknown. Romosozumab produced no remarkable differences in the incidence of cardiovascular events compared with a placebo group in the FRAME study; however, in the ARCH study, the incidence of cardiovascular events was significantly higher than that in an alendronate administration group (Cosman et al., 2016; Saag et al., 2017). Therefore, clinicians should be vigilant during the administration of romosozumab to patients at high risk of cardiovascular events.\n\nAs limitations of this study, the following factors require further consideration: 1) not all patients were in a state of sufficient vitamin D or calcium, 2) for patients with a history of previous osteoporosis medication, no washout period of the previous drug was set; there was a possibility that the previous drug affected the results, 3) as the observation period of this study was short at 1 year, longer follow-up for adverse events and new fractures is needed, and 4) to investigate the relationship between a risk of cardiovascular events and romosozumab, studies involving more subjects are required. Lastly, since this study mainly focused on changes in BMD, it lacked the statistical power to evaluate the antifracture efficacy of romosozumab in all of the subgroups. In clinical practice, BMD improvement is a valuable indicator of osteoporosis treatment.\n\n5 Conclusions\n\nIn conclusion, romosozumab is now attracting considerable attention as a new therapeutic drug for osteoporosis with its dual effect of promoting bone formation and suppressing bone resorption. In this study, romosozumab showed good therapeutic effects on BMD and was generally well tolerated in a real-world setting, regardless of osteoporosis type or treatment history. More clinical data are needed to evaluate its efficacy with existing therapeutic agents, optimal treatment conditions, and the sequential therapies following its use.\n\nTransparency document\n\nTransparency document.\n\nImage 1\n\nCRediT Authorship contribution Statement\n\nTK: Data Curation, Methodology, Writing - Original Draft, Visualization.\n\nTS: Investigation, Methodology.\n\nMN: Investigation, Data Curation, Methodology.\n\nMS: Data Curation, Formal Analysis.\n\nAM: Investigation.\n\nJT: Investigation, Supervision.\n\nYN: Conceptualization, Investigation, Writing – Review & Editing, Project Administration, Supervision.\n\nFunding\n\nThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\n\nDeclaration of competing interest\n\nThe authors declare no competing interests.\n\nAppendix A Supplementary data\n\nSupplementary material\n\nImage 2\n\nAcknowledgements\n\nWe would like to thank Dr. Masataka Shiraki for engaging in discussions and Mr. Trevor Ralph for English language editing.\n\nThe Transparency document associated with this article can be found, in online version.\n\nAppendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.bonr.2021.101068.\n==== Refs\nReferences\n\nAssessment of Fracture Risk and Its Application to screening for Postmenopausal Osteoporosis Report of A WHO Study Group vol. 843 1994 World Health Organization Technical Report Series. Research Support, Non-U.S. Gov’t Review Technical Report 1 129 (Epub 1994/01/01)\nCoresh J. Astor B.C. Greene T. Eknoyan G. Levey A.S. Prevalence of chronic kidney disease and decreased kidney function in the adult US population: Third National Health and Nutrition Examination Survey. American Journal of Kidney Diseases: the official Journal of the National Kidney Foundation Comparative Study Research Support, Non-U.S. Gov’t Research Support, U.S. Gov’t, P.H.S. 41 1 2003 1 12 Jan. (Epub 2002/12/25)\nCosman F. Crittenden D.B. Adachi J.D. Binkley N. Czerwinski E. Ferrari S. Romosozumab Treatment in Postmenopausal Women with Osteoporosis. The New England journal of medicine Multicenter Study Randomized Controlled Trial Research Support, Non-U.S. Gov’t 375 16 2016 1532 1543 Oct 20. (Epub 2016/11/01)\nCummings SR, San Martin J, McClung MR, Siris ES, Eastell R, Reid IR, et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. The New England journal of medicine. Multicenter Study Randomized Controlled Trial Research Support, Non-U.S. Gov't Aug 20 2009;361(8):756–65. (Epub 2009/08/13).\nCummings S.R. Ferrari S. Eastell R. Gilchrist N. Jensen J.B. McClung M. Vertebral fractures after discontinuation of denosumab: a post hoc analysis of the randomized placebo-controlled FREEDOM trial and its extension Journal of Bone and Mineral Research: The Official Journal of the American Society for Bone and Mineral Research. Randomized Controlled Trial Research Support, Non-U.S. Gov’t 33 2 2018 190 198 Feb. (Epub 2017/11/07)\nDiez-Perez A. Marin F. Eriksen E.F. Kendler D.L. Krege J.H. Delgado-Rodriguez M. Effects of teriparatide on hip and upper limb fractures in patients with osteoporosis: a systematic review and meta-analysis Bone. Meta-Analysis Research Support, Non-U.S. Gov’t Systematic Review 120 2019 1 8 (Epub 2018/10/01)\nEbina K. Hirao M. Tsuboi H. Nagayama Y. Kashii M. Kaneshiro S. Effects of prior osteoporosis treatment on early treatment response of romosozumab in patients with postmenopausal osteoporosis Bone. Nov 140 2020 115574 (Epub 2020/08/11)\nGasser J.A. Kneissel M. Thomsen J.S. Mosekilde L. PTH and interactions with bisphosphonates J. Musculoskelet. Neuronal Interact. 1 1 Sep 2000 53 56 (Epub 2005/03/11) 15758526\nHolick M.F. Binkley N.C. Bischoff-Ferrari H.A. Gordon C.M. Hanley D.A. Heaney R.P. Guidelines for preventing and treating vitamin D deficiency and insufficiency revisited The Journal of Clinical Endocrinology and Metabolism. Research Support, Non-U.S. Gov’t 97 4 2012 1153 1158 (Epub 2012/03/24)\nIshibashi H. Crittenden D.B. Miyauchi A. Libanati C. Maddox J. Fan M. Romosozumab increases bone mineral density in postmenopausal Japanese women with osteoporosis: a phase 2 study Bone. Clinical Trial, Phase II Randomized Controlled Trial 103 2017 209 215 Oct. (Epub 2017/07/09)\nKendler D.L. Bone H.G. Massari F. Gielen E. Palacios S. Maddox J. Bone mineral density gains with a second 12-month course of romosozumab therapy following placebo or denosumab Osteoporos Int. Clinical Trial, Phase II Multicenter Study Randomized Controlled Trial 30 12 2019 2437 2448 Dec. (Epub 2019/10/20)\nLangdahl B.L. Libanati C. Crittenden D.B. Bolognese M.A. Brown J.P. Daizadeh N.S. Romosozumab (sclerostin monoclonal antibody) versus teriparatide in postmenopausal women with osteoporosis transitioning from oral bisphosphonate therapy: a randomised, open-label, phase 3 trial Lancet. 390 10102 2017 Sep 30. 1585-94. (Epub 2017/08/02)\nLeder B.Z. Tsai J.N. Uihlein A.V. Wallace P.M. Lee H. Neer R.M. Denosumab and teriparatide transitions in postmenopausal osteoporosis (the DATA-Switch study): extension of a randomised controlled trial Lancet. Randomized Controlled Trial Research Support, N.I.H., Extramural Research Support vol. 386 2015 Non-U.S. Gov’t Sep 19. 9999. 1147-55. (Epub 2015/07/07)\nMarcus R. Wang O. Satterwhite J. Mitlak B. The skeletal response to teriparatide is largely independent of age, initial bone mineral density, and prevalent vertebral fractures in postmenopausal women with osteoporosis J Bone Miner Res. Clinical Trial Randomized Controlled Trial Research Support, Non-U.S. Gov’t vol. 18 1 2003 18 23 (Epub 2003/01/04)\nMcClung M.R. San Martin J. Miller P.D. Civitelli R. Bandeira F. Omizo M. Opposite bone remodeling effects of teriparatide and alendronate in increasing bone mass. Archives of internal medicine Clinical Trial Comparative Study Randomized Controlled Trial Research Support 165 2005 Non-U.S. Gov’t Aug 8–22. 15. 1762-8. (Epub 2005/08/10)\nNakamura Y. Uchiyama S. Kamimura M. Ikegami S. Komatsu M. Kato H. Increased serum 25(OH)D3 levels in post-menopausal Japanese women with osteoporosis after 3-year bisphosphonate treatment Tohoku J. Exp. Med. 242 3 Jul 2017 241 246 (Epub 2017/07/26) 28740036\nNenonen A. Cheng S. Ivaska K.K. Alatalo S.L. Lehtimaki T. Schmidt-Gayk H. Serum TRACP 5b is a useful marker for monitoring alendronate treatment: comparison with other markers of bone turnover Journal of Bone and Mineral Research: The Official Journal of the American Society for Bone and Mineral Research. Randomized Controlled Trial Research Support, Non-U.S. Gov’t 20 10 2005 1804 1812 (Epub 2005/12/17)\nOminsky M.S. Brown D.L. Van G. Cordover D. Pacheco E. Frazier E. Differential temporal effects of sclerostin antibody and parathyroid hormone on cancellous and cortical bone and quantitative differences in effects on the osteoblast lineage in young intact rats Bone. Research Support, Non-U.S. Gov’t 81 2015 380 391 (Epub 2015/08/12)\nOrimo H. Nakamura T. Hosoi T. Iki M. Uenishi K. Endo N. Japanese 2011 guidelines for prevention and treatment of osteoporosis--executive summary Arch. Osteoporos. 7 2012 3 20 (Epub 2012/12/04) 23203733\nPayne RB, Little AJ, Williams RB, Milner JR. Interpretation of serum calcium in patients with abnormal serum proteins. Br. Med. J. Dec 15 1973;4(5893):643–6. (Epub 1973/12/15).\nSaag K.G. Petersen J. Brandi M.L. Karaplis A.C. Lorentzon M. Thomas T. Romosozumab or Alendronate for Fracture Prevention in Women with Osteoporosis. The New England journal of medicine Clinical Trial, Phase III Comparative Study Multicenter Study Randomized Controlled Trial Research Support, Non-U.S. Gov’t 377 15 2017 1417 1427 Oct 12. (Epub 2017/09/12)\nShepherd J.A. Fan B. Lu Y. Lewiecki E.M. Miller P. Genant H.K. Comparison of BMD precision for prodigy and Delphi spine and femur scans. Osteoporosis international: a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA Comparative Study Multicenter Study Research Support, Non-U.S. Gov’t 17 9 2006 1303 1308 (Epub 2006/07/11)\nSoen S. Fukunaga M. Sugimoto T. Sone T. Fujiwara S. Endo N. Diagnostic criteria for primary osteoporosis: year 2012 revision J. Bone Miner. Metab. 31 3 May 2013 247 257 (Epub 2013/04/05) 23553500\nTamaki J. Iki M. Sato Y. Kajita E. Nishino H. Akiba T. Total 25-hydroxyvitamin D levels predict fracture risk: results from the 15-year follow-up of the Japanese Population-based Osteoporosis (JPOS) Cohort Study Osteoporos. Int. 28 6 Jun 2017 1903 1913 (Epub 2017/03/01) 28243705\nTaylor S. Ominsky M.S. Hu R. Pacheco E. He Y.D. Brown D.L. Time-dependent cellular and transcriptional changes in the osteoblast lineage associated with sclerostin antibody treatment in ovariectomized rats Bone. Research Support, Non-U.S. Gov’t 84 2016 148 159 (Epub 2016/01/02)\n\n",
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"issn_linking": "2352-1872",
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"journal": "Bone reports",
"keywords": "Adverse event; Bone mineral density; Bone turnover marker; Osteoporosis; Romosozumab",
"medline_ta": "Bone Rep",
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"pubdate": "2021-06",
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"title": "Real-world effects and adverse events of romosozumab in Japanese osteoporotic patients: A prospective cohort study.",
"title_normalized": "real world effects and adverse events of romosozumab in japanese osteoporotic patients a prospective cohort study"
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"abstract": "To determine intraocular pressure (IOP) changes after intravitreal bevacizumab or ranibizumab injection administered for various retinal disorders.\nA retrospective chart review of 796 eyes of 574 patients receiving intravitreal ranibizumab (0.5 mg) and/or bevacizumab (1.25 mg) injection for different retinal diseases from March 2009 to December 2016 was performed. Ocular hypertension (OHT) was defined as IOP >21 mmHg or an increase in IOP of >5 mmHg from the baseline. IOP at the baseline and at various time periods after the injection was evaluated in the injected eyes and fellow control eyes.\nOne hundred and thirty-one eyes received either a single dose of bevacizumab or ranibizumab intravitreal injection unilaterally, 222 patients received single injection in both the eyes (n = 444 eyes), and 221 eyes received multiple doses of the injection. OHT was noted in 11 eyes (1.38%), of which 3 eyes (0.38%) had transient OHT and 8 eyes (1%) had delayed and sustained OHT and among them, 3 eyes (0.4%) progressed to glaucoma. Preinjection IOP was significantly higher in the treated eyes when compared to the control untreated eyes (P = 0.006).\nIncidence of delayed and sustained OHT is low after a single or multiple intravitreal bevacizumab and ranibizumab injections. Clinicians should be aware of possibility of OHT or glaucoma after the procedure.",
"affiliations": "Department of Glaucoma, Anand Eye Institute, Hyderabad, Telangana, India.;Department of Retina, Anand Eye Institute, Hyderabad, Telangana, India.;Department of Retina, Anand Eye Institute, Hyderabad, Telangana, India.;Department of Statistics, Apollo Institute of Medical Sciences and Research, Hyderabad, Telangana, India.",
"authors": "Mansoori|Tarannum|T|;Agraharam|Satish Gooty|SG|;Manwani|Sunny|S|;Balakrishna|Nagalla|N|",
"chemical_list": null,
"country": "India",
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"doi": "10.4103/JOCO.JOCO_5_20",
"fulltext": "\n==== Front\nJ Curr Ophthalmol\nJ Curr Ophthalmol\nJCO\nJournal of Current Ophthalmology\n2452-2325\nWolters Kluwer - Medknow India\n\nJCO-33-6\n10.4103/JOCO.JOCO_5_20\nOriginal Article\nIntraocular Pressure Changes after Intravitreal Bevacizumab or Ranibizumab Injection: A Retrospective Study\nMansoori Tarannum 1\nAgraharam Satish Gooty 2\nManwani Sunny 2\nBalakrishna Nagalla 3\n1 Department of Glaucoma, Anand Eye Institute, Hyderabad, Telangana, India\n2 Department of Retina, Anand Eye Institute, Hyderabad, Telangana, India\n3 Department of Statistics, Apollo Institute of Medical Sciences and Research, Hyderabad, Telangana, India\nAddress for correspondence: Tarannum Mansoori, Department of Glaucoma, Sita Lakhsmi Eye Center, Anand Eye Institute, 7-147/1, Nagendra Nagar Colony, Habsiguda, Hyderabad - 500 007, Telangana, India. E-mail: tarannummansoori@yahoo.com\nJan-Mar 2021\n26 3 2021\n33 1 611\n09 1 2020\n28 5 2020\n11 7 2020\nCopyright: © 2021 Journal of Current Ophthalmology\n2021\nhttps://creativecommons.org/licenses/by-nc-sa/4.0/ This 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.\nPurpose:\n\nTo determine intraocular pressure (IOP) changes after intravitreal bevacizumab or ranibizumab injection administered for various retinal disorders.\n\nMethods:\n\nA retrospective chart review of 796 eyes of 574 patients receiving intravitreal ranibizumab (0.5 mg) and/or bevacizumab (1.25 mg) injection for different retinal diseases from March 2009 to December 2016 was performed. Ocular hypertension (OHT) was defined as IOP >21 mmHg or an increase in IOP of >5 mmHg from the baseline. IOP at the baseline and at various time periods after the injection was evaluated in the injected eyes and fellow control eyes.\n\nResults:\n\nOne hundred and thirty-one eyes received either a single dose of bevacizumab or ranibizumab intravitreal injection unilaterally, 222 patients received single injection in both the eyes (n = 444 eyes), and 221 eyes received multiple doses of the injection. OHT was noted in 11 eyes (1.38%), of which 3 eyes (0.38%) had transient OHT and 8 eyes (1%) had delayed and sustained OHT and among them, 3 eyes (0.4%) progressed to glaucoma. Preinjection IOP was significantly higher in the treated eyes when compared to the control untreated eyes (P = 0.006).\n\nConclusions:\n\nIncidence of delayed and sustained OHT is low after a single or multiple intravitreal bevacizumab and ranibizumab injections. Clinicians should be aware of possibility of OHT or glaucoma after the procedure.\n\nBevacizumab\nIntraocular pressure\nIntravitreal injection\nMultiple injections\nOcular hypertension\nRanibizumab\n==== Body\nINTRODUCTION\n\nIntravitreal injection of anti-vascular endothelial growth factor (VEGF) agents is the mainstay for the treatment of choroidal neovascularization, secondary to the neovascular age-related macular degeneration (ARMD) or pathological myopia, macular edema secondary to the retinal vein occlusion (RVO) and diabetic retinopathy (DR).1234 Commonly used intravitreal VEGF-antagonists are ranibizumab (Lucentis; Genentech/Novartis, Inc., San Francisco, CA, USA) and bevacizumab (Avastin; Genentech/Hoffmann-La Roche Inc., CA, USA).\n\nSerious adverse events after anti-VEGF injections are uncommon and include inflammation, endophthalmitis, cataract progression, vitreous or subretinal hemorrhage, retinal detachment, ocular hypertension (OHT), and glaucoma.56 Intraocular pressure (IOP) elevation after an anti-VEGF injection can be acute and transient because of an increase in the ocular volume or a sustained rise in IOP, which may be related to the pharmacologic drug properties.7891011121314151617 Mechanism for the delayed OHT after an intravitreal anti-VEGF is not well understood. It is hypothesized that it could be due to the direct trabecular meshwork damage, secondary to the mechanical effect of anti-VEGF agent, or particles obstructing aqueous outflow,1819 drug toxicity,20 drug-induced trabeculitis or uveitis, and preexisting glaucoma.12 Number of injections15 and interval between the injections10 can also be attributed to increase in the IOP due to accumulation of immune complexes or small anti-VEGF particles. Another theory of sustained the IOP, increase is that the anti-VEGF agent may develop silicone oil micro droplets from the syringe barrel, rubber stopper, and/or protein aggregates in the repackaged bevacizumab during storage and transportation in the plastic syringes, which can obstruct the aqueous outflow.181920 Most of the previous studies looked at an IOP rise or OHT/glaucoma after the intravitreal injection in the eyes with ARMD.910111213141516 The purpose of this study was to evaluate the IOP changes in the injected eye as well as the untreated, contralateral eye after a single or multiple, repeated intravitreal bevacizumab and/or ranibizumab injections for the various retinal disorders.\n\nMETHODS\n\nA retrospective review of medical records of 609 consecutive patients receiving intravitreal ranibizumab or bevacizumab at our institute was performed after obtaining approval of the Anand Eye Institute Review Board. Patients were included if they had received at least one intravitreal ranibizumab or bevacizumab injection and had a minimum follow-up of 1 month after the injection. Exclusion criteria were: Age <18 years, iris or angle neovascularization, preexisting glaucoma or OHT, patients on anti-glaucoma medications (AGMs), active uveitis, history of intraocular steroid injection, and vitreoretinal surgery.\n\nData were collected on the diagnosis, indication, number and interval between the injections, follow-up duration, ocular surgeries prior to or postinjection, and IOP measurement with Goldmann applanation tonometry at each visit.\n\nFor patients receiving injection on the their first visit, IOP from that visit was used as the baseline. Those receiving multiple injections, baseline IOP was calculated as the most recent IOP recorded before the last received anti-VEGF injection. IOP at the baseline, 1 day, 1 week, 1 month, 3 months, 6 months, and yearly till the last follow-up visit after the injection were analyzed in the injected eye and non-injected fellow eyes. After written informed consent, under topical anesthesia, 1.25 mg of bevacizumab (Avastin; Genentech/Hoffmann-La Roche Inc., CA, USA) or 0.5 mg of ranibizumab (Lucentis; Genentech/Novartis, Inc., San Francisco, CA, USA) was injected with a 30G needle through the inferotemporal pars plana region at 3.5 mm from the limbus in pseudophakic and 4 mm from the limbus, in phakic patient. Paracentesis was not performed for any of the patients.\n\nOHT was defined as >21 mmHg1012 or an increase of >5 mmHg from the baseline.1517 Glaucoma was defined as IOP >21 mmHg and glaucomatous optic atrophy. As preexisting glaucoma or OHT was one of the exclusion criteria of the study, none of the study or fellow eyes were on AGM or had undergone prior glaucoma filtering surgery.\n\nDescriptive analysis was calculated as the mean and standard deviation. The test of homogeneity of variances was tested with Levene's statistics. IOP difference between the injected and control eyes was measured using t-test. IOP difference between the baseline preinjection IOP and at various time interval during the follow-up was calculated using repeated measures analysis of variance/paired t-test with post hoc of least significant difference. The prevalence or frequency of IOP difference between the eyes receiving bevacizumab and ranibizumab was analyzed using Chi-square/Fisher's exact test. General estimating equations were used to account for correlation between the eyes of individual patients. The statistical analysis was performed using commercial SPSS software (version 19, IBM, Chicago, IL, USA). A P < 0.05 was considered statistically significant.\n\nRESULTS\n\nA total of 796 eyes of 574 patients met the inclusion criteria, and 35 patients were excluded. Seven hundred and ninety-six eyes had received a total of 1588 intravitreal bevacizumab (n = 1333) or ranibizumab (n = 255). Forty eyes had a history of receiving intravitreal anti-VEGF, prior to coming to our institute. Demographics and baseline characteristics of the patients are presented in Table 1.\n\nTable 1 Baseline and clinical characteristic of the study population receiving intravitreal bevacizumab and ranibizumab injections\n\nAnti-VEGF injection\tBevacizumab (n=1333)\tRanibizumab (n=255)\tP\tOverall injections\t\nMean age±SD at first injection (years)\t57.6±11.5\t56.6±10.5\t0.41\t58.08±11.5\t\nGender (male:female)\t874:459\t155:100\t0.14\t1029:559\t\nLaterality of eye (right/left)\t654/678\t138/117\t0.15\t792/795\t\nCo-morbidities\t\t\t\t\t\n DM\t926\t168\t0.14\t1094\t\n HTN\t799\t139\t0.11\t938\t\n CAD\t122\t32\t0.09\t154\t\nNumber of injections in eyes\t1333\t255\t1.0\t1588\t\nIndications for injection\t\t\t\t\t\n Diabetic macular edema\t495\t69\t0.002\t564\t\n CRVO\t60\t6\t0.12\t66\t\n Branch retinal vein occlusion\t142\t11\t0.002\t153\t\n Neovascular age-related macular degeneration\t196\t50\t0.05\t246\t\n Idiopathic polypoidal choroidal vasculopathy\t10\t22\t<0.0001\t32\t\n Central serous chorio retinopathy\t1\t7\t<0.0001\t8\t\n PDR–VH\t340\t79\t0.07\t419\t\n Myopic choroidal neovascularization\t33\t3\t0.2\t36\t\n Eales disease\t11\t2\t0.95\t13\t\n Best disease\t2\t4\t0.001\t6\t\n Idiopathic CNVM\t7\t0\t0.61\t7\t\n Parafoveal telangiectasia\t36\t2\t0.07\t38\t\nLens status\t\t\t\t\t\n Phakic/cataract\t1016\t203\t0.24\t1219\t\n PS\t307\t52\t0.33\t359\t\n Aphakia\t3\t7\t\t10\t\nNumber of multiple injections in eyes\t\t\t\t\t\n 2-3\t46\t25\t<0.0001\t71\t\n 4-5\t23\t9\t0.06\t32\t\n 6-7\t12\t1\t0.41\t13\t\n 8-9\t5\t0\t0.33\t5\t\n 10-11\t1\t0\t1.00\t1\t\nMean baseline intraocular pressure±SD (mmHg)\t13.54±2.48\t13.56±2.59\t0.71\t13.6±2.51\t\nVEGF: Vascular endothelial growth factor, CNVM: Choroidal neovascular membrane, SD: Standard deviation, DM: Diabetes mellitus, CAD: Coronary artery disease, HTN: Hypertension, CRVO: Central retinal vein occlusion, PDR-VH: Proliferative diabetic retinopathy vitreous hemorrhage, PS: Pseudophakia\n\nMean age at treatment was 58.1 ± 11.5 years (range, 21–95), and 35.3% were female. The mean follow-up duration was 13 ± 17.2 months (range, 1–96 months). Macular edema secondary to DR was the most frequent indication for the injection (62.2%) [Table 1]. There was no significant difference between the eyes receiving bevacizumab or ranibizumab with regards to the age, gender ratio, lens status, and baseline IOP [Table 1].\n\nOne hundred and thirty-one eyes received single injection, 221 eyes multiple injections (n = 1013), and 222 patients received an injection in both the eyes (n = 444 eyes). In the eyes receiving multiple injections, 25 eyes were treated with ranibizumab, 181 received bevacizumab, and 15 received both. The mean number of total injections/patient was 3.1 ± 1.5 (range, 2–11). Time interval between the multiple injections was 8.3 ± 13.1 months (range, 1–96).\n\nIn the non-injected, fellow eyes (n = 352) of patients receiving anti-VEGF, 28 eyes had scarred choroidal neovascular membrane (CNVM), 78 eyes had proliferative DR, 28 eyes had dry ARMD, 6 eyes had best disease, 7 eyes had Eales disease, 26 eyes had old branch RVO, 41 eyes had non-proliferative diabetic retinopathy (non-PDR), 5 eyes had absolute glaucoma, and 133 eyes did not have any ocular pathology.\n\nTo know the influence of anti-VEGF on IOP change, baseline IOP measured before each injection was compared to the IOP at subsequent visits. Mean baseline IOP was 13.6 ± 2.5 mmHg and 13.2 ± 2.4 mmHg in the injected and non-injected eyes, respectively (P = 0.06). IOP difference between the treated and non-treated fellow eyes was significant at day 1 (P = 0.004) and 1 year (P = 0.004). Mean paired difference increase in the IOP from baseline to after the injection was statistically significant at 1 day, 1 month, and 3 months of follow-up [Table 2].\n\nTable 2 Mean paired intraocular pressure difference when compared to the baseline at each visit in the eyes receiving intravitreal ranibizumab or bevacizumab injections and non-injected fellow eyes\n\nTime interval from baseline IOP measurement to the follow-up period after the injection (number of eyes at follow-up period)\tTreated eyes\tFellow control eyes\t\n\t\t\nMean paired IOP difference\tSD\tP\tMean paired IOP difference\tSD\tP\t\n1 day (n=796)\t0.2917\t2.3551\t<0.0001\t0.1811\t2.0828\t0.086\t\n1 week (n=796)\t0.2196\t2.8504\t0.186\t0.3333\t2.5590\t0.305\t\n1 month (n=796)\t0.2787\t2.5491\t<0.0001\t0.1494\t2.3450\t0.235\t\n3 months (n=783)\t0.3814\t2.4777\t<0.0001\t0.1784\t2.2148\t0.212\t\n6 months (n=625)\t0.1283\t2.5935\t0.211\t0.1105\t2.1776\t0.507\t\n1 year (n=513)\t0.0093\t2.4748\t0.931\t0.1064\t2.1034\t0.549\t\n2 year (n=226)\t0.0760\t2.1088\t0.638\t0.3793\t2.7310\t0.461\t\n3 years (n=157)\t0.0115\t1.8646\t0.954\t0.8235\t3.3955\t0.332\t\n4 years (n=52)\t−0.0923\t1.7829\t0.678\t1.2000\t4.1312\t0.382\t\n5 years (n=52)\t−0.3529\t1.5152\t0.184\t0.0000\t2.8284\t1.000\t\n6 years (n=25)\t−0.1538\t1.7246\t0.753\t−3.0000\t1.4142\t0.205\t\n7 years (n=8)\t0.3333\t0.8165\t0.363\t\t\t\nIOP: Intraocular pressure, SD: Standard deviation\n\nComparison of baseline IOP to the IOP measurements at subsequent visits during follow-up did not show any significant difference in the fellow control eyes. There was no difference of IOP between bevacizumab and ranibizumab injected eyes at the baseline or during the subsequent follow-up visits, postinjection (all P > 0.05). In the treated eyes, 11 eyes (1.38%) had OHT after anti-VEGF [Table 3], 2 eyes of which had OHT in both eyes following bilateral injection. In 3 eyes (0.4%), IOP elevation was transient and returned to the baseline levels without AGM after a week. Eight eyes (1%) had sustained IOP elevation, and IOP was controlled with AGM. Three out of 11 eyes experienced IOP elevation of >5 mmHg from baseline during the follow-up, and 8/11 experienced IOP of >21 mmHg postinjection. The mean age of patients in this subgroup was 58.4 ± 9.4 years, 54.5% were male, and macular edema secondary to DR (45.4%) was the most common indication for injection.\n\nTable 3 Clinical summary of 11 eyes of 9 patients with ocular hypertension or glaucoma following anti-vascular endothelial growth factor intravitreal injection\n\nCase\tEye laterality\tGender/age (years)\tIndication for injection\tAnti-VEGF intravitreal injection\tTotal number of injections prior to IOP rise\tBaseline IOP (mmHg)\tTime of rise in IOP\tPostinjection maximum IOP rise (mmHg)\tNumber of AGM\tSystemic comorbidity\tLens status\t\nSustained IOP rise\t\t\t\t\t\t\t\t\t\t\t\t\n 1\tRE\tMale/62\tPDR CSME\tBevacizumab\t2\t12\t6 months\t24\t2\tDM/HTN/CAD\tNS\t\n 2\tLE\tMale/62\tPDR CSME\tBevacizumab\t2\t12\t6 months\t27\t2\tDM/HTN/CAD\tNS\t\n 3\tRE\tMale/49\tCRVO CME\tBevacizumab\t2\t16\t2 years\t28\t1\t-\tClear\t\n 4\tLE\tFemale/63\tARMD CNVM\tBevacizumab\t2\t14\t3 months\t26\t1\tDM/HTN/CAD\tNS\t\n 5\tLE\tFemale/39\tMyopic CNVM\tBevacizumab\t1\t12\t4 years\t24\t1\t-\tClear\t\n 6\tRE\tMale/53\tPDR VH\tBevacizumab\t2\t16\t1.5 years\t34\t2\tDM\tClear\t\n 7\tRE\tMale/71\tPDR CSME\tRanibizumab\t2\t18\t1 day\t23*\t2\tDM\tPS\t\n 8\tLE\tFemale/65\tPDR CSME\tBevacizumab\t1\t14\t3 months\t26\t2\tDM/HTN/CAD\tClear\t\nTransient IOP rise\t\t\t\t\t\t\t\t\t\t\t\t\n 9\tRE\tFemale/68\tMyopic CNVM\tRanibizumab\t2\t18\t1 day\t24*\tNone\t-\tClear\t\n 10\tLE\tMale/64\tPDR VH\tBevacizumab\t3\t12\t1 day\t22*\tNone\tDM/HTN\tNS\t\n 11\tRE\tFemale/57\tPDR CSME\tBevacizumab\t1\t14\t1 day\t22*\tNone\tDM\tNS\t\n*>5 mmHg from baseline. VEGF: Vascular endothelial growth factor, IOP: Intraocular pressure, AGM: Anti-glaucoma medication, RE/LE: Right eye, left eye, PDR CSME: Proliferative diabetic retinopathy, clinical significant macular edema, CRVO CME: Central retinal vein occlusion, cystoid macular edema, ARMD CNVM: Age-related macular degeneration, choroidal neovascular membrane, PDR VH: Proliferative diabetic retinopathy, vitreous hemorrhage, Myopic CNVM: Myopic choroidal neovascular membrane, DM: Diabetes mellitus, HTN: Hypertension, CAD: Coronary artery disease, NS: Nuclear sclerosis, PS: Pseudophakia\n\nMean time to develop OHT after the last injection was 9.9 ± 14.9 months (range, 1 day to 4 years), after a mean 1.8 ± 0.6 number of injections, mean baseline IOP was 14.9 ± 3.6 mmHg, and the average peak IOP in sustained IOP elevation eyes was 24.9 ± 4.1 mmHg. Average time interval between the injections in patients receiving multiple injections was 14.6 ± 15.7 months (range, 1–96 months), and in those with OHT, it was 8.7 ± 13.1 months (range, 1–39). In 3/8 patients with sustained IOP rise, 5 had PDR, 1 had ARMD with CNVM, 1 had myopic CNVM, and 1 had central RVO with CNVM [Table 3]. Three eyes progressed to glaucoma and 1 eye (case 1) underwent combined cataract and trabeculectomy surgery, 2 years after the injection [Table 2].\n\nIOP elevation after multiple injections was seen in 8 eyes (3.6%). The prevalence of OHT between patients who received multiple injections and those with single injection was not significant (P = 0.7). The prevalence of OHT between bevacizumab (9 eyes) and ranibizumab subgroup (2 eyes) was not significant (P = 0.98).\n\nDISCUSSION\n\nIn our study, we found transient OHT in three eyes postinjection, which after a week returned to the baseline, without any treatment. Previous studies7814 have reported transient IOP spikes immediately after the intravitreal ranibizumab or bevacizumab due to an increase in the vitreous volume, altering aqueous outflow.\n\nA study12 reported that the patients receiving intravitreal bevacizumab are more prone to IOP elevation, whereas another study13 noted more cases of OHT in the patients receiving ranibizumab, and others9 did not find any difference between bevacizumab and ranibizumab attributing to the IOP elevation. As bevacizumab is a full-length antibody, the crystallizable fragment is involved in the binding of the immune molecules, such as complement factors, and has the potential to trigger an immune response, leading to the complement mediated cytotoxicity. However, Kernt et al.21 found no in vivo trabecular meshwork toxicity with the standard bevacizumab concentration. We did not find any difference in IOP changes between bevacizumab and ranibizumab at the baseline or during subsequent follow-up visits.\n\nThe prevalence of sustained IOP rise after ranibizumab and/or bevacizumab has been reported to vary from 1.6–11%.9101112131516 The definition of sustained IOP rise varies between the studies, but most of them have a criterion of IOP >21 mmHg on 2 consecutive visits or an increase of 5 mmHg or more from the baseline, preinjection measurements. Compared to these studies, the prevalence of sustained OHT in our study was low (1%), which could be because of the stringent criteria used to define OHT, exclusion of patients receiving intravitreal steroids, preexisting glaucoma, or OHT (to remove the bias in finding prevalence of OHT postinjection). Preexisting glaucoma or OHT has been implicated as a causative factor for the postinjection OHT as these eyes have a compromised outflow system and are more prone to develop OHT.1217 However, other studies failed to find such an association.1016 Another possibility is that the delayed OHT may be due to the cumulative effect of anti-VEGF agent seen after the multiple injections, and in our study, the maximum number of injections given was 11, for a patient. A direct comparison with previous studies cannot be made as they all have reported OHT in eyes receiving injections for only neovascular ARMD, whereas our study has included all the eyes receiving injections for various vitreoretinal disorders, and the most common indication for the intravitreal injection was macular edema secondary to the DR [Table 4].1012131516\n\nTable 4 Review of previous studies with sustained intraocular pressure rise after ranibizumab or bevacizumab intravitreal injection\n\nStudy\tControls\tOverall prevalence of OHT (%)\tInclusion of eyes with preexisting history of OHT or glaucoma\tMean number of injections at the time of IOP rise\tPostinjection IOP range\t\nGood et al.12\t-\t13/215 (6)\tYes\tMedian - 5\t23-36\t\nMathalone et al.10\t-\t22/201 (11)\tYes\t5\t22-36\t\nAdelman et al.13\t-\t4/116 (3.45)\tNo\t13.3\t28-36\t\nHoang et al.15\tFellow eyes\t32/449 (7.1)\tYes\t25.8\t\t\nWehrli et al.16\tFellow eyes\t5/302 (1.6)\tYes\t8\t25-29\t\nOur study\tFellow eyes\t8/796 (1)\tNo\t1.8\t23-34\t\nOHT: Ocular hypertension, IOP: Intraocular pressure\n\nMultiple number of injections has been implicated as a causative factor for OHT after anti-VEGF, as there is a possibility of small particles (immune complexes) accumulating, occluding trabecular meshwork, and reducing aqueous outflow.11 Hoang et al.15 reported that 11.6% of treated and 5.3% of control eyes experienced long-term OHT, and the total number of injections showed a statistically significant association with IOP elevation (P = 0.05) in eyes receiving ≥29 injections compared with eyes receiving ≤ 12 injections in 449 eyes receiving anti-VEGF bilaterally. Good et al.12 reported sustained IOP elevations in 13/215 eyes (6%) after a median of 9 injections of ranibizumab and/or bevacizumab in exudative ARMD. Higher OHT prevalence was found in the eyes receiving bevacizumab (9.9%) compared with those receiving ranibizumab (3.1%) (P = 0.049). This was significantly higher in patients with preexisting glaucoma than in those without glaucoma (33% vs. 3.1%; P < 0.001). No association between the development of delayed OHT and number of injections was found. In our study, untreated, contralateral control eyes did not show significant IOP elevation during the follow-up. Two hundred and twenty-one eyes (27.8%) received >2 injections (range, 2–11) with a mean follow-up of 13 months after the initial injection. Eight out of 221 (3.6%) eyes receiving multiple injections developed a long-term IOP increase when compared to 3/575 (0.52%) eyes receiving a single injection (P = 0.74), with a mean time period of 10 months for the measured peak IOP after the last injection. No significant association between mean IOP and the mean number of injections was observed. This is in agreement with other studies, which did not find the number of injections to be a risk factor for IOP elevation.1214\n\nDelayed and sustained OHT could be due to inhibition of VEGF in the trabecular meshwork, causing reduced aqueous outflow facility. Mathalone et al.10 reported that if the interval between injections was <8 weeks (17.6%), the risk of OHT was higher, compared to those with an interval of >8 weeks (6%, P = 0.009) in 22/201 eyes (11%) receiving bevacizumab for neovascular ARMD. Another study did not observe such correlation.12 In our study, for the eyes with OHT, the average time interval between multiple injections was 8 months (range, 1–39 months), and in eyes without OHT receiving multiple injections, it was 15 months (range, 1–96 months). This could be another possible explanation for the low rate of delayed OHT, as many patients received multiple, repeat injections with an increased time interval between injections, allowing the anti-VEGF agent to clear from the eye.\n\nWe found that the mean baseline IOP was higher in patients receiving anti-VEGF when compared to the fellow untreated eyes. This difference in IOP was significant on day 1 and at 1 year of follow-up between the two groups. This could be another predisposing factor for OHT in the eyes treated with anti-VEGF and needs to be explored in future prospective studies. We cannot directly compare our results with previous studies because of many variables studied, a lack of controls in most studies, the inclusion of patients with preexisting glaucoma, different anti-VEGF or a combination of the ≥2 anti-VEGF agents used, indication of treatment (most studies-neovascular ARMD),91012131516 differences in intervals between injections and total number of injections. In addition, there are differences in the syringes used for injection, preparation, handling, freezing, and storage of bevacizumab.\n\nA limitation of this study is its retrospective nature and variable postinjection follow-up visits. In eyes with IOP ≤21 mmHg, IOP was not re-checked. Strengths of this study include its large sample size, long follow-up duration, inclusion of the fellow eye as control, standardized treatment protocol of injection procedure, and inclusion of all the eyes receiving intravitreal anti-VEGF for the various retinal conditions.\n\nIn conclusion, after a single or multiple intravitreal bevacizumab or ranibizumab, IOP should be monitored at every visit, even though the incidence of OHT is low.\n\nFinancial support and sponsorship\n\nNil.\n\nConflicts of interest\n\nThere are no conflicts of interest.\n==== Refs\nREFERENCES\n\n1 Brown DM Michels M Kaiser PK Heier JS Sy JP Ianchulev T Ranibizumab versus verteporfin photodynamic therapy for neovascular age-related macular degeneration: Two-year results of the ANCHOR study Ophthalmology 2009 116 57 6500000 19118696\n2 Wolf S Balciuniene VJ Laganovska G Menchini U Ohno-Matsui K Sharma T RADIANCE: A randomized controlled study of ranibizumab in patients with choroidal neovascularization secondary to pathologic myopia Ophthalmology 2014 121 682 9200 24326106\n3 Brown DM Campochiaro PA Singh RP Li Z Gray S Saroj N Ranibizumab for macular edema following central retinal vein occlusion: Six-month primary end point results of a Phase III study Ophthalmology 2010 117 1124 330 20381871\n4 Haritoglou C Kook D Neubauer A Wolf A Priglinger S Strauss R Intravitreal bevacizumab (Avastin) therapy for persistent diffuse diabetic macular edema Retina 2006 26 999 1005 17151486\n5 CATT Research Group Martin DF Maguire MG Ying GS Grunwald JE Fine SL Ranibizumab and bevacizumab for neovascular age-related macular degeneration N Engl J Med 2011 364 1897 908 21526923\n6 Sampat KM Garg SJ Complications of intravitreal injections Curr Opin Ophthalmol 2010 21 178 83 20375895\n7 Kim JE Mantravadi AV Hur EY Covert DJ Short-term intraocular pressure changes immediately after intravitreal injections of anti-vascular endothelial growth factor agents Am J Ophthalmol 2008 146 930 40 18775528\n8 Bakri SJ Pulido JS McCannel CA Hodge DO Diehl N Hillemeier J Immediate intraocular pressure changes following intravitreal injections of triamcinolone, pegaptanib, and bevacizumab Eye (Lond) 2009 23 181 5 17693999\n9 Tseng JJ Vance SK Della Torre KE Mendonca LS Cooney MJ Klancnik JM Sustained increased intraocular pressure related to intravitreal antivascular endothelial growth factor therapy for neovascular age-related macular degeneration J Glaucoma 2012 21 241 7 21423038\n10 Mathalone N Arodi-Golan A Sar S Wolfson Y Shalem M Lavi I Sustained elevation of intraocular pressure after intravitreal injections of bevacizumab in eyes with neovascular age-related macular degeneration Graefes Arch Clin Exp Ophthalmol 2012 250 1435 40 22434210\n11 Kahook MY Kimura AE Wong LJ Ammar DA Maycotte MA Mandava N Sustained elevation in intraocular pressure associated with intravitreal bevacizumab injections Ophthalmic Surg Lasers Imaging 2009 40 293 5 19485295\n12 Good TJ Kimura AE Mandava N Kahook MY Sustained elevation of intraocular pressure after intravitreal injections of anti-VEGF agents Br J Ophthalmol 2011 95 1111 4 20702430\n13 Adelman RA Zheng Q Mayer HR Persistent ocular hypertension following intravitreal bevacizumab and ranibizumab injections J Ocul Pharmacol Ther 2010 26 105 10 20187807\n14 Falkenstein IA Cheng L Freeman WR Changes of intraocular pressure after intravitreal injection of bevacizumab (avastin) Retina 2007 27 1044 7 18040242\n15 Hoang QV Mendonca LS Della Torre KE Jung JJ Tsuang AJ Freund KB Effect on intraocular pressure in patients receiving unilateral intravitreal anti-vascular endothelial growth factor injections Ophthalmology 2012 119 321 6 22054994\n16 Wehrli SJ Tawse K Levin MH Zaidi A Pistilli M Brucker AJ A lack of delayed intraocular pressure elevation in patients treated with intravitreal injection of bevacizumab and ranibizumab Retina 2012 32 1295 301 22466465\n17 Kim YJ Sung KR Lee KS Joe SG Lee JY Kim JG Long-term effects of multiple intravitreal antivascular endothelial growth factor injections on intraocular pressure Am J Ophthalmol 2014 157 1266 710 24561173\n18 Liu L Ammar DA Ross LA Mandava N Kahook MY Carpenter JF Silicone oil microdroplets and protein aggregates in repackaged bevacizumab and ranibizumab: Effects of long-term storage and product mishandling Invest Ophthalmol Vis Sci 2011 52 1023 34 21051703\n19 Bakri SJ Ekdawi NS Intravitreal silicone oil droplets after intravitreal drug injections Retina 2008 28 996 1001 18698303\n20 Kahook MY Liu L Ruzycki P Mandava N Carpenter JF Petrash JM High-molecular-weight aggregates in repackaged bevacizumab Retina 2010 30 887 92 20458261\n21 Kernt M Welge-Lüssen U Yu A Neubauer AS Kampik A Bevacizumab is not toxic to human anterior- and posterior-segment cultured cells Ophthalmologe 2007 104 965 71 17653724\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "2452-2325",
"issue": "33(1)",
"journal": "Journal of current ophthalmology",
"keywords": "Bevacizumab; Intraocular pressure; Intravitreal injection; Multiple injections; Ocular hypertension; Ranibizumab",
"medline_ta": "J Curr Ophthalmol",
"mesh_terms": null,
"nlm_unique_id": "101678509",
"other_id": null,
"pages": "6-11",
"pmc": null,
"pmid": "34084950",
"pubdate": "2021",
"publication_types": "D016428:Journal Article",
"references": "20381871;18698303;24561173;17653724;20187807;22466465;18040242;20375895;19485295;22434210;21526923;20458261;24326106;20702430;21423038;21051703;19118696;22054994;18775528;17693999;17151486",
"title": "Intraocular Pressure Changes after Intravitreal Bevacizumab or Ranibizumab Injection: A Retrospective Study.",
"title_normalized": "intraocular pressure changes after intravitreal bevacizumab or ranibizumab injection a retrospective study"
} | [
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"companynumb": "IN-002147023-NVSC2021IN236263",
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"activesubstancename": "RANIBIZUMAB"
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"abstract": "Bone health assessment and the prescription of medication for secondary fracture prevention have become an integral part of the acute management of patients with hip fracture. However, there is little evidence regarding compliance with prescription guidelines and subsequent adherence to medication in this patient group.\n\n\n\nThe World Hip Trauma Evaluation (WHiTE) is a multicentre, prospective cohort of hip fracture patients in NHS hospitals in England and Wales. Patients aged 60 years and older who received operative treatment for a hip fracture were eligible for inclusion in WHiTE. The prescription of bone protection medications was recorded from participants' discharge summaries, and participant-reported use of bone protection medications was recorded at 120 days following surgery.\n\n\n\nOf 5456 recruited patients with baseline data, 2853 patients (52%) were prescribed bone protection medication at discharge, of which oral bisphosphonates were the most common, 4109 patients (75%) were prescribed vitamin D or calcium, and 606 patients (11%) were not prescribed anything. Of those prescribed a bone protection medication, only 932 patients (33%) reported still taking their medication 120 days later.\n\n\n\nThese data provide a reference for current prescription and adherence rates. Adherence with oral medication remains poor in patients with hip fracture. Cite this article: Bone Joint J 2019;101-B:1402-1407.",
"affiliations": "Oxford Trauma, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences (NDORMS), Kadoorie Centre, University of Oxford, Oxford, UK.;Oxford Trauma, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences (NDORMS), Kadoorie Centre, University of Oxford, Oxford, UK.;Oxford Trauma, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences (NDORMS), Kadoorie Centre, University of Oxford, Oxford, UK.;Oxford Trauma, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences (NDORMS), Kadoorie Centre, University of Oxford, Oxford, UK.;Oxford Trauma, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences (NDORMS), Kadoorie Centre, University of Oxford, Oxford, UK.;Oxford Trauma, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences (NDORMS), Kadoorie Centre, University of Oxford, Oxford, UK.",
"authors": "Cehic|Matthew|M|;Lerner|Robin G|RG|;Achten|Juul|J|;Griffin|Xavier L|XL|;Prieto-Alhambra|Daniel|D|;Costa|Matthew L|ML|",
"chemical_list": "D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D006887:Hydroxycholecalciferols; D019379:Teriparatide; D014807:Vitamin D; D000069448:Denosumab; D002118:Calcium; C008088:alfacalcidol",
"country": "England",
"delete": false,
"doi": "10.1302/0301-620X.101B11.BJJ-2019-0387.R1",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2049-4394",
"issue": "101-B(11)",
"journal": "The bone & joint journal",
"keywords": "Femoral neck fractures; Observational study; Osteoporosis",
"medline_ta": "Bone Joint J",
"mesh_terms": "D000368:Aged; D050071:Bone Density Conservation Agents; D002118:Calcium; D015331:Cohort Studies; D000069448:Denosumab; D004164:Diphosphonates; D006620:Hip Fractures; D006801:Humans; D006887:Hydroxycholecalciferols; D055118:Medication Adherence; D008875:Middle Aged; D011182:Postoperative Care; D011183:Postoperative Complications; D011446:Prospective Studies; D019379:Teriparatide; D006113:United Kingdom; D014807:Vitamin D",
"nlm_unique_id": "101599229",
"other_id": null,
"pages": "1402-1407",
"pmc": null,
"pmid": "31674239",
"pubdate": "2019-11",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D064888:Observational Study",
"references": null,
"title": "Prescribing and adherence to bone protection medications following hip fracture in the United Kingdom: results from the World Hip Trauma Evaluation (WHiTE) cohort study.",
"title_normalized": "prescribing and adherence to bone protection medications following hip fracture in the united kingdom results from the world hip trauma evaluation white cohort study"
} | [
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"companynumb": "GB-AMGEN-GBRSP2019199668",
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"activesubstancename": "DENOSUMAB"
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"abstract": "We report a case of Achilles tendinitis after intake of ciprofloxacin for treatment of respiratory tract infection. Fluoroquinolone-induced tendinopathy is an uncommon but increasingly recognised adverse effect of this antibiotic class. Most of the cases occur in the Achilles tendon and may lead to tendon rupture. Possible predisposing risk factors include use of steroid, patients with renal impairment or renal transplant, old age, and being an athlete. The drug should be stopped once this condition is suspected. Symptomatic treatment should be given and orthopaedic referral is desirable if tendon rupture occurs.",
"affiliations": "Department of Medicine, Tung Wah Hospital, 12 Po Yan Street, Sheung Wan, Hong Kong.;Department of Medicine, Tung Wah Hospital, 12 Po Yan Street, Sheung Wan, Hong Kong.",
"authors": "Tam|P K|PK|;Ho|Carmen T K|CT|",
"chemical_list": "D000890:Anti-Infective Agents; D024841:Fluoroquinolones",
"country": "China",
"delete": false,
"doi": "10.12809/hkmj134105",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1024-2708",
"issue": "20(6)",
"journal": "Hong Kong medical journal = Xianggang yi xue za zhi",
"keywords": "Achilles tendon; Fluoroquinolones",
"medline_ta": "Hong Kong Med J",
"mesh_terms": "D000125:Achilles Tendon; D000890:Anti-Infective Agents; D003937:Diagnosis, Differential; D005260:Female; D024841:Fluoroquinolones; D006801:Humans; D008875:Middle Aged; D012141:Respiratory Tract Infections; D052256:Tendinopathy",
"nlm_unique_id": "9512509",
"other_id": null,
"pages": "545-7",
"pmc": null,
"pmid": "25488035",
"pubdate": "2014-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Fluoroquinolone-induced Achilles tendinitis.",
"title_normalized": "fluoroquinolone induced achilles tendinitis"
} | [
{
"companynumb": "HK-LUPIN PHARMACEUTICALS INC.-2015-01125",
"fulfillexpeditecriteria": "2",
"occurcountry": "HK",
"patient": {
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"activesubstance": {
"activesubstancename": "CIPROFLOXACIN"
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"drugadditio... |
{
"abstract": "Epilepsy is a common, often severe, feature of LAMA2-related muscular dystrophy (LAMA2-RD) and could represent its onset and main manifestation, even in the absence of overt muscle involvement. To date, there is no systematic characterization of epilepsy in LAMA2-RD, and its impact on neurodevelopment and on the clinical course remains poorly established. In view of this knowledge gap, we conducted a systematic review of the literature and, as an illustrative example, reported the clinical case of a boy with late-onset LAMA2-related limb-girdle muscular dystrophy presenting with severe epilepsy. Our analyses of the literature data revealed a mean age at first seizure of 8 years, with significant differences between early- versus late-onset disease (5.78 ± 4.11 and 9.00 ± 2.65 years, respectively; p = 0.0007), and complete versus partial merosin deficiency (5.33 ± 3.70 and 10.36 ± 5.49 years, respectively; p = 0.0176). A generalized onset was the most common seizure presentation, regardless of merosin expression levels or the timing of muscular distrophy onset. Cortical malformations were not significantly associated with an earlier epilepsy onset, and were found to be quasi-significantly associated with a greater incidence of focal, or focal and generalized, onset seizures. No clear conclusions could be reached on the electrophysiological and neurodevelopmental features of the disorder, or on the relative efficacy of anti-epileptic treatments; further research on these aspects is needed. This systematic review helps to show that epilepsy in LAMA2-RD may be more than an ancillary manifestation of the disease, but rather one of its core features. A targeted and prompt electroencephalographic and epilepsy assessment, in addition to the specific neuromuscular workup, is therefore mandatory in early clinical management to pursue the best possible outcome for affected children.",
"affiliations": "Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.;Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.;Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.;Department of Developmental Neuroscience, IRCCS Fondazione Stella Maris, Calambrone, Pisa, Italy.;Department of Developmental Neuroscience, IRCCS Fondazione Stella Maris, Calambrone, Pisa, Italy. Electronic address: federico.sicca@gmail.com.",
"authors": "Salvati|Andrea|A|;Bonaventura|Eleonora|E|;Sesso|Gianluca|G|;Pasquariello|Rossella|R|;Sicca|Federico|F|",
"chemical_list": "D007797:Laminin",
"country": "England",
"delete": false,
"doi": "10.1016/j.seizure.2021.07.020",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1059-1311",
"issue": "91()",
"journal": "Seizure",
"keywords": "Epilepsy; LAMA2; Merosin; Muscular dystrophy; Seizure",
"medline_ta": "Seizure",
"mesh_terms": "D002648:Child; D004569:Electroencephalography; D004827:Epilepsy; D006801:Humans; D007797:Laminin; D008297:Male; D009136:Muscular Dystrophies; D049288:Muscular Dystrophies, Limb-Girdle",
"nlm_unique_id": "9306979",
"other_id": null,
"pages": "425-436",
"pmc": null,
"pmid": "34325301",
"pubdate": "2021-10",
"publication_types": "D016428:Journal Article; D016454:Review; D000078182:Systematic Review",
"references": null,
"title": "Epilepsy in LAMA2-related muscular dystrophy: A systematic review of the literature.",
"title_normalized": "epilepsy in lama2 related muscular dystrophy a systematic review of the literature"
} | [
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"companynumb": "IT-UCBSA-2022013775",
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"occurcountry": "IT",
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"activesubstancename": "LEVETIRACETAM"
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"abstract": "FMF is a prototype of autoinflammatory diseases associated with excess IL1 production. Anti-IL1 treatments are the first-line alternatives in colchicine-resistant/intolerant FMF patients. We aimed to investigate the efficacy and safety of anti-IL1 treatment in paediatric FMF patients in our local [Hacettepe univErsity eLectronIc research fOrmS (HELIOS)] registry.\n\n\n\nHELIOS is a web-based biologic drug registry for paediatric rheumatology patients. We have analysed the clinical features, disease activity parameters, treatment responses and safety outcomes in FMF patients treated with anti-IL1 agents.\n\n\n\nForty paediatric FMF patients (34 continuous and six on-demand use) were included. Among the continuously treated group (61.7% female), the mean age at the start of colchicine was 5.55 (3.87) years. Age at onset of the anti-IL1 treatment was 11.47 (5.41) years with a mean follow-up duration of 3.87 (1.96) years. Apart from two, all patients had biallelic exon-10 mutations. We also gave anti-IL1 treatment on an on-demand basis in six patients. Anakinra was used as the first-line anti-IL1 treatment. During the last visit, six patients were treated with anakinra and 28 patients with canakinumab. Anti-IL1 treatment decreased the CRP levels and number and severity of the attacks. There were three hospitalizations reported due to mild infections. Eleven patients had local skin reactions, two patients had leucopenia with anakinra and one patient had thrombocytopenia with canakinumab. There was no malignancy or other severe adverse reactions.\n\n\n\nAnakinra and canakinumab are efficient and safe alternatives in colchicine-resistant or -intolerant paediatric FMF patients. We also, for the first time, report on-demand use of anti-IL1 in paediatric FMF patients.",
"affiliations": "Department of Paediatrics, Division of Paediatric Rheumatology.;Department of Computer Engineering, Hacettepe University, Ankara, Turkey.;Department of Paediatrics, Division of Paediatric Rheumatology.;Department of Paediatrics, Division of Paediatric Rheumatology.;Department of Paediatrics, Division of Paediatric Rheumatology.;Department of Paediatrics, Hacettepe University, Ankara, Turkey.;Department of Paediatrics, Division of Paediatric Rheumatology.;Department of Paediatrics, Division of Paediatric Rheumatology.;Department of Paediatrics, Division of Paediatric Rheumatology.",
"authors": "Sag|Erdal|E|;Akal|Fuat|F|;Atalay|Erdal|E|;Akca|Ummusen Kaya|UK|;Demir|Selcan|S|;Demirel|Dilara|D|;Batu|Ezgi Deniz|ED|;Bilginer|Yelda|Y|;Ozen|Seza|S|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; C541220:canakinumab; D003078:Colchicine",
"country": "England",
"delete": false,
"doi": "10.1093/rheumatology/keaa121",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1462-0324",
"issue": "59(11)",
"journal": "Rheumatology (Oxford, England)",
"keywords": "FMF; HELIOS; anakinra; anti-IL1; canakinumab; colchicine; intolerant; resistant",
"medline_ta": "Rheumatology (Oxford)",
"mesh_terms": "D061067:Antibodies, Monoclonal, Humanized; D002648:Child; D002675:Child, Preschool; D003078:Colchicine; D004351:Drug Resistance; D010505:Familial Mediterranean Fever; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D008297:Male; D012042:Registries; D014421:Turkey",
"nlm_unique_id": "100883501",
"other_id": null,
"pages": "3324-3329",
"pmc": null,
"pmid": "32306038",
"pubdate": "2020-11-01",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Anti-IL1 treatment in colchicine-resistant paediatric FMF patients: real life data from the HELIOS registry.",
"title_normalized": "anti il1 treatment in colchicine resistant paediatric fmf patients real life data from the helios registry"
} | [
{
"companynumb": "IL-ALKEM LABORATORIES LIMITED-IL-ALKEM-2020-08006",
"fulfillexpeditecriteria": "1",
"occurcountry": "IL",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "COLCHICINE"
},
"druga... |
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"abstract": "BACKGROUND\nBortezomib administration leads to a transient decrease in CD4(+) T cells, increasing the susceptibility to opportunistic infections. The activation and proliferation of CD4(+) T cells are particularly important in the host's defense against tuberculosis infection. The aim of this study was to determine the incidence and clinical significance of tuberculosis infection in patients with multiple myeloma (MM) treated with a bortezomib-containing regimen.\n\n\nMETHODS\nWe retrospectively investigated the incidence of Mycobacterium tuberculosis in 115 patients with MM who were given a bortezomib-containing regimen and studied the disease prognosis.\n\n\nRESULTS\nAll patients received chemotherapy prior to bortezomib administration, and the median duration from diagnosis to bortezomib administration was 12.4 months (range, 0.2-230). We diagnosed tuberculosis in 8 patients (8/115, 7%): 7 patients had a pulmonary granulomatous lesion prior to chemotherapy and 1 developed reactivation of tuberculosis, but none of them died of uncontrolled tuberculosis infection. In 50% of patients with tuberculosis, bortezomib-containing therapy was interrupted. This resulted in significantly lower response rates to the bortezomib-containing therapy (P<0.05) and significantly shorter overall survival times amongst tuberculosis vs. non-tuberculosis patients (P=0.017).\n\n\nCONCLUSIONS\nTuberculosis infection was not uncommon among the patients with MM who were treated with bortezomib-containing therapy, and tuberculosis infection in these patients resulted in an interruption of bortezomib administration, which significantly affected patient outcomes. Therefore, early diagnosis and treatment of tuberculosis infection are critical to avoid worsening outcomes in such patients.",
"affiliations": "Department of Hematology-Oncology, Chonnam National University Hwasun Hospital, Hwasun, Korea.",
"authors": "Ahn|Jae-Sook|JS|;Rew|Sung Yoon|SY|;Yang|Deok-Hwan|DH|;Jung|Sung-Hoon|SH|;Kang|Seung-Ji|SJ|;Kim|Mi-Young|MY|;Lee|Seung-Shin|SS|;Kim|Yeo-Kyeoung|YK|;Kim|Hyeoung-Joon|HJ|;Lee|Je-Jung|JJ|",
"chemical_list": null,
"country": "Korea (South)",
"delete": false,
"doi": "10.5045/br.2013.48.1.35",
"fulltext": "\n==== Front\nBlood ResBRBlood research2287-979X2288-0011Korean Society of Hematology; Korean Society of Blood and Marrow Transplantation; Korean Society of Pediatric Hematology-Oncology; Korean Society on Thrombosis and Hemostasis 10.5045/br.2013.48.1.35Original ArticlePoor prognostic significance of Mycobacterium tuberculosis infection during bortezomib-containing chemotherapy in patients with multiple myeloma Ahn Jae-Sook 1*Rew Sung Yoon 1*Yang Deok-Hwan 1Jung Sung-Hoon 1Kang Seung-Ji 2Kim Mi-Young 1Lee Seung-Shin 1Kim Yeo-Kyeoung 1Kim Hyeoung-Joon 1Lee Je-Jung 131 Department of Hematology-Oncology, Chonnam National University Hwasun Hospital, Hwasun, Korea.2 Department of Infectious Disease, Chonnam National University Hwasun Hospital, Hwasun, Korea.3 The Brain Korea 21 Project, Center for Biomedical Human Resources at Chonnam National University, Gwangju, Korea.\nCorrespondence to Je-Jung Lee, M.D., Ph.D. Department of Hematology-Oncology, Chonnam National University Hwasun Hospital, 322, Seoyang-ro, Hwasun 519-763, Korea. The Brain Korea 21 Project, Center for Biomedical Human Resources at Chonnam National University, Gwangju, Korea. Tel: +82-61-379-7638, Fax: +82-61-379-7628, drjejung@chonnam.ac.kr*Jae-Sook Ahn and Sung Yoon Rew contributed equally to this work.\n\n3 2013 25 3 2013 48 1 35 39 16 8 2012 23 1 2013 13 2 2013 © 2013 Korean Society of Hematology2013This 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.Background\nBortezomib administration leads to a transient decrease in CD4+ T cells, increasing the susceptibility to opportunistic infections. The activation and proliferation of CD4+ T cells are particularly important in the host's defense against tuberculosis infection. The aim of this study was to determine the incidence and clinical significance of tuberculosis infection in patients with multiple myeloma (MM) treated with a bortezomib-containing regimen.\n\nMethods\nWe retrospectively investigated the incidence of Mycobacterium tuberculosis in 115 patients with MM who were given a bortezomib-containing regimen and studied the disease prognosis.\n\nResults\nAll patients received chemotherapy prior to bortezomib administration, and the median duration from diagnosis to bortezomib administration was 12.4 months (range, 0.2-230). We diagnosed tuberculosis in 8 patients (8/115, 7%): 7 patients had a pulmonary granulomatous lesion prior to chemotherapy and 1 developed reactivation of tuberculosis, but none of them died of uncontrolled tuberculosis infection. In 50% of patients with tuberculosis, bortezomib-containing therapy was interrupted. This resulted in significantly lower response rates to the bortezomib-containing therapy (P<0.05) and significantly shorter overall survival times amongst tuberculosis vs. non-tuberculosis patients (P=0.017).\n\nConclusion\nTuberculosis infection was not uncommon among the patients with MM who were treated with bortezomib-containing therapy, and tuberculosis infection in these patients resulted in an interruption of bortezomib administration, which significantly affected patient outcomes. Therefore, early diagnosis and treatment of tuberculosis infection are critical to avoid worsening outcomes in such patients.\n\nBortezomibMycobacterium tuberculosisMultiple myeloma\n==== Body\nINTRODUCTION\nTuberculosis (TB), caused by an infection of Mycobacterium tuberculosis, is the the most common cause of death from a single infectious agent among adults. Approximately one-third of the world's population (2 billion people) is thought to have latent M. tuberculosis, while an estimated 9 million people develop active disease from M. tuberculosis every year [1, 2]. The progression from latent to active TB commonly occurs in immunocompromised patients and is mainly related to dysfunctional cell-mediated immunity. Moreover, hematologic malignancies such as leukemia or lymphoma are thought to be risk factors for TB infection during cytotoxic chemotherapy [3]. Multiple myeloma (MM) is known to be associated with the immune abnormality hypogammaglobulinemia, which primarily affects humoral immunity. Recent studies suggested that the number of CD4+ T cells in MM patients is reduced at initial diagnosis and that the decline in CD4+ T-cell number was more severe in patients with refractory MM [4]. In addition, chemotherapeutic regimens for MM are known to induce immunosuppression.\n\nBortezomib is a proteasome inhibitor and one of the novel agents used in the treatment of MM. Bortezomib is known to induce apoptosis in rapidly proliferating and neoplastic cells, and a recent study showed that bortezomib prevents the activation of nuclear factor (NF)-kappa B. This leads to the inhibition of T-cell activation, including that of CD4+ T cells, which fulfill essential immune functions [5, 6]. Activation and proliferation of CD4+ T cells are crucial to the host's defense against TB infection [7]; thus, the suppression of T-cell immunity resulting from bortezomib-containing treatments potentially increases the risk of TB in MM patients [8]. The aim of our study was to investigate the incidence of TB in MM patients treated with a bortezomib-containing regimen.\n\nMATERIALS AND METHODS\nWe retrospectively investigated the incidence of TB infection in 115 patients diagnosed with MM, who were treated with bortezomib-containing salvage chemotherapy between November 2004 and July 2010. Eighty-two patients received treatment with bortezomib (1.3 mg/m2 i.v. on days 1, 4, 8, and 11), cyclophosphamide (150 mg/m2 orally on days 1-4), thalidomide (50-100 mg/day orally every day), and dexamethasone (20 mg/m2 i.v. on days 1, 4, 8, and 11 every 3 weeks) (Vel-CTD), while 33 patients were given Vel-CD; Vel-CD is similar to Vel-CTD but does not contain thalidomide [9]. We retrospectively reviewed the medical records, including the clinical history, chest radiographs, and computed tomography (CT) scans prior to bortezomib-containing chemotherapy to assess evidence of previous TB infection and possible reactivation of the disease in the patients. TB was diagnosed on the basis of respiratory symptoms, chest CT scans, sputum M. tuberculosis culture, or acid-fast bacillus microscopy. Bronchoalveolar lavage or transbronchial biopsy was also performed for the diagnostic work-up in some patients suspected of having TB. We then investigated the clinical outcome, the control of myeloma tumor burden, and the cumulative dose of bortezomib in MM patients with a confirmed diagnosis of TB. We used the International Myeloma Working Group (IMWG) uniform response criteria to assess the treatment response in MM patients [10].\n\nCategorical data and continuous variables were assessed using Fisher's exact and the Mann-Whitney U-tests, respectively. Overall survival (OS) was defined as the initiation of bortezomib-containing treatment to the date of the last follow-up or death. OS was analyzed using Kaplan-Meier survival curve estimates, and the differences between patients with (TB+) and without TB (TB-) was compared using stratified log-rank tests. A value of P <0.05 was considered statistically significant, and 95% confidence intervals were reported. All statistical analyses were performed using Statistical Package for the Social Sciences version 17.0 (SPSS, Chicago, IL, USA).\n\nRESULTS\nThe median age of patients was 63 years (range, 39-82 years). All patients received chemotherapy prior to the initiation of a bortezomib-containing regimen, and the median number of prior regimens was 1 (range, 1-4). Patients received a median of 8 (range, 1-22) cycles of bortezomib-containing salvage chemotherapy. The median duration from diagnosis of MM to the bortezomib-containing chemotherapy was 12.4 months (range, 0.2-230 months), and 24% of patients previously received autologous stem cell transplantation (Table 1). Neither interferon-γ release assay (IGRAs) nor TB skin test was performed prior to the initiation of bortezomib-containing therapy. All patients were routinely evaluated for TB infection using simple chest radiography at the start of bortezomib-containing salvage chemotherapy, and 13 (11.3%) of the 115 patients underwent chest CT for the evaluation of associated lung abnormalities. One patient was diagnosed with active pulmonary TB prior to receiving bortezomib-containing chemotherapy, while 8 (7%) of 115 patients were diagnosed with TB infection during bortezomib-containing treatment (Table 1). The median duration from the start of bortezomib-containing treatment to the confirmed diagnosis was 58 days (range, 7-247 days). In all the patients who were diagnosed with TB during bortezomib-containing treatment, pulmonary infiltration was detected using chest CT. In 5 of these patients, TB infection was documented through sputum culture and in 1 patient, through sputum acid-fast bacillus microscopy. Two patients were diagnosed without bacteriologic confirmation because it was not possible to perform bronchoscopic evaluation due to grade 4 asthenia; nevertheless, the typical characteristics of TB on CT, such as bronchiectasis and centrilobular nodules with branching linear structures (tree-in-bud opacities) were observed. In addition, clinical symptoms were consistent with TB, and these patients did not have evidence of other non-TB diseases. Seven of the 115 patients showed signs of previous pulmonary granulomatous lesions at diagnosis of MM, but only 1 patient experienced reactivation of TB during bortezomib treatment. The baseline characteristics of patients enrolled in the study are reported in Table 1.\n\nThere was no statistical difference in age, performance status, paraprotein subtype, stage at the start of bortezomib-containing chemotherapy, and prior treatment between patients with (TB+) or without TB infection (TB-). The male gender was more frequently associated with TB+ (P =0.02). The median duration from the diagnosis of MM to the initiation of a bortezomib-containing regimen was 12.4 months in TB+ patients and 13.1 months in TB- patients (P =0.28). There was no difference according to the treated combination chemotherapies between groups (Table 1). All TB+ patients were treated with combination of isoniazid, ethambutol, rifampicin, and pyrazinamide (HERZ), and the intention was to treat all patients with this anti-TB regimen for a period of 6 months. However, all but 3 of the TB+ patients died of disease progression within the 6-month treatment period (Table 2), and only the surviving 3 completed the 6-month anti-TB regimen. None of the patients died of uncontrolled pulmonary TB infection; however, 4 patients had to discontinue bortezomib treatment because of grade 3 or 4 asthenia. TB+ patients received a median of 4 cycles of bortezomib-containing chemotherapy, and the cumulative dose of bortezomib was 18.4 mg/m2 (range, 11.4-41.6 mg/m2). The TB+ patients tended to interrupt bortezomib-containing therapy. Patients who interrupted bortezomib-containing therapy experienced MM progression within a few months. The best response rate was significantly lower in the TB+ group (Table 1). The median duration of follow-up for all patients was 21.1 months (range, 5.5-75 months). The median OS was 11.0±2.6 months (95% CI: 5.8-16.1 months) and 30.9±6.1 months (95% CI: 18.9-42.9 months) in the TB+ and TB- groups, respectively (P =0.017) (Fig. 1).\n\nDISCUSSION\nThe treatment outcomes of novel agents for MM are promising, but these therapies are thought to have specific toxicities that differ from traditionally used agents. Bortezomib is known to have important adverse effects, including peripheral neuropathy, myelosuppression, and gastrointestinal disturbances. Heider et al. [6] reported a decline of CD4+ T cells in 77% of MM patients who were treated with bortezomib. In addition, the median CD4+ lymphocyte count significantly declined in all patients. Considering these results, the occurrence of herpes zoster in patients with MM treated with bortezomib could be explained by the decline in CD4+ counts. The effect of bortezomib treatment could potentially also influence the susceptibility of these patients to infections associated with low CD4+ T cells, such as M. tuberculosis infection [7]. We reviewed a large number of patients with MM who were treated with bortezomib-containing therapies. We found that the incidence of TB in bortezomib-treated patients (7%) was much greater than the annual incidence of TB in a general population aged 60-69 years (164.3 per 100,000 people) as reported by the Korea Centers for Disease Control and Prevention for 2007.\n\nA limitation of our study was that bortezomib was administered in combination with other agents, and these agents may well have influenced patients' susceptibility to TB infection. Bortezomib was given in combination with thalidomide. Thalidomide is considered an adjuvant treatment for TB in some studies [11, 12], because it co-stimulates T lymphocytes and is thought to have a greater effect on CD8+ than on CD4+ T cells [13]. Bortezomib was also used with other immunosuppressant agents, specifically cyclophosphamide and dexamethasone. In this study, patients received low-dose cyclophosphamide (150 mg/m2 on days 1-4, every cycle). A previous study showed that low-dose cyclophosphamide selectively depletes CD4+CD25+ T cells [14]. Steroids are known to be an independent risk factor, and patients receiving a daily dose of ≥15 mg of corticosteroid for ≥1 month had an increased risk of developing TB [15]. To identify the influence of bortezomib on patients' susceptibility to TB infection, a direct comparison between patients who receive bortezomib and patients who receive steroid-containing salvage chemotherapy minus bortezomib is required [16].\n\nIn our study, 4 (50%) of the patients diagnosed with active pulmonary TB had interrupted consecutive treatment with bortezomib-containing regimens because of severe asthenia. This caused poor prognosis in all patients, even though 3 of the 4 patients showed a partial response to bortezomib-containing treatment at diagnosis with active pulmonary TB. In 2 patients, consecutive treatment of the bortezomib-containing regimen was interrupted for more than 5 weeks because of anti-TB treatment, and these patients showed disease progression within 5 months after initiation of an anti-TB regimen. The remaining 2 patients received continuous treatment for MM, and they were alive at the last follow-up. Patients with TB tended to receive fewer cycles of chemotherapy and lower bortezomib cumulative dosages compared with patients without TB, although statistical significance was not reached. We speculate that fewer cycles of chemotherapy and lower bortezomib cumulative dosages would affect best response rates and survival in MM patients with TB. Our findings emphasize that effective screening and early diagnosis for pulmonary TB infection are important in the treatment of MM patients. We propose that chest radiography screening should be performed prior to bortezomib treatment for the detection of healed or active pulmonary TB lesions. Even though skin testing with purified protein derivative of tuberculin (TST) is widely used to screen latent M. tuberculosis infection, it has relatively low sensitivity and specificityand is not possible to discriminate between latent infection and active disease. IGRAs are more specific than TST in terms of less cross-reactivity with BCG vaccination [1, 17]. Therefore, screening with IGRAs for patients with MM prior to bortezomib-containing chemotherapy should be considered in the diagnosis of latent tuberculosis. In addition, isoniazid prophylaxis should be given, if the IGRAs screening test results are positive. A key factor in the diagnosis of TB is a high degree of suspicion. If patients show pulmonary symptoms and have radiologic findings of atypical pulmonary infiltration during bortezomib-containing chemotherapy, active TB should be suspected and early diagnostic procedures such as sputum examination and chest CT should be performed.\n\nNo potential conflicts of interest relevant to this article were reported.\n\nFig. 1 Overall survival analyses in multiple myeloma patients with or without tuberculosis infection during bortezomib-containing chemotherapy (P=0.017).\n\nTable 1 Patient characteristics and the results of bortezomib-containing chemotherapy in patients with and without tuberculosis infection.\n\na)P value is the comparison according to the tuberculous infection. b)P value is the comparison according to the intact immunoglobulin versus light chain disease.\n\nAbbreviations: TB, tuberculosis; ECOG, Eastern Cooperative Oncology Group; ISS, international staging system; Vel-CD, bortezomib, cyclophosphamide, and dexamethasone; Vel-CTD, vel-CD and thalidomide; CR, complete response; VGPR, very good partial response; PR, partial response; SD, stable disease.\n\nTable 2 Characteristics of multiple myeloma patients diagnosed with tuberculosis infection.\n\nAbbreviations: M, male; F, female; DSS, Durie-Salmon stage; Dx, diagnosis; ISS, international staging system; Vel, bortezomib; CTD, cyclophosphamide, thalidomide, dexamethasone; TD, thalidomide, dexamethasone; dexa, dexamethasone; VAD, vincristine, adriamycin, dexamethasone; CD, cyclophosphamide, dexamethasone; MTP, melphalan, prednisolone, thalidomide; Tx, treatment; TB, tuberculosis; VGPR, very good partial response; PR, partial response; SD, stable disease; CR, complete remission; N, no; Y, yes; CT, computed tomography; AFB, acid-fast bacillus; MM, multiple myeloma; Auto-PBSCT, autologous stem cell transplantation.\n==== Refs\n1 Mazurek GH Jereb J Vernon A LoBue P Goldberg S Castro K Updated guidelines for using interferon gamma release assays to detect mycobacterium tuberculosis infection - United States, 2010 MMWR Recomm Rep 2010 59 1 25 20577159 \n2 Dolin PJ Raviglione MC Kochi A Global tuberculosis incidence and mortality during 1990-2000 Bull World Health Organ 1994 72 213 220 8205640 \n3 Wu CY Hu HY Pu CY Aerodigestive tract, lung and haematological cancers are risk factors for tuberculosis: an 8-year population-based study Int J Tuberc Lung Dis 2011 15 125 130 21276308 \n4 Ogawara H Handa H Yamazaki T High Th1/Th2 ratio in patients with multiple myeloma Leuk Res 2005 29 135 140 15607360 \n5 Berges C Haberstock H Fuchs D Proteasome inhibition suppresses essential immune functions of human CD4+ T cells Immunology 2008 124 234 246 18217957 \n6 Heider U Rademacher J Kaiser M Kleeberg L von Metzler I Sezer O Decrease in CD4+ T-cell counts in patients with multiple myeloma treated with bortezomib Clin Lymphoma Myeloma Leuk 2010 10 134 137 20371447 \n7 Flynn JL Chan J Immunology of tuberculosis Annu Rev Immunol 2001 19 93 129 11244032 \n8 Schütt P Brandhorst D Stellberg W Immune parameters in multiple myeloma patients: influence of treatment and correlation with opportunistic infections Leuk Lymphoma 2006 47 1570 1582 16966269 \n9 Kim YK Sohn SK Lee JH Clinical efficacy of a bortezomib, cyclophosphamide, thalidomide, and dexamethasone (Vel-CTD) regimen in patients with relapsed or refractory multiple myeloma: a phase II study Ann Hematol 2010 89 475 482 19921192 \n10 Rajkumar SV Harousseau JL Durie B Consensus recommendations for the uniform reporting of clinical trials: report of the International Myeloma Workshop Consensus Panel 1 Blood 2011 117 4691 4695 21292775 \n11 Schoeman JF Fieggen G Seller N Mendelson M Hartzenberg B Intractable intracranial tuberculous infection responsive to thalidomide: report of four cases J Child Neurol 2006 21 301 308 16900926 \n12 Stefan DC Andronikou S Freeman N Schoeman J Recovery of vision after adjuvant thalidomide in a child with tuberculous meningitis and acute lymphoblastic leukemia J Child Neurol 2009 24 166 169 19182153 \n13 Gori A Rossi MC Marchetti G Clinical and immunological benefit of adjuvant therapy with thalidomide in the treatment of tuberculosis disease AIDS 2000 14 1859 1861 10985328 \n14 Motoyoshi Y Kaminoda K Saitoh O Different mechanisms for anti-tumor effects of low- and high-dose cyclophosphamide Oncol Rep 2006 16 141 146 16786137 \n15 Jick SS Lieberman ES Rahman MU Choi HK Glucocorticoid use, other associated factors, and the risk of tuberculosis Arthritis Rheum 2006 55 19 26 16463407 \n16 Engelhardt M Kleber M Udi J Consensus statement from European experts on the diagnosis, management, and treatment of multiple myeloma: from standard therapy to novel approaches Leuk Lymphoma 2010 51 1424 1443 20509769 \n17 Fauci AS Braunwald E Kasper DL Harrison's principles of internal medicine 2008 17th ed New York, NY McGraw-Hill Medical 1006 1020\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2287-979X",
"issue": "48(1)",
"journal": "Blood research",
"keywords": "Bortezomib; Multiple myeloma; Mycobacterium tuberculosis",
"medline_ta": "Blood Res",
"mesh_terms": null,
"nlm_unique_id": "101605247",
"other_id": null,
"pages": "35-9",
"pmc": null,
"pmid": "23589793",
"pubdate": "2013-03",
"publication_types": "D016428:Journal Article",
"references": "16966269;10985328;16463407;20509769;20577159;8205640;21276308;11244032;18217957;19921192;16786137;15607360;16900926;20371447;19182153;21292775",
"title": "Poor prognostic significance of Mycobacterium tuberculosis infection during bortezomib-containing chemotherapy in patients with multiple myeloma.",
"title_normalized": "poor prognostic significance of mycobacterium tuberculosis infection during bortezomib containing chemotherapy in patients with multiple myeloma"
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"abstract": "BACKGROUND\nIdentification of predictors of clinical response to certolizumab-pegol (certolizumab) may aid the decision-making process for treating patients with rheumatoid arthritis (RA), spondyloarthritis (SpA), and psoriatic arthritis (PsA).\n\n\nOBJECTIVE\nThe aim of our study was to evaluate the effectiveness of certolizumab and identify any predictors of favorable outcome in patients with RA, PsA, or SpA.\n\n\nMETHODS\nWe studied 355 RA, SpA, and PsA patients starting treatment with certolizumab. Endpoints of the study were drug survival and identification of predictors of clinical outcome. Drug retention was analyzed via the Kaplan-Meier method, and hazard ratios (HRs) were estimated using Cox regression models.\n\n\nRESULTS\nOf 355 certolizumab initiators, 178 had RA, 94 had PsA, and 83 had SpA. Biologic-naïve RA patients had significantly higher survival rates (73.3%) than switchers taking certolizumab as a second-line (49.0%) or third- or next-line biologic agent (51.2%; p = 0.0001). Instead, PsA and SpA patients showed similar drug retention rates regardless of the line of treatment. A significant clinical improvement from baseline was seen at 3 months for RA (28 joint-Disease Activity Score [DAS28]; p = 0.001), PsA (Disease Activity Index for PsA [DAPSA]; p = 0.001), and SpA (Bath Ankylosing Disease Index; p = 0.01). Biologic-naïve patients had the lowest HR (0.31; p = 0.001) of discontinuing certolizumab for RA, and the highest HR (7.94; p = 0.01) of achieving minimal disease activity (MDA) for PsA. For PsA, a predictor of late MDA was the achievement of low/remission DAPSA at 3 months, and 3-month low/remission DAS28 predicted late remission for RA.\n\n\nCONCLUSIONS\nOur study revealed that the best predictor of certolizumab effectiveness in unselected patients with RA, PsA, or SpA was a biologic-naïve status and achievement of an early response within 3 months.",
"affiliations": "Rheumatology Unit, Department of Emergency and Organ Transplantation, University of Bari, Pz. G. Cesare, 11, 70124, Bari, Italy. florenzo.iannone@uniba.it.;Unità Operativa di Reumatologia ASL Taranto, Viale Virgilio 31, 74121, Taranto, Italy.;Rheumatology Service, ASL LE-DSS Casarano-Gallipoli (LE), Lungo Mare Marconi G 1, 73014, Gallipoli, Italy.;Unità Operativa di Reumatologia ASL BT, Viale Ippocrate 15, 76121, Barletta, Italy.;Rheumatology Hospital Unit, A.O.U. Foggia, Viale Pinto Luigi 251, 71122, Foggia, Italy.;U.O. of Rheumatology, \"V.Fazzi\" Hospital, Lecce, Via Croce di Lecce 10, 73016, San Cesario di Lecce, Italy.;UOC Reumatologia Universitaria, University of Foggia, Viale Pinto Luigi 251, 71122, Foggia, Italy.;Ambulatorio di Reumatologia Ospedale di Brindisi, Strada Statale Per Mesagne 7, 72100, Brindisi, Italy.;Unità Operativa di Reumatologia ASL Taranto, Viale Virgilio 31, 74121, Taranto, Italy.;Ambulatorio di Reumatologia Ospedale di Brindisi, Strada Statale Per Mesagne 7, 72100, Brindisi, Italy.;Ambulatorio di Reumatologia Ospedale di Brindisi, Strada Statale Per Mesagne 7, 72100, Brindisi, Italy.;UOC Reumatologia Universitaria, University of Foggia, Viale Pinto Luigi 251, 71122, Foggia, Italy.;U.O. of Rheumatology, \"V.Fazzi\" Hospital, Lecce, Via Croce di Lecce 10, 73016, San Cesario di Lecce, Italy.;Rheumatology Unit, Department of Emergency and Organ Transplantation, University of Bari, Pz. G. Cesare, 11, 70124, Bari, Italy.",
"authors": "Iannone|Florenzo|F|http://orcid.org/0000-0003-0474-5344;Semeraro|Angelo|A|;Carlino|Giorgio|G|;Santo|Leonardo|L|;Bucci|Romano|R|;Quarta|Laura|L|;Maruotti|Nicola|N|;Zuccaro|Carmelo|C|;Marsico|Antonio|A|;Falappone|Paola Chiara Francesca|PCF|;Mazzotta|Daniela|D|;Cantatore|Francesco Paolo|FP|;Muratore|Maurizio|M|;Lapadula|Giovanni|G|",
"chemical_list": "D000068582:Certolizumab Pegol",
"country": "New Zealand",
"delete": false,
"doi": "10.1007/s40261-019-00782-9",
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"issue": "39(6)",
"journal": "Clinical drug investigation",
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"medline_ta": "Clin Drug Investig",
"mesh_terms": "D000328:Adult; D015535:Arthritis, Psoriatic; D001172:Arthritis, Rheumatoid; D000068582:Certolizumab Pegol; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D016016:Proportional Hazards Models; D012042:Registries; D012189:Retrospective Studies; D025241:Spondylarthritis; D016896:Treatment Outcome",
"nlm_unique_id": "9504817",
"other_id": null,
"pages": "565-575",
"pmc": null,
"pmid": "30941736",
"pubdate": "2019-06",
"publication_types": "D016428:Journal Article",
"references": "16620398;16871531;19015207;19297344;20589696;22514189;23942868;24013647;25063827;26644232;26808074;27118021;27696727;28087505;28214596;28216195;28264816;29148406;29246527;29683356;30076523;3358796",
"title": "Effectiveness of Certolizumab-Pegol in Rheumatoid Arthritis, Spondyloarthritis, and Psoriatic Arthritis Based on the BIOPURE Registry: Can Early Response Predict Late Outcomes?",
"title_normalized": "effectiveness of certolizumab pegol in rheumatoid arthritis spondyloarthritis and psoriatic arthritis based on the biopure registry can early response predict late outcomes"
} | [
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"abstract": "Renal angiomyolipoma is a rare tumor that can be either sporadic or found together with tuberous sclerosis or pulmonary lymphangioleiomyomatosis. These tumors are hormone sensitive and therefore tend to grow during pregnancy and their main complication is the risk of rupture. Optimal management is still controversial because there are very few cases reported in the literature. We expect that the case of our patient, who delivered her baby vaginally at 36 weeks of gestation and underwent definitive treatment (nephrectomy) thereafter, to further enhance the knowledge about the management of these rare tumors during pregnancy.",
"affiliations": "Çukurova University Faculty of Medicine, Department of Obstetrics and Gynecology, Adana, Turkey.;Çukurova University Faculty of Medicine, Department of Obstetrics and Gynecology, Adana, Turkey.;Çukurova University Faculty of Medicine, Department of Obstetrics and Gynecology, Adana, Turkey.;Çukurova University Faculty of Medicine, Department of Obstetrics and Gynecology, Adana, Turkey.",
"authors": "Çetin|Cihan|C|;Büyükkurt|Selim|S|;Demir|Cansun|C|;Evrüke|Cüneyt|C|",
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"fulltext": "\n==== Front\nTurk J Obstet GynecolTurk J Obstet GynecolTJODTurkish Journal of Obstetrics and Gynecology2149-93222149-9330Galenos Publishing 10.4274/tjod.328482078Case ReportRenal angiomyolipoma during pregnancy: Case report and literature review Çetin Cihan 1*Büyükkurt Selim 1Demir Cansun 1Evrüke Cüneyt 1\n1 \nÇukurova University Faculty of Medicine, Department of Obstetrics and Gynecology, Adana, Turkey\n* Address for Correspondence: Çukurova University Faculty of Medicine, Department of Obstetrics and Gynecology, Adana, Turkey GSM: +90 533 224 10 33 E-mail: cihancetin00@gmail.com6 2015 15 6 2015 12 2 118 121 15 3 2015 14 4 2015 © Turkish Journal of Obstetrics and Gynecology published by Galenos Publishing House.2017This 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 work is properly cited.Renal angiomyolipoma is a rare tumor that can be either sporadic or found together with tuberous sclerosis or pulmonary lymphangioleiomyomatosis. These tumors are hormone sensitive and therefore tend to grow during pregnancy and their main complication is the risk of rupture. Optimal management is still controversial because there are very few cases reported in the literature. We expect that the case of our patient, who delivered her baby vaginally at 36 weeks of gestation and underwent definitive treatment (nephrectomy) thereafter, to further enhance the knowledge about the management of these rare tumors during pregnancy.\n\nAngiomyolipomanephrectomyPregnancy\n==== Body\nINTRODUCTION\nRenal angiomyolipoma (RA) are rare tumors with an incidence of 0.3% in the general population and are even rarer among women who are pregnant(1). These tumors arise from epithelioid cells around blood vessels, can be sporadic, but may also be associated with tuberous sclerosis complex (TSC) or pulmonary lymphangioleiomyomatosis (LAM)(2). Although symptoms like hematuria or flank pain may occur, they are more frequently detected incidentally during imaging for unrelated reasons.\n\nThese hormone-sensitive tumors (estrogen, progesterone) may rupture during pregnancy due to elevated levels of estrogen and progesterone; most of the cases in the literature ruptured during pregnancy. We present a patient who was pregnant whose renal mass was diagnosed during pregnancy. The patient was managed conservatively in the antenatal period without any complication, and then given definitive treatment after the birth. We reviewed the literature about cases of RA that have been managed during pregnancy.\n\nCASE REPORT\nA primigravida women aged 26 years was referred to our clinic during her 34th week of gestation with left flank pain. Her medical history was not significant for any disease. The patient had no costovertebral angle tenderness on either side. Her urine analysis revealed pyuria but not hematuria. A urinary tract infection was treated with oral ampicillin. The patient’s vital signs were stable and there was no fever. Fetal biometric measures were compatible with 34 weeks and the amniotic fluid index was normal on ultrasound evaluation. A urinary system ultrasound revealed a 9.9x5.8-cm hypoechoic solid lesion on the left kidney that had distorted the renal calices. Magnetic resonance imaging (MRI) results showed a lobulated, heterogeneously contrasted 11x6.5x5.5-cm soft tissue mass lesion arising from the middle segment of the left kidney that contained necrotic areas (Figure 1). Renal function tests were within the normal range. The patient delivered vaginally after cervical ripening with dinoprostone and induction with 4 oxytocine, consecutively, at 36 weeks of gestation due to the patient’s anxiety about the risk of tumor rupture. The neonate was a 2430 g girl with 1st/5th min Apgar scores 9/10, respectively. The neonate was discharged without any problems. Two weeks after the delivery, the patient underwent laparoscopic a radical left nephrectomy. Pathologic evaluation of the specimen showed epitheloid angiomyolipoma with intact tumor-free borders around the mass (Figure 2). After being discharged from hospital, the patient had no complaints in the third month after the operation. The patient had normal neurologic, pulmonary, and skin examination, by which we excluded TSC and LAM.\n\nDISCUSSION\nMore than 25% of RA’s carry estrogen and progesterone receptors like in pulmonary LAM(3,4). Therefore, they are thought to grow during pregnancy or with oral contraceptive use. Symptoms may occur during these periods in previously asymptomatic patients. There are few case reports about RA’s during pregnancy in the literature and these are summarized in Table 1.\n\nAlthough most angiomyolipomas are located in the kidneys, they can also be diagnosed in other organs like liver, spleen or uterus as they arise from epitheloid cells around blood vessels(5). Some cases can present with sudden abdominal or flank pain and with symptoms of hypovolemic shock, which suggests rupture of the tumor into the retroperitoneal area; however, they are frequently asymptomatic. In cases of rupture, hemodynamic stability is of critical importance regarding the selection of optimal treatment strategy. For hemodynamically unstable patients, emergency surgery or arterial embolization (if available) are the main options of treatment. For asymptomatic patients, a conservative approach may be chosen, especially during pregnancy(5). For these patients, definitive treatment may be postponed until the postpartum period(6). Similarly, we delayed the definitive treatment of the tumor to the postpartum period. However, there is as yet no consensus in the literature as to how long the conservative approach is suitable. Close follow-up of patients who are pregnant may be preferred because of the high risk of rupture.\n\nMost of the cases during pregnancy reported in the literature ruptured during pregnancy (21/26, 81%). To the best of our knowledge, only four (15%) of the 26 cases reported (including ours) have not ruptured during pregnancy (Table 1). These were managed with nephrectomy during or after pregnancy(7,8,9).\n\nThe mean age and mean gestational age of the patients in the literature at the time of diagnosis was 31.4 years and 27.7 weeks, respectively. Twenty-one of these cases (81%) ruptured (Table 1). The average size of the tumors measured with ultrasound or MRI was 10.1 cm and tumor size did not correlate with the risk of rupture. The tumor in our case was 11 cm and rupture did not occur tumor, whereas in dos Santos et al.’s case, rupture was reported with a tumor that measured 5 cm(11). Therefore, estimation of the risk of rupture using only tumor size would not be accurate.\n\nMost patients with RA in the literature delivered their babies via cesarean section (15/26, 56%), whereas only 5 (19%) were delivered vaginally (Table 1). However, vaginal delivery can be considered as a safe approach for these patients. Mode of delivery for these patients should be decided based on obstetric indications, because cesarean section does not reduce the risk of rupture. Vacuum extraction can also be an alternative option for these patients in order to shorten the second stage of the labor. In our case, we did not need vacuum extraction due to precipitous labor.\n\nCurrent treatment options for RA include partial/total nephrectomy (open or laparoscopic), cryoablation, radiofrequency ablation, or arterial embolization(3). Fourteen (54%) of the patients reported in the literature needed nephrectomy, whereas 12 (46%) were treated conservatively with or without arterial embolization (Table 1). Embolization can also be performed after 12 weeks of gestation with minimal fetal radiation exposure(3). This can be performed using devices such as coils, gelfoam, or polyvinylalcohol(3). The main complications of embolization are Post-embolization syndrome (POS) (inflammation, fever, leukocytosis, and flank pain) and liquefactive necrosis(3). POS generally resolves spontaneously, whereas percutaneous drainage might be needed for liquefactive necrosis(3). In contrast to embolization or ablation, surgery has the important advantage of allowing for pathologic evaluation for a definitive diagnosis. Differential diagnosis of these lesions includes renal cell carcinoma, oncocytoma, and metastatic lesions from primary tumors elsewhere. Radiographic features can usually distinguish these from each other. For those patients in whom radiographic evaluation is not enough for definitive diagnosis as in our case, either biopsy or nephrectomy (as a definitive treatment) can be performed.\n\nIn conclusion, renal angiomyolipomas are rare tumors but physicians who encounter renal masses during pregnancy should keep these in mind, because they can grow and be symptomatic for the first time during pregnancy. MRI is usually enough for diagnosis, but for uncertain cases, biopsy or surgery can be performed. Treatment strategies should be individualized due to insufficient data in the literature to support any one in particular. More experience with these strategies is needed before an optimal treatment method can be recommended. It is our hope that the distinctive features of our case will further enhance the knowledge of the management of these rare tumors during pregnancy.\n\nInformed Consent: It was taken.\n\nPeer-review: External and Internal peer-reviewed.\n\nConcept: Cihan Çetin, Design: Cihan Çetin, Selim Büyükkurt, Data Collection or Processing: Cihan Çetin, Cüneyt Evrüke, Analysis or Interpretation: Cihan Çetin, Cineyt Evrüke, Cansun Demir, Literature Search: Cihan Çetin, Selim Büyükkurt, Writing: Cihan Çetin, Selim Büyükkurt, Cansun Demir, Cüneyt Evrüke.\n\nConflict of Interest: No conflict of interest was declared by the authors.\n\nFinancial Disclosure: The authors declared that this study has received no financial support.\n\nTable 1 Literature review of renal angiomyolipoma cases during pregnancy\nFigure 1 Magnetic resonance imaging of the renal tumor a) coronal section, b) axial section (arrow indicating the tumor)\nFigure 2 a) Hematoxylin&Eosin stain under x40 magnification, spindle cells in fascicular pattern, starting from the perivascular area, b) x100 magnification, c) x200 magnification, smooth muscle cells component, d) x400 magnification, e) x100 magnification, HMB-45 positivity in immunohistochemistry, f) x40 magnification, tumor area in the upper part, normal renal tissue below\n==== Refs\nReferences\n1 Gimeno Argente V Bosquet Sanz M Bonillo Garcia MA Gomez Perez L Pontones Moreno JL Jimenez Cruz JF Conservative surgery of bilateral renal angiomyolipoma during pregnancy Actas Urol Esp 2006 30 633 7 16921843 \n2 Martignoni G Pea M Reghellin D Zamboni G Bonetti F PEComas: The past, the present and the future Virchows Arch 2008 452 119 32 18080139 \n3 Morales JP Georganas M Khan MS Dasgupta P Reidy JF Embolization of a bleeding renal angiomyolipoma in pregnancy: Case report and review Cardiovasc Intervent Radiol 2005 28 265 8 15696353 \n4 Ohori NP Yousem SA Sonmez-Alpan E Colby TV Estrogen and progesterone receptors in lymphangioleiomyomatosis, epithelioid hemangioendothelioma, and sclerosing hemangioma of the lung Am J Clin Pathol 1991 96 529 35 1716416 \n5 Illescas Molina T Montalvo Montes J Contreras Cecilia E Gonzalez Gonzalez A Herraiz Martinez MA Angiomyolipomas, tuberous sclerosis and pregnancy Ginecol Obstet Mex 2009 77 380 6 19902629 \n6 Tanaka M Kyo S Inoue M Kojima T Conservative management and vaginal delivery following ruptured renal angiomyolipoma Obstet Gynecol 2001 98 932 3 11704209 \n7 Govednik-Horny C Atkins M Angiomyolipoma with vascular invasion during pregnancy Ann Vasc Surg 2011 25 1138 \n8 Lopater J Hartung O Bretelle F Bastide C Management of angiomyolipoma vena cava thrombus during pregnancy Obstet Gynecol 2011 117 440 3 21252782 \n9 Bidault V Pignot G Rocher L Glas L Patard JJ Renal angiomyolipoma with inferior vena cava thrombosis during pregnancy Prog Urol 2015 25 288 92 25638747 \n10 Preece P Mees B Norris B Christie M Wagner T Dundee P Surgical management of haemorrhaging renal angiomyolipoma in pregnancy Int J Surg Case Rep 2015 7 89 92 \n11 Santos MM Proenca SM Reis MI Viana RM Martins LM Colaço JM Nunes FM Spontaneous rupture of renal angiomyolipoma during pregnancy Rev Bras Ginecol Obstet 2014 36 377 380 25184352 \n12 Davis NF Kelly R Lee MJ Mohan P Selective arterial embolisation of bilateral angiomyolipomata in a symptomatic pregnant female BMJ Case Rep 2013 2013 \n13 Pontis A Piras B Meloni A De Lisa A Melis GB Angioni S Rupture of renal angiomyolipoma in pregnancy J Obstet Gynaecol 2013 33 628 9 23919867 \n14 Iruloh C Keriakos R Smith DJ Cleveland T Renal angiomyolipoma and lymphangioleiomyomatosis in pregnancy J Obstet Gynaecol 2013 33 542 6 23919845 \n15 Ferianec V Gabor M Cano M Papcun P Holoman K Severe retroperitoneal haemorrhage in the first trimester of a multiple pregnancy after spontaneous rupture of renal angiomyolipoma Arch Gynecol Obstet 2013 288 1193 4 23708391 \n16 Bolufer E Lopez-Fontana G Castillo OA Robot assisted partial nephrectomy (Da Vinci) in an angiomyolipoma associated to Wünderlich Syndrome Arch Esp Urol 2012 65 831 4 23154607 \n17 Gyimadu AO Kara O Basaran D Esinler I Conservative management of a retroperitoneal hemorrhage following a ruptured renal angiomyolipoma in pregnancy J Obstet Gynaecol Res 2011 37 156 9 21159033 \n18 Zapardiel I Delafuente-Valero J Bajo-Arenas JM Renal angiomyolipoma during pregnancy: review of the literature Gynecol Obstet Invest 2011 72 217 9 21876331 \n19 Komeya M Matsumoto T Fujinami K Senga Y Asakura T Goto A Rupture of renal angiomyolipoma during pregnancy: A case report Hinyokika Kiyo 2010 56 261 4 20519923 \n20 Binkowska M Debska M Mazurek M Slapa R Debski R Embolization of renal angiomyolipoma in pregnancy: case report Ginekol Pol 2009 80 449 52 19642603 \n21 Kontos S Politis V Fokitis I Lefakis G Koritsiadis G Simaioforidis V et al Rupture of renal angiomyolipoma during pregnancy: a case report Cases J 2008 1 245 18928528 \n22 Koh JL Lee YH Kang CY Lin CN Simultaneous cesarean section and radical nephrectomy for angiomyolipoma with spontaneous bleeding during pregnancy: a case report J Reprod Med 2007 52 338 40 17506380 \n23 Storm DW Mowad JJ Conservative management of a bleeding renal angiomyolipoma in pregnancy Obstet Gynecol 2006 107 490 2 16449160 \n24 Raft J Lalot JM Meistelman C Longrois D Influence of pregnancy on renal angiomyolipoma Gynecol Obstet Fertil 2005 33 898 906 16256402 \n25 Oka D Mizutani S Takao T Inoue H Nishimura K Miyoshi S Spontaneous rupture of a renal angiomyolipoma in pregnancy: a case report Hinyokika Kiyo 1999 45 423 5 10442286 \n26 Yanai H Sasagawa I Kubota Y Ishigooka M Hashimoto T Kaneko H et al Spontaneous hemorrhage during pregnancy secondary to renal angiomyolipoma Urol Int 1996 56 188 91 8860742 \n27 Lee JD Chang HC Chu SH Hsueh S Soong YK Massive retroperitoneal hemorrhage from spontaneous rupture of a renal angiomyolipoma during pregnancy A case report. J Reprod Med 1994 39 477 80 7932404\n\n",
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"journal": "Turkish journal of obstetrics and gynecology",
"keywords": "Angiomyolipoma; Pregnancy; nephrectomy",
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"pages": "118-121",
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"title": "Renal angiomyolipoma during pregnancy: Case report and literature review.",
"title_normalized": "renal angiomyolipoma during pregnancy case report and literature review"
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"abstract": "Primary central nervous system (CNS) lymphoma is a rare, aggressive extranodal non-Hodgkin lymphoma confined to the brain, eyes, CSF, or spinal cord without systemic, non-CNS involvement. This article reviews the clinical presentation, imaging characteristics, diagnostic workup, novel pathophysiologic insights, and treatment of immunocompetent patients with primary CNS lymphoma.\n\n\n\nThe prognosis of primary CNS lymphoma has significantly improved over the past few decades because of the introduction of and widespread use of high-dose methotrexate, which is now the backbone of all first-line combination chemotherapy treatments. Despite this progress, durable remission is still observed in only approximately 50% of patients. Novel insights into the pathophysiology of primary CNS lymphoma have identified the B-cell receptor pathway as well as the suppressed tumor immune microenvironment and immune evasion as key mechanisms in the pathogenesis of primary CNS lymphoma. Novel, small molecules and agents targeting these aberrant pathways have been introduced into clinical trials of recurrent/refractory primary CNS lymphomas. Agents such as the Bruton tyrosine kinase (BTK) inhibitor ibrutinib or immunomodulatory drugs such as lenalidomide and pomalidomide have shown promising response rates in the relapsed setting.\n\n\n\nDiagnosis of primary CNS lymphoma requires a high level of suspicion because clinical signs and deficits can vary and depend on the involved CNS compartments. Rapid initiation of therapy is essential for recovery and prognosis. The optimal treatment regimen has not been defined, but methotrexate-based chemotherapy regimens are considered the standard treatment approach for induction treatment. Novel, targeted agents have recently been introduced into the therapeutic arsenal.",
"affiliations": null,
"authors": "Grommes|Christian|C|",
"chemical_list": "D008727:Methotrexate",
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"issue": "26(6)",
"journal": "Continuum (Minneapolis, Minn.)",
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"medline_ta": "Continuum (Minneap Minn)",
"mesh_terms": "D002490:Central Nervous System; D016543:Central Nervous System Neoplasms; D006801:Humans; D008228:Lymphoma, Non-Hodgkin; D008727:Methotrexate; D009364:Neoplasm Recurrence, Local; D059016:Tumor Microenvironment",
"nlm_unique_id": "9509333",
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"pages": "1476-1494",
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"references": null,
"title": "Central Nervous System Lymphomas.",
"title_normalized": "central nervous system lymphomas"
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"abstract": "Muscle involvement is a common manifestation of both clinical and subclinical hypothyroidism, with serum creatine kinase (CK) elevation being probably the most common manifestation, and is seen in up to 90% of patients, but is usually mild (less than 10 times the upper limit of normal). Rhabdomyolysis is a distinctively uncommon presentation of hypothyroidism described usually in the setting of precipitating events such as strenuous exercise, alcohol, or statin use. Rarely rhabdomyolysis and myoedema seen in hypothyroidism can be complicated by the development of anterior compartment syndrome leading to neurovascular compression. We describe a case of a patient with hypothyroidism who developed acute onset bilateral foot drop on initiation of statins. This case highlights the need for cautious use of statins in patients at risk for rhabdomyolysis.",
"affiliations": "Department of Neurology, Govind Ballabh Pant Hospital, New Delhi, India.;Department of Neurology, Govind Ballabh Pant Hospital, New Delhi, India.;Department of Neurology, Govind Ballabh Pant Hospital, New Delhi, India.;Department of Neurology, Govind Ballabh Pant Hospital, New Delhi, India.;Department of Neurology, Govind Ballabh Pant Hospital, New Delhi, India.",
"authors": "Chaudhary|Neera|N|;Duggal|Ashish Kumar|AK|;Makhija|Prashant|P|;Puri|Vinod|V|;Khwaja|Geeta Anjum|GA|",
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"fulltext": "\n==== Front\nAnn Indian Acad NeurolAnn Indian Acad NeurolAIANAnnals of Indian Academy of Neurology0972-23271998-3549Medknow Publications & Media Pvt Ltd India AIAN-18-33110.4103/0972-2327.157251Case ReportStatin-induced bilateral foot drop in a case of hypothyroidism Chaudhary Neera Duggal Ashish Kumar Makhija Prashant Puri Vinod Khwaja Geeta Anjum Department of Neurology, Govind Ballabh Pant Hospital, New Delhi, IndiaFor correspondence: Dr. Neera Chaudhary, Department of Neurology, Academic Block, Room No. 511, Govind Ballabh Pant Hospital, New Delhi - 110 002, India. E-mail: neerachaudhry@gmail.comJul-Sep 2015 18 3 331 334 05 10 2014 19 11 2014 25 12 2014 Copyright: © Annals of Indian Academy of Neurology2015This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Muscle involvement is a common manifestation of both clinical and subclinical hypothyroidism, with serum creatine kinase (CK) elevation being probably the most common manifestation, and is seen in up to 90% of patients, but is usually mild (less than 10 times the upper limit of normal). Rhabdomyolysis is a distinctively uncommon presentation of hypothyroidism described usually in the setting of precipitating events such as strenuous exercise, alcohol, or statin use. Rarely rhabdomyolysis and myoedema seen in hypothyroidism can be complicated by the development of anterior compartment syndrome leading to neurovascular compression. We describe a case of a patient with hypothyroidism who developed acute onset bilateral foot drop on initiation of statins. This case highlights the need for cautious use of statins in patients at risk for rhabdomyolysis.\n\nAnterior tibial compartment syndromefoot dropstatins\n==== Body\nIntroduction\nA variety of central and peripheral nervous system manifestations are common in patients with hypothyroidism. Muscle involvement is a common manifestation of hypothyroidism and its severity may vary from asymptomatic elevation of serum creatine kinase (CK) to disabling muscle weakness.[1] Rhabdomyolysis is a rare but important neuromuscular complication of hypothyroidism and is usually precipitated by strenuous exercise or statin use.[23] Rhabdomyolysis can cause a number of systemic complications, most notably acute renal failure. In addition rarely, muscle edema and rhabdomyolysis can cause increased pressure in the anterior tibial compartment resulting in neurovascular compression. We describe a patient with acute onset bilateral foot drop as a result of acute anterior tibial compartment syndrome (ATCS) in the setting of uncontrolled hypothyroidism and statin use.\n\nCase Report\nA 51-year-old male presented to us with complaints of acute onset bilateral foot drop of 1-dayduration. On detailed evaluation he came out with a history of hoarseness of voice for 2 months prior to the onset of foot drop. He described that his voice had become heavy and thick, making it difficult for others to understand him. He was investigated and was found to have hypothyroidism (thyroid-stimulating hormone (TSH) = 112.42μIU/ml) and his lipid profile was deranged, with elevated serum cholesterol (428 mg%) and low-density lipoprotein (LDL) cholesterol (348 mg%) for which he was prescribed levothyroxine (LT4; 50 μg/day) and atorvastatin (40 mg/day) by a private practitioner. One week into the treatment he developed severe pain in his legs which was predominantly localized in the shin along with swelling and redness and within 4 days of this pain he developed sudden onset weakness in both feet in the form of being unable to move his toes and had difficulty in clearing his feet off the ground, for which he presented to our hospital. He denied any history of unusual or excessive exercise, fever, or having taken alcohol. On examination at the time of admission, his vital were stable with a pulse rate of 62/min and blood pressure of 110/72 mmHg. Non-pitting edema with overlying erythema was present on both legs without any muscle wasting and both dorsalis pedis were well palpable. Neurological examination revealed weakness of dorsiflexion at ankle joint (Medical Research Council (MRC1/5)) and eversion at subtalar joint (MRC1/5) with normal inversion, thereby, suggesting bilateral common peroneal palsy. Deep tendon reflexes were normal except ankle reflex which was absent. Other than loss of vibration at big toe, sensory examination was unremarkable.\n\nHemogram revealed hemoglobin concentration of 12.7 g%. The white blood cell count was 16,700 cells/mm3 with 84% polymorphs and toxic granules. Kidney function tests and serum bilirubin were normal, but serum glutamic oxaloacetic transaminase (SGOT) and serum glutamatepyruvate transaminase (SGPT) were mildly elevated (91 and 122 IU/L, respectively). Creatine phosphokinase (CPK) was markedly raised at 6,459IU/L. Free triiodothyronine (T3;1.50 pg/ml) and free thyroxine (T4;0.557 ng/ml) were low and TSH was raised markedly (49.53 μIU/ml). Nerve conduction studies revealed extremely low amplitudes in left common peroneal nerve, while right common peroneal was nonexcitable. Other than markedly reduced compound muscle action potentials in both common peroneal nerves, nerve conduction studies were normal. An ultrasound of the legs revealed bulky superficial muscles of anterolateral aspect of right leg with loss of normal fibrillarypattern and ill-defined hypoechoic areas. Magnetic resonance imaging (MRI) of the legs revealed heterogeneous hypointense signal on T1-weighted imaging (T1WI) and a hyperintense signal on T2-short tau inversion recovery (STIR) weighted images in the anterior and lateral compartment muscles with loss of striations which was consistent with swelling, inflammation, and necrosis of these muscles [Figure 1]. A diagnosis of hypothyroidism with severe myopathy with rhabdomyolysis and acute ATCS causing bilateral common peroneal nerve palsy was made. Atorvastatin was stopped, and patient was continued on LT4 with subsequent improvement in the pain and swelling of the legs, but there was only minimal improvement in the weakness of the feet.\n\nFigure 1 Axial T2-STIR weighted images of legs showing heterogeneous hyperintense signal in the tibialis anterior and peronei on the right side and tibialis anterior on left side. STIR = Short tau inversion recovery\n\nDiscussion\nMuscle involvement is a common manifestation of both clinical and subclinical hypothyroidism.[1] Symptomatic muscle disease, however, is less common. Myopathymay develop concurrently with hypothyroidism or may prefacebiochemical hypothyroidism.[4] The clinical features of hypothyroid myopathy include weakness, cramps, aching or painful muscles, sluggish movements and reflexes, and myoedema (mounding up of the muscle on percussion).[5] There may also be an increase in muscle bulk. CK elevation, although common is usually less than 10 times the upper limit of normal in hypothyroidism.[1] Rarely rhabdomyolysis associated with hypothyroidism, in some cases leading to renal failure has been reported in literature as well.[6] This may occur spontaneously or may be precipitated by strenuous exercise, alcohol consumption, or use of statins as was seen in our case as well. Clinically patients present with a classical triad of muscle pain, weakness, and dark urine; though more than half of patients may not report muscular symptoms or dark urine.[7] Although the CK level does not correlate with the severity of the myopathic process, but CK levels greater than 1,500 IU/L are usually associated with rhabdomyolysis as was seen in our case.[8] The other characteristic finding seen in rhabdomyolysis is the reddish-brown discoloration of urine because of myoglobinuria. This may be observed in only half of cases because filtered load of myoglobin may be insufficient or has largely resolved before the patient seeks medical attention due to its rapid clearance as may have happened in our case. Complications include fluid and electrolyte abnormalities, hepatic injury, cardiac dysrhythmias, acute kidney injury, disseminated intravascular coagulation, and compartment syndrome.[9] ATCS as a complication of rhabdomyolysis secondary to hypothyroidism is a rather rare condition. ATCS is most commonly unilateral. Bilateral involvement though seen is rare and present only in around <10% of cases.[10] ATCS can result from causes that decrease the size of the compartment or by those increasing its contents. In hypothyroidism, several factors may be conducive to the development of ATCS. The contents of the anterior tibial compartment can increase because of interstitial edema and in some cases from true muscle hypertrophy. Skeletal muscle hypertrophy occurs in 1% of cases of myxedema myopathy and is referred to as Hoffman's syndrome in adults and as Kocher-Debre-Semelaigne syndrome in infants and children.[11] In our case also there was radiological evidence of enlargement of muscles of the anterior compartment with loss of fibrillary pattern resulting in increased compartment size and compression of the neural structures. Additionally, extravasation of protein-rich fluid in the interstitium because of an increase in the capillary permeability and slow lymphatic drainage can also result in increasing the size of the compartment.[12] A decrease in the compartment size can occur because of connective tissue proliferation in myxedema, and thus contribute to the development of ATCS which could cause compression of the deep peroneal nerve and resultant foot drop.[13] Alternatively, deposition of glycosaminogly cans in the perineural sheath of the deep peroneal nerve could also be responsible for the bilateral symmetrical foot drop observed in our patient.[5] Yasuoka et al., had reported a case of unilateral deep peroneal nerve palsy associated with hypothyroidism which recovered completely with LT4 replacement. They postulated that focal edema and glycosaminogly can deposition in the perineural sheath was responsible for the reversible conduction block of the deep peroneal nerve.[14]\n\nATCS in the setting of uncontrolled hypothyroidism was first reported by Thacker et al., in 1993.[15] ATCS complicating rhabdomyolysis in the setting of hypothyroidism is distinctly rare and to our knowledge there are only five case reported so far [Table 1]. Although surgical release has been tried in ATCS associated with hypothyroidism, it has not been much rewarding and conservative management has yielded similar results, unlike traumatic ATCS in which surgical decompression has consistently yielded good results.[17]\n\nTable 1 Summary of cases of anterior compartment syndrome complicating rhabdomyolysis in patients with hypothyroidism\n\nOur patient had symptoms of hypothyroidism and investigations revealed an altered lipid profile, because of which he was started on atorvastatin along with LT4. The addition of lipid lowering agents in a patient predisposed to myopathy can have disastrous consequences as was evident in this case. It is important to realize that hypothyroidism itself can be responsible for dyslipidemia. In fact American Thyroid Association recommends that patients with newly diagnosed hyperlipidemia be screened for hypothyroidism prior to starting a lipid-lowering agent.[20] In addition, hypothyroidism is a known risk factor for statin-induced myopathy.[21] It is pertinent that all patients with hyperlipidemia associated with overt hypothyroidism be treated with LT4 therapy first before starting statins, because 4-6 weeks of replacement therapy may correct dyslipidemia in patients with overt hypothyroidism. This is necessary because it has been observed that these patients often have a poor therapeutic response to satins and concomitant use of lipid-lowering drugs with LT4in such patients carries a higher risk of myopathy including rhabdomyolysis as was evident in our patient. If the lipid profile remains deranged after 4-6 weeks of LT4therapy, lipid-lowering medications may be started if the TSH levels have become normal.[22] Even then it is necessary to keep an eye for symptoms of myopathy since rhabdomyolysis and its complications can be a cause of severe morbidity and mortality.\n\nTo conclude, anterior compartment syndrome (ACS) and rhabdomyolysis are rare complications of hypothyroid myopathy. In the present era, when use of statins is highly prevalent, physicians should be aware of this complication of statin use in patients with hypothyroidism. Two important clinical learning points are emphasized by this case. Firstly in patients with overt hypothyroidism, LT4 therapy alone may be sufficient to correct dyslipidemia and use of statins in uncontrolled hypothyroidism may be deleterious even when used in combination with LT4. Secondly, hypothyroidism should be ruled out in cases of spontaneous nontraumatic anterior compartment syndrome. It is important to be aware of these complications because early diagnosis can help in preventing unnecessary surgical therapy and potential disability.\n\nSource of Support: Nil\n\nConflicts of Interest: None declared.\n==== Refs\n1 Duyff RF Van den Bosch J Laman DM van Loon BJ Linssen WH Neuromuscular findings in thyroid dysfunction: A prospective clinical and electrodiagnostic study J Neurol Neurosurg Psychiatry 2000 68 750 5 10811699 \n2 Riggs JE Acute exertional rhabdomyolysis in hypothyroidism: The result of a reversible defect in glycogenolysis? Mil Med 1990 155 171 2 2110339 \n3 Antons KA Williams CD Baker SK Phillips PS Clinical perspectives of statin-induced rhabdomyolysis Am J Med 2006 119 400 9 16651050 \n4 Kung AW Ma JT Yu YL Wang CC Woo EK Lam KS Myopathy in acute hypothyroidism Postgrad Med J 1987 63 661 3 3422868 \n5 Swanson JW Kelly JJ Jr McConahey WM Neurologic aspects of thyroid dysfunction Mayo Clin Proc 1981 56 504 12 7266060 \n6 Kursat S Alici T Colak HB A case of rhabdomyolysis induced acute renal failure secondary to statin-fibrate-derivative combination and occult hypothyroidism Clin Nephrol 2005 64 391 3 16312269 \n7 Knochel JP Rhabdomyolysis and myoglobinuria Annu Rev Med 1982 33 435 43 6282181 \n8 Melli G Chaudhry V Cornblath DR Rhabdomyolysis: An evaluation of 475 hospitalized patients Medicine (Baltimore) 2005 84 377 85 16267412 \n9 Huerta-Alardín AL Varon J Marik PE Bench-to-bedside review: Rhabdomyolysis — An overview for clinicians Crit Care 2005 9 158 69 15774072 \n10 Mubarak SJ Hargens AR Acute compartment syndromes Surg Clin North Am 1983 63 539 65 6346542 \n11 Ramsay ID Endocrine myopathies Practitioner 1982 226 1075 80 7111140 \n12 Parving HH Hansen JM Nilsen SV Rossing N Munck O Lassen NA Mechanisms of edema formation in myxedema — increased protein extravasation and relatively slow lymphatic drainage N Engl J Med 1979 301 460 5 460364 \n13 Bland JH Frymoyer JW Rheumatic syndromes of myxedema N Engl J Med 1970 282 1171 4 5309661 \n14 Yasuoka T Yokota T Tsukagoshi H Deep peroneal nerve palsy associated with hypothyroidism No To Shinkei 1993 45 563 6 8395865 \n15 Thacker AK Agrawal D Sarkari NB Bilateral anterior tibial compartment syndrome in association with hypothyroidism Postgrad Med J 1993 69 881 3 8290438 \n16 Bhansali A Chandran V Ramesh J Kashyap A Dash RJ Acute myoedema: An unusual presenting manifestation of hypothyroid myopathy Postgrad Med J 2000 76 99 100 10644388 \n17 Muir P Choe MS Croxson MS Rapid development of anterotibial compartment syndrome and rhabdomyolysis in a patient with primary hypothyroidism and adrenal insufficiency Thyroid 2012 22 651 3 22568398 \n18 Hsu SI Thadhani RI Daniels GH Acute compartment syndrome in a hypothyroid patient Thyroid 1995 5 305 8 7488873 \n19 Ramdass MJ Singh G Andrews B Simvastatin-induced bilateral leg compartment syndrome and myonecrosis associated with hypothyroidism Postgrad Med J 2007 83 152 3 17344566 \n20 Ladenson PW Singer PA Ain KB Bagchi N Bigos ST Levy EG American thyroid association guidelines for detection of thyroid dysfunction Arch Intern Med 2000 160 1573 5 10847249 \n21 Morris MS Bostom AG Jacques PF Selhub J Rosenberg IH Hyperhomocysteinemia and hypercholesterolemia associated with hypothyroidism in the third US National Health and Nutrition Examination Survey Atherosclerosis 2001 155 195 200 11223442 \n22 Monzani F Caraccio N Kozakowa M Dardano A Vittone F Virdis A Effect of levothyroxine replacement on lipid profile and intima media thickness in subclinical hypothyroidism: A double blind, placebo- controlled study J Clin Endocrinol Metab 2004 89 2099 106 15126526\n\n",
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"issue": "18(3)",
"journal": "Annals of Indian Academy of Neurology",
"keywords": "Anterior tibial compartment syndrome; foot drop; statins",
"medline_ta": "Ann Indian Acad Neurol",
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"title": "Statin-induced bilateral foot drop in a case of hypothyroidism.",
"title_normalized": "statin induced bilateral foot drop in a case of hypothyroidism"
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"abstract": "BACKGROUND\nMost patients with pancreatic masses pose a diagnostic challenge when a benign lesion is suspected, and often, resection is needed before a benign diagnosis is confirmed.\n\n\nMETHODS\nA 57 years old male patient presented with a pancreatic head mass, obstructive jaundice and submandibular lymph node enlargement. He also had a history of recurrent eye pain and redness, skin lesions, and benign prostatic hypertrophy. MRI showed a pancreatic head mass with double duct sign, aortic thickening, bilateral renal lesions, diffuse lymph node enlargement, and prostatic enlargement. FDG-PET/CT demonstrated abnormal uptake corresponding to the MRI lesions, and there were elevated IgG4 levels on blood investigations. Biopsy of an inguinal lymph node revealed infiltrates with IgG4 plasma cells, consistent with the diagnosis of IgG4 disease. The patient was treated with IV steroids and showed significant improvement.\n\n\nCONCLUSIONS\nIgG4 related disease is a rare entity that is characterized by lesions that show heavy infiltration with IgG4 positive plasma cells, storiform fibrosis, and obliterative phlebitis. The pancreas is the most commonly involved organ, but several other organ systems are involved, and this helps in clinical suspicion of the diagnosis. A biopsy from any easily accessible site that shows the characteristic histological features is sufficient for diagnosis. Patients respond quickly to steroids, but recurrence is frequent.\n\n\nCONCLUSIONS\nIgG4 related disease is a rare cause of pancreatic tumorous lesions that need a high index of suspicion for diagnosis and should be differentiated from pancreatic neoplastic lesions.",
"affiliations": "Department of Surgery, Division of Organ Transplant, Hamad General Hospital, Doha, PO Box 3050, Qatar. Electronic address: isulieman@hamad.qa.;Department of Radiology, Hamad General Hospital, Doha, PO Box 3050, Qatar. Electronic address: AMAHFOUZ@hamad.qa.;Department of Pathology, Hamad General Hospital, Doha, PO Box 3050, Qatar. Electronic address: EALKUWARI@hamad.qa.;Department of Nuclear Medicine, Hamad General Hospital, Doha, PO Box 3050, Qatar. Electronic address: LSZABADOS@hamad.qa.;Department of Surgery, Division of Organ Transplant, Hamad General Hospital, Doha, PO Box 3050, Qatar. Electronic address: wshehata@hamad.qa.;Department of Surgery, Division of Organ Transplant, Hamad General Hospital, Doha, PO Box 3050, Qatar. Electronic address: AElaffandi@hamad.qa.;Department of Surgery, Division of Organ Transplant, Hamad General Hospital, Doha, PO Box 3050, Qatar. Electronic address: HKhalaf2@hamad.qa.",
"authors": "Sulieman|Ibnouf|I|;Mahfouz|Ahmed|A|;AlKuwari|Einas|E|;Szabados|Lajos|L|;Elmoghazy|Walid|W|;Elaffandi|Ahmed|A|;Khalaf|Hatem|H|",
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"doi": "10.1016/j.ijscr.2018.07.030",
"fulltext": "\n==== Front\nInt J Surg Case RepInt J Surg Case RepInternational Journal of Surgery Case Reports2210-2612Elsevier S2210-2612(18)30280-310.1016/j.ijscr.2018.07.030ArticleIgG4-related disease mimicking pancreatic cancer: Case report and review of the literature Sulieman Ibnouf isulieman@hamad.qaa⁎Mahfouz Ahmed AMAHFOUZ@hamad.qabAlKuwari Einas EALKUWARI@hamad.qacSzabados Lajos LSZABADOS@hamad.qadElmoghazy Walid wshehata@hamad.qaaElaffandi Ahmed AElaffandi@hamad.qaaKhalaf Hatem HKhalaf2@hamad.qaaa Department of Surgery, Division of Organ Transplant, Hamad General Hospital, Doha, PO Box 3050, Qatarb Department of Radiology, Hamad General Hospital, Doha, PO Box 3050, Qatarc Department of Pathology, Hamad General Hospital, Doha, PO Box 3050, Qatard Department of Nuclear Medicine, Hamad General Hospital, Doha, PO Box 3050, Qatar⁎ Corresponding author. isulieman@hamad.qa31 7 2018 2018 31 7 2018 50 100 105 12 7 2018 26 7 2018 © 2018 The Authors2018This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Highlights\n• Pancreatic masses pose a diagnostic challenge, and cancer has to be always considered.\n\n• IgG4-related disease is a rare cause of pancreatic masses.\n\n• Biopsy from the pancreas is not always required if histopathology from a more accessible peripheral site lesion confirms the diagnosis.\n\n• Multiorgan involvement and aortitis should raise suspicion of IgG4-related disease.\n\n\n\nIntroduction\nMost patients with pancreatic masses pose a diagnostic challenge when a benign lesion is suspected, and often, resection is needed before a benign diagnosis is confirmed.\n\nPresentation of case\nA 57 years old male patient presented with a pancreatic head mass, obstructive jaundice and submandibular lymph node enlargement. He also had a history of recurrent eye pain and redness, skin lesions, and benign prostatic hypertrophy. MRI showed a pancreatic head mass with double duct sign, aortic thickening, bilateral renal lesions, diffuse lymph node enlargement, and prostatic enlargement. FDG-PET/CT demonstrated abnormal uptake corresponding to the MRI lesions, and there were elevated IgG4 levels on blood investigations. Biopsy of an inguinal lymph node revealed infiltrates with IgG4 plasma cells, consistent with the diagnosis of IgG4 disease. The patient was treated with IV steroids and showed significant improvement.\n\nDiscussion\nIgG4 related disease is a rare entity that is characterized by lesions that show heavy infiltration with IgG4 positive plasma cells, storiform fibrosis, and obliterative phlebitis. The pancreas is the most commonly involved organ, but several other organ systems are involved, and this helps in clinical suspicion of the diagnosis. A biopsy from any easily accessible site that shows the characteristic histological features is sufficient for diagnosis. Patients respond quickly to steroids, but recurrence is frequent.\n\nConclusion\nIgG4 related disease is a rare cause of pancreatic tumorous lesions that need a high index of suspicion for diagnosis and should be differentiated from pancreatic neoplastic lesions.\n\nAbbreviations\nIgG4, immunoglobulin-G4 related diseaseFNAC, fine needle aspiration cytologyIgG, immunoglobulin GBPH, benign prostatic hyperplasiaAST, aspartate aminotransferaseALT, alanine aminotransferaseMRI, magnetic resonance imagingMRCP, magnetic resonance cholangio-pancreatographyGFR, glomerular filtration rateAFP, alfa feto proteinCEA, carcinoembryonic antigenHBV, hepatitis B virusHCV, hepatitis C virusEUS, endoscopic ultrasoundFDG-PET, fluorodeoxyglucose positron emission tomographyAIP, autoimmune pancreatitisKeywords\nIgG4 related diseasePancreas lesionsAutoimmune pancreatitisCase report\n==== Body\n1 Introduction\nMost patients with a pancreatic mass pose a diagnostic challenge when a benign lesion is suspected, and often, resection is needed before a benign pathology is confirmed. IgG4 Related Disease (IgG4-RD) is a rare cause of pancreatic mass lesions that should be kept in the differential diagnosis, as a pancreatic biopsy may be avoided if the disease is suspected and identified.\n\nThe patient in this case report was treated at our General Hospital, which is an academic medical center and part of a Medical Corporation. This manuscript has been reported following the SCARE guidelines [1].\n\n2 Presentation of the case\nWe are presenting the case of a 57 years old male patient who was referred to us with a pancreatic head mass and obstructive jaundice. He is a known case of hyperuricemia, gouty arthritis, chronic renal impairment, Diabetes Mellitus, and hypertension.\n\nHis condition started about two years before this presentation with recurrent nasal obstruction and eye dryness and itching, with multiple visits to the emergency department. He was diagnosed as allergic rhinitis and conjunctivitis and was maintained on antihistamines and eye drops. Six months after onset, he developed bilateral submandibular swellings, more on the left side, and cervical ultrasound examination showed enlargement of multiple cervical lymph nodes with an appearance most likely representing proliferative lymphadenopathy. Fine needle aspiration cytology (FNAC) did not show any evidence of malignancy, and the diagnosis of reactive lymphadenopathy was confirmed. A few months later, the patient presented to the dermatology clinic with hyperpigmented skin lesions in the groin and hyperkeratotic lesions in both feet and received topical treatments with no improvement. He was kept on regular follow up and was seen by hematology to rule out the possibility of malignancy, and multiple investigations were done, including a serum immunoglobulin levels that showed a high IgG level of >2000, but no diagnosis was reached at that time. The patient again frequently presented to the emergency department with recurrent symptoms of eye pain and redness and was treated with antihistamines and antibiotics. He also developed obstructive urinary symptoms, and was diagnosed with benign prostatic hypertrophy (BPH) and was started on tamsulosin.\n\nOne month before his presentation, routine lab tests showed high AST and ALT levels, and he was referred to Gastroenterology. By the time he was seen he had developed jaundice, dark urine, and pale stools, with 8 Kg unintentional weight loss (over four weeks) and mild dilatation of the biliary system on ultrasound examination. MRI/MRCP (Fig. 1) revealed dilated biliary and pancreatic ducts (double duct sign) with a pancreatic head mass, multiple wedge-shaped lesions in both kidneys, significant aortic thickening suggestive of aortitis/Peri-aortitis, and cervical, mediastinal and intra-abdominal lymph node enlargement. His liver function tests were significantly abnormal (total bilirubin: 151, direct bilirubin: 113, ALP: 251, ALT: 30, AST: 50), and renal functions tests still showed renal impairment with a GFR of 51 ml/min, but the blood cell counts were normal. Serology for HBV and HCV were negative, and his AFP, CA 19-9, CA 15.3, and CEA were within normal. Total IgG was elevated at 2560, with elevation in all the subclasses as follows: IgG1: 1420, IgG2: 831, IgG3: 265, IgG4: 1980 (mg/dl). C3 and C4 were within normal, and his urine analysis showed no proteinuria. Endoscopic ultrasound (EUS) showed enlarged mediastinal lymph nodes and a bulky pancreatic head suggestive of pancreatic malignancy or autoimmune pancreatitis, and EUS guided FNAC samples taken from both sites showed only a few atypical cells, with no evidence of malignancy or metastatic carcinoma. An FDG PET/CT scan (Fig. 2) showed intense circumferential uptake in the abdominal aorta corresponding to the MRI findings, and suggestive of aortitis. Hypermetabolic enlarged lymph nodes were seen above and below the diaphragm as well as an irregular small pulmonary infiltrate, and the lacrimal and major salivary glands were also hypermetabolic. The pancreatic head mass and the renal cortical lesions seen on MRI showed intense FDG uptake as well, and the overall picture was suggestive of lymphoma.Fig. 1 MR imaging of the abdomen in IgG4-related disease.\n\nA) Magnetic resonance cholangiopancreatography (MRCP) shows interruption of the dilated pancreatic duct (arrow) and the common bile duct (hollow arrow) at the pancreatic head (double duct sign).\n\nB) Coronal T2-weighted MR image shows a pancreatic head lesion (arrow) obstructing the common bile duct (hollow arrow).\n\nC) Coronal T2-weighted MR image shows multiple bilateral renal lesions.\n\nD) Transverse steady-state free precession MR image shows thickening of the wall of the abdominal aorta (arrow).\n\nFig. 1Fig. 2 FDG PET/CT: FDG PET/CT maximum intensity projection (upper row) and fused trans-axial images (lower row) showing multiple lymph nodal involvement, lacrimal/salivary gland uptake, a right pulmonary focus, a hypermetabolic pancreatic head lesion, renal cortical lesions, and intense circumferential uptake in the abdominal aorta.\n\nFig. 2\n\nThe patient was discussed in the hepatobiliary multi-disciplinary meeting with the principal differential diagnoses reached being lymphoma or Immunoglobulin-4 related disease (IgG4-RD), and lymph node biopsy was recommended. He underwent inguinal lymph node biopsy. Histopathological examination of the lymph node, which measured 1.8 cm in maximum dimension, showed many lymphoid follicles with prominent germinal centers consistent with reactive follicular hyperplasia. In addition, there was a marked expansion of paracortical areas with a dense plasma cell infiltrate. Areas of fibrosis including fibrotic thickened blood vessels were noted. The inflammatory infiltrates extended into para-nodal tissue. Immunohistochemistry studies confirmed a reactive nature of the lymphoid follicles (CD10+, BCL6+, and BCL2-). The plasma cells-infiltrate was CD138+, most of which were IgG positive cells and more than 30 IgG4 positive cells were seen per high power field. Kappa and Lambda immunohistochemical stains showed no light chain restriction. The overall morphology and Immunohistochemistry were consistent with IgG4-related disease (Fig. 3).Fig. 3 Histopathology.\n\nA) Low power examination of the lymph node showed a lymphoid follicle with a reactive germinal center and part of an expanded paracortical area with dense infiltrate.\n\nB) High power examination showed a marked plasma cells infiltrate.\n\nC) Immunohistochemical stain for CD138 highlighted many plasma cells, some of which are seen inside the germinal center.\n\nD) IgG4 Immunohistochemical stain revealed more than 30 cells seen per high power field.\n\nFig. 3\n\nThese findings confirmed the diagnosis of IgG4-RD with multiple manifestations including a pancreatic lesion, aortitis and peri-aortitis, bilateral renal lesions, diffuse lymph node involvement, lacrimal and salivary gland lesions, and cutaneous manifestations, with a possible pulmonary lesion. The patient was started on intravenous pulsed steroids (Methylprednisolone 500 mg daily) for three days, followed by oral prednisolone 40 mg daily and he showed a rapid clinical response. The bilirubin level dropped to 54 mmol/l at four weeks. Eight months after the onset of treatment, the patient was asymptomatic, with complete resolution of the lymphadenopathy, jaundice, skin lesions, allergic and conjunctival manifestations, and the obstructive urinary symptoms.\n\n3 Discussion\nIgG4 related disease is a recently described entity, first designated in 2003, that includes variable organ manifestations, many of which used to have different groupings and nomenclatures [2]. The diagnosis relies on the characteristic pathological features that are identical in all of the involved organs and include: heavy plasmacytic infiltrates with IgG4 producing plasma cells, storiform fibrosis, and obliterative phlebitis [3]. The possible mechanisms for etiology and pathogenesis include autoimmunity (whether being an autoimmune disorder itself or a down-regulatory mechanism for another autoimmune entity), and allergy, but this is still not fully understood [3,4].\n\nThe disease affects many organs and organ systems in the body, and this leads to variable presentations that may seem nonspecific or unrelated, contributing to the long delay before diagnosis, as seen in this patient who was diagnosed after two years of follow up and investigations. However, the most common manifestations are autoimmune pancreatitis, salivary gland disease, orbital/lacrimal gland disease, and retroperitoneal fibrosis [5,6]\n\nThis patient presented at the age of 57 years, which is consistent with the epidemiology of the IGG4-RD as it mainly affects middle-aged and elderly males, except in limited cervicofacial disease, where men and women are affected equally [7]. At presentation, multiple organ involvement is present in 60–90% of the cases, and most of the patients have lymphadenopathy, most frequently involving the cervical, mediastinal, and retroperitoneal lymph nodes. However, some patients may present initially with lymphadenopathy only, as seen in this patient, making the diagnosis difficult, even with a biopsy. Weight loss is common and progressive during the long workup stage despite the patient being generally well with no systemic manifestations, as evident in this patient. Allergic symptoms were also noted in this patient and as have been described in many patients with IGG4-RD [7,8].\n\nAutoimmune pancreatitis is the typical and most common manifestation. It can present with diffuse enlargement of the gland or as in our case, with a pancreatic mass, making differentiation from pancreatic cancer difficult [9]. Closely associated is IgG4 related sclerosing cholangitis, which should be distinguished from primary sclerosing cholangitis and cancer. The diagnosis is challenging but is mainly based on identifying the characteristic histological features in other organs due to the difficulty in obtaining adequate biopsies from the bile ducts [10].\n\nSalivary and lacrimal gland involvement is also common in IgG4-RD. It may present with dryness, enlargement, and tumors, and is one of the causes of proptosis and orbital pseudotumor [11]. Lacrimal gland involvement most likely explains the recurrent eye symptoms in our patient, especially that the PET scan showed lacrimal gland uptake, although pure allergic conjunctivitis and rhinitis could also be the cause as they are common in IgG4-RD. Our patient’s images showed impressive aortitis and peri-aortitis seen as a thickening in the MRI and increased uptake in the FDG-PET scans, and this is one of the features of the disease, where the infrarenal aorta is most frequently involved. Aortitis and peri-aortitis can lead to dissection or aneurysms as a complication, and this is more likely with pre-existing aneurysms [12]. The disease may also affect other parts of the retroperitoneum resulting in fibrosis.\n\nThis patient had renal involvement evident as wedge-shaped lesions on the MRI and focal cortical uptakes on PET-CT, and this is consistent with the diagnosis. Renal involvement in IgG4-RD includes tubulointerstitial nephritis, glomerulonephritis, and membranous nephropathy [13]. Ureteric involvement in retroperitoneal fibrosis can also result in obstruction and hydroureter and hydronephrosis. Skin manifestations have also been described, and this includes macules, papules, plaques, and bullae, and these cutaneous manifestations can sometimes be mistaken for lymphoma. The skin lesions in this patient (bilateral foot macules and desquamation) could be part of the disease process, supported by the resolution of the lesion on steroid treatment, but this needs to be confirmed by skin biopsy. Other organs that can be involved include the pericardium, the breasts, and the central nervous system [7]. Of note is that prostatitis has also been described as part of the disease, and whether the prostatic enlargement and increased FDG uptake in this patient is part of IGG4-RD remains to be proved, but the improvement of symptoms upon steroid treatment is in support of this.\n\nThe diagnosis of IGG4-RD relies on clinical evaluation, laboratory tests, and imaging, but the gold standard remains biopsy and histopathology. Diagnostic criteria that classify the diagnosis based on these findings into definite, possible and probable have been described by Umehara and colleagues [14]. Thorough clinical history and examination are very important given the broad patterns of organ involvement, and clinical findings are sufficient if the biopsy is positive in one site. Biopsies are best obtained from the affected organs by core needle from the obvious lesions, and fine needle aspiration cytology is not useful for the diagnosis [15]. The characteristic histological features include: dense lymphoplasmacytic infiltrates with high levels of IgG4 producing plasma cells, storiform fibrosis, obliterative phlebitis, and eosinophilic infiltrates. Recent diagnostic guidelines suggest that more than 30–50 IgG4 staining cells per high power field (HPF) are needed for diagnosis [16,17]. Plasma IgG4 levels are usually elevated (>135 mg/dl), but they are not diagnostic alone as they may be raised in other conditions. IgG4 levels also do not correlate with the activity of the disease. Blood plasmablast levels are characteristically elevated, and they correlate well with the activity of the disease; however the tests are not widely available. Recently, Hubers and Beuers demonstrated that measuring the serum IgG/IgG4 RNA ratio with PCR can accurately distinguish IgG4-RD from primary sclerosing cholangitis and pancreatic and biliary malignancy [18]. After establishing the diagnosis, patients require imaging studies such as CT scans and FDG-PET of the neck, chest, abdomen, and pelvis, to determine the extent of the disease. Renal involvement is assessed by urine analysis for proteinuria and serum C3 and C4 levels (which are characteristically low in Tubulointerstitial Nephritis) [13].\n\nMost of the current guidelines for the management of IGG4-RD are derived from observational trials with few RCTs addressing the issue [8]. The standard treatment is steroids (Prednisolone 40 mg/day), and a good response within 2–4 weeks is characteristic of the disease and may help to establish the diagnosis [8,19,20,15]. Non-response to steroids is unusual, and the diagnosis of IgG4-RD should be questioned in these cases. Induction steroid therapy is started on all symptomatic patients and in some asymptomatic patients, depending on the pattern of disease involvement (mild lymphadenopathy does not need treatment), and some patients may require maintenance steroid therapy. Relapse is treated either with further steroid courses or with steroid-sparing agents including azathioprine and mycophenolate mofetil. Rituximab, a B cell-depleting agent, also results in good response [21].\n\n4 Conclusion\nIGG4-RD is one of the causes of a pancreatic mass that should be kept in the differential diagnosis, especially in the setting of multiple organ involvement. Blood investigations help in detecting the disease, but the gold-standard for diagnosis is formal histopathology from any of the accessible lesions. The pancreatic lesion should not be biopsied if the diagnosis can be confirmed by biopsy from a more accessible peripheral site, and rapid response to steroids is characteristic.\n\nConflict of interest\nNo conflict of interest.\n\nFunding\nThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\n\nEthical approval\nThe case report was approved by the Medical Research Centre of Hamad Medical Corporation (ABHATH) on March 20, 2018.\n\nProtocol ID MRC-04-18-077.\n\nConsent\nA written informed consent was obtained from the patient and is ready for review.\n\nAuthor contribution\nIbnouf Sulieman: Main author. Contributed to the wiring of the case report, discussion and literature review, obtaining the required consents and ethical approvals, and the writing up of the manuscript.\n\nAhmed Mahfouz: Senior radiologist: Had major input in the diagnosis and interpretation of the images; provided the images for publication with the comments; reviewed and edited the manuscript.\n\nEinas AlKuwari: Pathologist: Established the pathological diagnosis; Provided the histopathology slide images; reviewed and edited the manuscript.\n\nLajos Szabados: Nuclear medicine: Diagnosis and interpretation of the PET scan images; Provided the images for the PET scan for publication with the comments; reviewed and edited the manuscript.\n\nWalid Elmoghazi: Surgeon: Reviewed and edited the manuscript.\n\nAhmed Elaffandi: Surgeon: Reviewed and edited the manuscript.\n\nHatem Khalaf: Surgeon: Main clinical care of the patient; Concept of the case report; Guidance and overall responsibility of the study; review and final approval of the manuscript.\n\nRegistration of research studies\nHMC Medical Research Center Protocol ID MRC-04-18-077.\n\nGuarantor\nDr. Hatem Khalaf.\n\nDr. Ibnouf Sulieman.\n==== Refs\nReferences\n1 Agha R.A. Fowler A.J. Saeta A. Barai I. Rajmohan S. Orgill D.P. The SCARE Statement: consensus-based surgical case report guidelines for the SCARE Group 1 Int. J. Surg. 34 2016 180 186 27613565 \n2 Kamisawa T. Funata N. Hayashi Y. Eishi Y. Koike M. Tsuruta K. Okamoto A. Egawa N. Nakajima H. A new clinicopathological entity of IgG4-related autoimmune disease J. Gastroenterol. 38 2003 982 984 14614606 \n3 Cheuk W. Chan J.K.C. IgG4-related sclerosing disease: a critical appraisal of an evolving clinicopathologic entity Adv. Anat. Pathol. 17 2010 303 332 20733352 \n4 Bozzalla Cassione E. Stone J.H. IgG4-related disease Curr. Opin. Rheumatol. 29 2017 223 227 28319486 \n5 Stone J.H. Zen Y. Deshpande V. IgG4-related disease N. Engl. J. Med. 366 2012 539 551 22316447 \n6 Kamisawa T. Zen Y. Pillai S. Stone J.H. IgG4-related disease Lancet 385 2015 1460 1471 25481618 \n7 Khosroshahi A. Stone J.H. A clinical overview of IgG4-related systemic disease Curr. Opin. Rheumatol. 23 2011 57 66 21124086 \n8 Brito-Zerón P. Ramos-Casals M. Bosch X. Stone J.H. The clinical spectrum of IgG4-related disease Autoimmun. Rev. 13 2014 1203 1210 25151972 \n9 Palazzo E. Palazzo C. Palazzo M. IgG4-related disease Jt. Bone Spine 81 2014 27 31 \n10 Detlefsen S. Klöppel G. IgG4-related disease: with emphasis on the biopsy diagnosis of autoimmune pancreatitis and sclerosing cholangitis Virchows Arch. 2017 545 556 \n11 Ebbo M. Patient M. Grados A. Groh M. Desblaches J. Hachulla E. Saadoun D. Audia S. Rigolet A. Terrier B. Perlat A. Guillaud C. Renou F. Bernit E. Costedoat-Chalumeau N. Harlé J.-R. Schleinitz N. Ophthalmic manifestations in IgG4-related disease: clinical presentation and response to treatment in a French case-series Medicine (Baltimore) 96 2017 e6205 \n12 Ozawa M. Fujinaga Y. Asano J. Nakamura A. Watanabe T. Ito T. Muraki T. Hamano H. Kawa S. Clinical features of IgG4-related periaortitis/periarteritis based on the analysis of 179 patients with IgG4-related disease: a case-control study Arthritis Res. Ther. 19 2017 1 9 28073368 \n13 Singh N. Nada R. Rawat A. Sharma A. Sinha S.K. Ramachandran R. Kumar V. Kohli H.S. Gupta K.L. Rathi M. Spectrum of IgG4-related kidney disease at a tertiary care center Indian J. Nephrol. 28 2018 209 214 29962671 \n14 Umehara H. Okazaki K. Masaki Y. Kawano M. Yamamoto M. Saeki T. Matsui S. Yoshino T. Nakamura S. Kawa S. Hamano H. Kamisawa T. Shimosegawa T. Shimatsu A. Nakamura S. Ito T. Notohara K. Sumida T. Tanaka Y. Mimori T. Chiba T. Mishima M. Hibi T. Tsubouchi H. Inui K. Ohara H. Comprehensive diagnostic criteria for IgG4-related disease (IgG4-RD), 2011 Mod. Rheumatol. 22 2012 21 30 22218969 \n15 Franchello A. Gonella F. Campra D. Limerutti G. Bruno M. De Angelis C. Cassine D. Fronda G. Silvestri S. A rare case of IgG4-related systemic disease manifesting with pancreatic head mass mimicking borderline resectable cancer Int. J. Surg. Case Rep. 5 2014 1095 1097 25460484 \n16 Deshpande V. Zen Y. Chan J.K. Yi E.E. Sato Y. Yoshino T. Kloppel G. Heathcote J.G. Khosroshahi A. Ferry J.A. Aalberse R.C. Bloch D.B. Brugge W.R. Bateman A.C. Carruthers M.N. Chari S.T. Cheuk W. Cornell L.D. Fernandez-Del Castillo C. Forcione D.G. Hamilos D.L. Kamisawa T. Kasashima S. Kawa S. Kawano M. Lauwers G.Y. Masaki Y. Nakanuma Y. Notohara K. Okazaki K. Ryu J.K. Saeki T. Sahani D.V. Smyrk T.C. Stone J.R. Takahira M. Webster G.J. Yamamoto M. Zamboni G. Umehara H. Stone J.H. Consensus statement on the pathology of IgG4-related disease Mod. Pathol. 25 2012 1181 1192 22596100 \n17 Khosroshahi A. Wallace Z.S. Crowe J.L. Akamizu T. Azumi A. Carruthers M.N. Chari S.T. Della-Torre E. Frulloni L. Goto H. Hart P.A. Kamisawa T. Kawa S. Kawano M. Kim M.H. Kodama Y. Kubota K. Lerch M.M. Lohr M. Masaki Y. Matsui S. Mimori T. Nakamura S. Nakazawa T. Ohara H. Okazaki K. Ryu J.H. Saeki T. Schleinitz N. Shimatsu A. Shimosegawa T. Takahashi H. Takahira M. Tanaka A. Topazian M. Umehara H. Webster G.J. Witzig T.E. Yamamoto M. Zhang W. Chiba T. Stone J.H. International consensus guidance statement on the management and treatment of IgG4-related disease Arthritis Rheumatol. (Hoboken, N.J.) 67 2015 1688 1699 \n18 Hubers L.M. Beuers U. IgG4-related disease of the biliary tract and pancreas: clinical and experimental advances Curr. Opin. Gastroenterol. 33 2017 310 314 28509786 \n19 Brito-Zerón P. Bosch X. Ramos-Casals M. Stone J.H. IgG4-related disease: Advances in the diagnosis and treatment Best Pract. Res. Clin. Rheumatol. 30 2016 261 278 27886799 \n20 Khosroshahi A. Stone J.H. Treatment approaches to IgG4-related systemic disease Curr. Opin. Rheumatol. 23 2011 67 71 21124087 \n21 Vasaitis L. IgG4-related disease: a relatively new concept for clinicians Eur. J. Intern. Med. 27 2016 1 9 26481243\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2210-2612",
"issue": "50()",
"journal": "International journal of surgery case reports",
"keywords": "Autoimmune pancreatitis; Case report; IgG4 related disease; Pancreas lesions",
"medline_ta": "Int J Surg Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101529872",
"other_id": null,
"pages": "100-105",
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"pmid": "30096533",
"pubdate": "2018",
"publication_types": "D016428:Journal Article",
"references": "28509786;28978347;25151972;21124086;25460484;22596100;25481618;28319486;29196804;14614606;27886799;25809420;26481243;29962671;23849464;21124087;22316447;27613565;20733352;22218969;28272212",
"title": "IgG4-related disease mimicking pancreatic cancer: Case report and review of the literature.",
"title_normalized": "igg4 related disease mimicking pancreatic cancer case report and review of the literature"
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"abstract": "Bu-Mel as preparative therapy prior to autologous stem cell rescue was recently shown to be superior to the conventional CEM regimen for HR NBL in Europe. There are no data available on the feasibility and toxicity of Bu-Mel as consolidation therapy following the COG-type induction regimens used in North America. We report early complications and outcomes of patients with HR NBL who received Bu-Mel for consolidation following COG-based induction. Retrospective analysis of all patients who had received Bu-Mel as preparative regimen prior to stem cell rescue for HR NBL was carried out. Toxicity, outcomes, and any delays to receiving radiation or anti-GD2 antibody therapy were analyzed. Six patients undergoing PBSCT had received Bu-Mel. The treatment was well tolerated. Mucositis was the main toxicity; three patients had developed neutropenia fever and none developed pulmonary toxicity. One patient had developed moderate SOS that responded to conservative management. All patients were able to receive and tolerate post-transplant local radiotherapy and ch.14.18 anti-GD2 antibody therapy without any delays. All patients are alive with no disease recurrence. The Bu-Mel regimen is well tolerated and is feasible post-COG-type induction platform.",
"affiliations": "Division of Hematology/Oncology/BMT, Nationwide Children's Hospital, Columbus, OH, USA.",
"authors": "Soni|Sandeep|S|;Pai|Vinita|V|;Gross|Thomas G|TG|;Ranalli|Mark|M|",
"chemical_list": "D002066:Busulfan; D008558:Melphalan",
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"doi": "10.1111/petr.12202",
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"issue": "18(2)",
"journal": "Pediatric transplantation",
"keywords": "autologous stem cell transplantation; high-dose therapy; high-risk neuroblastoma; preparative therapy",
"medline_ta": "Pediatr Transplant",
"mesh_terms": "D002066:Busulfan; D002648:Child; D002675:Child, Preschool; D060830:Consolidation Chemotherapy; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008558:Melphalan; D009447:Neuroblastoma; D036102:Peripheral Blood Stem Cell Transplantation; D012008:Recurrence; D012189:Retrospective Studies; D013280:Stomatitis; D016896:Treatment Outcome",
"nlm_unique_id": "9802574",
"other_id": null,
"pages": "217-20",
"pmc": null,
"pmid": "24341617",
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"publication_types": "D016428:Journal Article",
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"title": "Busulfan and melphalan as consolidation therapy with autologous peripheral blood stem cell transplantation following Children's Oncology Group (COG) induction platform for high-risk neuroblastoma: early results from a single institution.",
"title_normalized": "busulfan and melphalan as consolidation therapy with autologous peripheral blood stem cell transplantation following children s oncology group cog induction platform for high risk neuroblastoma early results from a single institution"
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"companynumb": "US-UCBSA-2014021673",
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"abstract": "OBJECTIVE\nTo report ischemic central retinal vein occlusion in one eye and recurrent serous retinal detachment in the other eye of a patient with idiopathic arterial pulmonary hypertension.\n\n\nMETHODS\nA 33-year-old woman was referred to our institution 2 months after an episode of central retinal vein occlusion in her right eye. She had arterial pulmonary hypertension for 2 years and was enrolled in a double-blind clinical trial of a novel vasodilator (bosentan) for arterial pulmonary hypertension. At presentation, corrected visual acuity was hand movements in the right eye and 20/20 in the left eye. Intraocular pressure was normal in both eyes. Fundoscopy showed an optic disk with blurred margins, venous engorgement, and diffuse intraretinal hemorrhages in the right eye. The left eye was unremarkable. An afferent relative pupillary defect was also noticed on examination. Fluorescein angiography and electroretinogram confirmed the diagnosis of ischemic central retinal vein occlusion. An intravitreal injection of bevacizumab was then performed in the right eye.\n\n\nRESULTS\nThe first day after injection, best-corrected visual acuity in the left eye fell to counting fingers and a serous detachment of the macula was detected. Oral acetazolamide was used, with prompt recovery of visual acuity in the left eye to 20/20 in 2 days. Another intravitreal injection of bevacizumab and panretinal photocoagulation were later performed in the right eye. Although visual acuity in the right eye improved to 20/400 2 months after bevacizumab injection, neovascular glaucoma developed in this eye. Moreover, serous retinal detachment recurred in the left eye. Topical antiglaucomatous drugs, further panretinal photocoagulation, and a new intavitreal injection of bevacizumab in the right eye as well as another course of acetazolamide controlled these complications. Final visual acuity was stable at 20/300 in the right eye and 20/20 in the left eye 2 months thereafter with normalization of intraocular pressure under hypotensive drops.\n\n\nCONCLUSIONS\nArterial pulmonary hypertension is a rare entity, infrequently leading to decreased vision. This report emphasizes the prompt response to acetazolamide as therapy for recurrent retinal detachment in one eye as well as the use of bevacizumab for the treatment of ischemic central retinal vein occlusion in the other eye and as an adjuvant to panretinal photocoagulation for neovascular glaucoma, which later developed. The disease must be remembered in the possible etiology of central retinal vein occlusion and of serous retinal detachment in the young patient.",
"affiliations": "From the São Geraldo Eye Hospital, Federal University of Minas Gerais and The Vision Institute, Belo Horizonte, Brazil.",
"authors": "Nehemy|Márcio B|MB|;Torquetti|Leonardo|L|;Vasconcelos-Santos|Daniel V|DV|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/ICB.0b013e318199b0f9",
"fulltext": null,
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"issn_linking": "1935-1089",
"issue": "4(2)",
"journal": "Retinal cases & brief reports",
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"medline_ta": "Retin Cases Brief Rep",
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"other_id": null,
"pages": "154-7",
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"pmid": "25390391",
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"publication_types": "D016428:Journal Article",
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"title": "Bilateral nonsimultaneous visual loss associated with idiopathic arterial pulmonary hypertension.",
"title_normalized": "bilateral nonsimultaneous visual loss associated with idiopathic arterial pulmonary hypertension"
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"companynumb": "BR-ACTELION-A-CH2014-108515",
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"abstract": "Until a few years ago, metastatic melanoma had a poor prognosis with limited treatment options. These therapeutics options and thereby median survival have increased obviously over 5 years with the arrival of immunotherapeutic drugs like ipilimumab, nivolumab, and pembrolizumab. Nowadays, ipilimumab is often used in patients with metastatic melanoma. In this paper, we report a case of a 68-year-old man who developed, and eventually died of, herpes encephalitis after introducing ipilimumab as treatment for metastatic melanoma. To our knowledge, this is the first report in which herpes encephalitis as a complication after ipilimumab and infliximab treatment is described and we would like to make physicians aware of this possible serious neurological complication, especially when a patient has a history of herpes simplex infection.",
"affiliations": "Department of Medical Oncology, Maastricht University Medical Center, Maastricht, The Netherlands.;Department of Neurology, Maastricht University Medical Centre, University Maastricht, Maastricht, The Netherlands.;Department of Neurology, Maastricht University Medical Centre, University Maastricht, Maastricht, The Netherlands.;Department of Medical Oncology, Maastricht University Medical Center, Maastricht, The Netherlands.",
"authors": "van Montfort|Lieke|L|;Loos|Caroline M|CM|;Anten|Monique|M|;Jansen|Rob L H|RLH|",
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"country": "Switzerland",
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"doi": "10.1159/000484553",
"fulltext": "\n==== Front\nCase Rep OncolCase Rep OncolCROCase Reports in Oncology1662-6575S. Karger AG Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH-4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.ch 10.1159/000484553cro-0010-1112Case ReportHerpes Encephalitis: A Mortal Complication in a Patient Treated with Immunosuppressive Drugs because of Immune-Related Adverse Events after Ipilimumab Treatment van Montfort Lieke aLoos Caroline M. bAnten Monique bJansen Rob L.H. a*aDepartment of Medical Oncology, Maastricht University Medical Center, Maastricht, The NetherlandsbDepartment of Neurology, Maastricht University Medical Centre, University Maastricht, Maastricht, The Netherlands*Rob L.H. Jansen, MD, PhD, Division of Medical Oncoloy, Department of Internal Medicine, Grow - School for, Oncology and Developmental Biology, Maastricht University Medical Centre, P. Debyelaan 25, NL-6229 HX Maastricht (The Netherlands), E-Mail rob.jansen@mumc.nlSep-Dec 2017 18 12 2017 18 12 2017 10 3 1112 1115 24 10 2017 24 10 2017 Copyright © 2017 by S. Karger AG, Basel2017This article is licensed under the Creative Commons Attribution-NonCommercial-4.0 International License (CC BY-NC) (http://www.karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes requires written permission.Until a few years ago, metastatic melanoma had a poor prognosis with limited treatment options. These therapeutics options and thereby median survival have increased obviously over 5 years with the arrival of immunotherapeutic drugs like ipilimumab, nivolumab, and pembrolizumab. Nowadays, ipilimumab is often used in patients with metastatic melanoma. In this paper, we report a case of a 68-year-old man who developed, and eventually died of, herpes encephalitis after introducing ipilimumab as treatment for metastatic melanoma. To our knowledge, this is the first report in which herpes encephalitis as a complication after ipilimumab and infliximab treatment is described and we would like to make physicians aware of this possible serious neurological complication, especially when a patient has a history of herpes simplex infection.\n\nKeywords\nMelanomaImmunotherapySide effectsNeuro-oncology tumor necrosis factorCTLA-4 antigenIpilimumabHerpes simplex encephalitis\n==== Body\nIntroduction\nA melanoma is a malignant tumour originating in melanocytes with, until recently, a poor prognosis and limited treatment options in case of metastatic disease as occurs in 11% of the patients. However, therapeutic options have increased obviously over the last years and nowadays, immune-stimulating drugs like cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) receptor inhibitors and programmed cell death protein 1 (PD1) antibodies are the main drugs in the treatment of metastatic melanoma [1].\n\nIpilimumab, a CTLA4 receptor inhibitor that interferes with the natural immune response of the body towards cancer cells, has become available for the treatment of patients with unresectable stage III or stage IV melanoma since 2011 [1]. As a result of its mechanism of action, ipilimumab can cause some serious immune-related adverse events (irAEs) [2, 3]. IrAEs are estimated to occur in 64% of the patients; however, the majority of this irAEs can be graded by using the common toxicity criteria as grade 1 or 2 adverse events. Grade 3 or 4 adverse events occur in 17.8% of the patients. The skin and gastrointestinal tract are most commonly affected. Endocrine, hepatic, and neurologic events are less common [4].\n\nHere we present a patient who developed herpes encephalitis after he was treated with immunosuppressive drugs because of irAEs caused by ipilimumab treatment.\n\nCase Presentation\nA left-handed 68-year-old Caucasian man was previously known with atrial fibrillation, herpes encephalitis (1990), and primary melanoma stage I in 2001. In 2014, metastatic disease was demonstrated and ipilimumab treatment (3 mg/kg) was initiated. Two months later he developed hypophysitis grade II and colitis grade III, treated with high doses of corticosteroids (up to 2 mg/kg). As the colitis was refractory on December 3, treatment with a TNF-alpha inhibitor (infliximab) was initiated.\n\nOn December 24, the patient presented at the local emergency department with acute confusion, speech disorder, and weakness of the right arm and leg. Brain CT showed an old left temporal lesion with no signs of recent ischemia or intracerebral hemorrhage, and intravenous thrombolysis was given for the treatment of an acute ischemic stroke. The patient was transported towards a tertiary centre for a possible intra-arterial thrombolytic treatment. However, during transport, the patient developed clonic seizures of the right side of the body and eventually a status epilepticus. The differential diagnosis included a symptomatic status epilepticus in acute stroke or a late-onset symptomatic status epilepticus related to the old lesion in the left temporal lobe. A brain CT angiography showed no occlusion of the left arteria cerebri media; therefore, there was no indication for intra-arterial treatment. The patient was admitted to the intensive care unit.\n\nBecause of respiratory insufficiency and a refractory status epilepticus, the patient was intubated and sedated. Four days after admission, the patient developed fever over 40°C, for which he was empirically treated with intravenous antibiotics. Additional laboratory tests showed normal infection parameters and no obvious focus for infection could be found (X-ray, urine, and blood cultures). On December 28, the patient developed new clonic seizures and eventually a new status epilepticus, which were treated with antiepileptic drugs. On January 1, a lumbar puncture was performed because of persistent epileptic seizures. Liquor examination demonstrated lymphocytic pleiocytosis (96 × 106/L leukocytes), elevated protein levels (1.0 g/L), and a positive polymerase chain reaction assay for herpes simplex virus type I (cycle threshold 38). Intravenous treatment with acyclovir was initiated for the duration of 10 days. On January 4, all sedative medication was ceased and no clinical signs of epilepsy were observed. On January 5, a brain MRI was performed, which showed findings compatible with the MR findings of herpes simplex encephalitis. On January 26, the patient died.\n\nThe final diagnosis was a status epilepticus caused by a reactivation of herpes simplex encephalitis in an immunocompromised patient, with a history of herpes encephalitis and metastatic melanoma, which was treated with ipilimumab, corticosteroids, and infliximab.\n\nDiscussion\nWe report here a case of a patient who developed herpes encephalitis while he was treated with immunosuppressive drugs such as infliximab and prednisolone because of the presence of irAEs caused by ipilimumab treatment. Based on the patients past history, the encephalitis most probably concerns a reactivation of the herpes simplex encephalitis of 1990. However, due to missing data about the encephalitis in 1990, a de novo infection caused by (another strain of) herpes simplex virus type 1 cannot be excluded. To our knowledge, this is the first description of a patient with (a reactivation of) herpes encephalitis after treatment with ipilimumab.\n\nHerpes encephalitis in immunocompromised patients, mainly in relation to TNF-alpha inhibitors such as infliximab, is reported in the literature in some case reports [5, 6, 7]. Among these, 5 cases are described of patients with TNF-alpha inhibitor therapy and herpes encephalitis. Infection of the herpes virus can be controlled by TNF signalling pathways by mediating cytotoxicity of the infected cells and by regulating immune responses [8]. Some animal models suggest a protective role for TNF-alpha signalling against herpes simplex encephalitis and thereby suggest that the use of TNF-alpha inhibitors could increase the risk of severe herpes encephalitis [9]. Nevertheless, according to the guidelines of infliximab used by gastroenterologists and rheumatologists, the safety tests that have to be performed before the start of infliximab are: screening for tuberculosis by a Mantoux or Quantiferon test; screening for hepatitis B by serum analysis; and anamnesis for a history of heart failure or demyelinating disease [10]. There are no guidelines that advise caution when there is a history of herpes encephalitis.\n\nConclusion\nWith the current knowledge, herpes encephalitis in the past medical history is not a contraindication for immunosuppressive treatment such as high doses of corticosteroids or infliximab. However, clinicians have to be aware of the potential association between the treatment of powerful immunosuppressive agents and a (reactivation of) herpes encephalitis. Furthermore, caution is recommended in the immunosuppressive treatment of these kinds of patients with a history of herpes encephalitis.\n\nStatement of Ethics\nThe authors have no conflicts of interest to disclose.\n\nDisclosure Statement\nThe authors have no ethical conflicts to declare.\n==== Refs\nReferences\n1 Postow MA Callahan MK Wolchok JD Immune Checkpoint Blockade in Cancer Therapy. J Clin Oncol 2015 33 1974 1982 25605845 \n2 Dequen P Lorigan P Jansen JP van Baardewijk M Ouwens MJ Kotapati S Systematic review and network meta-analysis of overall survival comparing 3 mg/kg ipilimumab with alternative therapies in the management of pretreated patients with unresectable stage III or IV melanoma. Oncologist 2012 17 1376 1385 23024154 \n3 Schadendorf D Hodi FS Robert C Weber JS Margolin K Hamid O Patt D Chen TT Berman DM Wolchok JD Pooled Analysis of Long-Term Survival Data From Phase II and Phase III Trials of Ipilimumab in Unresectable or Metastatic Melanoma. J Clin Oncol 2015 33 1889 1894 25667295 \n4 Ibrahim RA Berman DM DePril V Ipilimumab safety profile: summary of findings from completed trials in advanced melanoma. J Clin Oncol 2011 15 (suppl) 8583 \n5 Bradford RD Pettit AC Wright PW Mulligan MJ Moreland LW McLain DA Gnann JW Bloch KC Herpes simplex encephalitis during treatment with tumor necrosis factor-alpha inhibitors. Clin Infect Dis 2009 49 924 927 19681709 \n6 Schepers K Hernandez A Andrei G Gillemot S Fiten P Opdenakker G Bier JC David P Delforge ML Jacobs F Snoeck R Acyclovir-resistant herpes simplex encephalitis in a patient treated with anti-tumor necrosis factor-alpha monoclonal antibodies. J Clin Virol 2014 59 67 70 24257111 \n7 Crusio RH Singson SV Haroun F Mehta HH Parenti DM Herpes simplex virus encephalitis during treatment with etanercept. Scand J Infect Dis 2014 46 152 154 24228826 \n8 Sedy JR Spear PG Ware CF Cross-regulation between herpesviruses and the TNF superfamily members. Nat Rev Immunol 2008 8 861 873 18949019 \n9 Lundberg P Welander PV Edwards CK 3rd van Rooijen N Cantin E Tumor necrosis factor (TNF) protects resistant C57BL/6 mice against herpes simplex virus-induced encephalitis independently of signaling via TNF receptor 1 or 2. J Virol 2007 81 1451 1460 17108044 \n10 Guideline of remicade, available at www.remicade.com .\n\n",
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"title": "Herpes Encephalitis: A Mortal Complication in a Patient Treated with Immunosuppressive Drugs because of Immune-Related Adverse Events after Ipilimumab Treatment.",
"title_normalized": "herpes encephalitis a mortal complication in a patient treated with immunosuppressive drugs because of immune related adverse events after ipilimumab treatment"
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"abstract": "Prior to Caesarean section (CS) for morbidly adherent placenta (MAP), endovascular balloons are often placed prophylactically to minimize hemorrhage. However, there have been few reports describing complications of this intervention.\n\n\n\nA 41-year-old woman with a diagnosis of placenta percreta had endovascular balloon catheters placed before CS. Intraoperatively the right internal iliac artery ruptured, requiring vascular repair, multiple transfusions of blood and plasma, and admission to the intensive care unit.\n\n\n\nProphylactic placement of endovascular balloons to reduce maternal hemorrhage at CS for MAP may result in complications. Until more evidence becomes available supporting their use, safety guidelines must be instated in centres using them.",
"affiliations": "Department of Obstetrics and Gynecology, McGill University Health Centre, Montreal QC.;Department of Obstetrics and Gynecology, The Ottawa Hospital, Ottawa ON.;Department of Obstetrics and Gynecology, Jewish General Hospital, Montreal QC.",
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"keywords": "Placenta percreta; complication; hemorrhage; internal iliac artery occlusive balloon",
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"mesh_terms": "D000328:Adult; D021721:Balloon Occlusion; D005260:Female; D006801:Humans; D007083:Iliac Artery; D010921:Placenta Accreta; D011247:Pregnancy; D012421:Rupture",
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"title": "Internal Iliac Artery Rupture Caused by Endovascular Balloons in a Woman with Placenta Percreta.",
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"abstract": "Fungal periprosthetic joint infections due to Aspergillus species are rare but are associated with significant cost and morbidity. We present a case of Asperigillus terreus prosthetic joint infection of the hip. The patient was successfully treated with a prolonged course of systemic antifungals along with surgical management.",
"affiliations": "Division of Infectious Diseases, Department of Medicine, Montefiore Medical Center, 111 E. 210th Street, Bronx, NY 10467, USA.;Department of Pharmacy, Montefiore Medical Center, 111 E. 210th Street, Bronx, NY 10467, USA.;Department of Orthopedic Surgery, Montefiore Medical Center, 111 E. 210th Street, Bronx, NY 10467, USA.;Microbiology Laboratory, Montefiore Medical Center, 111 E. 210th Street, Bronx, NY 10467, USA.;Microbiology Laboratory, Montefiore Medical Center, 111 E. 210th Street, Bronx, NY 10467, USA.;Department of Pharmacy, Montefiore Medical Center, 111 E. 210th Street, Bronx, NY 10467, USA.;Division of Infectious Diseases, Department of Medicine, Montefiore Medical Center, 111 E. 210th Street, Bronx, NY 10467, USA.",
"authors": "Bartash|Rachel|R|;Guo|Yi|Y|;Pope|John B|JB|;Levi|Michael H|MH|;Szymczak|Wendy|W|;Saraiya|Nidhi|N|;Nori|Priya|P|",
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"fulltext": "\n==== Front\nMed Mycol Case RepMed Mycol Case RepMedical Mycology Case Reports2211-7539Elsevier S2211-7539(17)30043-X10.1016/j.mmcr.2017.07.006Case ReportPeriprosthetic hip joint infection with Aspergillus terreus: A clinical case and a review of the literature Bartash Rachel rbartash@montefiore.orga⁎Guo Yi bPope John B. cLevi Michael H. dSzymczak Wendy dSaraiya Nidhi bNori Priya aa Division of Infectious Diseases, Department of Medicine, Montefiore Medical Center, 111 E. 210th Street, Bronx, NY 10467, USAb Department of Pharmacy, Montefiore Medical Center, 111 E. 210th Street, Bronx, NY 10467, USAc Department of Orthopedic Surgery, Montefiore Medical Center, 111 E. 210th Street, Bronx, NY 10467, USAd Microbiology Laboratory, Montefiore Medical Center, 111 E. 210th Street, Bronx, NY 10467, USA⁎ Corresponding author. rbartash@montefiore.org25 7 2017 12 2017 25 7 2017 18 24 27 20 4 2017 19 7 2017 24 7 2017 © 2017 The Authors2017This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Fungal periprosthetic joint infections due to Aspergillus species are rare but are associated with significant cost and morbidity. We present a case of Asperigillus terreus prosthetic joint infection of the hip. The patient was successfully treated with a prolonged course of systemic antifungals along with surgical management.\n\nKeywords\nFungal prosthetic joint infectionAspergillus terreus\n==== Body\n1 Introduction\nWhile periprosthetic joint infections (PJI) complicate only 2% of all joint replacements, they are associated with significant cost and morbidity [1], [2]. Fungal prosthetic joint infections are particularly rare, comprising approximately 1% of all PJIs [3] with the majority of cases attributed to Candida species, and only a few reported cases of PJI due to Aspergillus species. Here we present a rare case of Asperigillus terreus PJI of the hip joint managed at our institution.\n\n2 Case\nThis is a 54-year-old man with a history of obesity (BMI 38) despite prior gastric bypass surgery, controlled diabetes mellitus (HbA1c range 5.2–6.5%), cleared hepatitis C infection, and left total hip arthroplasty for osteoarthritis in October 2015 (day 0). Approximately 1 month later he developed purulent drainage from an ulcer proximal to the wound for which he received incision and drainage (I&D) and polyethylene liner exchange (day 36). All wound cultures were negative and frozen section was not consistent with infection. He quickly developed recurrence of drainage and underwent left hip I&D and explant of prosthesis with placement of an antibiotic impregnated spacer in December 2015 (day 46). Multiple intraoperative cultures grew methicillin-resistant Staphylococcus aureus (MRSA). He developed ongoing serous drainage for which he required repeat I&D approximately 2 weeks later (day 56). He was discharged to a skilled nursing facility (SNF) to complete 8 weeks of IV vancomycin. His wound healed and inflammatory markers normalized (see Fig. 1).Fig. 1 ESR and CRP Trend.\n\nFig. 1\n\nIn March 2016 (day 148), the patient underwent left hip revision arthroplasty, but quickly developed worsening pain and copious drainage from the surgical wound. He again required I&D, removal of prosthesis and antibiotic spacer placement (day 161). Intraoperative cultures again showed copious MRSA in addition to Enterobacter cloacae in only 1 specimen. He was briefly treated with piperacillin/tazobactam and IV vancomycin as an inpatient, then completed another 6 week course of IV vancomycin upon discharge. Thereafter, he was maintained on per os doxycycline 100 mg twice daily for an additional 6 weeks. His wound healed and inflammatory markers again normalized. Joint aspiration off antibiotics, showed no growth on cultures. The patient unfortunately developed another recurrence of PJI in August of 2016 in the setting of an elective dental extraction, which was treated with periprocedural amoxicillin. Inflammatory markers were again elevated. Fluid aspiration showed 39,000 WBC with 98% neutrophils. Fluid culture grew Streptococcus mitis. Patient then received repeat I&D and replacement of antibiotic impregnated spacer at that time (day 295). Postoperative course was complicated by dislocation of spacer and periprosthetic fracture requiring revision surgery. He was ultimately discharged to a skill nursing facility to complete 8 weeks of high dose ceftriaxone followed by 4 weeks of amoxicillin, completed in November 2016.\n\nDespite prolonged antibiotic therapy, the patient continued to complain of left hip and groin pain associated with difficult ambulation. Exam of his left hip revealed no erythema or warmth and his previous surgical wounds were intact without drainage.\n\nHe underwent CT guided hip joint aspiration for further work up which revealed 148 white blood cells with 59% neutrophils and 64,000 red blood cells (day 401). Multiple cultures grew Aspergillus terreus, which was identified by macroscopic and microscopic morphology (see Image 1). Repeat aspiration revealed 1196 white blood cells with 60% neutrophils (day 408). Bacterial and fungal cultures again grew Aspergillus terreus. ESR and CRP increased to 56 mm/h and 2.4 mg/dL, respectively. Aspergillus galactomanan was normal at 0.1. Susceptibility testing results from the University of Texas reference laboratory are shown in Table 1. He was started on delayed-release oral posaconzole, which was gradually titrated up from 300 mg (mg) daily to 400 mg every morning and 300 mg every evening, based on posaconazole troughs of 0.7–1.2 micrograms per milliliter. Following 1 month of therapy, the patient reported a decrease in his hip pain and improvement in ambulation. In March 2017 (day 498), he underwent revision of the left hip implant using 2 g of vancomycin and 3 g of voriconazole impregnated into a cement spacer. Intraoperatively there was no evidence of active infection and multiple cultures were negative for bacterial or fungal species. Two months later (day 577) he underwent repeat aspiration while holding his posaconazole to ensure there was no inhibition of fungal growth. Cultures from this procedure were negative. Tentative plan for the patient is to continue posaconazole until ultimate revision arthroplasty in the coming weeks.Image 1 A. terreus growth on plates and culture of joint fluid.\n\nImage 1Table 1 Susceptibilities of A. terreus by broth microdilution.\n\nTable 1Antifungal agent\tMinimum inhibitory concentration\t\nAmphotericin B\t2 mcg/mla\t\nCapsofungin\t0.125 mcg/mla, b\t\nMicafungin\t< 0.015 mcg/mla, b\t\nFluconazole\t> 64.0 mcg/mla\t\nVoriconazole\t0.25 mcg/mla\t\na breakpoint not defined.\n\nb reported value for echinocandins is minimum effective concentration.\n\n\n\n3 Discussion\n3.1 Discussion\nAspergillus species joint infections are exceedingly rare. A review of the literature from 1967 to 2015 identified only 31 reported cases [4]. The majority of these were caused by Aspergillus fumigatus (77%), followed by Aspergillus flavus (13%) [4]. To our knowledge, ours is only the 2nd PJI due to A. terreus described in the literature [5]. While other reviews have reported on cases of A. terreus osteoarticular infections, these were not specifically attributed to a PJI [6].\n\nAspergillus species are found worldwide in soil and decaying matter. Invasive Aspergillus infections and Aspergillus joint infections are typically seen in patients with significant underlying immunosuppression. In a review of 31 cases by Gamaletsou et al., 26% had an underlying hematologic malignancy while 19% and 6% had undergone solid organ and bone marrow transplantation, respectively [4]. Neutropenia and treatment with corticosteroids were also commonly reported risk factors. Twenty-six percent of patients had a history of orthopedic surgery [4], though it is uncertain if the involved joints were surgically manipulated. A series of fungal PJIs described by Kuiper et al. reported that 16% of patients were classified as “immunocompromised” while 26% of patients had underlying diabetes [7]. Of note, the majority of fungal PJIs they reviewed were due to Candida species, which may be associated with different risk factors, such as prolonged hospitalization.\n\nFew cases of Aspergillus PJI have been reported in patients without obvious immunosuppression, as in the case we described herein [3], [8]. Though the source of infection in our patient remains unclear, we hypothesize that the patient's primary risk for infection was recurrent operations on the same unstable hip joint and multiple prior courses of antibiotics, which likely selected for growth of a mold species. As there have been no other cases of A. terreus at our institution, we believe it is unlikely that there is an ongoing environmental issue with this organism and therefore, suspect that contamination during surgery was less likely.\n\nWhile 87% of patients present with pain and 26% of patients present with swelling, erythema and draining fluid are less common clinical presentations (10% and 6% respectively) [4]. In patients with septic arthritis due to Aspergillus species the knee remains the most common site (35%), followed by intervertebral joint (26%) and hip (16%) [4]. Gamaletsou et al. reported that 10% of the 31 reported cases of Aspergillus septic arthritis occurred in prosthetic joints [4]. The other reported Aspergillus terreus PJI occurred in a total elbow arthroplasty [5]. Therefore, ours is perhaps one of the first cases of Aspergillus terreus involving a total hip arthroplasty.\n\nGiven the non-specific clinical presentation, the diagnosis of these infections can be challenging. Studies suggest that inflammatory markers are often elevated, as in our patient, but these too are non-specific [4], [7]. A. terreus infections may produce high levels of galactomannan [9], though this was not seen with our patient. It should be noted that these high levels of galactomannan have been seen in invasive pulmonary aspergillosis [9] and it is unclear if these levels should be expected in joint infections caused by A. terreus. Therefore, while serum fungal markers may be helpful, a definite diagnosis can only be made on microbiologic culture, either from synovial fluid culture or direct tissue culture. If Aspergillus species is isolated from a joint, it should be considered a true pathogen and managed with systemic antifungals and a 2-step surgical approach according to a review by Kuiper et al., which assessed 164 fungal PJIs (94 knee arthroplasties and 70 hip arthroplasties) [7].\n\nSuccessful treatment of Aspergillus species and fungal PJIs described in the literature often requires both a surgical and medical approach [3], [4], [7]. Systemic antifungals, such as triazoles, amphotericin B, and echinocandins have all been used to treat invasive aspergillosis [10], [11]. According to the Infectious Diseases Society of America Practice Guidelines for the Diagnosis and Management of Aspergillosis 2016, triazoles are the preferred agents for treatment in most patients, while amphotericin B deoxycholate and its lipid formulations are appropriate alternatives for initial or salvage therapy. Echinocandins are generally recommended for salvage therapy only [10]. However, these guidelines address all invasive Aspergillus infections and are not specific for native or prosthetic joint infections. In case reviews of Aspergillus joint infections, triazoles, amphotericin B, and echinocandins have all been used in conjunction with surgical management [4], [5], [7].\n\nA. terreus infections are associated with higher mortality and treatment failure than infections with other Apergillus species\n[12]. Aspergillus terreus is unique due to in vitro and in vivo resistance to the fungicidal effect of amphotericin B [13]. Therefore, our patient was treated with delayed-release posaconazole oral tablets. Though voriconazole is recommended by guidelines for Aspergillus species infections [10], there are no recommendations specifically for A. terreus infections or PJIs. We selected posaconazole rather than voriconazole given its better tolerability and its lack of reliance on the cytochrome P450 system for metabolism. Furthermore, prolonged voriconazole is associated with periostosis, which may have a negative impact on bone healing following joint surgery, as in our patient. Since our patient improved on posaconazole without the development of side effects, we decided to continue treatment rather than switch to voriconazole after the susceptibilities were available (Table 1).\n\nWe treated our patient with the delayed-release formulation of posaconazole as it has improved bioavailability and is not significantly affected by food or gastric acid suppression therapy compared to the oral suspension [14]. Delayed-release tablets also demonstrate higher serum concentrations than the oral suspension in patients with hematologic malignancies and solid organ transplants, without affecting the side effect profile [15], [16]. To ensure therapeutic efficacy, drug level monitoring once steady state is achieved, and corresponding dose adjustment based on drug levels is recommended.\n\nWhile there are no established guidelines, the majority of available literature recommends systemic antifungal therapy along with surgical management for maximal chance of cure of fungal PJIs, thus this was the management strategy we employed [5], [7]. A study by Deelstra et al. describes successful use of an antifungal cement spacer as adjunctive treatment to augment activity of systemic antifungals [17]. The goal of installation of antifungal and antibacterial agents into the bone cement spacer is to provide localized drug delivery, which may achieve higher drug levels at the site of infection [18]. However, the elution characteristics of antifungal agents may vary in vitro and in vivo depending on the use of a nonbiodegradable or biodgradable material and the porosity of the substance, which can impact the duration, rate, and the amount of antifungal released from the cement [19], [20]. Grimsrud et al. examined the in vitro elution characteristic of voriconazole from nonabsorbable polymethyl-methacrylate beads and from absorbable calcium sulfate beads, and found the rate of elution decreased before 48 h, then voriconazole concentrations remained relatively constant with enough antifungal activity to inhibit growth of the control yeasts for 2 weeks [19]. Although case reports of amphotericin B, voriconazole, fluconazole, and itraconazole spacers have been reported with favorable outcomes, the sustained bone durability was not thoroughly assessed and the duration of follow up was limited [20]. Based on the limited data, it is difficult to make general recommendations on the use of antifungal agents in cement spacers, though available data also does not demonstrate excess harm.\n\n4 Conclusion\nFungal PJIs are extremely rare, with Aspergillus species comprising a small number of these infections. Here we present a case of Aspergillus terreus PJI of the hip managed at our institution, which we believe is one of very few reported cases [5]. Consistent with the management strategy recommended in available literature, our patient was treated with a combined surgical and medical approach involving joint I&D, voriconazole impregnated cement, and many weeks of oral delayed-release posaconazole. Close monitoring of clinical status, inflammatory markers, and posaconazole levels is planned to ensure maximal chance of cure.\n\nEthical form Please note that this journal requires full disclosure of all sources of funding and potential conflicts of interest. The journal also requires a declaration that the author(s) have obtained written and signed consent to publish the case report from the patient or legal guardian(s).\n\nThe statements on funding, conflict of interest and consent need to be submitted via our Ethical Form that can be downloaded from the submission site http://www.ees.elsevier.com/mmcr.\n\nConflict of interest\nThere are none.\n\nAcknowledgements\nJosh Nosanchuk MD\n\nMarne Garretson MPH\n\nHitesh Patel\n\nAnthony Braffi\n==== Refs\nReferences\n1 Zimmerli W. Trampuz A. Ochsner P.E. Prosthetic-joint infections N. Engl. J. Med. 351 16 2004 1645 1654 15483283 \n2 Darouiche R.O. Treatment of infections associated with surgical implants N. Engl. J. Med. 350 14 2004 1422 1429 15070792 \n3 Yilmaz M. Mete B. Ozaras R. Kaynak G. Tabak F. Tenekecioglu Y. Aspergillus fumigatus infection as a delayed manifestation of prosthetic knee arthroplasty and a review of the literature Scand. J. Infect. Dis. 43 8 2011 573 578 21526903 \n4 Gamaletsou M.N. Rammaert B. Bueno M.A. Sipsas N.V. Moriyama B. Kontoyiannis D.P. Aspergillus arthritis: analysis of clinical manifestations, diagnosis, and treatment of 31 reported cases Med. Mycol. 55 3 2017 246 254 27609563 \n5 Kwong C.A. Puloski S.K. Hildebrand K.A. Fungal periprosthetic joint infection following total elbow arthroplasty: a case report and review of the literature J. Med. Case Rep. 11 1 2017 20 28109195 \n6 Kumashi P.R. Safdar A. Chamilos G. Chemaly R.F. Raad I.I. Kontoyiannis D.P. Fungal osteoarticular infections in patients treated at a comprehensive cancer centre: a 10-year retrospective review Clin. Microbiol. Infect. 12 7 2006 621 626 16774557 \n7 Kuiper J.W. van den Bekerom M.P. van der Stappen J. Nolte P.A. Colen S. 2-stage revision recommended for treatment of fungal hip and knee prosthetic joint infections Acta Orthop. 84 6 2013 517 523 24171675 \n8 Austin K.S. Testa N.N. Luntz R.K. Greene J.B. Smiles S. Aspergillus infection of total knee arthroplasty presenting as a popliteal cyst Case Report. Rev. Lit. J. Arthroplast. 7 3 1992 311 314 \n9 Mokaddas E. Burhamah M.H. Ahmad S. Khan Z.U. Invasive pulmonary aspergillosis due to Aspergillus terreus: value of DNA, galactomannan and (1->3)-beta-D-glucan detection in serum samples as an adjunct to diagnosis J. Med. Microbiol. 59 Pt 12 2010 1519 1523 20724511 \n10 Patterson T.F. Thompson G.R. 3rd Denning D.W. Fishman J.A. Hadley S. Herbrecht R. Practice guidelines for the diagnosis and management of Aspergillosis: 2016 update by the Infectious Diseases Society of America Clin. Infect. Dis. 63 4 2016 e1 e60 27365388 \n11 Ashbee H.R. Barnes R.A. Johnson E.M. Richardson M.D. Gorton R. Hope W.W. Therapeutic Drug Monitoring (TDM) of antifungal agents: guidelines from the British Society for Medical Mycology J. Antimicrob. Chemother. 69 5 2014 1162 1176 24379304 \n12 Steinbach W.J. Benjamin D.K. Jr. Kontoyiannis D.P. Perfect J.R. Lutsar I. Marr K.A. Infections due to Aspergillus terreus: a multicenter retrospective analysis of 83 cases Clin. Infect. Dis. 39 2 2004 192 198 15307028 \n13 Sutton D.A. Sanche S.E. Revankar S.G. Fothergill A.W. Rinaldi M.G. In vitro amphotericin B resistance in clinical isolates of Aspergillus terreus, with a head-to-head comparison to voriconazole J. Clin. Microbiol. 37 7 1999 2343 2345 10364610 \n14 Wiederhold N.P. Pharmacokinetics and safety of posaconazole delayed-release tablets for invasive fungal infections Clin. Pharmacol. 8 2016 1 8 26730212 \n15 Durani U. Tosh P.K. Barreto J.N. Estes L.L. Jannetto P.J. Tande A.J. Retrospective comparison of posaconazole levels in patients taking the delayed-release tablet versus the oral suspension Antimicrob. Agents Chemother. 59 8 2015 4914 4918 26055378 \n16 Jung D.S. Tverdek F.P. Kontoyiannis D.P. Switching from posaconazole suspension to tablets increases serum drug levels in leukemia patients without clinically relevant hepatotoxicity Antimicrob. Agents Chemother. 58 11 2014 6993 6995 25199774 \n17 Deelstra J.J. Neut D. Jutte P.C. Successful treatment of Candida albicans-infected total hip prosthesis with staged procedure using an antifungal-loaded cement spacer J. Arthroplast. 28 2 2013 374 (e5-8) \n18 Henry S.L. Galloway K.P. Local antibacterial therapy for the management of orthopaedic infections Pharmacokinet. Consid. Clin. Pharmacokinet. 29 1 1995 36 45 \n19 Grimsrud C. Raven R. Fothergill A.W. Kim H.T. The in vitro elution characteristics of antifungal-loaded PMMA bone cement and calcium sulfate bone substitute Orthopedics 34 8 2011 e378 e381 21815580 \n20 Percival K.M. Brock J.T. Peterson N.D. Delivery of antifungal agents from bone cement Curr. Fungal Infect. Rep. 10 1 2016 30 36\n\n",
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"abstract": "OBJECTIVE\nTo evaluate the therapeutic benefit of self-retained cryopreserved amniotic membrane in conjunction with oral antiviral therapy in herpetic epithelial keratitis.\n\n\nMETHODS\nRetrospective review of 4 patients with primary (1 eye) and recurrent (3 eyes) unilateral herpetic epithelial keratitis treated with cryopreserved amniotic membrane through the placement of the PROKERA Slim (PKS) (Bio-Tissue, Inc) in conjunction with oral acyclovir. Their symptoms, conjunctival inflammation, corneal staining, and visual acuity were compared before and after treatment.\n\n\nRESULTS\nHerpetic epithelial keratitis presented as dendritic (3 eyes) and geographic (1 eye) epithelial lesions. After epithelial debridement and placement of the PKS for 5 ± 3.7 days, all patients reported significant relief of symptoms, rapid corneal epithelialization, and reduction of ocular surface inflammation. The visual acuity was also improved in all eyes from 0.7 ± 0.7 to 0.4 ± 0.7 logarithm of the minimum angle of resolution (P = 0.2). They remained symptom-free during a follow-up period of 2.7 to 50.8 (20.3 ± 21.7) months.\n\n\nCONCLUSIONS\nThe PKS in conjunction with oral acyclovir facilitates the ease of early intervention to accelerate restoration of a normal corneal epithelium in herpetic epithelial keratitis.",
"affiliations": "*Ocular Surface Center, Miami, FL; and †Department of Ophthalmology, Florida International University, Herbert Wertheim College of Medicine, Miami, FL.",
"authors": "Cheng|Anny M S|AMS|;Tseng|Scheffer C G|SCG|",
"chemical_list": "D000998:Antiviral Agents; D000212:Acyclovir",
"country": "United States",
"delete": false,
"doi": "10.1097/ICO.0000000000001316",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0277-3740",
"issue": "36(11)",
"journal": "Cornea",
"keywords": null,
"medline_ta": "Cornea",
"mesh_terms": "D000212:Acyclovir; D000284:Administration, Oral; D000368:Aged; D000369:Aged, 80 and over; D000650:Amnion; D000998:Antiviral Agents; D003131:Combined Modality Therapy; D015925:Cryopreservation; D003646:Debridement; D019573:Epithelium, Corneal; D005260:Female; D006801:Humans; D016849:Keratitis, Herpetic; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D014792:Visual Acuity",
"nlm_unique_id": "8216186",
"other_id": null,
"pages": "1383-1386",
"pmc": null,
"pmid": "28834819",
"pubdate": "2017-11",
"publication_types": "D016428:Journal Article",
"references": "16423052;11594984;10195741;11588424;22608476;24519420;27116665;17525662;23878196;6696872;17637463;17363059;20490993;22944008;14507749;11188989;21436959;24046171;25879115;8938570;84900;11481259;19491101;19255156;26769483;10442895;23974879;22222510;10906085",
"title": "Self-Retained Amniotic Membrane Combined With Antiviral Therapy for Herpetic Epithelial Keratitis.",
"title_normalized": "self retained amniotic membrane combined with antiviral therapy for herpetic epithelial keratitis"
} | [
{
"companynumb": "US-BAUSCH-BL-2017-032387",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DEXAMETHASONE"
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"drugadditional": "3",
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{
"abstract": "Complex neuropsychiatric-cardiac syndromes can be genetically determined. For the first time, the authors present a syndromal form of short QT syndrome in a 34-year-old German male patient with extracardiac features with predominant psychiatric manifestation, namely a severe form of secondary high-functioning autism spectrum disorder (ASD), along with affective and psychotic exacerbations, and severe dental enamel defects (with rapid wearing off his teeth) due to a heterozygous loss-of-function mutation in the CACNA1C gene (NM_000719.6: c.2399A > C; p.Lys800Thr). This mutation was found only once in control databases; the mutated lysine is located in the Cav1.2 calcium channel, is highly conserved during evolution, and is predicted to affect protein function by most pathogenicity prediction algorithms. L-type Cav1.2 calcium channels are widely expressed in the brain and heart. In the case presented, electrophysiological studies revealed a prominent reduction in the current amplitude without changes in the gating behavior of the Cav1.2 channel, most likely due to a trafficking defect. Due to the demonstrated loss of function, the p.Lys800Thr variant was finally classified as pathogenic (ACMG class 4 variant) and is likely to cause a newly described Cav1.2 channelopathy.",
"affiliations": "Section for Experimental Neuropsychiatry, Department of Psychiatry and Psychotherapy, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79104 Freiburg, Germany.;Institute for Physiology and Pathophysiology, Vegetative Physiology and Marburg Center for Mind, Brain and Behavior-Philipps-University Marburg, 35037 Marburg, Germany.;Institute for Physiology and Pathophysiology, Vegetative Physiology and Marburg Center for Mind, Brain and Behavior-Philipps-University Marburg, 35037 Marburg, Germany.;Institute for Physiology and Pathophysiology, Vegetative Physiology and Marburg Center for Mind, Brain and Behavior-Philipps-University Marburg, 35037 Marburg, Germany.;Department of Psychiatry and Psychotherapy, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79104 Freiburg, Germany.;Institute of Human Genetics, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany.;Institute of Human Genetics, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany.;Institute of Human Genetics, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany.;Department of Psychiatry and Psychotherapy, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79104 Freiburg, Germany.;Section for Experimental Neuropsychiatry, Department of Psychiatry and Psychotherapy, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79104 Freiburg, Germany.;Department of Molecular Neurology, University Hospital Erlangen, 91054 Erlangen, Germany.;Department of Neurology, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany.;Section for Experimental Neuropsychiatry, Department of Psychiatry and Psychotherapy, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79104 Freiburg, Germany.;Institute for Genetics of Heart Diseases, Department of Cardiovascular Medicine, University Hospital Münster, 48149 Münster, Germany.;Institute for Physiology and Pathophysiology, Vegetative Physiology and Marburg Center for Mind, Brain and Behavior-Philipps-University Marburg, 35037 Marburg, Germany.;Institute for Genetics of Heart Diseases, Department of Cardiovascular Medicine, University Hospital Münster, 48149 Münster, Germany.;Section for Experimental Neuropsychiatry, Department of Psychiatry and Psychotherapy, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79104 Freiburg, Germany.",
"authors": "Endres|Dominique|D|;Decher|Niels|N|;Röhr|Isabell|I|0000-0002-2601-3147;Vowinkel|Kirsty|K|;Domschke|Katharina|K|;Komlosi|Katalin|K|;Tzschach|Andreas|A|0000-0002-6840-965X;Gläser|Birgitta|B|;Schiele|Miriam A|MA|;Runge|Kimon|K|0000-0002-0263-4360;Süß|Patrick|P|;Schuchardt|Florian|F|;Nickel|Kathrin|K|;Stallmeyer|Birgit|B|;Rinné|Susanne|S|;Schulze-Bahr|Eric|E|;Tebartz van Elst|Ludger|L|0000-0002-2274-5447",
"chemical_list": "C079146:CACNA1C protein, human; D020746:Calcium Channels, L-Type",
"country": "Switzerland",
"delete": false,
"doi": "10.3390/ijms21228611",
"fulltext": "\n==== Front\nInt J Mol Sci\nInt J Mol Sci\nijms\nInternational Journal of Molecular Sciences\n1422-0067 MDPI \n\n33203140\n10.3390/ijms21228611\nijms-21-08611\nCase Report\nNew Cav1.2 Channelopathy with High-Functioning Autism, Affective Disorder, Severe Dental Enamel Defects, a Short QT Interval, and a Novel CACNA1C Loss-of-Function Mutation\nEndres Dominique 12*† Decher Niels 3† Röhr Isabell 3 Vowinkel Kirsty 3 Domschke Katharina 24 Komlosi Katalin 5 https://orcid.org/0000-0002-6840-965XTzschach Andreas 5 Gläser Birgitta 5 Schiele Miriam A. 2 https://orcid.org/0000-0002-0263-4360Runge Kimon 12 Süß Patrick 6 Schuchardt Florian 7 Nickel Kathrin 12 Stallmeyer Birgit 8 Rinné Susanne 3 Schulze-Bahr Eric 8‡ https://orcid.org/0000-0002-2274-5447Tebartz van Elst Ludger 12‡ 1 Section for Experimental Neuropsychiatry, Department of Psychiatry and Psychotherapy, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79104 Freiburg, Germany; kimon.runge@uniklinik-freiburg.de (K.R.); kathrin.nickel@uniklinik-freiburg.de (K.N.); tebartzvanelst@uniklinik-freiburg.de (L.T.v.E.)\n2 Department of Psychiatry and Psychotherapy, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79104 Freiburg, Germany; katharina.domschke@uniklinik-freiburg.de (K.D.); miriam.schiele@uniklinik-freiburg.de (M.A.S.)\n3 Institute for Physiology and Pathophysiology, Vegetative Physiology and Marburg Center for Mind, Brain and Behavior-Philipps-University Marburg, 35037 Marburg, Germany; decher@staff.uni-marburg.de (N.D.); info@isabell-roehr.de (I.R.); kirsty.vowinkel@staff.uni-marburg.de (K.V.); rinne@staff.uni-marburg.de (S.R.)\n4 Center for Basics in Neuromodulation, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany\n5 Institute of Human Genetics, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany; katalin.komlosi@uniklinik-freiburg.de (K.K.); andreas.tzschach@uniklinik-freiburg.de (A.T.); birgitta.glaeser@uniklinik-freiburg.de (B.G.)\n6 Department of Molecular Neurology, University Hospital Erlangen, 91054 Erlangen, Germany; Patrick.Suess@uk-erlangen.de\n7 Department of Neurology, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany; florian.schuchardt@uniklinik-freiburg.de\n8 Institute for Genetics of Heart Diseases, Department of Cardiovascular Medicine, University Hospital Münster, 48149 Münster, Germany; Birgit.Stallmeyer@ukmuenster.de (B.S.); eric.schulze-bahr@ukmuenster.de (E.S.-B.)\n* Correspondence: dominique.endres@uniklinik-freiburg.de; Tel.: +49-761-270-66360† These authors contributed equally to this work.\n\n‡ These authors contributed equally to this work.\n\n\n15 11 2020 \n11 2020 \n21 22 861120 9 2020 07 11 2020 © 2020 by the authors.2020Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).Complex neuropsychiatric-cardiac syndromes can be genetically determined. For the first time, the authors present a syndromal form of short QT syndrome in a 34-year-old German male patient with extracardiac features with predominant psychiatric manifestation, namely a severe form of secondary high-functioning autism spectrum disorder (ASD), along with affective and psychotic exacerbations, and severe dental enamel defects (with rapid wearing off his teeth) due to a heterozygous loss-of-function mutation in the CACNA1C gene (NM_000719.6: c.2399A > C; p.Lys800Thr). This mutation was found only once in control databases; the mutated lysine is located in the Cav1.2 calcium channel, is highly conserved during evolution, and is predicted to affect protein function by most pathogenicity prediction algorithms. L-type Cav1.2 calcium channels are widely expressed in the brain and heart. In the case presented, electrophysiological studies revealed a prominent reduction in the current amplitude without changes in the gating behavior of the Cav1.2 channel, most likely due to a trafficking defect. Due to the demonstrated loss of function, the p.Lys800Thr variant was finally classified as pathogenic (ACMG class 4 variant) and is likely to cause a newly described Cav1.2 channelopathy.\n\nCACNA1CCaV1.2autismshort QT syndromedental enamel defect\n==== Body\n1. Introduction\nAutism spectrum disorders (ASD) are frequent neurodevelopmental disorders characterized by social interaction difficulties, stereotypical procedures, routines and rituals, or special interests caused predominantly idiopathic or of unknown cause (“primary forms”); in a subset, a specific cause can be identified, and some of these secondary cases (“secondary forms”) are part of genetically determined syndromes, e.g., fragile X syndrome [1]. Within these, Timothy syndrome is an extremely rare one characterized by long QT syndrome (LQTS) in the surface electrocardiography (ECG), skeletal abnormalities (e.g., cutaneous syndactyly), and neuropsychiatric features, such as autism [2,3,4], and is caused by gain-of-function mutations in the CACNA1C gene. Of note, some CACNA1C mutations may have an isolated cardiac, non-syndromal phenotype (only with QTc prolongation [5]). In contrast, patients with a short QT syndrome (SQTS) have not been described with extra-cardiac features so far.\n\n2. Case Presentation\nThe authors present for the first time a syndromal form of SQTS in a 34-year-old German male patient that is characterized by extracardiac features, namely a severe form of secondary ASD together with affective and psychotic exacerbations, wearing of his teeth, and a short QT interval in the surface ECG due to a heterozygous loss-of-function mutation in the CACNA1C gene. The functional consequences of the genetic mutation were further analyzed using electrophysiological investigations of the mutant Cav1.2 calcium channel expressed in Xenopus oocytes [2]. The patient has given his signed written informed consent for this case report, including the presented images, the genetic information, and all other data, to be published.\n\n2.1. Clinical Case Description\nSince the first decade, the patient has suffered from the whole spectrum of autistic symptoms. The detailed diagnosis was performed according to the scheme established by the Freiburg Center for the Diagnosis and Treatment of Autism (http://www.uniklinik-freiburg.de/psych/live/patientenversorgung/schwerpunkte/schwerpunkt-asperger.html, accessed on 14 November 2020 [6,7,8]). His medical history showed alterations in (1) gaze control and holistic visual recognition (he had to learn to look into the eyes of others, uses analytical facial expression recognition, recognizes other people by certain characteristics); (2) problems with social communication (he lacks the tools to build relationships, is burdened by social contacts, small talk and telephoning cause him problems, plans social situations in detail in advance); (3) reduced social integration (has only a few close friends, needs his time alone); (4) interactional imagination abnormalities and sense of justice (he hated “doing things as if he were playing games”, his sense of justice is 10/10, he is very honest); (5) linguistic pragmatics (as a child, he read dictionaries to understand proverbs, is often interpreting things literally); (6) routines and rituals (plans his everyday life in detail, is stressed by changes of plan, usually eats and drinks the same things); (7) motor clumsiness (he always had difficulties in sports, he had two “left hands” and two “left feet”); (8) sensory hypersensitivity (for loud noises and light, tormented in former times already by stroking by the mother); (9) strong perception of details (e.g., finds comma errors in texts, has difficulties with the “overall picture”); (10) special memory capacity (always knows exactly where what stood when he had read something); and (11) special interests for computer science [6]. The Autism Diagnostic Observation Schedule, Second Edition (ADOS-2; at the age of the patient of 34 years) confirmed clear autistic communication and interaction behavior confirming a syndrome diagnosis (14 points; cut off > 10 [9]). The testing of the recognition of emotions (“gnosis facialis”) revealed indications of relative deficits in recognizing fear (http://www.gnosisfacialis.de/infoERT.html, accessed on 14 November 2020. In the Movie for the Assessment of Social Cognition (MASC), the patient scored borderline [10]. Difficulties in communication in social intuition were partially compensated by the patient in an analytical–cognitive way. In summary, two expert raters confirmed the presence of a high-functional ASD syndrome. His intelligence level was above average (he reached high school graduation “Abitur” in Germany with average grade 1.3; range: 1–6, optimal: 1, worst: 6) and later studied computer science.\n\nAt the age of 15 years, the patient developed his first depressive episode and, at the age of 17 years, his first hypomanic episode. Until publication of this case report, the patient suffered from recurrent depressive episodes, but hypomanic phases did not occur anymore after the age of 21 years. His first psychiatric presentation took place at the age of 18 years following mutistic states (i.e., he was unable to speak); there were no indications of schizophrenia or causation by illegal drugs. Video telemetry revealed no evidence of epileptic seizures. At the age of 18 years, monomorphic ventricular extrasystoles (VES) were noticed for the first time during a physical examination for military service suitability. At the age of 29 years, the teeth suddenly discolored and then receded (Figure 1A). During this time, the patient suffered from significant polydipsia (requiring around 10 L of drinks/day) and was treated with lithium, methylphenidate, pregabalin, and lorazepam. Polydipsia was mainly caused by lithium treatment with increased serum levels at that time (1.6−1.8 mmol/L; reference 0.4–1.2 mmol/L). Calcium serum levels were within the normal range, and, thereby, phosphate and parathyroid levels were not determined. In the further course, 13 teeth had to be extracted and were supplemented by dental prostheses; other teeth were crowned. At the age of 29 years, he also developed a paranoid hallucinatory episode with hearing voices and ideas of persecution under the treatment with methylphenidate, nortriptyline, quetiapine, pregabalin, and lorazepam. Recurrently, the patient received benzodiazepines, but, after this was stopped (by antagonization with flumazenil), a generalized tonic-clonic seizure occurred at the age of 29 years.\n\nElectroencephalography at age 29, 33, and 34 years was inconspicuous. Analysis of the cerebrospinal fluid (CSF) revealed a borderline blood-brain barrier dysfunction (with CSF protein levels of 579 mg/L; reference: < 450 mg/L). The immunological screening showed an antinuclear antibody (ANA) titer of 1:100 (reference: < 1:50) and an IgA deficiency (0.26 g/L; reference: 0.7−4 g/L).\n\nA highly symptomatic occurrence of the monomorphic VES was noted again during the subsequent in-patient hospital treatment at the age of 29 years. Further cardiologic evaluation showed ~12,000 VES/day during Holter ECG, and subsequently, due to the severe overall clinical course, the patient underwent ablation therapy in the area of the middle cardiac vein or coronary sinus twice, which reduced VES burden (remaining: 3600 VES/day). There was no evidence of a structural heart disease as assessed by transthoracic echocardiography. The family history was positive with his father suffering from depression, alcohol-dependency, tachycardia (treated with ß-blockers), and unclear dental damage (the patient had no contact with the father; therefore, further information is missing). The age of the mother at birth of the patient was 41 years, and the age of the father was 35 years.\n\nOver the years, due to the severe course of the psychiatric symptoms, multiple psychopharmacological treatment trials have been carried out using varying and sometimes high doses (sertraline, fluoxetine, escitalopram, paroxetine, venlafaxine, vortioxetine, bupropion, nortriptyline, amitriptyline, clomipramine, lithium, methylphenidate, haloperidol, aripiprazole, perazine, promethazine, quetiapine, valproate, lamotrigine, carbamazepine, oxcarbazepine, pregabalin, levetiracetam, zonisamide, lacosamide, lorazepam, clonazepam, oxazepam, clobazam).\n\nAfter complete discontinuation of psychotropic medication at the age of 31 years, a cardiac re-evaluation was performed, and a short QTc interval of 324 ms (Figure 1C; reference: > 350 ms) was noted for the first time. Overall, this resembled a (paradoxical) shortening of the QTc interval during a heart rate (HR) of 57 bpm; at a HR of 111 bpm, the QTc interval normalized (408 ms). There was no evidence of T-wave alternans. Due to suspected SQTS, quinidine treatment (3 × 200 mg/day) has been initialized to normalize repolarization, but also to reduce symptomatic VES burden and thereby indirectly to improve mental strength and personal stability. Of note, during treatment QTc intervals completely recovered (at 57/min: QRS 114 ms, QTc around 425 ms; T-wave: broad-based, biphasic; no early repolarization signs or Brugada sign; Figure 1C), and the burden of symptomatic VES was nearly absent (now: 16 VES/day).\n\n2.2. Genetic Analyses\nGenetic testing of genes related to SQTS (KCNQ1, KCNH2, KCNJ2, CACNA1C) revealed a heterozygous nucleotide variant in CACNA1C (NM_000719.6: c.2399A > C; p.Lys800Thr), which was very rare in control databases (MAF gnomAD: 0.00043%) and predicted to affect protein function by 16 of the 23 pathogenicity prediction algorithms (VarCards). The mutated lysine is located in the cytoplasmic loop between repeat II and repeat III of the Cav1.2 calcium channel and is highly conserved. To exclude pathogenic copy number variations (CNV) as a possible additional cause of ASD and the psychiatric symptoms, microarray-analysis was performed (CytoSureTM Constitutional v3 Array 180k, Oxford Gene Technology) in the patient. Molecular karyotyping did not show any pathogenic or relevant CNVs.\n\n2.3. Electrophysiological Analyses\nHeterologous expression studies of the mutant Cav1.2 calcium channel in Xenopus oocytes showed an isolated reduction in the current amplitude of the L-type calcium channels (Figure 2B,C) without a change in kinetic properties (Figure 2D−I) when compared with native (wild-type) channels. Here, the normalized bell-shaped current-voltage relationship and the voltage-dependence of activation were unaltered (Figure 2D−E). In addition, the voltage-dependence of inactivation (Figure 2F−G), the extent of inactivation (Figure 2H), and the kinetics of inactivation (Figure 2I) were similar as in wild-type channels. Thus, the genetic variant is responsible for an isolated reduction of the macroscopic current amplitudes of approximately 40% (Figure 2C). The lack of changes in the channel kinetics and maintained voltage-dependence of channel gating behavior suggest that this reduced current amplitude is most likely caused by an intracellular trafficking defect of the mutant Cav1.2 calcium channel.\n\nWith respect to these functional data, the p.Lys800Thr variant was classified as likely pathogenic (class 4 variant) according to the ACMG guidelines [11].\n\n3. Discussion\nThe authors present a patient with a previously unpublished loss-of-function mutation of the CACNA1C gene with a novel, syndromal phenotype characterized by ASD, affective and psychotic exacerbations, dental enamel defect, and a short QT interval in the surface ECG. \n\nThe mutated CACNA1C gene (Chr. 12p13.3; 2,138 amino acids) encodes the α-subunit of the L-type calcium channel CaV1.2. These calcium channels are highly expressed in the brain and heart [3]. Genetic changes in CACNA1C are associated with Timothy syndrome or early repolarization disturbances/Brugada-like electrocardiography. However, patients with Timothy syndrome typically have gain-of-function mutations in the CACNA1C gene (e.g., p.Gly406Arg [2]), leading to maintained depolarizing L-type calcium current with long QT syndrome in the surface ECG and early sudden cardiac death (at an average age of 2.5 years; 3). Additionally, other cardiac features (AV conduction block with bradycardia, tachyarrhythmia, or congenital heart defects), neuropsychiatric involvement (developmental delays, seizures, ASD), hand/foot and facial findings (e.g., cutaneous syndactyly, low-set ears), hypoglycemia, and infections can be found in patients with Timothy syndrome [2]. Poor dental enamel was also reported earlier [3,12].\n\nThe presented case also suffered from high-functioning ASD, but he additionally presented with depressive and hypomanic episodes, as well as one paranoid hallucinatory episode. Such complex psychiatric syndromes are often found in patients with secondary, organic forms [1]. The genetic variant that has been classified finally as a likely pathogenic variant could explain the poor response to different psychotropic drugs in the patient’s history. However, pharmacogenetic studies, e.g., on drug metabolism, have not been carried out. There were no signs of dysmorphia on the hands/feet or face in the presented patient. In addition, he suffered from poor dental enamel with severe caries, initially misinterpreted as “meth mouth” because of high-dose methylphenidate medication. Surprisingly, a short QT interval was first noted when the patient was off psychotropic drugs that typically prolong the QT interval and, in this particular case, led to a normalization. He also had a high burden of VES. Only just about 250 cases with short QT syndrome are currently known, however, these have either isolated cardiac phenotypes or acquired, concomitant conditions (e.g., electrolyte disturbances or carnitine deficiency), and to date only about 30 genetic variants in eight potential disease genes were identified (summarized in [13]). Most of these cases are due to gain-of-function mutations in the potassium channel genes (KCNH2, KCNQ1, and KCNJ2), whereas loss-of-function mutations in CACNA1C leading to SQTS are extremely rare, and, in these cases, the shortened QT interval is accompanied with a Brugada ECG phenotype (not seen in the present case). Due to controversial or absent functional data and contradictory in silico predictions, some of variants were re-classified as variants of uncertain significance following ACMG criteria (class 3 variant) in a recent publication [14]. Very recently, a CACNA1C loss-of-function variant has been linked with SQTS in combination with early repolarization patterns in the surface ECG [15].\n\nThe heterozygous c.2399 A > C variant in the presented patient is yet unreported, leading to a non-synonymous amino acid exchange in the α-subunit of the L-type calcium channel CaV1.2 (p.(Lys800Thr)). A causality of the mutation is possible because the gene mutation is located in a conserved gene region and is very rare in control databases. Most pathogenicity prediction programs that evaluate amino acid exchange in silico suggest a biochemical and thus pathogenic effect (VarCards: 16/23) as it has been shown by the in vitro data upon heterologous expression experiments. The variant finally could be classified as a class 4 variant (“likely pathogenic”) according to the ACMG/AMP guideline [11]. Our functional studies revealed an isolated reduction of the current amplitudes (Figure 2C) without changes in the gating behavior of the channel. Therefore, a weak trafficking defect is the most likely mechanism of action for this atypical Cav1.2 channelopathy with brain, cardiac and dental enamel involvement.\n\n4. Conclusions\nIn summary, this is a paradigmatic case of a secondary genetic variant of a complex, partially atypical mental disorder with heart and dental involvement. Many such secondary genetic variants probably occur, each of which is very rare, but, taken together, these rare variants might be causing a relevant subgroup of mental disorders. In the presented patient, a pathological variant can be assumed, which led to an atypical form of SQTS with a clinical spectrum that partially overlaps with that of Timothy syndrome. Associations between CaV1.2 channel (CACNA1C) polymorphisms and different psychiatric disorders, including autism, depression, bipolar disorder, and schizophrenia, were recently reported [16,17,18,19]. Further research will need to show whether similar cases exist and elucidate the therapeutic consequences that can be inferred from mutant Cav1.2 channel.\n\nAcknowledgments\nDominique Endres was funded by the Berta-Ottenstein-Programme for Advanced Clinician Scientists, Faculty of Medicine, University of Freiburg. Patrick Süß is a member of the research training group GRK2162 funded by the DFG (270949263/GRK2162) and is supported by the University Hospital Erlangen (ELAN project P059, IZKF clinician scientist program). Niels Decher was funded by the DFG (DE 1482/9-1). Florian Schuchardt received financial support from Forschungskommission, Medical Faculty, Albert-Ludwigs-University Freiburg.\n\nPublisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAuthor Contributions\nD.E., P.S., F.S., E.S.-B., and L.T.v.E. treated the patient. D.E. performed the data research and wrote the paper. F.S. supported the literature search. N.D., I.R., K.V., and S.R. performed the experimental tests of calcium channels. E.S.-B. and B.S. performed CACNA1C testing and cardiac investigations and interpretation. E.S.-B. strongly revised the initial version of the paper. K.K. and A.T. examined the patient for signs of dysmorphia. B.G. performed and interpreted the microarray-analysis. N.D., M.A.S., K.R., K.N., and K.D. supported the overall interpretation and critically revised the manuscript. All authors were critically involved in the theoretical discussion and composition of the manuscript. All authors read and approved the final version of the manuscript.\n\nFunding\nThe article processing charge was funded by the Baden-Wuerttemberg Ministry of Science, Research and Art and the University of Freiburg in the funding program Open Access Publishing.\n\nConflicts of Interest\nDominique Endres: None. Niels Decher: None. Isabell Röhr: None. Kirsty Vowinkel: None. Katharina Domschke: Steering Committee Neurosciences, Janssen. Katalin Komlosi: None. Andreas Tzschach: None. Birgitta Gläser: None. Miriam A. Schiele: None. Kimon Runge: None. Patrick Süß: None. Florian Schuchardt: None. Kathrin Nickel: None. Birgit Stallmeyer: None. Susanne Rinné: None. Eric Schulze-Bahr: None. Ludger Tebartz van Elst: Advisory boards, lectures, or travel grants within the last three years: Roche, Eli Lilly, Janssen-Cilag, Novartis, Shire, UCB, GSK, Servier, Janssen and Cyberonics.\n\nFigure 1 (A) The dental status at 29 years of age and the corresponding dental radiography showed a reduced density of several coronas and mild hypoplasia of the maxilla and mandible. (B) The cerebral magnetic resonance imaging of the patient revealed slight hippocampal damage on the left in the area of the corpus and the cauda, together with otherwise inconspicuous cerebral anatomic findings. (C) The baseline electrocardiography displayed a short QTc interval (heart rate 57/min, QT 330 ms, QTc: 324 ms; reference: > 350 ms; 3a) and normalization during treatment with quinidine (3 × 200 mg/d; QTc: 425 ms; reference: < 350 ms; 3b). (D) The DNA sequence electropherogram revealed a heterozygous state at position 2399 (c.2399A > C) in the CACNA1C gene predicted to result in p.Lys800Thr.\n\nFigure 2 Own experimental analyses in the presented patient illustrated an isolated reduction in the current amplitude of L-type calcium channels without a change in kinetic properties. Two-electrode voltage-clamp measurements were performed in Xenopus oocytes, as previously described [2]. Ba2+ was used as a charge carrier, and for all experiments, Cav1.2 was co-expressed with the α2δ and β2b subunits [2]. In detail, the figure shows the following: (A) High evolutionary conservation of the K800 residue between different orthologues. (B) Representative current traces of wild-type (WT) Cav1.2 and mutant Cav1.2K800T recorded with the indicated voltage protocol, in order to analyze the current amplitudes and the voltage-dependence of activation properties. (C) Reduced peak current amplitudes, analyzed at + 20 mV. (D) Normalized bell-shaped current voltage-relationship and (E) conductance-voltage (GV) relationship. The voltage of half-maximal activation (V1/2 act.) is indicated in the upper corner. (F) Representative current traces of wild-type Cav1.2 and Cav1.2K800T recorded with the indicated voltage protocol, in order to analyze the inactivation properties. (G) Analyses of the voltage of half-maximal inactivation (V1/2 inact.). The V1/2 inact. values are provided in the upper corner. (H) Percentage of voltage-dependent inactivation of wild-type and Cav1.2K800T analyzed at different voltage potentials. (I) Analyses of the time constant of voltage-dependent inactivation (τ inact.) of wild-type and Cav1.2K800T analyzed at different voltage potentials. Numbers of experiments are indicted in the panels. Data are presented as mean ± s.e.m. * indicates p < 0.05.\n==== Refs\nReferences\n1. Tebartz van Elst L. Pick M. Biscaldi M. Fangmeier T. Riedel A. High-functioning autism spectrum disorder as a basic disorder in adult psychiatry and psychotherapy: Psychopathological presentation, clinical relevance and therapeutic concepts Eur. Arch. Psychiatry Clin. Neurosci. 2013 263 Suppl. S2 189 196 10.1007/s00406-013-0459-3 22825739 \n2. Splawski I. Timothy K.W. Sharpe L.M. Decher N. Kumar P. Bloise R. Napolitano C. Schwartz P.J. Joseph R.M. Condouris K. CaV1.2 Calcium Channel Dysfunction Causes a Multisystem Disorder Including Arrhythmia and Autism Cell 2004 119 19 31 10.1016/j.cell.2004.09.011 15454078 \n3. Napolitano C. Splawski I. Timothy K.W. Bloise R. Priori S.G. Timothy Syndrome GeneReviews® Adam M.P. Ardinger H.H. Pagon R.A. Wallace S.E. Bean L.J.H. Stephens K. Amemiya A. University of Washington Seattle, WA, USA 2006 \n4. Walsh M.A. Turner C. Timothy K.W. Seller N. Hares D.L. James A.F. Hancox J.C. Uzun O. Boyce D. Stuart A.G. A multicentre study of patients with Timothy syndrome Europace 2018 20 377 385 10.1093/europace/euw433 28371864 \n5. Wemhöner K. Friedrich C. Stallmeyer B. Coffey A.J. Grace A. Zumhagen S. Seebohm G. Ortiz-Bonnin B. Rinné S. Sachse F.B. Gain-of-function mutations in the calcium channel CACNA1C (Cav1.2) cause non-syndromic long-QT but not Timothy syndrome J. Mol. Cell. Cardiol. 2015 80 186 195 10.1016/j.yjmcc.2015.01.002 25633834 \n6. Tebartz van Elst L. Das Asperger-Syndrom im Erwachsenenalter und Andere Hochfunktionale Autismus-Spektrum-Störungen 2nd ed. Medizinisch Wissenschaftliche Verlagsgesellschaft Berlin, Germany 2015 \n7. Tebartz van Elst L. Maier S.E. Fangmeier T. Endres D. Mueller G.T. Nickel K. Ebert D. Lange T. Hennig J. Biscaldi M. Disturbed cingulate glutamate metabolism in adults with high-functioning autism spectrum disorder: Evidence in support of the excitatory/inhibitory imbalance hypothesis Mol. Psychiatry 2014 19 1314 1325 10.1038/mp.2014.62 25048006 \n8. Endres D. Tebartz van Elst L. Meyer S.A. Feige B. Nickel K. Bubl A. Riedel A. Ebert D. Lange T. Glauche V. Glutathione metabolism in the prefrontal brain of adults with high-functioning autism spectrum disorder: An MRS study Mol. Autism 2017 8 10 10.1186/s13229-017-0122-3 28316774 \n9. Lord C. Risi S. Lambrecht E.H. Jr. Leventhal B. DiLavore P.C. Pickles A. Rutter M. The Autism Diagnostic Observation Schedule—Generic: A Standard Measure of Social and Communication Deficits Associated with the Spectrum of Autism J. Autism Dev. Disord. 2000 30 205 223 10.1023/A:1005592401947 11055457 \n10. Dziobek I. Fleck S. Kalbe E. Rogers K. Hassenstab J. Brand M. Kessler J. Woike J.K. Wolf O.T. Convit A. Introducing MASC: A Movie for the Assessment of Social Cognition J. Autism Dev. Disord. 2006 36 623 636 10.1007/s10803-006-0107-0 16755332 \n11. Richards S. Aziz N. Bale S. Bick D. Das S. Gastier-Foster J. Grody W.W. Hegde M. Lyon E. Spector E. 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 17 405 423 10.1038/gim.2015.30 25741868 \n12. Papineau S.D. Wilson S. Dentition abnormalities in a Timothy syndrome patient with a novel genetic mutation: A case report Pediatr. Dent. 2014 36 245 249 24960393 \n13. Campuzano O. Sarquella-Brugada G. Cesar S. Arbelo E. Brugada J. Brugada R. Recent Advances in Short QT Syndrome Front. Cardiovasc. Med. 2018 5 149 10.3389/fcvm.2018.00149 30420954 \n14. Campuzano O. Fernandez-Falgueras A. Maulen X.L. Sarquella-Brugada G. Cesar S. Coll M. Mates J. Arbelo E. Jordà P. Pérez-Serra A. Short QT Syndrome: A Comprehensive Genetic Interpretation and Clinical Translation of Rare Variants J. Clin. Med. 2019 8 1035 10.3390/jcm8071035 31315195 \n15. Chen Y. Barajas-Martinez H. Zhu D. Wang X. Chen C. Zhuang R. Shi J. Wu X. Tao Y. Jin W. Novel trigenic CACNA1C/DES/MYPN mutations in a family of hypertrophic cardiomyopathy with early repolarization and short QT syndrome J. Transl. Med. 2017 15 1 10 10.1186/s12967-017-1180-1 28049494 \n16. Liao P. Soong T.W. CaV1.2 channelopathies: From arrhythmias to autism, bipolar disorder, and immunodeficiency Pflug. Arch. 2010 460 353 359 10.1007/s00424-009-0753-0 19916019 \n17. Kabitzke P. Brunner D. He D. Fazio P. Cox K. Sutphen J. Thiede L. Sabath E. Hanania T. Alexandrov V. Comprehensive analysis of two Shank3 and the Cacna1c mouse models of autism spectrum disorder Genes Brain Behav. 2017 17 4 22 10.1111/gbb.12405 28753255 \n18. Moon A.L. Haan N. Wilkinson L.S. Thomas K.L. Hall J. CACNA1C: Association With Psychiatric Disorders, Behavior, and Neurogenesis Schizophr. Bull. 2018 44 958 965 10.1093/schbul/sby096 29982775 \n19. Li J. Zhao L. You Y. Lu T. Jia M. Yu H. Ruan Y. Yue W. Liu J. Lu L. Schizophrenia Related Variants in CACNA1C also Confer Risk of Autism PLoS ONE 2015 10 e0133247 10.1371/journal.pone.0133247 26204268\n\n",
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"title": "New Cav1.2 Channelopathy with High-Functioning Autism, Affective Disorder, Severe Dental Enamel Defects, a Short QT Interval, and a Novel CACNA1C Loss-Of-Function Mutation.",
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"abstract": "Despite improvements in the treatment of advanced non-small cell lung cancer (NSCLC), certain patient populations remain underrepresented in clinical trials. Many patients have benefited from platinum doublets, including nab-paclitaxel-based regimens, but there are patients with comorbidities who particularly require careful balancing of efficacy and safety. Clinical trial data are limited for patients who are elderly or have renal impairment, diabetes, or impaired performance status.\nTo better understand outcomes in these patient populations, we performed a pooled analysis using data from the ABOUND clinical trial program (ABOUND.SQM, ABOUND.PS2, ABOUND.70+) and the key phase III trial of nab-paclitaxel/carboplatin in advanced NSCLC. The populations included in this pooled analysis consisted of elderly patients (≥ 70 years) and patients with renal impairment (eGFR < 60 ml/min/1.73 m2), diabetes, or poor performance status (ECOG PS 2).\nMedian progression-free survival (PFS) ranged from 4.1 months in patients with ECOG PS 2 (95% CI, 2.04-5.09 months) to 7.7 months in patients with diabetes (95% CI, 5.88-10.12 months). PFS for elderly patients and patients with renal impairment was 6.9 months each (95% CI, 6.01-7.98 months and 4.47-9.79 months, respectively). Median overall survival (OS) was 18.2 months (95% CI, 10.94-28.22 months), 17.4 months (95% CI, 14.59-20.14 months), and 16.1 months (95% CI, 14.09-18.50 months) in patients with renal impairment, patients with diabetes, and elderly patients, respectively. Patients with ECOG PS 2 exhibited the shortest median OS: 5.6 months (95% CI, 3.98-11.37 months). Overall response rates were 56.9%, 54.6%, 45.9%, and 29.4% in patients with diabetes, elderly patients, patients with renal impairment, and patients with ECOG PS 2, respectively. Most treatment-related adverse events were hematologic. The most common grade 3/4 hematologic adverse events in patients with renal impairment, elderly patients, patients with diabetes, and patients with poor performance status included neutropenia, anemia, and thrombocytopenia.\nAlthough survival data in patients with ECOG PS 2 were notably inferior to the other cohorts, our findings are consistent with those previously reported in the population-specific studies of the ABOUND trials and lend additional support for the use of nab-paclitaxel-based regimens in historically understudied and vulnerable populations.",
"affiliations": "Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, United States.;SUNY Upstate Medical University, Department of Medicine, Syracuse, NY, United States.;S.G. Moscati Hospital, Division of Medical Oncology, Avellino, Italy.;Baylor Charles A. Sammons Cancer Center, Texas Oncology PA, Dallas, TX, United States.;Washington University School of Medicine in St Louis, St Louis, MO, United States.;Sarah Cannon Research Institute, Lung Cancer Research Program, Nashville, TN, United States.;Churchill Hospital-Oxford University Hospitals, Oxford, United Kingdom.;Internistische Onkologie der Thoraxtumoren, Thoraxklinik im Universitätsklinikum Heidelberg, Translational Lung Research Center Heidelberg (TLRC-H), Heidelberg, Germany.;Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, United States.;Bristol Myers Squibb, Princeton, NJ, United States.;Bristol Myers Squibb, Princeton, NJ, United States.;PRA Health Sciences, Lenexa, KS, United States.;Bristol Myers Squibb, Princeton, NJ, United States.;AdventHealth Cancer Institute, Thoracic Cancer, Orlando, FL, United States.",
"authors": "Langer|Corey J|CJ|;Gajra|Ajeet|A|;Gridelli|Cesare|C|;Konduri|Kartik|K|;Morgensztern|Daniel|D|;Spigel|David|D|;Talbot|Denis|D|;Thomas|Michael|M|;Weiss|Jared|J|;Pilot|Richard|R|;Bhore|Rafia|R|;Wolfsteiner|Marianne|M|;Ong|Teng Jin|TJ|;Socinski|Mark|M|",
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"fulltext": "\n==== Front\nFront Oncol\nFront Oncol\nFront. Oncol.\nFrontiers in Oncology\n2234-943X Frontiers Media S.A. \n\n10.3389/fonc.2020.485587\nOncology\nOriginal Research\nnab-Paclitaxel/Carboplatin in Vulnerable Populations With Advanced Non-Small Cell Lung Cancer: Pooled Analysis\nLanger Corey J. 1* Gajra Ajeet 2 Gridelli Cesare 3 Konduri Kartik 4 Morgensztern Daniel 5 Spigel David 6 Talbot Denis 7 Thomas Michael 8 Weiss Jared 9 Pilot Richard 10 Bhore Rafia 10 Wolfsteiner Marianne 11 Ong Teng Jin 10 Socinski Mark 12 1Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, United States\n2SUNY Upstate Medical University, Department of Medicine, Syracuse, NY, United States\n3S.G. Moscati Hospital, Division of Medical Oncology, Avellino, Italy\n4Baylor Charles A. Sammons Cancer Center, Texas Oncology PA, Dallas, TX, United States\n5Washington University School of Medicine in St Louis, St Louis, MO, United States\n6Sarah Cannon Research Institute, Lung Cancer Research Program, Nashville, TN, United States\n7Churchill Hospital—Oxford University Hospitals, Oxford, United Kingdom\n8Internistische Onkologie der Thoraxtumoren, Thoraxklinik im Universitätsklinikum Heidelberg, Translational Lung Research Center Heidelberg (TLRC-H), Heidelberg, Germany\n9Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, United States\n10Bristol Myers Squibb, Princeton, NJ, United States\n11PRA Health Sciences, Lenexa, KS, United States\n12AdventHealth Cancer Institute, Thoracic Cancer, Orlando, FL, United States\nEdited by: Taofeek K. Owonikoko, Emory University, United States\n\nReviewed by: Natalie Vokes, Dana–Farber Cancer Institute, United States; Andrea Camerini, Azienda Usl Toscana nord ovest, Italy\n\n*Correspondence: Corey J. Langer, Corey.Langer@pennmedicine.upenn.eduThis article was submitted to Thoracic Oncology, a section of the journal Frontiers in Oncology\n\n\n26 1 2021 \n2020 \n10 48558715 6 2020 29 10 2020 Copyright © 2021 Langer, Gajra, Gridelli, Konduri, Morgensztern, Spigel, Talbot, Thomas, Weiss, Pilot, Bhore, Wolfsteiner, Ong and Socinski2021Langer, Gajra, Gridelli, Konduri, Morgensztern, Spigel, Talbot, Thomas, Weiss, Pilot, Bhore, Wolfsteiner, Ong and SocinskiThis is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.Introduction\nDespite improvements in the treatment of advanced non-small cell lung cancer (NSCLC), certain patient populations remain underrepresented in clinical trials. Many patients have benefited from platinum doublets, including nab-paclitaxel–based regimens, but there are patients with comorbidities who particularly require careful balancing of efficacy and safety. Clinical trial data are limited for patients who are elderly or have renal impairment, diabetes, or impaired performance status.\n\nMethods\nTo better understand outcomes in these patient populations, we performed a pooled analysis using data from the ABOUND clinical trial program (ABOUND.SQM, ABOUND.PS2, ABOUND.70+) and the key phase III trial of nab-paclitaxel/carboplatin in advanced NSCLC. The populations included in this pooled analysis consisted of elderly patients (≥ 70 years) and patients with renal impairment (eGFR < 60 ml/min/1.73 m2), diabetes, or poor performance status (ECOG PS 2).\n\nResults\nMedian progression-free survival (PFS) ranged from 4.1 months in patients with ECOG PS 2 (95% CI, 2.04–5.09 months) to 7.7 months in patients with diabetes (95% CI, 5.88–10.12 months). PFS for elderly patients and patients with renal impairment was 6.9 months each (95% CI, 6.01–7.98 months and 4.47–9.79 months, respectively). Median overall survival (OS) was 18.2 months (95% CI, 10.94–28.22 months), 17.4 months (95% CI, 14.59–20.14 months), and 16.1 months (95% CI, 14.09–18.50 months) in patients with renal impairment, patients with diabetes, and elderly patients, respectively. Patients with ECOG PS 2 exhibited the shortest median OS: 5.6 months (95% CI, 3.98–11.37 months). Overall response rates were 56.9%, 54.6%, 45.9%, and 29.4% in patients with diabetes, elderly patients, patients with renal impairment, and patients with ECOG PS 2, respectively. Most treatment-related adverse events were hematologic. The most common grade 3/4 hematologic adverse events in patients with renal impairment, elderly patients, patients with diabetes, and patients with poor performance status included neutropenia, anemia, and thrombocytopenia.\n\nConclusions\nAlthough survival data in patients with ECOG PS 2 were notably inferior to the other cohorts, our findings are consistent with those previously reported in the population-specific studies of the ABOUND trials and lend additional support for the use of nab-paclitaxel–based regimens in historically understudied and vulnerable populations.\n\nchemotherapyadvanced non-small cell lung cancernab-Paclitaxelplatinum-based therapyvulnerable populationsBristol-Myers Squibb10.13039/100002491\n==== Body\nIntroduction\nTreatment of advanced non-small cell lung cancer (NSCLC) has greatly improved over the past 2 decades, and the recent advances with immunotherapy in advanced NSCLC are particularly encouraging (1, 2). However, some patient groups, including the elderly and patients with renal impairment, diabetes, or poor performance status, present unique treatment challenges because of comorbid conditions, perceptions of increased toxicity, short life expectancy, or compromised treatment efficacy, and underrepresentation in clinical trials (3–5). In addition, most clinical trials in advanced cancers stipulate normal renal function as an inclusion criterion, and elderly patients have historically been either excluded from or underrepresented in clinical trials despite accounting for the majority of lung cancer cases (6, 7). Immunotherapy has demonstrated benefit in patients with advanced NSCLC but has not yet been fully studied in many of these vulnerable populations (8). Although immunotherapy alone or in combination with chemotherapy is now a standard of care in a significant proportion of patients with advanced NSCLC, cytotoxic chemotherapy in the first and subsequent lines of therapy remains relevant.\n\nPlatinum-based combination chemotherapy, including nab-paclitaxel/carboplatin, has been shown to benefit many patient subgroups and was the recommended first-line treatment strategy for most patients prior to the advent of immunotherapy (9–11). Subset analyses of a key phase III trial indicated that treatment with nab-paclitaxel/carboplatin was associated with a clinical benefit and tolerable safety profile in various advanced NSCLC populations (12–14). The ABOUND clinical trial program assessed the role of nab-paclitaxel–based regimens in patients with squamous histology and also enrolled many patients who fell into these underserved subset categories. The ABOUND.70+ and ABOUND.PS2 studies highlighted the benefit and tolerability of nab-paclitaxel/carboplatin in elderly patients (≥ 70 years) and in patients with Eastern Cooperative Oncology Group performance status (ECOG PS) 2, respectively (15, 16).\n\nThe goal of this pooled analysis was to evaluate outcomes associated with nab-paclitaxel/carboplatin treatment of NSCLC in more vulnerable populations including the elderly and in patients with renal impairment, diabetes, or ECOG PS 2.\n\nMaterials and Methods\nThis pooled analysis of ABOUND.SQM, ABOUND.PS2, ABOUND.70+, and the phase III study by Socinski et al. analyzed vulnerable populations with advanced NSCLC (Supplemental Tables 1\nand\n2; D Spigel, Unpublished data, 2019) (15–17). Study designs, methods, dosing, and schedule details have been previously published and are summarized in Supplemental Table 3. Treatment arms containing nab-paclitaxel/carboplatin were pooled across these four studies (patients from the ABOUND.SQM trial who received induction therapy with nab-paclitaxel/carboplatin followed by maintenance with best supportive care were excluded from this pooled analysis). In each of these studies and at each participating site, the studies were approved by IRB and the patients/participants provided written informed consent to participate in the studies.\n\nDemographics and baseline patient characteristics were summarized in terms of frequencies or descriptive statistics for categorical or continuous data, respectively. The Kaplan-Meier product-limit method was used to estimate progression-free survival (PFS) and overall survival (OS) curves for each vulnerable population; median PFS and OS were defined as the shortest survival time in months in which estimated survival probability was ≤ 0.5. The Brookmeyer-Crowley method was used to estimate 95% CIs for medians. Median PFS and OS in the vulnerable population compared with those of the overall population of the pooled studies are presented in forest plots. No statistical comparisons were performed due to the heterogeneity of the pooled populations.\n\nPopulation Definitions\nThe patients included in this pooled analysis were not restricted to a single analytic cohort. For example, patients were placed in the poor performance status group if they had ECOG PS 2; however, this did not exclude them from other groups, if they qualified.\n\nRenal Impairment: Renal impairment was defined by estimated glomerular filtration rate (eGFR; ml/min/1.73 m2). Moderate renal impairment included patients with an eGFR from ≥ 30 to < 60 ml/min/1.73 m2. Severe renal impairment included patients with an eGFR from ≥ 15 to < 30 ml/min/1.73 m2.\n\nElderly Patients: Elderly patients were defined as those 70 years of age or older. Age cutoff for elderly patients was chosen for the ABOUND.70+ trial and the phase III trial subgroup analysis and was maintained for this pooled analysis.\n\nPatients With Diabetes: Patients with diabetes included those classified at baseline by the preferred terms “type 2 diabetes mellitus,” “diabetes mellitus,” and “glucose tolerance impaired” within the system organ class “metabolism and nutrition disorders.”\n\nPoor Performance Status: Poor performance status was defined as ECOG PS 2.\n\nResults\nPatients\nA total of 840 patients in this pooled population were analyzed. Of these, 66 (7.9%) had moderate or severe renal impairment, 293 (34.9%) were ≥ 70 years of age, 110 (13.1%) had a diagnosis of diabetes (including 7 patients classified as glucose tolerance impaired), and 42 (5.0%) had ECOG PS 2. Baseline characteristics were generally similar across these patient populations although weight and body mass index were highest in patients with diabetes and renal impairment (Table 1). The median age for each population ranged from 66.0 to 74.0 years. Patients were predominantly male, although gender was more evenly balanced among patients with renal impairment. Smoking status was similar across most populations, although patients with renal impairment included the highest proportion of never smokers (15.2%).\n\nTable 1 Baseline characteristics.\n\nCharacteristic\tRenal Impairment(n = 66)\tElderly(n = 293)\tDiabetesa(n = 110)\tPoor PS(n = 42)\t\nAge, median (range), years\t72.5\t74.0\t71.0\t66.0\t\n(45.0-85.0)\t(70.0–93.0)\t(50.0–89.0)\t(44.0–84.0)\t\nAge group, years, n (%)\t\t\t\t\t\n < 65\t16 (24.2)\t0\t30 (27.3)\t19 (45.2)\t\n ≥ 65\t50 (75.8)\t293 (100.0)\t80 (72.7)\t23 (54.8)\t\n < 70\t23 (34.8)\t0\t49 (44.5)\t24 (57.1)\t\n ≥ 70\t43 (65.2)\t293 (100.0)\t61 (55.5)\t18 (42.9)\t\n < 75\t39 (59.1)\t148 (50.5)\t75 (68.2)\t31 (73.8)\t\n ≥ 75\t27 (40.9)\t145 (49.5)\t35 (31.8)\t11 (26.2)\t\nGender, n (%)\t\t\t\t\t\n Male\t32 (48.5)\t184 (62.8)\t78 (70.9)\t26 (61.9)\t\n Female\t34 (51.5)\t109 (37.2)\t32 (29.1)\t16 (38.1)\t\nWeight, median (range), kg\t76.3\t69.0b\t80.0\t70.1\t\n(36.2–120.2)\t(36.2–117.2)\t(46.0–124.7)\t(42.9–111.1)\t\nBody mass index, median (range), kg/m2\t27.6\t24.9c\t27.7\t24.4\t\n(17.5–47.0)\t(16.0–40.5)\t(17.6–41.5)\t(15.7–41.5)\t\nRace, n (%)\t\t\t\t\t\n Asian\t1 (1.5)\t18 (6.1)\t12 (10.9)\t0\t\n African heritage\t6 (9.1)\t16 (5.5)\t10 (9.1)\t3 (7.1)\t\n White\t58 (87.9)\t249 (85.0)\t86 (78.2)\t39 (92.9)\t\n American Indian or Alaska native\t0\t2 (0.7)\t0\t0\t\n Other\t1 (1.5)\t3 (1.0)\t0\t0\t\n Unknown\t0\t5 (1.7)\t2 (1.8)\t0\t\nECOG PS, n (%)\t\t\t\t\t\n 0\t18 (27.3)\t86 (29.4)\t30 (27.3)\t0\t\n 1\t42 (63.6)\t189 (64.5)\t67 (60.9)\t0\t\n 2\t6 (9.1)\t18 (6.1)\t13 (11.8)\t42 (100.0)\t\nHistology, n (%)\t\t\t\t\t\n Adenocarcinoma\t17 (25.8)\t33 (11.3)\t21 (19.1)\t1 (2.4)\t\n Squamous cell carcinoma\t14 (21.2)\t99 (33.8)\t24 (21.8)\t14 (33.3)\t\n Non-squamous cell carcinoma\t23 (34.8)\t98 (33.4)\t36 (32.7)\t25 (59.5)\t\n Other\t3 (4.5)\t6 (2.0)\t1 (0.9)\t1 (2.4)\t\n Unknown\t9 (13.6)\t57 (19.5)\t28 (25.5)\t1 (2.4)\t\nStage, n (%)\t\t\t\t\t\n I\t1 (1.5)\t1 (0.3)\t2 (1.8)\t0\t\n II\t0\t3 (1.0)\t2 (1.8)\t0\t\n IIIA\t2 (3.0)\t12 (4.1)\t5 (4.5)\t0\t\n IIIB\t2 (3.0)\t37 (12.6)\t15 (13.6)\t2 (4.8)\t\n IV\t60 (90.9)\t236 (80.5)\t86 (78.2)\t40 (95.2)\t\n Unknown\t1 (1.5)\t4 (1.4)\t0\t0\t\nPrior therapy, n (%)\t\t\t\t\t\n Radiotherapy\t10 (15.2)\t49 (16.7)\t23 (20.9)\t12 (28.6)\t\n Chemotherapy\t0\t2 (0.7)\t3 (2.7)\t0\t\n Radiotherapy and chemotherapy\t0\t3 (1.0)\t1 (0.9)\t0\t\n Unknown\t56 (84.8)\t239 (81.6)\t83 (75.5)\t30 (71.4)\t\nSmoking status, n (%)\t\t\t\t\t\n Never smoked\t10 (15.2)\t18 (6.1)\t6 (5.5)\t0\t\n Quit smoking\t11 (16.7)\t35 (11.9)\t21 (19.1)\t1 (2.4)\t\n Currently smoking\t7 (10.6)\t21 (7.2)\t4 (3.6)\t2 (4.8)\t\n Unknown\t38 (57.6)\t219 (74.7)\t79 (71.8)\t39 (92.9)\t\nCountry, n (%)\t\t\t\t\t\n Australia\t0\t1 (0.3)\t0\t0\t\n Canada\t2 (3.0)\t4 (1.4)\t1 (0.9)\t1 (2.4)\t\n Germany\t2 (3.0)\t7 (2.4)\t6 (5.5)\t0\t\n Italy\t0\t3 (1.0)\t0\t0\t\n Japan\t1 (1.5)\t15 (5.1)\t9 (8.2)\t0\t\n Russia\t11 (16.7)\t17 (5.8)\t9 (8.2)\t0\t\n Spain\t1 (1.5)\t3 (1.0)\t3 (2.7)\t0\t\n Ukraine\t6 (9.1)\t13 (4.4)\t1 (0.9)\t0\t\n United States\t43 (65.2)\t230 (78.5)\t81 (73.6)\t41 (97.6)\t\nMetformin therapy, n (%)\t\t\t\t\t\n Yes\t7 (10.6)\t37 (12.6)\t59 (53.6)\t7 (16.7)\t\n No\t59 (89.4)\t256 (87.4)\t51 (46.4)\t35 (83.3)\t\nPeripheral neuropathy at baseline, n (%)\t\t\t\t\t\n No peripheral neuropathy\t49 (74.2)\t233 (79.5)\t71 (64.5)\t4 (9.5)\t\n Grade 1\t10 (15.2)\t35 (11.9)\t21 (19.1)\t0\t\n Grade 2\t0\t2 (0.7)\t1 (0.9)\t0\t\n Unknown\t7 (10.6)\t23 (7.8)\t17 (15.5)\t38 (90.5)\t\nRenal impairment, eGFR ml/min/1.73 m2, n (%)\t\t\t\t\t\n Moderate (eGFR ≥ 30–< 60)\t65 (98.5)\t42 (14.3)\t14 (12.7)\t6 (14.3)\t\n Severe (eGFR ≥ 15–< 30)\t1 (1.5)\t1 (0.3)\t0\t0\t\nECOG PS, Eastern Oncology Cooperative Group performance status; eGFR, estimated glomerular filtration rate. a Includes seven patients classified as “glucose tolerance impaired.” b For weight of elderly population, n = 292. c For body mass index of elderly population, n = 291.\n\nOverall, the treatment discontinuation rate was 97% among patients with renal impairment, patients aged ≥ 70 years, and patients with diabetes and 100% among patients with ECOG PS 2. Patients with ECOG PS 2 had a lower rate of discontinuation due to progressive disease (31.0% vs 39.3% to 43.9% in the other populations) but higher rates of discontinuation due to death (7.1% vs 1.5% to 3.1%), adverse events (33.3% vs 15.9% to 17.1%), and symptomatic deterioration (11.9% vs 3.0% to 6.3%) compared with patients in the other cohorts.\n\nEfficacy\nProgression-Free Survival\nPatients with diabetes had the longest median PFS (7.7 months; 95% CI, 5.88–10.12 months), followed by elderly patients (6.9 months; 95% CI, 6.01–7.98 months) and patients with renal impairment (6.9 months; 95% CI, 4.47–9.79) (Figures 1A, B). Patients with ECOG PS 2 demonstrated the shortest median PFS (4.1 months; 95% CI, 2.04–5.09 months).\n\nFigure 1 Kaplan-Meier curve (A) and forest plot (B) of PFS by population. PFS, progression-free survival; PS, performance status; LCL, lower confidence limit; UCL, upper confidence limit.\n\nDesignated subsets of the pooled populations underwent further comparative PFS analyses. No meaningful difference in median PFS was observed in patients with (n = 66) vs without (n = 774) renal impairment (6.9 months [95% CI, 4.47–9.79 months] vs 6.2 months [95% CI, 5.62–6.77 months]; Supplemental Figure 1A). The median PFS was similar in patients aged ≥ 70 years (n = 293) vs those aged < 70 years (n = 547) (6.9 months [95% CI, 6.01–7.98 months] vs 5.7 months [95% CI, 5.49–6.67 months]; Supplemental Figure 1B). No meaningful difference in median PFS was noted between patients with diabetes (n = 110) and those without diabetes (n = 730) (7.7 months [95% CI, 5.88–10.12 months] vs 6.0 months [95% CI, 5.55–6.57]; Supplemental Figure 1C) or in patients with diabetes who received metformin (n = 59) vs those who did not (n = 51) (6.8 months [95% CI, 4.40–10.38 months] vs 8.4 months [95% CI, 6.83–10.15 months]; Supplemental Figure 1D).\n\nOverall Survival\nOverall, the longest median OS was observed in patients with renal impairment (18.2 months; 95% CI, 10.94–28.22 months), followed by patients with diabetes (17.4 months; 95% CI, 14.59–20.14 months) and by elderly patients (16.1 months; 95% CI, 14.09–18.50 months) (Figures 2A, B). Patients with ECOG PS 2 had the shortest median OS (5.6 months; 95% CI, 3.98–11.37 months). The corresponding 1-year OS rates were highest in patients with diabetes (71.1%; 95% CI, 61.11%–78.99%), followed by patients with renal impairment (61.3%; 95% CI, 47.95%–72.15%) and elderly patients (60.3%; 95% CI, 54.15%–65.84%). Patients with ECOG PS 2 had the lowest rate of survival at 1-year (28.4%; 95% CI, 14.73%–43.78%). The 2-year OS rates were highest in patients with renal impairment (36.2%; 95% CI, 22.00%–50.57%), followed by patients with diabetes (34.0%; 95% CI, 23.53%–44.66%) and elderly patients (31.8%; 95% CI, 25.40%–38.31%). No patients with an ECOG PS 2 survived to 2 years.\n\nFigure 2 Kaplan-Meier curve (A) and forest plot (B) of OS by population. OS, overall survival; PS, performance status; LCL, lower confidence limit; UCL, upper confidence limit.\n\nFurther comparative survival analyses were performed on specific populations. The median OS was numerically longer in patients with (n = 66) vs without (n = 774) renal impairment (18.2 months [95% CI, 10.94–28.22 months] vs 13.0 months [95% CI, 12.22–14.55 months]; Supplemental Figure 2A). A longer median OS was observed in patients aged ≥ 70 years (n = 293) than in those under 70 years old (n = 547) (16.1 months [95% CI, 14.09–18.50 months] vs 12.4 months [95% CI, 11.17–13.73 months]; Supplemental Figure 2B). The median OS was also longer in patients with diabetes (n = 110) than in those without diabetes (n = 730) (17.4 months [95% CI, 14.59–20.14 months] vs 12.6 months [95% CI, 11.63–14.39 months]; Supplemental Figure 2C). However, the median OS was numerically shorter in patients with diabetes who received metformin (n = 59) (15.2 months [95% CI, 13.14–19.52 months]) vs those who did not (n = 51) (19.9 months [95% CI, 16.30–28.22 months]) (Supplemental Figure 2D).\n\nOverall Response\nAssessment of best overall response (by investigator in all studies except for the phase III trial by Socinski et al, which was performed by an independent radiology review committee) revealed that patients with diabetes exhibited the highest response rate [overall response rate (ORR): 56.9%; disease control rate (DCR): 88.2%], followed by elderly patients (ORR: 54.6%; DCR: 87.8%) and patients with renal impairment (ORR: 45.9%; DCR: 82.0%). Patients with ECOG PS 2 had the lowest response rate (ORR: 29.4%; DCR: 85.3%) (Figure 3).\n\nFigure 3 Response rate by population. CR, complete response; DCR, disease control rate; NE, not evaluable; ORR, overall response rate; PD, progressive disease; PR, partial response; PS, performance status; SD, stable disease. Based on patients with baseline and at least one post baseline tumor assessment.\n\nTreatment Exposure\nAcross populations, the median relative dose intensity (percentage of planned dose received) for nab-paclitaxel was 72.4% to 79.9% (Table 2). The median number of treatment cycles ranged from 4.0 to 6.0. Dose modifications, including reductions, interruptions, and delays, are described in Table 2.\n\nTable 2 Treatment exposure and dose modification.\n\nParameter\tRenal Impairment (n = 66)\tElderly (n = 287)\tDiabetes (n = 107)\tPoor PS (n = 42)\t\nTreatment Exposure\t\nNo. of cycles, median (range)\t5.0 (1.0–26.0)\t6.0 (1.0–48.0)\t6.0 (1.0–34.0)\t4.0 (1.0–18.0)\t\nPatients who received ≤ 6 cycles, n (%)\t48 (72.7)\t198 (69.0)\t64 (59.8)\t32 (76.2)\t\nDose intensity, median (range)\t\t\t\t\t\n Carboplatin, mg•min/ml/wk\t1.9 (0.2–201.7)\t1.4 (0.1–226.9)\t1.4 (0.3–255.6)\t1.4 (0.4–226.0)\t\n nab-Paclitaxel, mg/m2/wk\t66.3 (26.7–102.4)\t62.2 (14.5–116.7)\t63.6 (14.5–100.8)\t55.1 (31.4–100.0)\t\nRelative dose intensity, median (range), %\t\t\t\t\t\n Carboplatin\t87.6 (19.6–116.7)\t82.5 (19.6–400.0)\t83.2 (21.6–125.0)\t83.8 (21.6–110.3)\t\n nab-Paclitaxel\t76.9 (26.7–102.4)\t72.4 (19.3–155.6)\t74.1 (19.3–105.2)\t79.9 (47.1–100.0)\t\nCumulative dose, median (range)\t\t\t\t\t\n Carboplatin, mg•min/ml\t30.0\t24.0\t24.0\t19.5\t\n\t(5.0–14252.0)\t(5.0–7974.0)\t(5.0–9466.0)\t(5.0–1840.0)\t\n nab-Paclitaxel, mg/m2\t1037.5\t1200.0\t1300.0\t600.0\t\n\t(100.0–5150.0)\t(100.0–9550.0)\t(100.0–6675.0)\t(100.0–3200.0)\t\nDose Modification\t\nPatients with ≥ 1 dose reduction, n (%)\t\t\t\t\t\n Carboplatin\n nab-Paclitaxel\t43 (65.2)\n43 (65.2)\t189 (65.9)\n200 (69.7)\t65 (60.7)\n69 (64.5)\t13 (31.0)\n15 (35.7)\t\nPatients with ≥ 1 dose interruption, n (%)\t\t\t\t\t\n Carboplatin\t0\t0\t2 (1.9)\t0\t\n nab-Paclitaxel\t0\t1 (0.3)\t2 (1.9)\t0\t\nPatients with ≥ 1 dose delay, n (%)\t\t\t\t\t\n Carboplatin\t55 (83.3)\t215 (74.9)\t79 (73.8)\t16 (38.1)\t\n nab-Paclitaxel\t64 (97.0)\t245 (85.4)\t93 (86.9)\t20 (47.6)\t\nECOG PS, Eastern Cooperative Oncology Group performance status.\n\nSafety\nFor patients with renal impairment, elderly patients, patients with diabetes, and patients with ECOG PS 2, treatment-related treatment emergent adverse event (TEAE) rates were 56.1%, 71.8%, 67.3%, and 85.7%, respectively; specifically for serious events, the rates were 10.6%, 13.2%, 13.1%, and 31.0%, respectively. The pooled analysis showed most treatment-related adverse events were hematologic in nature (Table 3). For patients with renal impairment, elderly patients, patients with diabetes, and patients with ECOG PS 2, grade 3/4 treatment-related hematologic adverse events included neutropenia (27.3%, 30.7%, 28.0%, and 16.7%, respectively), anemia (15.2%, 13.6%, 13.1%, and 16.7%, respectively), and thrombocytopenia (9.1%, 9.4%, 8.4%, and 4.8%, respectively). Additional adverse events of interest are shown in Table 3. Of note, grade 3/4 peripheral neuropathy was most common in patients with diabetes (18.7%), followed by elderly patients (12.9%), patients with renal impairment (7.6%), and patients with ECOG PS 2 (2.4%). Also noteworthy was a single occurrence of grade 3/4 acute kidney injury among patients with renal impairment. Grade 5 TEAEs were mainly cardiac in nature; elderly patients, patients with ECOG PS 2, and patients with diabetes experienced four (cardiac arrest, 2; cardiorespiratory arrest, 1; myocardial infarction, 1), three (cardiac arrest, 2; arrythmia, 1), and one (myocardial infarction) events, respectively. Additional grade 5 TEAEs were related to infections [two events in the elderly population (pneumonia, 1; sepsis, 1)], general disorders [one event each in the diabetes (disease progression) and elderly (death) populations], renal and urinary disorders [one event each (renal failure) in the renal impairment and elderly populations], and respiratory, thoracic, and mediastinal disorders [one event each in the renal impairment (pulmonary embolism) and elderly (acute respiratory failure) populations].\n\nTable 3 Treatment-related TEAEs (≥ 5%) and other AEs of interest.\n\nGrade 3/4 Adverse Event, n (%)\tRenal Impairment(n = 66)\tElderly(n = 287)\tDiabetes(n = 107)\tPoor PS(n = 42)\t\nTreatment-Related TEAEs\t\nNeutropenia\t18 (27.3)\t88 (30.7)\t30 (28.0)\t7 (16.7)\t\nAnemia\t10 (15.2)\t39 (13.6)\t14 (13.1)\t7 (16.7)\t\nLeukopenia\t6 (9.1)\t27 (9.4)\t10 (9.3)\t3 (7.1)\t\nThrombocytopenia\t6 (9.1)\t27 (9.4)\t9 (8.4)\t2 (4.8)\t\nFatigue\t5 (7.6)\t24 (8.4)\t6 (5.6)\t2 (4.8)\t\nNeutrophil count decreased\t1 (1.5)\t20 (7.0)\t2 (1.9)\t0\t\nPneumonia\t1 (1.5)\t5 (1.7)\t2 (1.9)\t3 (7.1)\t\nAsthenia\t2 (3.0)\t4 (1.4)\t1 (0.9)\t3 (7.1)\t\nAEs of Interest\t\nPeripheral neuropathya,b\t5 (7.6)\t37 (12.9)\t20 (18.7)\t1 (2.4)\t\nInfections and infestationsa,c\t7 (10.6)\t25 (8.7)\t8 (7.5)\t9 (21.4)\t\nFebrile neutropenia\t1 (1.5)\t6 (2.1)\t2 (1.9)\t3 (7.1)\t\nMyalgia and arthralgiaa,d\t0\t2 (0.7)\t1 (0.9)\t0\t\nAE, adverse event; PS, performance status; TEAE, treatment-emergent adverse event.\n\naReported as a grouped term. bPeripheral neuropathy grouped term includes peripheral sensory neuropathy, neuropathy peripheral, muscular weakness, peripheral motor neuropathy, paresthesia, gait disturbance, hypoesthesia, peripheral sensorimotor neuropathy, areflexia, burning sensation, peroneal nerve palsy, polyneuropathy, and muscle atrophy. cInfections and infestations grouped term includes biliary sepsis, cellulitis, device-related infection, diarrhea infectious, diverticulitis, infective exacerbation of chronic obstructive airways disease, esophageal candidiasis, oral candidiasis, osteomyelitis, pneumonia, pneumonia streptococcal, sepsis, Serratia infection, urinary tract infection, and wound infection (2 elderly patients [0.7%] experienced grade 5 infections/infestations [pneumonia and sepsis, 1 patient each]). dMyalgia and arthralgia grouped term includes arthralgia and myalgia.\n\nDiscussion\nOverall, the efficacy and safety results of this pooled analysis demonstrate that nab-paclitaxel–based regimens are reasonably well tolerated and may benefit patients with advanced NSCLC who are elderly (≥ 70 years) or have diabetes, renal impairment (eGFR < 60 ml/min/1.73 m2), or poor performance status (ECOG PS 2). Based on their efficacy and toxicity profiles, to date, nab-paclitaxel–based regimens are broadly applicable to the general NSCLC population and have been used as a platform for the development of new immunotherapy/chemotherapy combinations (18, 19). Patients with poor PS may fare worse, potentially due to premature treatment discontinuation (as supported by the higher rates of treatment discontinuation due to death, adverse events, or symptomatic deterioration in this population relative to the others in our analysis), but still stand to derive some benefit from this strategy.\n\nDefining overall fitness of patients with advanced NSCLC and the influence of specific factors on suitability for chemotherapy, as they relate to types of chemotherapy or the option to withhold chemotherapy altogether, has been an ongoing area of interest for facilitating clinical practice decisions (20). Generally, there are few absolute restrictions that preclude chemotherapy (including those based on age or renal function), except for patients with poor PS, for whom the use of combination and in some cases single-agent regimens should be limited.\n\nCarboplatin is an appropriate platinum backbone for patients with insufficient renal function, as cisplatin-based chemotherapy has been associated with severe nephrotoxicity as well as other toxicities including greater nausea and vomiting, ototoxicity, and neuropathy (21, 22). Further, nab-paclitaxel is predominantly eliminated via fecal rather than renal excretion (12). Collectively, these properties suggest that, when used together, nab-paclitaxel and carboplatin is a reasonable treatment option for patients with renal impairment. The current pooled analysis revealed 1 grade 3/4 acute kidney injury and 1 grade 5 renal event in patients with renal impairment. Further, patients with renal impairment unexpectedly demonstrated longer median OS than those without impairment (18.2 vs 13.0 months). This likely reflects the imbalance in patient numbers, which included only 66 patients with vs 774 patients without renal impairment, thereby resulting in a wide 95% CI for the renal impairment cohort and crossing of the survival curves.\n\nIn elderly patients, including those with ECOG PS 2, taxane-based chemotherapy doublets have demonstrated significantly longer PFS than vinorelbine or gemcitabine monotherapy (median PFS, 6.0 vs 2.8 months; P < 0.001) albeit with more frequent toxicity (23). Furthermore, the subgroup analysis of elderly patients enrolled in the pivotal phase III study demonstrated significantly longer median OS in those treated with nab-paclitaxel/carboplatin (19.9 months) compared with solvent-based paclitaxel/carboplatin (10.4 months; P = 0.009) (14, 17). The current analysis demonstrated numerically longer median OS in elderly patients than in patients < 70 years old, which suggests that nab-paclitaxel is a suitable combination partner in this older, vulnerable population. The data presented here, as well as data reported elsewhere, support the notion that cytotoxic chemotherapy doublets are efficacious and feasible for elderly patients.\n\nThe impact of concurrent diagnoses of diabetes and lung cancer on survival outcomes is variable (13). Several studies have demonstrated that patients with diabetes mellitus in addition to NSCLC experience a shorter OS than patients without diabetes (24–26). However, some evidence exists for prolonged survival in patients with diabetes compared with those without diabetes (27). In this pooled analysis, patients with diabetes exhibited longer median OS than those without diabetes (17.4 vs 12.6 months). The explanation for these results remains unknown.\n\nSome studies have suggested an association between metformin treatment and improved outcomes in patients with diabetes and various solid tumors (27). In our pooled analysis presented, patients with diabetes who were treated with metformin had a shorter median OS than those who were not treated with metformin (15.2 vs 19.9 months). These results are consistent with the subgroup analysis of patients with NSCLC and diabetes by Hirsh et al. (13). Together, these results suggest that the hypothesized beneficial effect associated with metformin may not be applicable to nab-paclitaxel treatment in patients with diabetes.\n\nA modest survival improvement in patients with NSCLC and ECOG PS 2 (including elderly patients) has been reported previously in those treated with combination chemotherapy vs single-agent regimens (median OS, 8.0 vs 6.6 months; P = 0.184) (28). Patients in the pooled analysis with ECOG PS 2 demonstrated a numerically lower median OS (5.6 months) than those in the Lilenbaum study. However, in the prospective ABOUND.PS2 study, median OS was 7.7 months (15). Patients with advanced NSCLC and ECOG PS 2 generally exhibit shorter OS than patients with ECOG PS 0 or 1. It is noteworthy that this subgroup of patients continues to demonstrate worse survival than the overall population, despite the use of checkpoint inhibitors (29). The presence of comorbidities poses a greater concern for these patients—for example, in the current analysis, 14% of patients with an ECOG PS 2 had moderate renal impairment at baseline, which is concerning given their age compared with other populations. Further studies are warranted to identify the reasons for such poor outcomes, which should include identification of predictive or prognostic biomarkers that may offer potential targets for therapeutic intervention.\n\nThe results from this pooled analysis contribute to our understanding of the role of combination chemotherapies in underrepresented patient populations, which historically have presented unique treatment challenges. Overarching themes spanning these populations include a lack of specific evidence from treatment experiences and the assumption that treatment may be associated with much worse toxicities due to comorbidities. The paucity of evidence has led to a lack of specific treatment recommendations in these patient populations. Thus, treatment decisions may be based on extrapolations from other trials or from prior experience. Perception of heightened toxicity may lead to undertreatment or, in some cases, to no treatment at all in patients who might otherwise benefit. The data presented here provide additional support for the role of nab-paclitaxel–based treatment regimens in elderly patients as well as patients with renal impairment, diabetes, and ECOG PS 2.\n\nOur study has limitations, which must be taken into consideration when examining the data. For example, the pooled analysis vs a randomized clinical trial in a dedicated population does not account for differences in dosing schedules and treatment regimens between trials. In addition, some populations, such as those with ECOG PS 2, included a relatively small number of patients; this is not surprising, as most of the studies excluded patients with ECOG PS > 1. While our analysis was designed to focus on populations that tend to be poorly represented in clinical trials, it is possible that the resultant small sample sizes may have influenced the unexpectedly favorable survival results. Furthermore, the patients included in this pooled analysis were not restricted to a single analytic cohort; therefore, it is important to keep in mind when considering outcomes that patients may have had additional comorbidities beyond those highlighted in the specific comparison.\n\nnab-Paclitaxel–based regimens are effective in populations frequently underrepresented in clinical trials, including elderly patients and patients with renal impairment, diabetes, and poor performance status. In addition, there does not appear to be an obvious exacerbation of toxicity in these populations. These results support the role of nab-paclitaxel–based chemotherapy regimens as a standard of care in a variety of patient populations, including those heretofore underserved in clinical trials, and make this regimen appealing as a platform for the development of immunotherapy.\n\nData Availability Statement\nThe datasets presented in this article are not readily available because requestors must complete a data request on the Vivli platform. If the request is approved, Celgene will upload the anonymized data into the Vivli platform for use by researchers. Requests to access the datasets should be directed to https://vivli.org/ourmember/celgene/.\n\nEthics Statement\nAll relevant ethical approvals from institutional review board/independent ethics committee have been obtained prior to study commencement. Written informed consent was obtained from all patients prior to study entry.\n\nAuthor Contributions\nCJL, DM, JW, RB, MW, TJO, and MS: conceived of and designed the study. CJL, AG, CG, KK, DM, DS, DT, MT, JW, and MS: contributed to data collection. CJL, RP, RB, MW, TJO, and MS: analyzed the data. All authors: interpreted the data. All authors: revised the report critically. All authors contributed to the article and approved the submitted version. All authors agreed to be accountable for all aspects of the work and to ensure that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.\n\nFunding\nCelgene, a wholly owned subsidiary of Bristol Myers Squibb, sponsored the study and was involved in the study design, data collection, and data analysis. All authors had full access to all collected data and had sole discretion in the data interpretation, writing of the report, and the decision to submit for publication. The corresponding authors had full access to all data in the study and had final responsibility for the decision to submit for publication.\n\nConflict of Interest\nCJL: Consultant/advisory fees, Celgene Corporation; other consulting fees: AstraZeneca, Bristol Myers Squibb, Genentech/Roche, Novartis, Pfizer, Takeda, Hospira, Merck, Boehringer Ingelheim. AG: Honoraria for Advisory Board, AstraZeneca; other fees, ICON Plc, CRO. CG: Advisory Board and Speakers’ Bureau member, MSD, Bristol Myers Squibb, Roche, AstraZeneca. DM: Advisory/Consultant, AbbVie, Bristol Myers Squibb, PharmaMar, Takeda. DS: Consulting or advisory role and research funding, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Celgene Corporation, Genentech/Roche, Lilly, Novartis, Pfizer; research funding, Merck, University of Texas Southwestern Medical Center—Simmons Cancer Center. MT: Grants, Celgene Corporation, Bristol Myers Squibb, Roche, AstraZeneca; consulting fees, Celgene Corporation, AbbVie, Bristol Myers Squibb, Boehringer Ingelheim, Lilly, MSD, Novartis, Roche. JW: Grants, Celgene Corporation; consulting fees, Celgene Corporation. RP: Employment, Bristol Myers Squibb. RB: Employment, Bristol Myers Squibb. MW: Consulting fees, Bristol Myers Squibb. TJO: Employment, Bristol Myers Squibb.\n\nThe remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n\nThe authors declare that this study received funding from Celgene, a wholly owned subsidiary of Bristol Myers Squibb. The funder had the following involvement with the study: study design, data collection and data analysis.\n\nAcknowledgments\nMedical writing assistance was provided by Alessandra Richardson, PhD, MediTech Media, Ltd, funded by Bristol Myers Squibb. All listed authors are fully responsible for all content and editorial decisions for this manuscript.\n\nSupplementary Material\nThe Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fonc.2020.485587/full#supplementary-material\n\nClick here for additional data file.\n==== Refs\nReferences\n1 \nManegold C Dingemans AC Gray JE Nakagawa K Nicolson M Peters S \nThe potential of combined immunotherapy and antiangiogenesis for the synergistic treatment of advanced NSCLC\n. J Thorac Oncol (2017 ) 12 :194 –207\n. 10.1016/j.jtho.2016.10.003 \n27729297 \n2 \nYu D Cheng X Liu Z Xu S \nComparative beneficiary effects of immunotherapy against chemotherapy in patients with advanced NSCLC: meta-analysis and systematic review\n. Oncol Lett (2017 ) 14 :1568–80. 10.3892/ol.2017.6274 \n\n3 \nBlanco JAG Toste IS Alvarez RF Cuadrado GR Gonzalvez AM Martín IJG \nAge, comorbidity, treatment decision and prognosis in lung cancer\n. Age Ageing (2008 ) 37 :715–8. 10.1093/ageing/afn226 \n\n4 \nWest H \nPatients with advanced non–small-cell lung cancer and marginal performance status: walking the tight rope towards improved survival\n. J Clin Oncol (2013 ) 31 :2841–3. 10.1200/JCO.2013.50.1502 \n\n5 \nQuoix E \nTherapeutic options in older patients with metastatic non-small cell lung cancer\n. Ther Adv Med Oncol (2012 ) 4 :247–54. 10.1177/1758834012455838 \n\n6 \nEuropean Medicines Agency \nGuideline on the evaluation of the pharmacokinetics of medicinal products in patients with decreased renal function\n. (2015 ). Available at: https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-evaluation-pharmacokinetics-medicinal-products-patients-decreased-renal-function_en.pdf.\n\n7 \nWoodward RM Brown ML Stewart ST Cronin KA Cutler DM \nThe value of medical interventions for lung cancer in the elderly: results from SEER-CMHSF\n. Cancer (2007 ) 110 :2511–18.\n\n8 \nGomes F Tay R Chiramel J Califano R \nThe role of targeted agents and immunotherapy in older patients with non-small cell lung cancer\n. Drugs Aging (2018 ) 35 :1 –16\n. 10.1007/s40266-018-0573-z \n29243033 \n9 \nAmerican Society of Clinical Oncology \nGuideline on stage IV non-small-cell lung cancer therapy updated\n. (2017 ). Available at: https://www.asco.org/about-asco/press-center/news-releases/guideline-stage-iv-non-small-cell-lung-cancer-therapy-updated (September 10, 2018).\n\n10 \nNovello S Barlesi F Califano R Cufer T Ekman S Levra MG \nMetastatic non-small-cell lung cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up\n. Ann Oncol (2016 ) 27 (suppl 5 ):v1 –27\n. 10.1093/annonc/mdw326 \n27664245 \n11 \nNational Comprehensive Cancer Network \nClinical Practice Guidelines in Oncology\n. Non-Small Cell Lung Cancer (2019 ) V3 Available at: https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf (October 4, 2020).\n\n12 \nLanger CJ Hirsh V Ko A Renschler MF Socinski MA \nWeekly nab-paclitaxel in combination with carboplatin as first-line therapy in patients with advanced non–small-cell lung cancer: analysis of safety and efficacy in patients with renal impairment\n. Clin Lung Cancer (2015 ) 16 :112–20. 10.1016/j.cllc.2014.09.003 \n\n13 \nHirsh V Ko A Pilot R Renschler MF Socinski MA \nWeekly nab-paclitaxel in combination with carboplatin as first-line therapy in patients with advanced non–small-cell lung cancer: analysis of safety and efficacy in patients with diabetes\n. Clin Lung Cancer (2016 ) 17 :367–74. 10.1016/j.cllc.2016.04.002 \n\n14 \nSocinski M Langer C Okamoto I Hon JK Hirsh V Dakhil SR \nSafety and efficacy of weekly nab®-paclitaxel in combination with carboplatin as first-line therapy in elderly patients with advanced non-small-cell lung cancer\n. Ann Oncol (2012 ) 24 :314–21. 10.1093/annonc/mds461 \n\n15 \nGajra A Karim NA Mulford DA Villaruz LC Matrana MR Ali HY \nnab-Paclitaxel–based therapy in underserved patient populations: the ABOUND.PS2 study in patients with NSCLC and a performance status of 2\n. Front Oncol (2018 ) 8 :253. 10.3389/fonc.2018.00253 \n30087850 \n16 \nLanger CJ Kim ES Anderson EC Jotte RM Modiano M Haggstrom DE \nnab-Paclitaxel-based therapy in underserved patient populations: the ABOUND.70+ study in elderly patients with advanced NSCLC\n. Front Oncol (2018 ) 8 :262. 10.3389/fonc.2018.00262 \n30087851 \n17 \nSocinski MA Bondarenko I Karaseva NA Makhson AM Vynnychenko I Okamoto I \nWeekly nab-paclitaxel in combination with carboplatin versus solvent-based paclitaxel plus carboplatin as first-line therapy in patients with advanced non-small-cell lung cancer: final results of a phase III trial\n. J Clin Oncol (2012 ) 30 :2055–62. 10.1200/JCO.2011.39.5848 \n\n18 \nPaz-Ares L Luft A Vicente D Tafreshi A Gümüş M Mazières J \nPembrolizumab plus chemotherapy for squamous non–small-cell lung cancer\n. N Engl J Med (2018 ) 379 :2040–51. 10.1056/NEJMoa1810865 \n\n19 \nSocinski MA Rittmeyer A Shapovalov D Orlandi F McCleod M Soo RA \nIMpower131: progression-free survival (PFS) and overall survival (OS) analysis of a randomised phase III study of atezolizumab + carboplatin + paclitaxel or nab-paclitaxel vs carboplatin + nab-paclitaxel in 1L advanced squamous NSCLC \n(2018 ). Available at: https://oncologypro.esmo.org/meeting-resources/esmo-2018-congress/IMpower131-Progression-free-survival-PFS-and-overall-survival-OS-analysis-of-a-randomised-Phase-III-study-of-atezolizumab-carboplatin-paclitaxel-or-nab-paclitaxel-vs-carboplatin-nab-paclitaxel-in-1L-advanced-squamous-NSCLC (Accessed October 25, 2018).\n\n20 \nDe Marinis F Bria E Baas P Tiseo M Camerini A Favaretto AG \nTreatment of unfit patients with advanced non-small-cell lung cancer: definition criteria according an expert panel\n. Clin Lung Cancer (2015 ) 16 :399 –405\n. 10.1016/j.cllc.2015.04.008 \n25989953 \n21 \nGo RS Adjei AA \nReview of the comparative pharmacology and clinical activity of cisplatin and carboplatin\n. J Clin Oncol (1999 ) 17 :409 . 10.1200/JCO.1999.17.1.409 \n10458260 \n22 \nHotta K Matsuo K Ueoka H Kiura K Tabata M Tanimoto M \nMeta-analysis of randomized clinical trials comparing cisplatin to carboplatin in patients with advanced non–small-cell lung cancer\n. J Clin Oncol (2004 ) 22 :3852–9. 10.1200/JCO.2004.02.109 \n\n23 \nQuoix E Zalcman G Oster J Westeel V Pichon E Lavolé A \nCarboplatin and weekly paclitaxel doublet chemotherapy compared with monotherapy in elderly patients with advanced non-small-cell lung cancer: IFCT-0501 randomised, phase 3 trial\n. Lancet (2011 ) 378 :1079–88. 10.1016/S0140-6736(11)60780-0 \n\n24 \nAbu Hejleh T Chrischilles EA Pendergast JF Porter AT Wallace RB \nSurvival of non-small cell lung cancer (NSCLC) patients with and without diabetes mellitus (DM): Findings from the Cancer Care Outcomes Research and Surveillance Consortium (CanCORS)\n. J Clin Oncol (2013 ) 31 (15 Suppl ):6602 . 10.1200/jco.2013.31.15_suppl.6602 \n\n25 \nEmerging Risk Factors Collaboration \nDiabetes mellitus, fasting glucose, and risk of cause-specific death\n. N Engl J Med (2011 ) 364 :829–41. 10.1056/NEJMoa1008862 \n\n26 \nShieh SH Probst JC Sung FC Tsai WC Li YS Chen CY \nDecreased survival among lung cancer patients with co-morbid tuberculosis and diabetes\n. BMC Cancer (2012 ) 12 :174 . 10.1186/1471-2407-12-174 \n22578056 \n27 \nHatlen P Grønberg BH Langhammer A Carlsen SM Amundsen T \nProlonged survival in patients with lung cancer with diabetes mellitus\n. J Thorac Oncol (2011 ) 6 :1810–7. 10.1097/JTO.0b013e31822a75be \n\n28 \nLilenbaum R Villaflor VM Langer C O’Byrne K O’Brien M Ross HJ \nSingle-agent versus combination chemotherapy in patients with advanced non-small cell lung cancer and a performance status of 2: prognostic factors and treatment selection based on two large randomized clinical trials\n. J Thorac Oncol (2009 ) 4 :869–74. 10.1097/JTO.0b013e3181a9a020 \n\n29 \nSpigel DR McCleod M Jotte RM Einhorn L Horn L Waterhouse DM \nSafety, efficacy, and patient-reported health-related quality of life and symptom burden with nivolumab in patients with advanced non-small cell lung cancer, including patients aged ≥ 70 years or with poor performance status (CheckMate 153)\n. J Thorac Oncol (2019 ) 14 :1628–39. 10.1016/j.jtho.2019.05.010\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2234-943X",
"issue": "10()",
"journal": "Frontiers in oncology",
"keywords": "advanced non-small cell lung cancer; chemotherapy; nab-Paclitaxel; platinum-based therapy; vulnerable populations",
"medline_ta": "Front Oncol",
"mesh_terms": null,
"nlm_unique_id": "101568867",
"other_id": null,
"pages": "485587",
"pmc": null,
"pmid": "33575203",
"pubdate": "2020",
"publication_types": "D016428:Journal Article",
"references": "22942907;21366474;23123509;30280635;25572008;27664245;25989953;22547591;15326195;28789381;30105645;22578056;23835705;17955504;27230605;19004964;10458260;27729297;30087850;30087851;21831418;21964531;31121324;19487960",
"title": "nab-Paclitaxel/Carboplatin in Vulnerable Populations With Advanced Non-Small Cell Lung Cancer: Pooled Analysis.",
"title_normalized": "nab paclitaxel carboplatin in vulnerable populations with advanced non small cell lung cancer pooled analysis"
} | [
{
"companynumb": "US-PFIZER INC-202100970000",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CARBOPLATIN"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nGraves' disease (GD) is an autoimmune disorder characterized by hyperthyroidism. Antithyroid drugs (ATDs) are available as therapy. Agranulocytosis is a rare but potentially fatal complication of this therapy. In this study, we report agranulocytosis induced by propylthiouracil (PTU) in a patient with GD and the difficulties of clinical management.\n\n\nMETHODS\nRNBA, male, 30 years old, with GD, treated with propylthiouracil (PTU). He progressed with pharyngotonsillitis. Then, PTU was suspended and antibiotic, filgrastim, propranolol, and prednisone were initiated. Due to the decompensation of hyperthyroidism, lithium carbonate, dexamethasone, and Lugol's solution were introduced. Total thyroidectomy (TT) was performed with satisfactory postoperative progression.\n\n\nCONCLUSIONS\nWe describe here the case of a young male patient with GD. For the treatment of hyperthyroidism, thioamides are effective options. Agranulocytosis induced by ATDs is a rare complication defined as the occurrence of a granulocyte count <500/mm3 after the use of ATDs. PTU was suspended, and filgrastim and antibiotics were prescribed. Radioiodine (RAI) or surgery are therapeutic alternatives. Due to problems with ATD use, a total thyroidectomy was proposed. The preoperative preparation was performed with beta-blocker, glucocorticoid, lithium carbonate, and Lugol solution. Cholestyramine is also an option for controlling hyperthyroidism. TT was performed without postoperative complications.\n\n\nCONCLUSIONS\nThionamide-induced agranulocytosis is a rare complication. With a contraindication to ATDs, RAI and surgery are definitive therapeutic options in GD. Beta-blockers, glucocorticoids, lithium carbonate, iodine, and cholestyramine may be an adjunctive therapy for hyperthyroidism.",
"affiliations": "Division of Endocrinology & Metabolism, Intern Medicine Department, Hospital das Clínicas, Faculty of Medicine, Federal University of Goiás (HC-UFG), Goiás, GO, Brasil.;Faculty of Nutrition. Federal University of Goiás (HC-UFG), Goiás, GO, Brasil.;Division of Endocrinology & Metabolism, Intern Medicine Department, Hospital das Clínicas, Faculty of Medicine, Federal University of Goiás (HC-UFG), Goiás, GO, Brasil.;Intern Medicine Department, Hospital das Clínicas, Faculty of Medicine, Federal University of Goiás (HC-UFG), Goiás, GO, Brasil.;Division of Endocrinology & Metabolism, Intern Medicine Department, Hospital das Clínicas, Faculty of Medicine, Federal University of Goiás (HC-UFG), Goiás, GO, Brasil.;Division of Endocrinology & Metabolism, Intern Medicine Department, Hospital das Clínicas, Faculty of Medicine, Federal University of Goiás (HC-UFG), Goiás, GO, Brasil.;Division of Endocrinology & Metabolism, Intern Medicine Department, Hospital das Clínicas, Faculty of Medicine, Federal University of Goiás (HC-UFG), Goiás, GO, Brasil.;Division of Endocrinology & Metabolism, Intern Medicine Department, Hospital das Clínicas, Faculty of Medicine, Federal University of Goiás (HC-UFG), Goiás, GO, Brasil.;Division of Endocrinology & Metabolism, Intern Medicine Department, Hospital das Clínicas, Faculty of Medicine, Federal University of Goiás (HC-UFG), Goiás, GO, Brasil.;Division of Endocrinology & Metabolism, Intern Medicine Department, Hospital das Clínicas, Faculty of Medicine, Federal University of Goiás (HC-UFG), Goiás, GO, Brasil.",
"authors": "Rabelo|Patrícia Novais|PN|http://orcid.org/0000-0002-8085-9581;Rabelo|Paula Novais|PN|http://orcid.org/0000-0002-4122-1198;Paula|Allyne Fernanda de|AF|http://orcid.org/0000-0001-8936-5169;Conceição|Samuel Amanso da|SAD|http://orcid.org/0000-0003-0796-6708;Viggiano|Daniela Pultrini Pereira de Oliveira|DPPO|http://orcid.org/0000-0003-0546-8772;Antunes|Daniela Espíndola|DE|http://orcid.org/0000-0003-4098-5273;Jatene|Estela Muszkat|EM|http://orcid.org/0000-0002-2882-5974;Paula|Sílvia Leda França Moura de|SLFM|http://orcid.org/0000-0003-2593-7505;Dias|Monike Lourenço|ML|http://orcid.org/0000-0003-3879-7185;Reis|Maria Aparecida Lopes|MAL|http://orcid.org/0000-0003-1792-0754",
"chemical_list": "D013956:Antithyroid Agents; D011441:Propylthiouracil",
"country": "Brazil",
"delete": false,
"doi": "10.1590/1806-9282.65.6.755",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0104-4230",
"issue": "65(6)",
"journal": "Revista da Associacao Medica Brasileira (1992)",
"keywords": null,
"medline_ta": "Rev Assoc Med Bras (1992)",
"mesh_terms": "D000328:Adult; D000380:Agranulocytosis; D013956:Antithyroid Agents; D006111:Graves Disease; D006801:Humans; D008297:Male; D011441:Propylthiouracil; D035583:Rare Diseases; D013960:Thyroid Function Tests; D013965:Thyroidectomy",
"nlm_unique_id": "9308586",
"other_id": null,
"pages": "755-760",
"pmc": null,
"pmid": "31340298",
"pubdate": "2019-07-22",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Propylthiouracil-induced agranulocytosis as a rare complication of antithyroid drugs in a patient with Graves' disease.",
"title_normalized": "propylthiouracil induced agranulocytosis as a rare complication of antithyroid drugs in a patient with graves disease"
} | [
{
"companynumb": "BR-SUN PHARMACEUTICAL INDUSTRIES LTD-2019R1-218900",
"fulfillexpeditecriteria": "1",
"occurcountry": "BR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PROPYLTHIOURACIL"
},
... |
{
"abstract": "Deep vein thrombosis (DVT) is a common disease that is diagnosed in approximately 1 in 1000 adults annually. Extensive DVT can lead to life- or limb-threatening diagnoses such as phlegmasia cerulea dolens (PCD), phlegmasia alba dolens, and venous gangrene. PCD, also known as massive iliofemoral venous thrombosis, is rare, and a severe complication of DVT.\n\n\n\nWe report a case of a 94-year-old bedridden woman with past medical history of dementia, hypertension, pulmonary embolism, DVT, and atrial fibrillation. The patient was admitted to the hospital for bright red blood per rectum and an elevated international normalized ratio (INR) of 5.7. On admission, her dose of warfarin was suspended and she was given 4 units of fresh frozen plasma as well as 10 mg of i.v. vitamin K. She was discharged home with an INR normalized to 1.3 and cessation of her rectal bleeding. At discharge, she was not restarted on warfarin, nor was any bridging therapy used. The patient returned to the Emergency Department a week later for worsening pain and bluish discoloration of her bilateral lower extremities. An ultrasound (US) examination showed that she had developed bilateral PCD, after INR reversal. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Emergency physicians commonly care for patients who present with acute DVT or treat patients on anticoagulant therapy who require cessation of medications or administration of prothrombotic agents to reverse bleeding. Cases of extensive clot burden leading to PCD have been reported in the literature, however, reports of bilateral PCD secondary to cessation of warfarin have been scarce. PCD should be considered carefully as one of the complications in warfarin reversal, as it requires immediate attention and surgical intervention to prevent limb loss.",
"affiliations": "Mount Sinai Medical Center, Miami Beach, Florida.;Mount Sinai Medical Center, Miami Beach, Florida.;Mount Sinai Medical Center, Miami Beach, Florida.;Mount Sinai Medical Center, Miami Beach, Florida.",
"authors": "Fong|Burr|B|;Novak|Daniel|D|;Dalley|Michael|M|;Alfred|Gregory|G|",
"chemical_list": "D000925:Anticoagulants; D014812:Vitamin K; D014859:Warfarin",
"country": "United States",
"delete": false,
"doi": "10.1016/j.jemermed.2017.12.055",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0736-4679",
"issue": "54(4)",
"journal": "The Journal of emergency medicine",
"keywords": "DVT; anticoagulants; complications; prothrombotic agents; venous stasis",
"medline_ta": "J Emerg Med",
"mesh_terms": "D000369:Aged, 80 and over; D000925:Anticoagulants; D005260:Female; D006470:Hemorrhage; D006801:Humans; D035002:Lower Extremity; D012007:Rectum; D014463:Ultrasonography; D020246:Venous Thrombosis; D014812:Vitamin K; D014859:Warfarin",
"nlm_unique_id": "8412174",
"other_id": null,
"pages": "533-536",
"pmc": null,
"pmid": "29449120",
"pubdate": "2018-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Bilateral Phlegmasia Cerulea Dolens After Warfarin Reversal for Acute Rectal Bleeding: A Case Report.",
"title_normalized": "bilateral phlegmasia cerulea dolens after warfarin reversal for acute rectal bleeding a case report"
} | [
{
"companynumb": "US-CIPLA LTD.-2019US00258",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "WARFARIN"
},
"drugadditional": "1",
... |
{
"abstract": "Epithelioid hemangioendothelioma (EHE) is a rare malignant vascular tumor with no standardized treatment. The mammalian target of rapamycin inhibitor, sirolimus, has been used successfully in adult EHE and other vascular tumors in children but has not been studied in pediatric EHE. The aim of this retrospective case series is to discuss the results of sirolimus for treatment in 6 pediatric patients with EHE. Four of 6 patients demonstrated partial response or disease stabilization with sirolimus treatment. No treatment dosing, trough goals, or duration of treatment recommendations can be made. Prospective studies are warranted to further investigate the use of sirolimus in treatment of EHE.",
"affiliations": "Department of Pediatrics, University of South Florida, Tampa.;Boston University School of Medicine.;Vascular Anomalies Center, Division of Hematology and Oncology, Boston Children's Hospital, Boston, MA.;Johns Hopkins All Children's Hospital Cancer and Blood Disorders Institute, St. Petersburg, FL.",
"authors": "Engel|Elissa R|ER|;Cournoyer|Eily|E|;Adams|Denise M|DM|;Stapleton|Stacie|S|",
"chemical_list": "D000903:Antibiotics, Antineoplastic; D020123:Sirolimus",
"country": "United States",
"delete": false,
"doi": "10.1097/MPH.0000000000001643",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1077-4114",
"issue": "42(8)",
"journal": "Journal of pediatric hematology/oncology",
"keywords": null,
"medline_ta": "J Pediatr Hematol Oncol",
"mesh_terms": "D000293:Adolescent; D000903:Antibiotics, Antineoplastic; D002648:Child; D005260:Female; D005500:Follow-Up Studies; D018323:Hemangioendothelioma, Epithelioid; D006801:Humans; D008297:Male; D011379:Prognosis; D012189:Retrospective Studies; D020123:Sirolimus",
"nlm_unique_id": "9505928",
"other_id": null,
"pages": "e826-e829",
"pmc": null,
"pmid": "31714437",
"pubdate": "2020-11",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "A Retrospective Review of the Use of Sirolimus for Pediatric Patients With Epithelioid Hemangioendothelioma.",
"title_normalized": "a retrospective review of the use of sirolimus for pediatric patients with epithelioid hemangioendothelioma"
} | [
{
"companynumb": "US-DRREDDYS-USA/USA/20/0129886",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "PACLITAXEL"
},
"drugadditional": null,
... |
{
"abstract": "METHODS\nWe report a case of granulomatous skin reaction after injection of an unknown botulinum neurotoxin (BoNT) A preparation. Four years after occurrence of skin lesions, systemic sarcoidosis became manifest.\n\n\nCONCLUSIONS\nIn addition to injection trauma, the BoNT A preparation may have acted as an immunogenic stimulus leading to cutaneous manifestation of sarcoidosis.",
"affiliations": "Dermatologikum Hamburg, Stephansplatz 5, 20354, Hamburg, Deutschland. breuer@dermatologikum.de.;Dermatologikum Hamburg, Stephansplatz 5, 20354, Hamburg, Deutschland.;Dermatologikum Hamburg, Stephansplatz 5, 20354, Hamburg, Deutschland.;Dermatologikum Hamburg, Stephansplatz 5, 20354, Hamburg, Deutschland.;Dermatologikum Hamburg, Stephansplatz 5, 20354, Hamburg, Deutschland.;Dermatologikum Hamburg, Stephansplatz 5, 20354, Hamburg, Deutschland.;Dermatologikum Hamburg, Stephansplatz 5, 20354, Hamburg, Deutschland.",
"authors": "Herbert|V G|VG|;Blödorn-Schlicht|N|N|;Böer-Auer|A|A|;Getova|V|V|;Steinkraus|V|V|;Reich|K|K|;Breuer|K|K|",
"chemical_list": "D019274:Botulinum Toxins, Type A",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00105-015-3651-8",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0017-8470",
"issue": "66(11)",
"journal": "Der Hautarzt; Zeitschrift fur Dermatologie, Venerologie, und verwandte Gebiete",
"keywords": "Foreign body granuloma; Foreign body reaction; Granuloma; Immunogenetic phenomena; Injection",
"medline_ta": "Hautarzt",
"mesh_terms": "D019274:Botulinum Toxins, Type A; D003937:Diagnosis, Differential; D042241:Early Diagnosis; D005260:Female; D015745:Granuloma, Foreign-Body; D006801:Humans; D007279:Injections, Subcutaneous; D008875:Middle Aged; D012507:Sarcoidosis; D012871:Skin Diseases; D063189:Symptom Assessment; D016896:Treatment Outcome",
"nlm_unique_id": "0372755",
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"pages": "863-6",
"pmc": null,
"pmid": "26129729",
"pubdate": "2015-11",
"publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article",
"references": "22092661;24124846;18539232;16495851;23607737;19673075;22344444;23863960;23008029;15830090",
"title": "Cutaneous granulomatous reactions at botulinum neurotoxin A injection sites: First manifestation of systemic sarcoidosis.",
"title_normalized": "cutaneous granulomatous reactions at botulinum neurotoxin a injection sites first manifestation of systemic sarcoidosis"
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"companynumb": "DE-MERZ NORTH AMERICA, INC.-15MRZ-00367",
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"abstract": "OBJECTIVE\nConsolidation/maintenance therapy induces deep remission in patients with multiple myeloma (MM); however, the most suitable regimen has been under investigation. The combination therapy with bortezomib, lenalidomide and dexamethasone (VRD) is a powerful regimen for relapsed/refractory as well as newly diagnosed MM as an induction therapy. However, severe adverse events (AEs) may become a problem when VRD is introduced without dose reduction as a consolidation/maintenance therapy.\n\n\nMETHODS\nIn this single-arm phase II study, we evaluated the efficacy of small-dose VRD regimen (sVRD) in the consolidation/maintenance setting. Sixteen patients who had partial response (PR) or better after any induction therapy were enrolled. Patients received at least six 28-day cycles of subcutaneous bortezomib (1.3 mg/m2 on days 1 and 15), lenalidomide (10 mg on days 1-21) and dexamethasone (40 mg on days 1, 8, 15 and 22).\n\n\nRESULTS\nThe overall response rate and the complete response (CR) rate were 100 and 43.8 %, respectively. In particular, one patient with CR and two patients with very good PR at enrollment achieved stringent CR during 6 courses of sVRD. With a median follow-up time of 29.4 months, the median progression-free survival (PFS) and overall survival (OS) were not reached, while the PFS and OS rates at 2.5 years were 66.6 and 77.3 %, respectively. Univariate analysis demonstrated that disease progression as a reason for discontinuation of sVRD had a negative impact on OS. There were no grade 3 or 4 hematologic or nonhematologic AEs.\n\n\nCONCLUSIONS\nOur sVRD regimen as a consolidation/maintenance therapy was highly effective and well tolerable.",
"affiliations": "Department of Medical Oncology and Hematology, Sapporo Medical University School of Medicine, South-1 West-16, Chuo-ku, Sapporo, Japan.;Department of Medical Oncology and Hematology, Sapporo Medical University School of Medicine, South-1 West-16, Chuo-ku, Sapporo, Japan. tsutomus@sapmed.ac.jp.;Gastroenterology and Hematology/Clinical Oncology, Internal Medicine, Steel Memorial Muroran Hospital, Muroran, Japan.;Department of Hematology, Kiyota Hospital, Sapporo, Japan.;Department of Medical Oncology and Hematology, Sapporo Medical University School of Medicine, South-1 West-16, Chuo-ku, Sapporo, Japan.;Department of Hematology and Oncology, Oji General Hospital, Tomakomai, Japan.;Department of Medical Oncology and Hematology, Sapporo Medical University School of Medicine, South-1 West-16, Chuo-ku, Sapporo, Japan.;Department of Hematology and Oncology, Asahikawa Red Cross Hospital, Asahikawa, Japan.;Department of Medical Oncology and Hematology, Sapporo Medical University School of Medicine, South-1 West-16, Chuo-ku, Sapporo, Japan.;Department of Medical Oncology and Hematology, Sapporo Medical University School of Medicine, South-1 West-16, Chuo-ku, Sapporo, Japan.;Department of Medical Oncology and Hematology, Sapporo Medical University School of Medicine, South-1 West-16, Chuo-ku, Sapporo, Japan.;Department of Medical Oncology and Hematology, Sapporo Medical University School of Medicine, South-1 West-16, Chuo-ku, Sapporo, Japan.;Department of Medical Oncology and Hematology, Sapporo Medical University School of Medicine, South-1 West-16, Chuo-ku, Sapporo, Japan.;Department of Medical Oncology and Hematology, Sapporo Medical University School of Medicine, South-1 West-16, Chuo-ku, Sapporo, Japan.;Department of Medical Oncology and Hematology, Sapporo Medical University School of Medicine, South-1 West-16, Chuo-ku, Sapporo, Japan.;Department of Medical Oncology and Hematology, Sapporo Medical University School of Medicine, South-1 West-16, Chuo-ku, Sapporo, Japan.;Department of Medical Oncology and Hematology, Sapporo Medical University School of Medicine, South-1 West-16, Chuo-ku, Sapporo, Japan.;Division of Internal Medicine, Higashi Sapporo Hospital, Sapporo, Japan.;Department of Medical Oncology and Hematology, Sapporo Medical University School of Medicine, South-1 West-16, Chuo-ku, Sapporo, Japan.",
"authors": "Ibata|Soushi|S|;Sato|Tsutomu|T|;Kuroda|Hiroyuki|H|;Nagamachi|Yasuhiro|Y|;Iyama|Satoshi|S|;Fujimi|Akihito|A|;Kamihara|Yusuke|Y|;Konuma|Yuichi|Y|;Yoshida|Masahiro|M|;Tatekoshi|Ayumi|A|;Hashimoto|Akari|A|;Horiguchi|Hiroto|H|;Ono|Kaoru|K|;Murase|Kazuyuki|K|;Takada|Kohichi|K|;Miyanishi|Koji|K|;Kobune|Masayoshi|M|;Hirayama|Yasuo|Y|;Kato|Junji|J|",
"chemical_list": "D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D018931:Antineoplastic Agents, Hormonal; D013792:Thalidomide; D000069286:Bortezomib; D003907:Dexamethasone; D000077269:Lenalidomide",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00280-016-3163-y",
"fulltext": "\n==== Front\nCancer Chemother PharmacolCancer Chemother. PharmacolCancer Chemotherapy and Pharmacology0344-57041432-0843Springer Berlin Heidelberg Berlin/Heidelberg 316310.1007/s00280-016-3163-yOriginal ArticleA phase II trial of small-dose bortezomib, lenalidomide and dexamethasone (sVRD) as consolidation/maintenance therapy in patients with multiple myeloma Ibata Soushi 1Sato Tsutomu 81-11-611-2111tsutomus@sapmed.ac.jp 1Kuroda Hiroyuki 2Nagamachi Yasuhiro 3Iyama Satoshi 1Fujimi Akihito 4Kamihara Yusuke 1Konuma Yuichi 5Yoshida Masahiro 1Tatekoshi Ayumi 1Hashimoto Akari 1Horiguchi Hiroto 1Ono Kaoru 1Murase Kazuyuki 1Takada Kohichi 1Miyanishi Koji 1Kobune Masayoshi 1Hirayama Yasuo 6Kato Junji 11 Department of Medical Oncology and Hematology, Sapporo Medical University School of Medicine, South-1 West-16, Chuo-ku, Sapporo, Japan 2 Gastroenterology and Hematology/Clinical Oncology, Internal Medicine, Steel Memorial Muroran Hospital, Muroran, Japan 3 Department of Hematology, Kiyota Hospital, Sapporo, Japan 4 Department of Hematology and Oncology, Oji General Hospital, Tomakomai, Japan 5 Department of Hematology and Oncology, Asahikawa Red Cross Hospital, Asahikawa, Japan 6 Division of Internal Medicine, Higashi Sapporo Hospital, Sapporo, Japan 13 10 2016 13 10 2016 2016 78 5 1041 1049 26 1 2016 6 10 2016 © The Author(s) 2016\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.Purpose\nConsolidation/maintenance therapy induces deep remission in patients with multiple myeloma (MM); however, the most suitable regimen has been under investigation. The combination therapy with bortezomib, lenalidomide and dexamethasone (VRD) is a powerful regimen for relapsed/refractory as well as newly diagnosed MM as an induction therapy. However, severe adverse events (AEs) may become a problem when VRD is introduced without dose reduction as a consolidation/maintenance therapy.\n\nMethods\nIn this single-arm phase II study, we evaluated the efficacy of small-dose VRD regimen (sVRD) in the consolidation/maintenance setting. Sixteen patients who had partial response (PR) or better after any induction therapy were enrolled. Patients received at least six 28-day cycles of subcutaneous bortezomib (1.3 mg/m2 on days 1 and 15), lenalidomide (10 mg on days 1–21) and dexamethasone (40 mg on days 1, 8, 15 and 22).\n\nResults\nThe overall response rate and the complete response (CR) rate were 100 and 43.8 %, respectively. In particular, one patient with CR and two patients with very good PR at enrollment achieved stringent CR during 6 courses of sVRD. With a median follow-up time of 29.4 months, the median progression-free survival (PFS) and overall survival (OS) were not reached, while the PFS and OS rates at 2.5 years were 66.6 and 77.3 %, respectively. Univariate analysis demonstrated that disease progression as a reason for discontinuation of sVRD had a negative impact on OS. There were no grade 3 or 4 hematologic or nonhematologic AEs.\n\nConclusion\nOur sVRD regimen as a consolidation/maintenance therapy was highly effective and well tolerable.\n\nKeywords\nMultiple myelomaConsolidation/maintenanceBortezomibLenalidomideDexamethasoneVRDissue-copyright-statement© Springer-Verlag Berlin Heidelberg 2016\n==== Body\nIntroduction\nOver the past 10 years, the median overall survival (OS) of patients with multiple myeloma (MM) has considerably increased due to the use of autologous hematopoietic stem cell transplantation (HSCT) and the introduction of the immunomodulatory drugs, thalidomide and lenalidomide, and the proteasome inhibitor, bortezomib, in transplant-eligible and transplant-ineligible patients [1].\n\nIn order to consolidate and maintain the outcome after induction therapy with these novel agents, consolidation/maintenance therapy has been an attractive choice. Consolidation (two to four cycles of combination therapies) and maintenance (continuous therapy, usually with single agents, until the time of disease progression) are commonly used in clinical practice after induction therapy, although no specific guidelines are available [2].\n\nThere have been many trials to support the use of consolidation/maintenance to maintain the response achieved after autologous HSCT or conventional treatments and to improve patient survival with single agent or combination therapy: thalidomide [3–8], lenalidomide [9–12], bortezomib [13], bortezomib plus thalidomide [14, 15] and bortezomib, thalidomide plus dexamethasone [16, 17]. However, no definitive information is available regarding which drug or which combination of drugs is the most favorable for consolidation/maintenance.\n\nConcerning this matter, Kikuchi et al. [18] published an informative study using in vitro isobologram analysis. They demonstrated that lenalidomide has strong combined effects with bortezomib on myeloma cells in the presence of stromal cells. The bortezomib-induced up-regulation of CCAAT/enhancer-binding protein homologous protein (CHOP), a pro-apoptotic transcription factor, was readily enhanced by lenalidomide in contact with stromal cells. Their findings are compatible with the report that the overall response rate (ORR) (i.e., very good partial response or better) of the combination of bortezomib, lenalidomide and dexamethasone (VRD) was higher than those of bortezomib, doxorubicin and dexamethasone (PAD), bortezomib, thalidomide and dexamethasone (VTD), or cyclophosphamide, bortezomib and dexamethasone (CVD) in newly diagnosed myeloma patients [19].\n\nThe combination regimen of VRD was first evaluated in patients with relapsed or relapsed/refractory MM in a phase I, dose-escalation study by Richardson et al. [20]. Then, they reported a phase II study to evaluate the efficacy and safety of VRD in the same relapsed or relapsed/refractory setting [21]. Also in a frontline setting, they reported favorable toxicity and promising response and survival of patients treated with the VRD regimen in a phase I/II study [22]. Some other reports confirmed the efficacy of the VRD regimen as a frontline [23] or second-line treatment [24, 25].\n\nEspecially, Roussel et al. [23] evaluated the efficacy of three courses of the VRD regimen as an induction treatment for previously untreated patients; their VRD regimen consisted of 3-week cycles of intravenous bortezomib 1.3 mg/m2 on days 1, 4, 8 and 11; oral lenalidomide 25 mg on days 1 to 14; and oral dexamethasone 40 mg on days 1, 8 and 15. They reported that the ORR at the completion of induction therapy was 58 %.\n\nIn consideration of this high efficacy, the combination of bortezomib, lenalidomide and dexamethasone is attractive for consolidation/maintenance treatment; however, adverse events (AEs) were not negligible with the full dosage of their VRD regimen. The most common toxicities with the VRD regimen were neurologic and hematologic, including grade 1–2 sensory neuropathy (55 %), grade 3–4 neutropenia (35 %) and thrombocytopenia (13 %) [23].\n\nTherefore, we conducted a phase II study reported herein evaluating the efficacy and safety of small-dose VRD (sVRD) in the consolidation/maintenance setting.\n\nMethods\nStudy design and objective\nThe aim of this multicenter, open-label, single-arm, phase II study was to determine the efficacy and safety of sVRD in Japanese patients with MM in the consolidation/maintenance setting. The primary end point of this study was the best ORR during 6 courses of sVRD. Secondary end points included progression-free survival (PFS), OS and safety. This study was conducted according to the Declaration of Helsinki and was approved by the institutional review board of each participating center. The institutional review board-approved consent form was signed by all patients before participating in this study. This trial is registered at www.umin.ac.jp (#UMIN8236).\n\nPatients\nEligible patients were age ≥20 and ≤80 years, with measurable symptomatic MM. Patients must have received at least 1 prior regimen and achieved at least a partial response (PR) by the International Myeloma Working Group (IMWG) Uniform Response Criteria. Other eligibility criteria included Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0–2, and an expected survival of more than 3 months. Adequate pulmonary, cardiac, renal and hepatic functions were required.\n\nTreatment\nPatients received subcutaneous bortezomib (1.3 mg/m2 on days 1 and 15), oral lenalidomide (10 mg on days 1–21) and oral dexamethasone (40 mg on days 1, 8, 15 and 22). The course was repeated every 4 weeks for 6 cycles. Patients with at least a PR at the end of cycle 6 could continue sVRD treatment. Patients discontinued therapy if they experienced progressive disease (PD) or unacceptable toxicity, if no more additional benefits could be expected or if the patient/investigator decided to discontinue therapy for any reason. Dose adjustments were permitted based on grade 3 or 4 AEs or based on an investigator’s decision; bortezomib could be reduced from 1.3 to 1.0 mg/m2, lenalidomide from 10 to 5 mg/day and dexamethasone from 40 to 20 mg/day. If a similar severity of toxicity occurred at the reduced dose, study treatment was discontinued. Antiviral prophylaxis, bisphosphonates, aspirin thromboprophylaxis and erythropoietic agents were permitted during the study. Granulocyte colony-stimulating factor was also allowed.\n\nAssessment of efficacy\nResponse assessments were conducted before enrollment and after each course of sVRD treatment. The ORR was defined as the proportion of patients whose best overall response was either a stringent complete response (sCR), complete response (CR), very good PR (VGPR) or PR based on responses as assessed using IMWG Uniform Response Criteria. sCR, CR, VGPR and PR required two consecutive assessments made at any time before progression or initiation of any new therapy. Patients were followed for disease progression and OS for up to 3 years after discontinuation or completion of therapy.\n\nAssessment of safety\nAEs were assessed at each visit and were graded according to National Cancer Institute Common Terminology Criteria (NCI-CTC) for AEs (Version 4.0). Data were collected until 30 days after the last dose of study drug, except for secondary primary malignancies (SPM) (which were assessed all along during follow-up). SPM was defined as any malignancy observed after introduction of sVRD treatment.\n\nStatistical methods\nThe median follow-up time was estimated using the reverse Kaplan–Meier method. PFS was calculated as the time from the start of treatment to the first documentation of PD or death if the patient died as a result of any cause before progression. OS was calculated as the time from the start of treatment to death. The Kaplan–Meier method was used to estimate the survival distribution. Univariate survival analysis was performed using the Kaplan–Meier method. The significance of differences in survival curves was assessed with the log-rank test. Multivariable analysis (Cox proportional hazards regression model) of OS was carried out on all covariates that showed a significant association with OS in univariate analysis. All analyses were conducted using GraphPad Prism version 5.0 (GraphPad Software, La Jolla, CA) and EZE (Saitama Medical Center, Jichi Medical University; http://www.jichi.ac.jp/saitama-sct/SaitamaHP.files/statmedEN.html) [26].\n\nResults\nPatients and treatments\nFrom June 2012 until November 2013, 16 MM patients were enrolled at 4 sites in Japan. The data cutoff date for this analysis was March 10, 2015. Patient demographics and baseline characteristics are summarized in Table 1. The median age was 67 years (range 53–78 years); 12 patients (75.0 %) were >65 years. Eleven patients (68.8 %) were male. The median time from diagnosis to enrollment was 17 months (range 4–95 months). ECOG PS was 0 in 50.0 %, 1 in 37.5 % and 2 in 12.5 % of the patients. They had either IgG (62.5 %) or IgA (37.5 %) myeloma and had either Kappa (81.3 %) or Lambda (18.7 %) light chain. After restaging at the time of enrollment, 81.3 % of patients had stage I and 18.7 % stage II according to the classification system of the International Staging System (ISS), and 87.5 % had stage I and 12.5 % stage III according to the system of Durie and Salmon (D-S). Fluorescence in situ hybridization (FISH) performed at the time of diagnosis showed that 1 (9.1 %) out of 11 patients had del 17, 4 (44.4 %) out of 9 del 13 and 3 (42.9 %) out of 7 t(4;14). The induction therapies before enrollment in this study were as follows: 87.5 % of patients were treated with dexamethasone, 81.3 % bortezomib, 43.8 % lenalidomide, 25.0 % doxorubicin, 18.8 % melphalan and 12.5 % cyclophosphamide. 43.8 % of patients had undergone radiation therapy. 25.0 % of patients had undergone at least one HSCT.Table 1 Characteristics of the patients with MM who received the sVRD regimen\n\nCharacteristic\tAll patients (n = 16)\t\nAge [mean (range)]\t67 (53–78)\t\nMale sex [n (%)]\t11 (68.8)\t\nMean time from diagnosis to enrollment [months (range)]\t17 (4–95)\t\nPS [n (%)]\t\n 0\t8 (50.0)\t\n 1\t6 (37.5)\t\n 2\t2 (12.5)\t\nType of myeloma [n (%)]\t\t\n IgG\t10 (62.5)\t\n IgA\t6 (37.5)\t\n Kappa\t13 (81.3)\t\n Lambda\t3 (18.7)\t\nISS stage at enrollment [n (%)]\t\n I\t13 (81.3)\t\n II\t3 (18.7)\t\n III\t0 (0)\t\nD–S stage at enrollment [n (%)]\t\n I\t14 (87.5)\t\n II\t0 (0)\t\n III\t2 (12.5)\t\nCytogenetic abnormalitiesa [n (%)]\t\n del 17\t1/11 (9.1)\t\n t(14;16)\t0/7 (0)\t\n del 13\t4/9 (44.4)\t\n t(4;14)\t3/7 (42.9)\t\nInduction regimen [n (%)]\t\n Any use of dexamethasone\t14 (87.5)\t\n Any use of bortezomib\t13 (81.3)\t\n Any use of lenalidomide\t7 (43.8)\t\n Any use of doxorubicin\t4 (25.0)\t\n Any use of melphalan\t3 (18.8)\t\n Any use of cyclophosphamide\t2 (12.5)\t\n Radiation\t7 (43.8)\t\n HSCT\t4 (25.0)\t\n\nISS International Staging System, D–S Durie and Salmon, HSCT hematopoietic stem cell transplantation\n\n\naData were obtained by fluorescence in situ hybridization (FISH)\n\n\n\n\nDuration of treatment\nAll patients could complete 6 courses of sVRD treatment (Table 2). The median duration of sVRD treatment was 8.0 courses (range 6–28 courses), with 56.3 % (n = 9) and 25.0 % (n = 4) undergoing >6 and >12 cycles, respectively. At the data cutoff date, all 16 patients had discontinued treatment. The reasons for treatment discontinuation were completion of 6 courses (n = 7, 43.8 %), disease progression (n = 3, 18.8 %), SPM of acute lymphoblastic leukemia (ALL) (n = 1, 6.3 %), AE of grade 2 pneumonia (n = 1, 6.3 %) or other (patient refusal or physician preference) (n = 4, 25.0 %).Table 2 Treatment duration of the sVRD regimen\n\n\tAll patients (n = 16)\t\nCompletion of 6 courses [n (%)]\t16 (100)\t\nMean treatment duration [courses (range)]\t8.0 (6–28)\t\nReason for discontinuation [n (%)]\t\n Completion of 6 courses\t7 (43.8)\t\n Disease progression\t3 (18.8)\t\n Second primary malignancy (acute lymphoblastic leukemia)\t1 (6.3)\t\n Adverse events (pneumonia)\t1 (6.3)\t\n Others\t4 (25.0)\t\n\n\n\nResponse\nAll 16 patients were response-evaluable. The ORR during 6 courses of sVRD treatment is shown in Table 3. 43.8 % had an sCR, 0 % CR, 6.3 % VGPR, 50.0 % PR and 0 % PD. The ORR and CR rate (i.e., at least CR) were 100 and 43.8 %, respectively. In detail, at enrollment, 4 patients were determined to be in sCR, 1 in CR, 2 in VGPR and 9 in PR. During 6 courses of sVRD, 4 patients with sCR at enrollment remained in sCR. One patient with CR and 2 with VGPR achieved sCR. In 9 patients with PR, 1 achieved VGPR, but 8 remained in PR. Nevertheless, 2 out of 8 patients with PR after 6 courses of sVRD finally achieved VGPR or sCR after a total of 18 or 24 courses of sVRD, respectively. Status at enrollment of a patient with del(17p) was PR, and his best overall response was the same PR. Table 4 demonstrates that all four patients (No. 5–8) who obtained deeper response during 6 courses of sVRD were treated without lenalidomide in induction therapies.Table 3 Best overall response during 6 courses of sVRD\n\nStatus at enrollment\tBest overall response\t\nsCR\tCR\tVGPR\tPR\tPD\t\nsCR (n = 4)\t4\t0\t0\t0\t0\t\nCR (n = 1)\t1\t0\t0\t0\t0\t\nVGPR (n = 2)\t2\t0\t0\t0\t0\t\nPR (n = 9)\t0\t0\t1\t8\t0\t\nTotal (n = 16) [n (%)]\t7 (43.8)\t0 (0)\t1 (6.3)\t8 (50.0)\t0 (0)\t\n\nsCR stringent complete response, CR complete response, VGPR very good partial response, PR partial response, PD progressive disease\n\n\nTable 4 Best overall response and induction regime\n\nPatient no.\tStatus at enrollment\tBest overall response\tInduction regimen\t\nBor\tLen\tDex\tDox\tMel\tCY\tRT\tHSCT\t\n1\tsCR\tsCR\t\t✓\t✓\t\t\t\t✓\t✓\t\n2\tsCR\tsCR\t✓\t✓\t✓\t\t\t\t\t✓\t\n3\tsCR\tsCR\t✓\t\t✓\t\t\t\t\t\t\n4\tsCR\tsCR\t✓\t✓\t✓\t\t\t\t✓\t\t\n5\tCR\tsCR\t✓\t\t✓\t\t\t\t\t\t\n6\tVGPR\tsCR\t✓\t○\t✓\t\t\t✓\t\t\t\n7\tVGPR\tsCR\t✓\t\t✓\t\t\t\t✓\t\t\n8\tPR\tVGPR\t✓\t\t✓\t\t✓\t\t\t\t\n9\tPR\tPR\t\t✓\t✓\t✓\t\t\t\t✓\t\n10\tPR\tPR\t✓\t\t\t\t✓\t\t\t\t\n11\tPR\tPR\t✓\t✓\t✓\t✓\t\t\t✓\t\t\n12\tPR\tPR\t✓\t\t\t\t✓\t\t\t\t\n13\tPR\tPR\t✓\t✓\t✓\t✓\t\t\t✓\t\t\n14\tPR\tPR\t\t✓\t✓\t✓\t\t\t\t✓\t\n15\tPR\tPR\t✓\t\t✓\t\t\t\t✓\t\t\n16\tPR\tPR\t✓\t\t✓\t\t\t✓\t✓\t\t\nTotal (n = 16)\t16\t16\t13\t7\t14\t4\t3\t2\t7\t4\t\n\nBor bortezomib, Len lenalidomide, Dex dexamethasone, Dox doxorubicin, Mel melphalan, CY cyclophosphamide, RT radiation, HSCT hematopoietic stem cell transplantation\n\n\n\n\nPFS and OS\nWith a median follow-up time of 29.4 months (range 16.1–33.1 months), 13 out of 16 patients are still alive, 11 of whom are progression-free for a maximum of 33.1 months. Three patients died and their cause of death was disease progression in all cases. One of these three patients who died had SPM of myelodysplastic syndrome (MDS). One had chromosomal abnormality of del(17p). It is noteworthy that the three patients who discontinued sVRD treatment due to PD were the same three patients who died in spite of various post-study therapies. Figure 1 shows the Kaplan–Meier estimates of PFS and OS. The median PFS was not reached, and the 2.5-year PFS was 66.6 % (95 % confidence interval [CI] 36.9–84.8 %). The median survival time (MST) was also not reached, and the 2.5-year survival rate was 77.3 % (95 % CI 44.3–92.2 %).Fig. 1 Kaplan–Meier curves of PFS and OS of MM patients who received the sVRD regimen. a PFS (the median PFS was not reached). b OS (the median OS was not reached)\n\n\n\n\nUnivariate analysis\nWhen analyzing prognostic factors for OS, univariate analysis using the log-rank test confirmed well-known prognostic parameters such as PS (P = 0.00569), albumin (P = 0.0000323), ISS (P = 0.0123) and del 17 (P = 0.00157) to be of prognostic relevance in our patient cohort (Table 5). Regarding best overall response during 6 courses of sVRD, OS was negatively influenced by PR compared with sCR, CR or VGPR (P = 0.0334). Furthermore, disease progression as a reason for discontinuation of sVRD had a negative impact on OS in comparison with other reasons (P = 0.0000374). These results indicated that refractoriness to the sVRD regimen could not be easily rescued by any post-study therapies. Nevertheless, none of the variables selected on univariate analysis was an independent prognostic marker for OS in the Cox proportional hazards regression model since the number of patients for multivariate analysis was small.Table 5 Univariate analysis (log-rank test) of prognostic factors for overall survival\n\nCharacteristic\tNumber of cases\t\nP value\t\nSex\t\n Male\t11\t0.27\t\n Female\t5\t\t\nAge (year)\t\t\t\n >67\t7\t0.766\t\n ≤67\t9\t\t\nPS\t\n ≥2\t2\t0.00569\t\n <2\t14\t\t\nBeta-2 microglobulin (mg/L)\t\t\t\n ≥2.5\t3\t0.507\t\n <2.5\t13\t\t\nAlbumin (g/dL)\t\t\t\n <3.5\t2\t0.0000323\t\n ≥3.5\t14\t\t\nISS stage at enrollment\t\t\t\n II, III\t3\t0.0123\t\n I\t13\t\t\ndel 13\t\n Yes\t4\t0.371\t\n No\t5\t\t\n\n4(4;14)\n\t\n Yes\t3\t0.386\t\n No\t4\t\t\ndel 17\t\n Yes\t1\t0.00157\t\n No\t10\t\t\nStatus at enrollment\t\n PR\t9\t0.0731\t\n sCR, CR, VGPR\t7\t\t\nBest overall response during 6 courses\t\n PR\t8\t0.0334\t\n sCR, CR, VGPR\t8\t\t\nReason for discontinuation\t\n Disease progression\t3\t0.0000374\t\n Others\t13\t\t\nSecond primary malignancy\t\n Yes\t2\t0.296\t\n No\t14\t\t\n\n\n\nSafety\nOne dose modification of dexamethasone from 40 to 20 mg/day was required because of grade 2 hypertension after the 3rd course of sVRD. One patient had discontinued all study drugs because of grade 2 pneumonia after 6 courses of sVRD. AEs are summarized in Table 6. Grade 2 sensory neuropathy was reported in two patients; however, neuropathy occurred in each patient during their induction therapies and lasted thereafter with no worsening. Grade 2 neutropenia occurred in 2 patients, pneumonia in 2, thrombocytopenia in 1, hypertension in 1, constipation in 1 and anemia in 1. There were no grade 3 or 4 hematologic or nonhematologic AEs.Table 6 Adverse events\n\nAdverse events\tGrade 2\n\nn (%)\tGrade 3\n\nn (%)\tGrade 4\n\nn (%)\t\nSensory neuropathy\t2 (12.5)a\n\t0 (0)\t0 (0)\t\nNeutropenia\t2 (12.5)\t0 (0)\t0 (0)\t\nPneumonia\t2 (12.5)\t0 (0)\t0 (0)\t\nThrombocytopenia\t1 (6.3)\t0 (0)\t0 (0)\t\nHypertension\t1 (6.3)\t0 (0)\t0 (0)\t\nConstipation\t1 (6.3)\t0 (0)\t0 (0)\t\nAnemia\t1 (6.3)\t0 (0)\t0 (0)\t\n\naPreexisting neuropathy with no worsening\n\n\n\n\nSecondary primary malignancies\nAfter enrollment, 2 new hematologic malignancies, i.e., ALL in one patient and MDS in another patient, were diagnosed (Table 7). The time from diagnosis to enrollment was 38 or 60 months in the patient with ALL or MDS, respectively. The former patient was pretreated with vincristine, adriamycin and dexamethasone (VAD) and autologous HSCT (ASCT) and then underwent 18 courses of sVRD treatment. He discontinued sVRD due to the occurrence of ALL. He has been alive after the standard induction/consolidation chemotherapy for ALL and allogeneic HSCT. The latter patient was pretreated with VAD and bortezomib plus dexamethasone (Bd) and then underwent sVRD treatment. After the 7th course, the sVRD regimen was stopped due to disease progression. The combination regimen of melphalan, prednisone and lenalidomide (MPR) was introduced as a post-study therapy, and a gradual dose reduction of melphalan was needed because of progressive pancytopenia. The diagnosis of MDS was made based on the findings of bone marrow aspiration. He finally died of PD.Table 7 Second primary malignancies (SPMs)\n\nSPM\t\nn (%)\tTime to enrollment (months)\tsVRD (courses)\tPrior therapies\t\nAcute lymphoblastic leukemia\t1 (6.3)\t38\t18\tVAD, ASCT\t\nMyelodysplastic syndrome\t1 (6.3)\t60\t7\tVAD, Bd\t\n\nVAD vincristine, adriamycin and dexamethasone, ASCT autologous hematopoietic stem cell transplantation, Bd bortezomib plus dexamethasone\n\n\n\n\nDiscussion\nThree previous reports investigated the regimen of bortezomib–lenalidomide–dexamethasone in the consolidation/maintenance setting [21, 23, 27] (Table 8). In the report by Roussel et al. [23], previously untreated patients were treated with the VRD regimen, as an induction therapy for three cycles and a consolidation therapy for two cycles after ASCT. Nooka et al. [27] treated previously untreated patients with the VRD regimen as a maintenance therapy after ASCT for three years. Richardson et al. [21] administered the VRD regimen in relapsed/refractory patients, as a re-induction therapy for eight cycles and a maintenance therapy until PD. In our trial, patients with at least PR after any induction therapy were enrolled to receive our sVRD regimen as a consolidation/maintenance therapy for at least 6 cycles.Table 8 VRD regimens used for consolidation and/or maintenance\n\n\tRoussel et al. J Clin Oncol 2014 (23)\tNooka et al. Leukemia 2014 (27)\tRichardson et al. Blood 2014 (21)\tOur trial\t\nPatients\tPreviously untreated\tPreviously untreated (high-risk)\tRelapsed/\nrefractory\t≥PR after any induction\t\nPhases of treatment\tInduction\n 3 cycles\nConsolidation (after ASCT)\n 2 cycles\tMaintenance (after ASCT)\n 3 years\tInduction\n 8 cycles\nMaintenance\n until PD\tConsolidation/maintenance\n ≥6 cycles\t\nCycle length\t21 days\t28 days\t21 days\t28 days\t\nBortezomib\t1.3 mg/m2\n\nIV\ndays 1, 4, 8, 11\t1.3 mg/m2\n\nIV or SC\ndays 1, 8, 15, 22\t1.0 mg/m2\n\nIV\ndays 1, 4, 8, 11\t1.3 mg/m2\n\nSC\ndays 1, 15\t\n<Average>\t1.7 mg/m2/week\t1.3 mg/m2/week\t1.3 mg/m2/week\t0.7 mg/m2/week\t\nLenalidomide\t25 mg/body\ndays 1–14\t10 mg/body\ndays 1–21\t15 mg/body\ndays 1–14\t10 mg/body\ndays 1–21\t\n<Average>\t17 mg/day\t7.5 mg/day\t10 mg/day\t7.5 mg/day\t\nDexamethasone\t40 mg/body\ndays 1, 8, 15\t40 mg/body\ndays 1, 8, 15, 22\t40 mg/body\ndays 1, 2, 4, 5, 8, 9, 11, 12\n(cycles 1–4)\t40 mg/body\ndays 1, 8, 15, 22\t\n<Average>\t40 mg/week\t40 mg/week\t107 mg/week\t40 mg/week\t\nPN (G1–2)\t55 %\tN.D.\t53 %a\n\t13 %b\n\t\nNP (G3–4)\t35 %\tN.D.\t30 %\t0 %\t\nTCP (G3–4)\t13 %\tN.D.\t22 %\t0 %\t\nDose modification\t39 %\t40 %\t66 %\t7 %\t\nORR\t100 %\t100 %\t64 %\t100 %\t\nOS\t100 % (3 years)\t93 % (3 years)\t65 % (2 years)\t77 % (2.5 years)\t\n\nPD progressive disease, IV intravenous, SC subcutaneous, ASCT autologous hematopoietic stem cell transplantation, PR partial response, PN peripheral neuropathy, N.D. not described, NP neutropenia, TCP thrombocytopenia, ORR overall response rate, OS overall survival\n\n\na6/36 patients had PN at baseline\n\n\nb2/2 patients had PN at baseline\n\n\n\n\nEven though the same terminology of VRD was used in the three previous reports, the dosages of bortezomib and lenalidomide were not the same. On average, Roussel et al. [23], Nooka et al. [27] and Richardson et al. [21] administered bortezomib at 1.7, 1.3 or 1.3 mg/m2/week and lenalidomide at 17, 7.5 or 10 mg/day, respectively. In our trial, bortezomib and lenalidomide were administered at 0.7 mg/m2/week and 7.5 mg/day, respectively. The dosages of bortezomib and lenalidomide used in our trial were the lowest compared with those reported by Roussel et al. [23], Nooka et al. [27] and Richardson et al. [21]. Improvement in tolerability and the preservation of efficacy compared with the three previous reports were important issues in our trial.\n\nThe most common toxicities related to the VRD regimen were neurologic and hematologic. Grade 1–2 peripheral neuropathy (PN) was reported in 55 or 53 % of patients by Roussel et al. [23] and Richardson et al. [21], respectively. In our trial, two patients (13 %) experienced grade 2 PN; however, their neuropathy was due to prior usage of bortezomib with no worsening after enrollment in our study. A lower occurrence of PN possibly reflects the lower dosage of bortezomib at 0.7 mg/m2/week. In addition, subcutaneous administration of bortezomib instead of intravenous injection may reduce the occurrence of PN since it is well known that PN of any grade was significantly less common with subcutaneous than with intravenous administration [28, 29]. As for hematologic toxicities, grade 3–4 neutropenia (NP) (35 or 30 %) and thrombocytopenia (TCP) (13 or 22 %) were reported by Roussel et al. [23] and Richardson et al. [21], respectively. In our trial, there were no cases of grade 3–4 NP and TCP, possibly reflecting the lower dosage of lenalidomide at 7.5 mg/day on average.\n\nFurthermore, the tolerability of each VRD regimen could be evaluated by the necessity of dose modification. In the reports by Roussel et al. [23], Nooka et al. [27] and Richardson et al. [21], at least one dose modification among bortezomib, lenalidomide and dexamethasone was required in 39, 40 or 66 % of patients, respectively. On the other hand, dose modification was required in only one patient (7 %) in our trial: The dose of dexamethasone was reduced from 40 to 20 mg/week due to grade 2 hypertension after the 3rd course of sVRD. Especially, in the report by Roussel et al. [23], patients were previously untreated and relatively young (range 33–65 years) compared with our patients (range 53–78 years); however, almost 40 % of patients could not complete five courses with their dosage of bortezomib (1.7 mg/m2/week) and lenalidomide (17 mg/day). All of our patients could complete six courses of our sVRD regimen. Taking AEs and dose modification into consideration, the dosage of bortezomib (0.7 mg/m2/week) and lenalidomide (7.5 mg/day) in our trial might be well rationalized.\n\nAs for the efficacy of each VRD regimen, the ORR could be comparable. In the reports by Roussel et al. [23], Nooka et al. [27] and Richardson et al. [21], the ORR was 100, 100 or 64 %, respectively. Further, OS was 100 % (3 years), 93 % (3 years) or 65 % (2 years), respectively. The ORR and OS in the report by Richardson et al. [21] were lower than those in the reports by Roussel et al. [23] and Nooka et al. [27] since the patients in the study of Richardson et al. [21] were relapsed/refractory. In our trial, the ORR and OS were 100 and 77 % (2.5 years), respectively. Needless to say, it is difficult to precisely compare the ORR and OS of our trial with those of other three reports because of many biases. Nevertheless, it can be speculated that the low dosage of bortezomib and lenalidomide in our trial did not necessarily result in decreased efficacy. We conclude that the dosage of bortezomib and lenalidomide in our sVRD regimen may be able to reduce AEs and have preserved efficacy simultaneously in the consolidation/maintenance setting.\n\nIn conclusion, our sVRD regimen as a consolidation/maintenance therapy was well tolerable and highly effective in patients with MM who achieved at least PR after any induction therapy. These results seem comparable to those of the other VRD regimens previously published [21, 23, 27] and hence support the rationale for our ongoing phase II study of the sVRD regimen in previously untreated transplant-ineligible patients with MM.\n\nThis work was written on behalf of the Hokkaido Clinical Hematology Study Group (HCHSG). We thank the patients who participated in this trial and their families; the study coordinators and the support staff at the clinical sites.\n\nCompliance with ethical standards\nConflict of interest\nAll authors declare no conflicts of interest.\n\nEthical approval\nAll procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.\n==== Refs\nReferences\n1. Palumbo A Mina R Cerrato C Cavallo F Role of consolidation/maintenance therapy in multiple myeloma Clin Lymphoma Myeloma Leuk 2013 13 Suppl 2 S349 S354 10.1016/j.clml.2013.05.009 24290220 \n2. Palumbo A Anderson K Multiple myeloma N Engl J Med 2011 364 1046 1060 10.1056/NEJMra1011442 21410373 \n3. Attal M Harousseau J-L Leyvraz S Maintenance therapy with thalidomide improves survival in patients with multiple myeloma Blood 2006 108 3289 3294 10.1182/blood-2006-05-022962 16873668 \n4. Spencer A Prince HM Roberts AW Consolidation therapy with low-dose thalidomide and prednisolone prolongs the survival of multiple myeloma patients undergoing a single autologous stem-cell transplantation procedure J Clin Oncol 2009 27 1788 1793 10.1200/JCO.2008.18.8573 19273705 \n5. Barlogie B Tricot G Anaissie E Thalidomide and hematopoietic-cell transplantation for multiple myeloma N Engl J Med 2006 354 1021 1030 10.1056/NEJMoa053583 16525139 \n6. Morgan GJ Gregory WM Davies FE The role of maintenance thalidomide therapy in multiple myeloma: MRC myeloma IX results and meta-analysis Blood 2012 119 7 15 10.1182/blood-2011-06-357038 22021371 \n7. Ludwig H Adam Z Tóthová E Thalidomide maintenance treatment increases progression-free but not overall survival in elderly patients with myeloma Haematologica 2010 95 1548 1554 10.3324/haematol.2009.020586 20418244 \n8. Lokhorst HM van der Holt B Zweegman S A randomized phase 3 study on the effect of thalidomide combined with adriamycin, dexamethasone, and high-dose melphalan, followed by thalidomide maintenance in patients with multiple myeloma Blood 2010 115 1113 1120 10.1182/blood-2009-05-222539 19880501 \n9. Palumbo A Hajek R Delforge M Continuous lenalidomide treatment for newly diagnosed multiple myeloma N Engl J Med 2012 366 1759 1769 10.1056/NEJMoa1112704 22571200 \n10. McCarthy PL Owzar K Hofmeister CC Lenalidomide after stem-cell transplantation for multiple myeloma N Engl J Med 2012 366 1770 1781 10.1056/NEJMoa1114083 22571201 \n11. Attal M Lauwers-Cances V Marit G Lenalidomide maintenance after stem-cell transplantation for multiple myeloma N Engl J Med 2012 366 1782 1791 10.1056/NEJMoa1114138 22571202 \n12. Palumbo A Gay F Falco P Bortezomib as induction before autologous transplantation, followed by lenalidomide as consolidation-maintenance in untreated multiple myeloma patients J Clin Oncol 2010 28 800 807 10.1200/JCO.2009.22.7561 20048187 \n13. Sonneveld P Schmidt-Wolf IGH van der Holt B Bortezomib induction and maintenance treatment in patients with newly diagnosed multiple myeloma: results of the randomized phase III HOVON-65/GMMG-HD4 trial J Clin Oncol 2012 30 2946 2955 10.1200/JCO.2011.39.6820 22802322 \n14. Palumbo A Bringhen S Rossi D Bortezomib–melphalan–prednisone–thalidomide followed by maintenance with bortezomib–thalidomide compared with bortezomib–melphalan–prednisone for initial treatment of multiple myeloma: a randomized controlled trial J Clin Oncol 2010 28 5101 5109 10.1200/JCO.2010.29.8216 20940200 \n15. Mateos M-V Oriol A Martínez-López J Bortezomib, melphalan, and prednisone versus bortezomib, thalidomide, and prednisone as induction therapy followed by maintenance treatment with bortezomib and thalidomide versus bortezomib and prednisone in elderly patients with untreated multiple myeloma Lancet Oncol 2010 11 934 941 10.1016/S1470-2045(10)70187-X 20739218 \n16. Ladetto M Pagliano G Ferrero S Major tumor shrinking and persistent molecular remissions after consolidation with bortezomib, thalidomide, and dexamethasone in patients with autografted myeloma J Clin Oncol 2010 28 2077 2084 10.1200/JCO.2009.23.7172 20308672 \n17. Cavo M Pantani L Petrucci MT Bortezomib-thalidomide-dexamethasone is superior to thalidomide–dexamethasone as consolidation therapy after autologous hematopoietic stem cell transplantation in patients with newly diagnosed multiple myeloma Blood 2012 120 9 19 10.1182/blood-2012-02-408898 22498745 \n18. Kikuchi J Koyama D Mukai HY Furukawa Y Suitable drug combination with bortezomib for multiple myeloma under stroma-free conditions and in contact with fibronectin or bone marrow stromal cells Int J Hematol 2014 99 726 736 10.1007/s12185-014-1573-3 24706190 \n19. Stewart AK Richardson PG San-Miguel JF How I treat multiple myeloma in younger patients Blood 2009 114 5436 5443 10.1182/blood-2009-07-204651 19861683 \n20. Richardson PG Weller E Jagannath S Multicenter, phase I, dose-escalation trial of lenalidomide plus bortezomib for relapsed and relapsed/refractory multiple myeloma J Clin Oncol 2009 27 5713 5719 10.1200/JCO.2009.22.2679 19786667 \n21. Richardson PG Xie W Jagannath S A phase 2 trial of lenalidomide, bortezomib, and dexamethasone in patients with relapsed and relapsed/refractory myeloma Blood 2014 123 1461 1469 10.1182/blood-2013-07-517276 24429336 \n22. Richardson PG Weller E Lonial S Lenalidomide, bortezomib, and dexamethasone combination therapy in patients with newly diagnosed multiple myeloma Blood 2010 116 679 686 10.1182/blood-2010-02-268862 20385792 \n23. Roussel M Lauwers-Cances V Robillard N Front-line transplantation program with lenalidomide, bortezomib, and dexamethasone combination as induction and consolidation followed by lenalidomide maintenance in patients with multiple myeloma: a phase II study by the Intergroupe Francophone du Myélo J Clin Oncol 2014 32 2712 2717 10.1200/JCO.2013.54.8164 25024076 \n24. Dimopoulos MA Beksac M Benboubker L Phase II study of bortezomib-dexamethasone alone or with added cyclophosphamide or lenalidomide for sub-optimal response as second-line treatment for patients with multiple myeloma Haematologica 2013 98 1264 1272 10.3324/haematol.2013.084376 23716559 \n25. Dimopoulos MA Kastritis E Christoulas D Treatment of patients with relapsed/refractory multiple myeloma with lenalidomide and dexamethasone with or without bortezomib: prospective evaluation of the impact of cytogenetic abnormalities and of previous therapies Leukemia 2010 24 1769 1778 10.1038/leu.2010.175 20739955 \n26. Kanda Y Investigation of the freely available easy-to-use software “EZR” for medical statistics Bone Marrow Transplant 2013 48 452 458 10.1038/bmt.2012.244 23208313 \n27. Nooka AK Kaufman JL Muppidi S Consolidation and maintenance therapy with lenalidomide, bortezomib and dexamethasone (RVD) in high-risk myeloma patients Leukemia 2014 28 690 693 10.1038/leu.2013.335 24220275 \n28. Arnulf B Pylypenko H Grosicki S Updated survival analysis of a randomized phase III study of subcutaneous versus intravenous bortezomib in patients with relapsed multiple myeloma Haematologica 2012 97 1925 1928 10.3324/haematol.2012.067793 22689676 \n29. Moreau P Pylypenko H Grosicki S Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferiority study Lancet Oncol 2011 12 431 440 10.1016/S1470-2045(11)70081-X 21507715\n\n",
"fulltext_license": "CC BY",
"issn_linking": "0344-5704",
"issue": "78(5)",
"journal": "Cancer chemotherapy and pharmacology",
"keywords": "Bortezomib; Consolidation/maintenance; Dexamethasone; Lenalidomide; Multiple myeloma; VRD",
"medline_ta": "Cancer Chemother Pharmacol",
"mesh_terms": "D000368:Aged; D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D018931:Antineoplastic Agents, Hormonal; D000971:Antineoplastic Combined Chemotherapy Protocols; D000069286:Bortezomib; D003907:Dexamethasone; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D000077269:Lenalidomide; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma; D016609:Neoplasms, Second Primary; D013792:Thalidomide; D016896:Treatment Outcome",
"nlm_unique_id": "7806519",
"other_id": null,
"pages": "1041-1049",
"pmc": null,
"pmid": "27738809",
"pubdate": "2016-11",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016448:Multicenter Study",
"references": "20308672;25024076;21410373;22498745;20048187;22802322;21507715;20739218;24429336;19786667;16873668;22571201;22689676;22571200;20385792;22021371;24706190;20739955;20940200;19861683;23208313;23716559;19880501;24290220;24220275;20418244;19273705;22571202;16525139",
"title": "A phase II trial of small-dose bortezomib, lenalidomide and dexamethasone (sVRD) as consolidation/maintenance therapy in patients with multiple myeloma.",
"title_normalized": "a phase ii trial of small dose bortezomib lenalidomide and dexamethasone svrd as consolidation maintenance therapy in patients with multiple myeloma"
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"abstract": "We present the case of a 59-year-old Midwestern farmer who presented with altered mental status, dysarthria, urinary incontinence, and a right-sided L5 dermatomal rash; he had recently received a course of oral corticosteroids for treatment of radicular low back pain. Lumbar puncture revealed the presence of varicella zoster virus (VZV) and IgM antibodies against a California-group encephalitis virus, later confirmed as Jamestown Canyon virus (JCV). Unfortunately, the patient's health declined despite aggressive treatment, developing progressive subarachnoid hemorrhage. He died after withdrawal of supportive care following 3 weeks in the intensive care unit. To our knowledge, this is the first documented case of encephalitis associated with coinfection by VZV and JCV. While the relative contributions of these viral pathogens to the patient's illness are difficult to ascertain, the clinical features of this case are consistent with co-pathogenesis, possibly driven by antecedent corticosteroid use. This case highlights the emerging role of viral coinfections in the etiology of viral illnesses.",
"affiliations": "Department of Medicine, Western Michigan University Homer Stryker MD School of Medicine, Kalamazoo, MI USA.;Department of Medicine, Western Michigan University Homer Stryker MD School of Medicine, Kalamazoo, MI USA.;Department of Emergency Medicine, Western Michigan University Homer Stryker MD School of Medicine, Kalamazoo, MI USA.;Department of Emergency Medicine, Western Michigan University Homer Stryker MD School of Medicine, Kalamazoo, MI USA.;Department of Emergency Medicine, Western Michigan University Homer Stryker MD School of Medicine, Kalamazoo, MI USA.;Department of Emergency Medicine, Western Michigan University Homer Stryker MD School of Medicine, Kalamazoo, MI USA.;Department of Medicine, Western Michigan University Homer Stryker MD School of Medicine, Kalamazoo, MI USA.",
"authors": "VanderVeen|Nathan|N|;Nguyen|Nikki|N|;Hoang|Kenny|K|;Parviz|Jason|J|;Khan|Tahuriah|T|;Zhen|Andrew|A|;Jagger|Brett W|BW|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.idcr.2020.e00966",
"fulltext": "\n==== Front\nIDCases\nIDCases\nIDCases\n2214-2509 Elsevier \n\nS2214-2509(20)30274-2\n10.1016/j.idcr.2020.e00966\ne00966\nCase Report\nEncephalitis with coinfection by Jamestown canyon virus (JCV) and varicella zoster virus (VZV)\nVanderVeen Nathan ab Nguyen Nikki a Hoang Kenny c Parviz Jason c Khan Tahuriah c Zhen Andrew c Jaggera Brett W. brett.jagger@med.wmich.edua⁎ a Department of Medicine, Western Michigan University Homer Stryker MD School of Medicine, Kalamazoo, MI USA\nb David Geffen School of Medicine at UCLA, Division of Medicine-Pediatrics, Los Angeles, CA USA\nc Department of Emergency Medicine, Western Michigan University Homer Stryker MD School of Medicine, Kalamazoo, MI USA\n⁎ Corresponding author at: Department of Medicine, Western Michigan University Homer Stryker MD School of Medicine, 1000 Oakland Drive, Kalamazoo, MI 49008 USA. brett.jagger@med.wmich.edu\n08 10 2020 \n2020 \n08 10 2020 \n22 e0096620 7 2020 18 9 2020 18 9 2020 © 2020 The Authors2020This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Highlights\n• Varicella Zoster Virus and Jamestown Canyon Virus encephalitis after steroid course.\n\n• Coinfection associated with severe disease.\n\n• Satisfaction of search may hinder identification of clinically relevant infections.\n\n\n\nWe present the case of a 59-year-old Midwestern farmer who presented with altered mental status, dysarthria, urinary incontinence, and a right-sided L5 dermatomal rash; he had recently received a course of oral corticosteroids for treatment of radicular low back pain. Lumbar puncture revealed the presence of varicella zoster virus (VZV) and IgM antibodies against a California-group encephalitis virus, later confirmed as Jamestown Canyon virus (JCV). Unfortunately, the patient’s health declined despite aggressive treatment, developing progressive subarachnoid hemorrhage. He died after withdrawal of supportive care following 3 weeks in the intensive care unit. To our knowledge, this is the first documented case of encephalitis associated with coinfection by VZV and JCV. While the relative contributions of these viral pathogens to the patient’s illness are difficult to ascertain, the clinical features of this case are consistent with co-pathogenesis, possibly driven by antecedent corticosteroid use. This case highlights the emerging role of viral coinfections in the etiology of viral illnesses.\n\nAbbreviations\nCNS, Central Nervous SystemCSF, Cerebrospinal FluidCT, Computed TomographyDHZ, Disseminated Herpes ZosterEEEV, Eastern Equine Encephalitis VirusHSV-1, Herpes simplex virus 1HZAE, Herpes Zoster-Associated EncephalitisICU, Intensive Care UnitJCV, Jamestown Canyon VirusLACV, La Crosse VirusMRI, Magnetic Resonance ImagingSVT, Supraventricular TachycardiaVZV, Varicella Zoster VirusKeywords\nVaricella zoster virus (VZV)James town canyon virus (JCV)EncephalitisCoinfection\n==== Body\nIntroduction\nAcute viral encephalitis is a potentially devastating infection of the brain associated with a variety of viral pathogens. Herpes Simplex Virus 1 (HSV-1) is the most common etiology, although other human herpesviruses including varicella-zoster virus (VZV) and arthropod-borne viruses are also occasional causes. VZV is a neurotropic virus that commonly infects unvaccinated children, manifesting as chickenpox after primary infection. Following infection, the virus is transported in a retrograde axonal fashion to neuronal cell bodies where it enters a latent phase. Reactivation from viral latency, often in the setting of advancing age, immunosuppressing treatments, and/or psychological stress, results in a painful dermatomal rash, known as zoster [1]; however, viral reactivation from latency can cause a variety of less common clinical syndromes, including encephalitis and CNS vasculopathy [1]. Mortality from VZV encephalitis is 9–20 %, occurring almost exclusively in elderly or immunocompromised individuals [2].\n\nArthropod-borne viruses (arboviruses) represent a second important category of encephalitis pathogens. The most common of these infections in the United States is West Nile Virus, although considerable annual variation occurs [3]. The California encephalitis virus group of bunyaviruses represents the second most common etiology of arboviral encephalitis and includes several related viruses such as La Crosse (LACV), California, and Jamestown Canyon (JCV) viruses. JCV is uncommonly diagnosed, but is most frequently seen in the upper Midwest; there have been 181 cases reported to date in the United States [4]. Infected individuals complain of nonspecific constitutional symptoms that can progress to neuroinvasive features such as meningismus, altered mental status, and/or coma in two-thirds of cases [5]. Death has only been reported in only 3 patients so far in the USA [4].\n\nWe report a unique case of acute encephalitis associated with VZV and JCV coinfection. Viral coinfections represent an emerging area of interest in clinical infectious disease and are increasingly being identified due to sensitive diagnostic techniques [1,2]. Coinfections have the potential to result in atypical manifestations of infection, potentially including worsened morbidity and/or mortality, and represent an opportunity for greater understanding of the pathogenesis of viral disease.\n\nCase description\nA 59-year-old Caucasian male famer, who resided in rural southwest Michigan presented to the emergency department with confusion, incoherent speech, and a fall at home. Aside from intermittent episodes of low back pain, he had previously been healthy, although he did not have a primary care physician due to a lack of health insurance. Approximately 6 weeks prior to presentation, he noted the onset of low back pain. The pain was severe, located on the lower lumbar spine, and associated with numbness and tingling of the right leg radiating to the ankle. The patient had regular chiropractic treatments for 4 weeks without improvement, and as a result, the patient was referred to a primary care physician. A 10-day course of prednisone was prescribed, ending 7 days prior to presentation, and only provided transient improvement. A few days after initiating the corticosteroid course, the patient’s wife noted the onset of painful fluid-filled blisters on his right lower extremity that were most pronounced over the right anterior ankle and along the webbed spaces between his second and third toes; these blisters subsequently became hemorrhagic and scabbed over by the time of presentation. Three days prior to presentation, the patient was noted to begin intermittently slurring his speech and having episodes of urinary incontinence. On the day of presentation, the patient attempted to use the bathroom but instead opened the door to the basement, consequently falling and prompting presentation to the emergency department (ED). No history of fevers, headache, or seizures were elicited from the patient or his family.\n\nIn the ED, physical exam revealed confusion (Glasgow Coma Scale score of 14 due to confused responses to questions), dysarthric speech, fresh abrasions to his bilateral knees, and scabbed-over cutaneous lesions along the L5 dermatome of the right lower extremity (Fig. 1). Social history was significant for long days spent working outdoors, including exposure to heavily wooded areas, frequent mosquito bites, a tick bite 3 months ago, exposure to dogs and goats, and no recent travel.Fig. 1 Right Lower 1 Extremity Dermatomal Rash.\n\nFig. 1\n\nInitial laboratory studies revealed hyponatremia (128 mmol/L), hemoconcentration (hemoglobin 17.7 g/dL), and hypochloremia (94 mmol/L), and urinalysis was positive for nitrites, bacteria, and pyuria. A urine culture grew Escherichia coli. The patient was diagnosed with a urinary tract infection and treated with ceftriaxone, as well as intravenous (IV) hydrocortisone due to concern for adrenal insufficiency.\n\nOn hospital day 2, acute kidney injury was noted, with elevation of serum creatinine from 1.1 mg/dL on presentation to 1.8 mg/dL. Renal ultrasound revealed bilateral hydronephrosis, and a urinary catheter was placed; following this, some improvement in the patient’s confusion was noted. However, the patient was unable to complete an MRI of his lumbar spine due to agitation. Incomplete images revealed L5-S1 disc protrusion with possible L5 nerve root compression. Neurosurgery was consulted and initiated dexamethasone while awaiting MRI of the spine with sedation. On hospital day 3, the patient’s confusion and slurred speech worsened. MRI of the spine with IV contrast performed under general anesthesia again showed L4-L5 disc extrusion and L5 nerve root compression but was also remarkable for diffuse leptomeningeal enhancement and CSF signal abnormality concerning for elevated protein concentration. MRI of the brain demonstrated abnormal signal of the bilateral medial frontal cortices, left insula, medial temporal lobe, amygdala, and hippocampus, and also found abnormal enhancement of lepto- and pachymeninges (Fig. 2). Due to these findings he was transferred to the ICU.Fig. 2 MRI Brain.\n\nFig. 2\n\nEmpiric treatment for CNS infection was initiated with ceftriaxone, vancomycin, ampicillin, and IV acyclovir. A lumbar puncture was performed, which revealed markedly elevated protein concentration, a mononuclear pleocytosis, xanthochromia, and normal glucose. A multiplex meningitis/encephalitis PCR panel (BioFire FilmArray, BioMérieux) revealed the presence of VZV DNA (Table 1). Given the patient’s outdoor exposures, peripheral serology for arboviruses was also performed, and found to be positive for California encephalitis IgG, at a titer of 1:256; IgM for California encephalitis was negative, as was testing for West Nile Virus, St Louis Encephalitis Virus, and both Western and Eastern Encephalitis viruses (EEEV). These peripheral serologies became available on hospital day 16, and prompted further testing of CSF at the CDC Division of Vector-borne Diseases (Ft. Collins, CO). These results, received approximately 5 months following the lumbar puncture, revealed capture ELISA positivity for Jamestown Canyon Virus CSF IgM, which was confirmed by plaque reduction neutralization test at a neutralizing antibody titer of 1:512. CSF testing for presence of EEEV and LACV IgM was negative by microsphere immunofluorescence assay and ELISA, respectively.Table 1 CSF Analysis.\n\nTable 1Glucose\t93 mg/dL\t\nProtein\t>2000 mg/dL\t\nColor\tRed-Orange\t\nDescription\tCloudy\t\nXanthochromia\t3+\t\nRBC\t43,800 cells/μL (tube 1)\n24,500 cells/μL (tube 4)\t\nWBC\t5300 cells/μL (tube 1)\n1360 cells/μL (tube 4)\t\nDifferential\t5% polymorphonuclear\n95 % mononuclear\n(tubes 1 & 4)\t\nMultiplex CSF pathogen PCRa\tVZV+\t\nCalifornia Encephalitis Virus IgM\tPositive\t\nJamestown Canyon Virus PRNT\t1:512\t\nLACV IgM\tNegative\t\na Negative for: Cryptococcus neoformans/gattii, cytomegalovirus, enterovirus, Escherichia coli K1, Haemophilus influenzae, Herpes Simplex Virus 1, Herpes Simplex Virus 2, Human Herpesvirus 6, Human Parechovirus, Listeria monocytogenes, Neisseria meningitidis, Streptococcus agalactiae, Streptococcus pneumoniae.\n\n\n\nAntibacterial therapy was stopped 6 days after initiation, and treatment with IV acyclovir for 3 weeks was recommended following the discovery of VZV DNA in the CSF. Repeated attempts to wean ventilator support were unsuccessful, and the patient remained unresponsive after sedation was weaned. At no point during the patient’s hospitalization did he develop a fever, and an electroencephalogram demonstrated only diffuse, generalized slowing, without epileptiform discharges. On hospital day 20, dilated, minimally reactive pupils were noted on exam. A computed tomography (CT) of the head with and without IV contrast demonstrated ongoing diffuse leptomeningeal enhancement, as well as layering of blood products in the occipital horns of the lateral ventricles with moderate ventriculomegaly. After a palliative care consultation, comfort care measures were initiated, and the patient died the following day.\n\nDiscussion\nWe present a case of viral encephalitis associated with co-infection by VZV and JCV in a Midwestern farmer with a history of extensive outdoor exposure and recent corticosteroid treatment. The diagnosis of viral encephalitis in this case was delayed by the presence of alternative potential explanations for the patient’s encephalopathy, namely urinary retention and urinary tract infection, and by the absence of fever and headache. Unfortunately, despite treatment with acyclovir, the patient’s condition relentlessly declined, and he ultimately succumbed to this infection.\n\nEncephalitis is one of several possible manifestations of VZV reactivation, which most commonly manifests as a dermatomal rash known as herpes zoster. Encephalitis in the setting of active or recent herpes zoster has been termed herpes zoster-associated encephalitis (HZAE) and may also accompany disseminated herpes zoster (DHZ). Use of corticosteroids may precipitate VZV reactivation [[9], [10], [11]], raising the possibility that the use of corticosteroids in this case may have contributed to progression from dermatomal zoster to invasive CNS disease. HZAE is a rare complication of zoster with an incidence of 1–2 per 10,000 zoster episodes and presents with delirium within days of the appearance of the rash [6,7]. However, as seen in our patient, the appearance of a skin rash has occasionally been noted to precede the onset of HZAE by several weeks [8]. While DHZ following steroid therapy may be refractory to antiviral treatment [9], HZAE is not typically fatal, particularly in the non-elderly and immunocompetent, even before the advent of acyclovir; mortality of HZAE is approximately 10 % [7,8].\n\nVZV vasculopathy is another CNS manifestation of VZV reactivation that may be relevant in explaining the features of this case. VZV vasculopathy occurs as a result of the ability of VZV to replicate within the arterial wall, potentially causing ischemic or hemorrhagic sequelae. Such patients can present with fever, headache, seizure, incoherent speech, aphasia, or facial paralysis, which can appear clinically similar to a stroke [7]. Although the entity is not well-studied, multiple cases of intracerebral hemorrhage, aneurysm formation, and cerebral infarctions in the setting of varicella zoster vasculopathy have been reported [10,11]. This patient’s initial CSF was notable for marked xanthochromia, and he subsequently developed further subarachnoid hemorrhage (SAH) later in his ICU course; however, no discrete foci of intraparenchymal or subarachnoid hemorrhage were identified on neuroimaging in this case. Nonetheless, VZV vasculopathy may have contributed to the xanthochromia and markedly elevated protein noted in this patient’s CSF and to subsequent progressive SAH.\n\nIn contrast to VZV, JCV is an orthobunyavirus of the California serogroup, a group that includes the more common LACV and causes 70–100 cases of encephalitis per year. First isolated in 1961 from Culiseta mosquitoes in Jamestown, Colorado, the incidence of this virus has been historically low, likely due to the lack of commercially available tests and rarity of severe disease: increased surveillance in an endemic region yielded a 4.5-fold increases in cases [12]. JCV has been isolated in at least 26 species of mosquitoes with various ecological breeding patterns, raising the concern for a diverse, broad transmission pattern [12]. White-tailed deer are thought to serve as an amplifier host, but large mammals like sheep, cattle, and horses are also susceptible to infection [13]. A sample of Michigan residents in 1986 showed that 27.7 % of the population had JCV neutralizing antibodies with a geographical distribution that correlated with the density of the white-tailed deer population in the state [13].\n\nJCV infection in humans was historically understood to cause a mild viral syndrome in Midwestern forest workers [14]. Symptoms generally develop between 2 days and 2 weeks after being bitten by an infected mosquito, and include fever, headache, nausea, and vomiting, with some patients also developing respiratory symptoms such as sore throat, runny nose, and cough. However, likely due to a lack of testing outside of critically ill patients, the rate of CNS disease is quite high, with reports of meningitis or meningoencephalitis as high as 54–79 % of those infected [5]. Despite the high incidence of neurological sequela, mortality is surprisingly rare, with only 3 total deaths reported in the US [4].\n\nDiagnosis is initially serologic, from peripheral blood and/or CSF specimens. However, confirmation of positive serology via PRNT or PCR testing is only currently available in a reference lab setting [12]. As there is currently no specific pharmacotherapy for JCV, treatment is supportive. While vaccine development has shown promise in animal models, none are currently available for human clinical use [15].\n\nTwo plausible etiologies of this patient’s CNS infection were identified but determining the degree to which VZV and JCV contributed to his illness is difficult. Certainly, the dermatomal rash, xanthochromia, CSF PCR positivity, and subsequent sub-arachnoid hemorrhage point to a prominent role for VZV in the pathogenesis of this patient’s illness. However, HZAE is not typically fatal, particularly in previously healthy individuals treated with acyclovir, and therefore, a role for JCV in explaining the severity of illness in this case should be entertained. This is particularly so given the presence of IgM with JCV plaque-neutralizing activity confirmed in CSF, which is diagnostic of invasive CNS infection. Intriguingly, 2019 also saw a remarkable increase in the incidence of human EEEV infections in Southwest Michigan. While Aedes and Ochlerotatus mosquitoes are thought to be the primary vectors of human infection by JCV, Culiseta also may act as a vector for both pathogens, suggesting a potential ecological link between the two viruses [12]. From a diagnostic standpoint, this case highlights the importance of maintaining a broad differential even when initial diagnostic data are suggestive of a particular diagnosis, and highlights coinfections as a possible explanation for more severe disease outcomes. As our patient was previously healthy and had no known immunocompromising conditions aside from a recent course of a glucocorticoid, this case also suggests clinical caution in steroid prescribing, and could provide an impetus for larger-scale studies of adverse outcomes after steroid courses.\n\nInformed consent\nWritten informed consent was obtained from the patient’s legally acceptable representative for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.\n\nConsent\nConsent was obtained by the patient’s wife for the publication of this case report and images associated with the patient.\n\nAuthor contribution\nNV: Conceptualization and acquisition of data, analysis, and interpretation of the draft; drafting the article and revising it critically for important intellectual content; final approval of the version to be submitted.\n\nNN: Conceptualization and acquisition of data, analysis, and interpretation of the draft; drafting the article and revising it critically for important intellectual content; final approval of the version to be submitted.\n\nKH: Conceptualization and acquisition of data, analysis, and interpretation of the draft; drafting the article and revising it critically for important intellectual content; final approval of the version to be submitted.\n\nJP: Conceptualization and acquisition of data, analysis, and interpretation of the draft; drafting the article and revising it critically for important intellectual content; final approval of the version to be submitted.\n\nTK: Conceptualization and acquisition of data, analysis, and interpretation of the draft; drafting the article and revising it critically for important intellectual content; final approval of the version to be submitted.\n\nAZ: Conceptualization and acquisition of data, analysis, and interpretation of the draft; drafting the article and revising it critically for important intellectual content; final approval of the version to be submitted.\n\nBWJ: Conceptualization and acquisition of data, analysis, and interpretation of the draft; drafting the article and revising it critically for important intellectual content; final approval of the version to be submitted.\n\nCRediT authorship contribution statement\nNathan VanderVeen: Conceptualization, Investigation, Visualization, Writing - original draft, Writing - review & editing. Nikki Nguyen: Writing - review & editing. Kenny Hoang: Writing - review & editing. Jason Parviz: Writing - review & editing. Tahuriah Khan: Writing - review & editing. Andrew Zhen: Writing - review & editing. Brett W. Jaggera: Conceptualization, Investigation, Validation, Supervision, Project administration, Writing - review & editing.\n\nDeclaration of Competing Interest\nThese authors deny any conflicts of interest.\n\nAcknowledgements\nThe authors wish to acknowledge the contribution of the CDC Division of Vector Borne Diseases in aiding the diagnostic workup in this case.\n==== Refs\nReferences\n1 Kennedy P.G.E. Gershon A.A. Clinical features of varicella-zoster virus infection. Viruses 2018 10 10.3390/v10110609 \n2 Grahn A. Studahl M. Varicella-zoster virus infections of the central nervous system - Prognosis, diagnostics and treatment J Infect 71 2015 281 293 10.1016/j.jinf.2015.06.004 26073188 \n3 Curren E.J. Lehman J. Kolsin J. West Nile virus and other nationally notifiable arboviral diseases — United States, 2017 Morb Mortal Wkly Rep Surveill Summ 67 2018 1137 1142 10.15585/mmwr.mm6741a1 \n4 Statistics & Maps | Jamestown Canyon virus | CDC n.d. https://www.cdc.gov/jamestown-canyon/statistics/index.html (accessed April 25, 2020).\n5 PR G Jamestown Canyon virus. Serv. MD, ed. Encycl. Arthropod-transmitted infect. Man domest. Anim. 2001 New York, NY:, p. 235–239 \n6 Gnann J.W. Jr. Varicella‐Zoster Virus: atypical presentations and unusual complications J Infect Dis 186 2002 S91 8 10.1086/342963 12353193 \n7 Jemsek J. Greenberg S.B. Taber L. Harvey D. Gershon A. Couch R.B. Herpes zoster-associated encephalitis: clinicopathologic report of 12 cases and review of the literature Medicine (Baltimore) 62 1983 81 97 6298562 \n8 Dworkin R.H. Johnson R.W. Breuer J. Recommendations for the management of herpes zoster Clin Infect Dis 44 2007 S1 26 10.1086/510206 17143845 \n9 Fujisato S. Urushibara T. Kasai H. Inafuku K. Fujinuma Y. Shinozaki T. A fatal case of atypical disseminated herpes zoster in a patient with meningoencephalitis and seizures associated with steroid immunosuppression Am J Case Rep 19 2018 1162 1167 10.12659/AJCR.910521 30270342 \n10 Fukumoto S. Kinjo M. Hokamura K. Tanaka K. Subarachnoid hemorrhage and granulomatous angiitis of the basilar artery: demonstration of the varicella-zoster-virus in the Basilar artery lesions Stroke 17 1986 1024 1028 10.1161/01.STR.17.5.1024 3020742 \n11 Nagel M.A. Cohrs R.J. Mahalingam R. The varicella zoster virus vasculopathies: clinical, CSF, imaging, and virologic features Neurology 70 2008 853 860 10.1212/01.wnl.0000304747.38502.e8 18332343 \n12 Matkovic E. Hoang Johnson D.K. Staples J.E. Enhanced arboviral surveillance to increase detection of Jamestown canyon virus infections, Wisconsin, 2011-2016 Am J Trop Med Hyg 100 2019 445 451 10.4269/ajtmh.18-0575 30526745 \n13 Grimstad P.R. Calisher C.H. Harroff R.N. Wentworth B.B. Jamestown Canyon virus (California serogroup) is the etiologic agent of widespread infection in Michigan humans Am J Trop Med Hyg 35 1986 376 386 10.4269/ajtmh.1986.35.376 3953951 \n14 Thompson W.H. Evans A.S. California encephalitis virus studies in Wisconsin Am J Epidemiol 81 1965 230 244 10.1093/oxfordjournals.aje.a120511 14261029 \n15 Bennett R.S. Gresko A.K. Nelson J.T. Murphy B.R. Whitehead S.S. A recombinant chimeric La crosse virus expressing the surface glycoproteins of Jamestown canyon virus is immunogenic and protective against challenge with either parental virus in mice or monkeys J Virol 86 2012 420 426 10.1128/jvi.02327-10 22013033\n\n",
"fulltext_license": "CC BY-NC-ND",
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"keywords": "CNS, Central Nervous System; CSF, Cerebrospinal Fluid; CT, Computed Tomography; Coinfection; DHZ, Disseminated Herpes Zoster; EEEV, Eastern Equine Encephalitis Virus; Encephalitis; HSV-1, Herpes simplex virus 1; HZAE, Herpes Zoster-Associated Encephalitis; ICU, Intensive Care Unit; JCV, Jamestown Canyon Virus; James town canyon virus (JCV); LACV, La Crosse Virus; MRI, Magnetic Resonance Imaging; SVT, Supraventricular Tachycardia; VZV, Varicella Zoster Virus; Varicella zoster virus (VZV)",
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"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Encephalitis with coinfection by Jamestown canyon virus (JCV) and varicella zoster virus (VZV).",
"title_normalized": "encephalitis with coinfection by jamestown canyon virus jcv and varicella zoster virus vzv"
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"abstract": "Vinca alkaloids are known to cause bilateral jaw pain that occurs once during the chemotherapy course. We report a patient with first bite syndrome (FBS) during active treatment with chemotherapy. A patient with Hodgkin lymphoma presented with unilateral jaw pain after beginning his chemotherapy regimen. Pain was worse with the first bite of each meal and dissipated over subsequent bites. Workup was negative for any lesions in the parotid, parapharyngeal space, or infratemporal fossa. Pain was timed closely with chemotherapy administration and would improve prior to next cycle. A trial of botulinum chemodenervation failed to completely relieve symptoms. The patient noted resolution of symptoms after the completion of chemotherapy. We report a case of FBS, which may represent the jaw pain seen commonly with administration of vinca alkaloids. There appears to be a correlation between onset and duration of first bite symptoms with chemotherapy administration.",
"affiliations": "1 Department of Otolaryngology-Head & Neck Surgery, Washington University School of Medicine in St Louis, St Louis, MO, USA.;2 Division of Oncology, Department of Internal Medicine, Washington University School of Medicine in St Louis, St Louis, MO, USA.;1 Department of Otolaryngology-Head & Neck Surgery, Washington University School of Medicine in St Louis, St Louis, MO, USA.",
"authors": "Valenzuela|Carla V|CV|;Bartlett|Nancy L|NL|;Bradley|Joseph P|JP|",
"chemical_list": "D000970:Antineoplastic Agents; D009465:Neuromuscular Agents; D014748:Vinca Alkaloids; D019274:Botulinum Toxins, Type A",
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"issue": "98(5)",
"journal": "Ear, nose, & throat journal",
"keywords": "Hodgkin lymphoma; chemotherapy; first bite syndrome; jaw pain",
"medline_ta": "Ear Nose Throat J",
"mesh_terms": "D000369:Aged, 80 and over; D000970:Antineoplastic Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D019274:Botulinum Toxins, Type A; D005157:Facial Pain; D006689:Hodgkin Disease; D006801:Humans; D008297:Male; D009367:Neoplasm Staging; D009465:Neuromuscular Agents; D000072078:Positron Emission Tomography Computed Tomography; D016896:Treatment Outcome; D014748:Vinca Alkaloids",
"nlm_unique_id": "7701817",
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"pages": "E30-E31",
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"pmid": "30961378",
"pubdate": "2019-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Chemotherapy-Induced First Bite Syndrome: A Case Report in a Patient With Hodgkin Lymphoma.",
"title_normalized": "chemotherapy induced first bite syndrome a case report in a patient with hodgkin lymphoma"
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"abstract": "A 76-year-old Japanese woman with recurrent hepatocellular carcinoma presented with acute exacerbation of idiopathic interstitial pneumonia (AE-IIP) after transcatheter arterial therapy using miriplatin. She had a history of preexisting IIP five years before presenting at our hospital. On day 4 after transcatheter arterial therapy, she complained of shortness of breath. Subsequently, she developed acute respiratory failure on day 11 after transcatheter arterial therapy. Chest computed tomography revealed extensive ground-glass opacity and traction bronchiectasis in bilateral lung fields; subsequently, she was diagnosed with AE-IIP triggered by transcatheter arterial therapy using miriplatin. Despite systemic administration of high-dose corticosteroid and cyclophosphamide, she died of respiratory failure on day 36.",
"affiliations": "Department of Respiratory Medicine, Kumamoto University Hospital, Japan.;Department of Respiratory Medicine, Kumamoto University Hospital, Japan.;Department of Respiratory Medicine, Kumamoto University Hospital, Japan.;Department of Respiratory Medicine, Kumamoto University Hospital, Japan.;Department of Respiratory Medicine, Kumamoto University Hospital, Japan.;Department of Gastroenterology and Hepatology, Graduate School of Medical Science, Kumamoto University, Japan.;Department of Respiratory Medicine, Kumamoto University Hospital, Japan.;Department of Respiratory Medicine, Kumamoto University Hospital, Japan.;Department of Respiratory Medicine, Kumamoto University Hospital, Japan.",
"authors": "Kakiuchi|Yosuke|Y|;Sakata|Shinya|S|;Nakamura|Kazuyoshi|K|;Okabayashi|Hiroko|H|;Akaike|Kimitaka|K|;Tokunaga|Takayuki|T|;Saeki|Sho|S|;Fujii|Kazuhiko|K|;Ichiyasu|Hidenori|H|",
"chemical_list": "D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; C406530:miriplatin; D003520:Cyclophosphamide",
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"doi": "10.2169/internalmedicine.1446-18",
"fulltext": "\n==== Front\nIntern MedIntern. MedInternal Medicine0918-29181349-7235The Japanese Society of Internal Medicine 3062681710.2169/internalmedicine.1446-18Case ReportAcute Exacerbation of Idiopathic Interstitial Pneumonia in a Patient with Hepatocellular Carcinoma after Transcatheter Arterial Therapy Using Miriplatin Kakiuchi Yosuke 1Sakata Shinya 1Nakamura Kazuyoshi 1Okabayashi Hiroko 1Akaike Kimitaka 1Tokunaga Takayuki 2Saeki Sho 1Fujii Kazuhiko 1Ichiyasu Hidenori 1\n1 Department of Respiratory Medicine, Kumamoto University Hospital, Japan\n2 Department of Gastroenterology and Hepatology, Graduate School of Medical Science, Kumamoto University, JapanCorrespondence to Dr. Hidenori Ichiyasu, ichiyasu@kumamoto-u.ac.jp\n\n10 1 2019 1 5 2019 58 9 1329 1333 24 4 2018 15 10 2018 Copyright © 2019 by The Japanese Society of Internal MedicineThe Internal Medicine is an Open Access journal distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (https://creativecommons.org/licenses/by-nc-nd/4.0/).A 76-year-old Japanese woman with recurrent hepatocellular carcinoma presented with acute exacerbation of idiopathic interstitial pneumonia (AE-IIP) after transcatheter arterial therapy using miriplatin. She had a history of preexisting IIP five years before presenting at our hospital. On day 4 after transcatheter arterial therapy, she complained of shortness of breath. Subsequently, she developed acute respiratory failure on day 11 after transcatheter arterial therapy. Chest computed tomography revealed extensive ground-glass opacity and traction bronchiectasis in bilateral lung fields; subsequently, she was diagnosed with AE-IIP triggered by transcatheter arterial therapy using miriplatin. Despite systemic administration of high-dose corticosteroid and cyclophosphamide, she died of respiratory failure on day 36. \n\nacute exacerbationidiopathic interstitial pneumoniamiriplatintranscatheter arterial therapy\n==== Body\nIntroduction\nHepatocellular carcinoma (HCC) is one of the most common types of cancer in Japan. Transcatheter arterial therapy, including transcatheter arterial chemoembolization (TACE) and transcatheter arterial infusion (TAI), has been widely used to treat advanced HCC (1). The 5-year survival rate of patients with advanced HCC who receive TACE has been reported to be as high as 26-39% (2,3). In 2009, the Japanese Ministry of Health, Labour and Welfare approved miriplatin, a lipophilic cisplatin derivative used in TACE and TAI, for the treatment of HCC. Several studies have reported the efficacy and safety of TACE using miriplatin for treating HCC (1,4-6). In recent years, TACE using miriplatin has become a standard protocol for treating HCC.\n\nMiriplatin is known to induce several adverse effects in the hepatobiliary, hematologic, and gastrointestinal systems. However, the incidence of adverse events of miriplatin in the pulmonary system has rarely been reported. Thus far, only two cases of miriplatin-induced interstitial lung disease (ILD) (7,8) have been reported. However, acute exacerbation (AE) of preexisting idiopathic interstitial pneumonia (IIP) caused by TACE and TAI using miriplatin has not been reported.\n\nWe herein report a patient with HCC who developed an AE of preexisting IIP after TACE and TAI using miriplatin.\n\nCase Report\nA 76-year-old woman with a 5-year history of chronic hepatitis C virus infection, liver cirrhosis, and HCC was admitted to our hospital. She had received TACE using epirubicin (50 mg/body) 5 years earlier. Chest computed tomography (CT) performed before TACE using epirubicin revealed bilateral subpleural reticulation. The differential diagnosis included secondary causes of ILD, such as connective tissue disease-associated ILD, vasculitis, hypersensitivity pneumonitis, pneumoconiosis, drug-induced pneumonia, infection, eosinophilic pneumonia, sarcoidosis, and others.\n\nLaboratory tests were negative for antineutrophil cytoplasmic antibody-associated vasculitis and autoantibodies associated with any connective tissue diseases. A physical examination revealed no findings such as rash or arthralgia. She had no history of antigen inhalation that might cause hypersensitivity pneumonitis or pneumoconiosis. In addition, she had not consumed any new drugs or supplements (9). Based on these findings and according to the American Thoracic Society/European Respiratory Society (ATS/ERS) International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias (10), she was ultimately diagnosed with IIP.\n\nChest CT demonstrated the slow progression of IIP over the past five years (Fig. 1). TACE using epirubicin for treating HCC was repeatedly administered until two years before she presented at our hospital. She received second-line treatment with TACE using miriplatin (120 mg/body) from 3 months before presenting at our hospital owing to HCC recurrence. Subsequently, she exhibited exertional dyspnea. Two months after the treatment initiation, CT revealed portal vein invasion of the HCC, so HCC was diagnosed as refractory to TACE using miriplatin, preventing further administration of TACE using miriplatin. Therefore, TAI using miriplatin (100 mg/body) was next initiated.\n\nFigure 1. The course of CT scans before transcatheter arterial therapy using miriplatin. A: Chest CT scan obtained five years before presenting at our hospital, when she was first diagnosed with IIP, showing bilateral subpleural reticulation. B: Results of chest CT performed two years ago. C: Results of chest CT performed six months ago, when HCC recurred, demonstrating the slow progression of IIP over the past four years. CT: computed tomography, IIP: idiopathic interstitial pneumonia\n\nOn day 4 after TAI initiation, the patient complained of dry cough and acute worsening dyspnea. On day 11, her peripheral oxygen saturation (SpO2) was 98% as evaluated during face mask administration of oxygen (5 L/min), indicating acute respiratory failure. An arterial blood gas analysis showed that the partial pressure of arterial oxygen (PaO2) was 131.6 mmHg with 5 L/min, and the PaO2/fraction of inspiratory oxygen (FiO2; P/F) ratio was estimated to be 329. On a physical examination, fine crackles were audible in the bilateral lower lung fields. Laboratory tests revealed elevated serum levels of the biomarkers Krebs von den Lungen-6 (KL-6: 4,303 U/mL), surfactant protein D (SP-D: 1,072 ng/mL), and lactate dehydrogenase (LDH: 648 U/mL). Serum levels of beta (β)-D-glucan and procalcitonin were below detectable limits, and cytomegalovirus-pp65 antigens in the blood were negative (Table). Chest radiography revealed bilateral ground-glass opacity and infiltrative shadow. High-resolution CT (HRCT) demonstrated even more extensive geographic distribution of ground-glass opacity and infiltrative shadow with traction bronchiectasis in both the lungs superimposed on underlying fibrotic opacities (Fig. 2). The miriplatin-triggered AE of preexisting IIP was diagnosed based on several factors: the clinical course of worsening preexisting IIP after the administration of miriplatin; an acute clinically worsening respiratory condition that developed within one month, meeting a new definition and diagnostic criteria for AE of idiopathic pulmonary fibrosis (IPF); new radiologic abnormalities on HRCT; and the absence of other obvious clinical causes, such as fluid overload and left heart failure (11).\n\nTable. Examination on Day 11 after Transcatheter Arterial Infusion Using Miriplatin.\n\nHematology\t\tSerology\t\nWBC\t\t7,200\t/μL\t\tCRP\t\t2.06\tmg/dL\t\nNeu\t\t79.4\t%\t\tKL-6\t\t4,303\tU/mL\t\nLym\t\t11.8\t%\t\tSP-D\t\t1,072\tng/mL\t\nMo\t\t4.8\t%\t\tANA (CLEIA)\t\t<10\t\t\nEo\t\t3.6\t%\t\tPR3-ANCA\t\t<3.5\tU/mL\t\nHb\t\t10.8\tg/dL\t\tMPO-ANCA\t\t<3.5\tU/mL\t\nPLT\t\t80×103\t/μL\t\tanti-ss-DNA Ab\t\t<25\tAU/mL\t\nBlood chemistry\t\tanti-RNP Ab\t\t<10\tU/mL\t\nTP\t\t6.4\tg/dL\t\tanti-Sm Ab\t\t<10\tU/mL\t\nAlb\t\t2.4\tg/dL\t\tanti-SS-A Ab\t\t<10\tU/mL\t\nNa\t\t135\tmmol/L\t\tanti-SS-B Ab\t\t<10\tU/mL\t\nK\t\t4.3\tmmol/L\t\tanti-Scl-70 Ab\t\t<10\tU/mL\t\nCl\t\t102\tmmol/L\t\tanti-Jo-1 Ab\t\t<10\tU/mL\t\nBUN\t\t18.2\tmg/dL\t\tanti-centromere Ab\t\t<10\tU/mL\t\nCre\t\t0.59\tmg/dL\t\tanti-ARS Ab\t\t(-)\t\t\nT-Bil\t\t2.2\tmg/dL\t\tRF\t\t35\tIU/mL\t\nAST\t\t122\tU/L\t\tanti-CCP Ab\t\t<4.5\tU/mL\t\nALT\t\t60\tU/L\t\tBiological test\t\nLDH\t\t540\tU/L\t\tβ-D glucan\t\t<6.0\tpg/mL\t\nPCT\t\t0.19\tng/mL\t\tCMV antigen\t\t(-)\t\t\nBNP\t\t129.4\tpg/mL\t\tBlood gas analysis (F.M.: 5L/min)\t\nCoagulation\t\tpH\t\t7.470\t\t\nPT\t\t61\t%\t\tPaO2\t\t131.6\tmmHg\t\nAPTT\t\t80\t%\t\tPaCO2\t\t30.9\tmmHg\t\nD-dimer\t\t4.8\tμg/mL\t\tHCO3-\t\t22.0\tmmol/L\t\nAb: antibody, ANA: anti-nuclear antibodies, ARS: aminoacyl tRNA synthetase, BNP: brain natriuretic peptide, CCP: cyclic citrullinated peptide, CLEIA: chemiluminescent enzyme immunoassay, CMV: cytomegalovirus, F.M.: face mask, KL-6: Krebs von den Lungen-6, MPO-ANCA: myeloperoxidase-anti neutrophil cytoplasmic antibody, PCT: procalcitonin, RF: rheumatoid factor, RNP: ribonucleoprotein, PR3-ANCA: proteinase 3-anti neutrophil cytoplasmic antibody, Scl-70: scleroderma-70, Sm: smith, SP-D: surfactant protein D, SS-A: Sjögren Syndrome-A, SS-B: Sjögren Syndrome-B, ss-DNA: single strand deoxyribonucleic acid\n\nFigure 2. Chest CT before and after transcatheter arterial therapy using miriplatin. A, B: Chest CT before transcatheter arterial therapy using miriplatin, showing interstitial pneumonia. C, D: Chest CT after transcatheter arterial therapy using miriplatin on day 11, demonstrating extensive ground-glass opacity, infiltrative shadow, and traction bronchiectasis in bilateral lungs. CT: computed tomography\n\nThus, miriplatin for treating HCC was discontinued, and systemic corticosteroid pulse therapy with intravenous methylprednisolone (1,000 mg/day for 3 days) was initiated. Despite 1 course of steroid pulse therapy, the P/F ratio decreased to 86.4, and the patient was intubated and mechanically ventilated. Thereafter, the patient was subsequently administered a pulse cyclophosphamide (500 mg/day) and an additional two courses of corticosteroid pulse therapy. However, her respiratory condition further deteriorated, and she ultimately died of respiratory failure on hospital day 36 (Fig. 3).\n\nFigure 3. The clinical course of the patient in our study. TAI: transcatheter arterial infusion\n\nDiscussion\nAE-IIP, including IPF, is a severe and life-threatening condition. In 2016, a new definition and diagnostic criteria for AE-IPF were proposed by an international working group (11). Based on the absence or presence of a cause, AE-IPF can be classified as an idiopathic or a triggered event (e.g. infection, post-procedural/postoperative, drug toxicity, and aspiration), resulting in worsening respiratory status (12). To our knowledge, this is the first case report of AE-IIP triggered by miriplatin for the treatment of HCC that was refractory to aggressive therapy with a combination of high-dose corticosteroid and cyclophosphamide.\n\nIn patients with lung cancer, several studies have reported that chemotherapy-related AE-ILD, including IIP, occurs in 5.6-43% of patients and leads to death in 27.9% patients (13-15). In addition, Kudoh et al. reported that preexisting ILD is a strong risk factor for AE-ILD in patients with non-small cell lung cancer (odds ratio, 4.80-25.27) compared with those without ILD (13). However, there have been no reports of AE-IIP after transcatheter arterial therapy, including TACE and TAI, in patients with HCC and preexisting IIP. Neu et al. reviewed case reports, case series, and original studies of pulmonary complications after TACE in patients with HCC. Pulmonary complications, including acute lung injury and acute respiratory distress syndrome, occur in 0.05-2.3% of patients and are assumed to be related to lung damage caused by pulmonary oil embolism and chemotherapeutic agents. One underlying mechanism explaining these complications is the migration of oil emulsions into the pulmonary vasculature via arteriovenous shunts within the lesion of HCC (16).\n\nTranscatheter arterial therapy, including TACE and TAI using lipiodol and anticancer agents, is widely used to treat HCC (17). In TACE, we administer anticancer agents and embolize the tumor nutrient arteries using gelatin sponge particles. Conversely, in TAI, although anticancer agents are injected, embolization using gelatin sponge particles is not performed. TACE is not always indicated, especially in patients with a poor liver function, large tumor size, and tumor metastasis in multiple lobes, because the risk associated with treatment-related death is relatively high in such patients (1,18). Anticancer agents such as epirubicin, doxorubicin, mitomycin C, cisplatin, and neocarzinostatin are commonly used in TACE. In October 2009, miriplatin, belonging to the family of platinum agents, was approved as a TACE agent for treating HCC. The results of several previous studies on TACE using miriplatin suggest that miriplatin may be one of the safest and most efficacious therapeutic agents (1,6,17). However, TACE is not recommended in patients with distant metastases and vascular invasion. In our case, TAI using miriplatin was selected because of the presence of portal vein invasion.\n\nOnly two cases of drug-induced ILD by transcatheter arterial therapy using miriplatin have been reported (7,8). Both patients demonstrated progressively worsening respiratory failure after the initial administration of miriplatin and recovered after treatment using corticosteroid pulse therapy and respiratory care, including mechanical ventilation or noninvasive positive pressure ventilation. Prior to transcatheter arterial therapy using miriplatin, the patients in these reported cases had no preexisting ILD, including IIP, or any respiratory symptoms. In contrast, our patient died of respiratory failure, despite treatment with a high-dose corticosteroid and cyclophosphamide and respiratory care with mechanical ventilation. In another report, the CT findings of a patient revealed a fibrotic nonspecific interstitial pneumonia pattern (8). Our patient's CT findings showed a diffuse alveolar damage (DAD) pattern. Patients with DAD patterns have poorer a prognosis than those without DAD patterns (19). In addition, our patient had a 5-year history of IIP and suffered shortness of breath in her daily life. Considering her clinical course, she was eventually diagnosed with AE-IIP triggered by transcatheter arterial therapy using miriplatin.\n\nSeveral limitations associated with the present case study warrant mention. Lipiodol is generally used for TACE and TAI. In our case, however, lipiodol was used for TACE and TAI while also using miriplatin before the development of AE-IIP. AE-IIP may therefore have been caused by either or both miriplatin or lipiodol. However, our patient had been previously administered lipiodol several times for the treatment of HCC. We therefore concluded that the administration of miriplatin rather than lipiodol triggered AE-IIP. The influence of lipiodol alone on lung complications in the present case is unclear; however, lipiodol and miriplatin may synergize and potentiate the risk of AE-IIP when used together.\n\nTo our knowledge, a case of fatal AE-IIP after transcatheter arterial therapy using miriplatin has not yet been reported. Serious complications of AE-IIP should be carefully monitored when providing transcatheter arterial therapy using miriplatin in patients with HCC with preexisting IIP.\n\n\nThe authors state that they have no Conflict of Interest (COI).\n==== Refs\n1. \nOtuji K , Takai K , Nishigaki Y , et al \nEfficacy and safety of cisplatin versus miriplatin in transcatheter arterial chemoembolization and transarterial infusion chemotherapy for hepatocellular carcinoma: a randomized controlled trial . Hepatol Res \n45 : 514 -522 , 2015 .24961745 \n2. \nTakayasu K , Arii S , Ikai I , et al \nProspective cohort study of transarterial chemoembolization for unresectable hepatocellular carcinoma in 8510 patients . Gastroenterology \n131 : 461 -469 , 2006 .16890600 \n3. \nYamakado K , Miyayama S , Hirota S , et al \nHepatic arterial embolization for unresectable hepatocellular carcinomas: do technical factors affect prognosis? \nJpn J Radiol \n30 : 560 -566 , 2012 .22644412 \n4. \nImai N , Ikeda K , Seko Y , et al \nPrevious chemoembolization response after transcatheter arterial chemoembolization (TACE) can predict the anti-tumor effect of subsequent TACE with miriplatin in patients with recurrent hepatocellular carcinoma . Oncology \n80 : 188 -194 , 2011 .21709428 \n5. \nAramaki T , Moriguti M , Bekku E , et al \nComparison of epirubicin hydrochloride and miriplatin hydrate as anticancer agents for transcatheter arterial chemoembolization of hepatocellular carcinoma . Hepatol Res \n43 : 475 -480 , 2013 .23046493 \n6. \nHanda T , Imai Y , Sugawara K , et al \nTranscatheter arterial chemoembolization for hepatocellular carcinoma: comparison of the therapeutic efficacies between miriplatin and epirubicin . Hepatol Res \n44 : 1072 -1080 , 2014 .23957866 \n7. \nKumasawa F , Miura T , Takahashi T , et al \nA case of miriplatin-induced lung injury . J Infect Chemother \n22 : 486 -489 , 2016 .26867794 \n8. \nMatsuura T , Kobayashi S , Otani K , et al \nA case of drug-induced pneumonitis caused by transcatheter arterial infusion with miriplatin for hepatocellular carcinoma . Kanzo \n53 : 284 -290 , 2012 (in Japanese, Abstract in English).\n9. \nRaqhu G , Collard HR , Eqan JJ , et al \nAn official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management . Am J Respir Crit Care Med \n183 : 788 -824 , 2011 .21471066 \n10. \nTravis WD , Costabel U , Hansell DM , et al \nAn official American Thoracic Society/European Respiratory Society statement: update of the international multidisciplinary classification of the idiopathic interstitial pneumonias . Am J Respir Crit Care Med \n188 : 733 -748 , 2013 .24032382 \n11. \nCollard HR , Ryerson CJ , Corte TJ , et al \nAcute exacerbation of idiopathic pulmonary fibrosis. An international working group report . Am J Respir Care Med \n194 : 265 -275 , 2016 .\n12. \nKondoh Y , Cottin V , Brown KK \nRecent lessons learned in the management of acute exacerbation of idiopathic pulmonary fibrosis . Eur Respir Rev \n26 : 170050 , 2017 .28954766 \n13. \nKudoh S , Kato H , Nishiwaki Y , et al \nInterstitial lung disease in Japanese patients with lung cancer: a cohort and nested case-control study . Am J Respir Crit Care Med \n177 : 1348 -1357 , 2008 .18337594 \n14. \nMinegishi Y , Sudoh J , Kuribayasi H , et al \nThe safety and efficacy of weekly paclitaxel in combination with carboplatin for advanced non-small cell lung cancer with idiopathic interstitial pneumonias . Lung Cancer \n71 : 70 -74 , 2011 .20493578 \n15. \nWatanabe N , Taniguchi H , Kondoh Y , et al \nEfficacy of chemotherapy for advanced non-small cell lung cancer with idiopathic pulmonary fibrosis . Respiration \n85 : 326 -331 , 2013 .23171837 \n16. \nNeu QM , Knowles H , Pockros PJ , Frentte CT \nPulmonary complications of transcatheter arterial chemoembolization for hepatocellular carcinoma . World J Respirol \n6 : 69 -75 , 2016 .27904836 \n17. \nKubota K , Hidaka H , Nakazawa T , et al \nProspective, randomized, controlled study of the efficacy of transcatheter arterial chemoembolization with miriplatin for hepatocellular carcinoma . Hepatol Res \n48 : 98 -106 , 2018 .\n18. \nLui X , Wang Z , Chen Z , et al \nEfficacy and safety of transcatheter arterial chemoembolization and transcatheter arterial chemotherapy infusion in hepatocellular carcinoma: a systematic review and meta-analysis . Oncol Res \n26 : 231 -239 , 2018 .28911342 \n19. \nBouros D , Nicholson AC , Polychronopoulos V , du Bois RM \nAcute interstitial pneumonia . Eur Respir J \n15 : 412 -418 , 2000 .10706513\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0918-2918",
"issue": "58(9)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": "acute exacerbation; idiopathic interstitial pneumonia; miriplatin; transcatheter arterial therapy",
"medline_ta": "Intern Med",
"mesh_terms": "D000368:Aged; D000970:Antineoplastic Agents; D006528:Carcinoma, Hepatocellular; D002406:Catheterization, Peripheral; D003520:Cyclophosphamide; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D054988:Idiopathic Interstitial Pneumonias; D007261:Infusions, Intra-Arterial; D008113:Liver Neoplasms; D009944:Organoplatinum Compounds; D012131:Respiratory Insufficiency; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "9204241",
"other_id": null,
"pages": "1329-1333",
"pmc": null,
"pmid": "30626817",
"pubdate": "2019-05-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "10706513;16890600;18337594;20493578;21471066;21709428;22644412;23046493;23171837;23957866;24032382;24961745;26867794;27299520;27904836;28656607;28911342;28954766",
"title": "Acute Exacerbation of Idiopathic Interstitial Pneumonia in a Patient with Hepatocellular Carcinoma after Transcatheter Arterial Therapy Using Miriplatin.",
"title_normalized": "acute exacerbation of idiopathic interstitial pneumonia in a patient with hepatocellular carcinoma after transcatheter arterial therapy using miriplatin"
} | [
{
"companynumb": "JP-GUERBET-JP-20190097",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ETHIODIZED OIL"
},
"drugadditional": null,
... |
{
"abstract": "A \"biosimilar\" is a biotechnological product with a lower cost profile and equivalent efficacy and safety to the originator, but post-marketing clinical evaluation of biosimilar products has not been adequately conducted. We prospectively investigated the utility of biosimilar filgrastim in 13 peripheral blood stem cell (PBSC) donors from June 2014 to January 2017. In addition, we retrospectively compared these to another 13 PBSC donors mobilized with the originator filgrastim in the same period. Donor characteristics were equivalent between the groups. The median number of CD34+ cells per donor body weight (BW) and blood volume processed (BV) were 4.87 × 106/kg and 25.5 × 103/mL in the biosimilar group and 4.93 × 106/kg and 16.6 × 103/mL in the originator group, respectively. There were no significant differences between the groups in the number of CD34+ cells per donor BW or BV. All adverse events associated with G-CSF were permissive. The total G-CSF cost was significantly lower in the biosimilar group than in the originator group. These findings suggest that biosimilar filgrastim has the same efficacy and short-term safety as originator filgrastim for PBSC mobilization in healthy donors, with economic superiority. Longer follow-up studies are needed to evaluate the incidence of long-term adverse events.",
"affiliations": "Department of Hematology, Nagano Red Cross Hospital, Nagano, Japan.;Department of Hematology, Kanazawa University Hospital, 13-1 Takaramachi, Kanazawa, Ishikawa, 920-8641, Japan. ishiyama-knz@umin.ac.jp.;Department of Hematology, Kanazawa University Hospital, 13-1 Takaramachi, Kanazawa, Ishikawa, 920-8641, Japan.;Department of Hematology, Kanazawa University Hospital, 13-1 Takaramachi, Kanazawa, Ishikawa, 920-8641, Japan.;Department of Hematology, Kanazawa University Hospital, 13-1 Takaramachi, Kanazawa, Ishikawa, 920-8641, Japan.;Department of Hematology, Kanazawa University Hospital, 13-1 Takaramachi, Kanazawa, Ishikawa, 920-8641, Japan.;Department of Hematology, Kanazawa University Hospital, 13-1 Takaramachi, Kanazawa, Ishikawa, 920-8641, Japan.;Department of Transfusion Medicine, Kanazawa University Hospital, Kanazawa, Japan.;Department of Transfusion Medicine, Kanazawa University Hospital, Kanazawa, Japan.;Department of Hematology, Ishikawa Prefectural Central Hospital, Kanazawa, Japan.;Department of Hematology, Aichi Medical University, Nagakute, Japan.;Department of Hematology, Kanazawa University Hospital, 13-1 Takaramachi, Kanazawa, Ishikawa, 920-8641, Japan.",
"authors": "Sato|Keijiro|K|;Ishiyama|Ken|K|http://orcid.org/0000-0002-6189-0620;Aoki|Go|G|;Maruyama|Hiroyuki|H|;Tsuji|Noriaki|N|;Tanabe|Mikoto|M|;Zaimoku|Yoshitaka|Y|;Sato|Hidehiro|H|;Yamazaki|Hirohito|H|;Yamaguchi|Masaki|M|;Takami|Akiyoshi|A|;Nakao|Shinji|S|",
"chemical_list": "D018952:Antigens, CD34; D059451:Biosimilar Pharmaceuticals; D016179:Granulocyte Colony-Stimulating Factor; D000069585:Filgrastim",
"country": "Japan",
"delete": false,
"doi": "10.1007/s12185-019-02733-8",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0925-5710",
"issue": "110(6)",
"journal": "International journal of hematology",
"keywords": "Biosimilar; Granulocyte colony-stimulating factor; Hematopoietic stem cell mobilization",
"medline_ta": "Int J Hematol",
"mesh_terms": "D000328:Adult; D018952:Antigens, CD34; D059451:Biosimilar Pharmaceuticals; D005260:Female; D000069585:Filgrastim; D016179:Granulocyte Colony-Stimulating Factor; D019650:Hematopoietic Stem Cell Mobilization; D006801:Humans; D007564:Japan; D008297:Male; D008875:Middle Aged; D000072916:Peripheral Blood Stem Cells; D011446:Prospective Studies; D012189:Retrospective Studies; D014019:Tissue Donors",
"nlm_unique_id": "9111627",
"other_id": null,
"pages": "648-653",
"pmc": null,
"pmid": "31542851",
"pubdate": "2019-12",
"publication_types": "D023362:Evaluation Study; D016428:Journal Article",
"references": "21719883;24179471;28801752;24965197;23420184;26011178;19057203;28258517;23208313;27565504;21509437;24816581",
"title": "Evaluation of a biosimilar granulocyte colony-stimulating factor for peripheral blood stem cell mobilization in Japanese healthy donors: a prospective study.",
"title_normalized": "evaluation of a biosimilar granulocyte colony stimulating factor for peripheral blood stem cell mobilization in japanese healthy donors a prospective study"
} | [
{
"companynumb": "JP-AMGEN-JPNNI2019166465",
"fulfillexpeditecriteria": "2",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FILGRASTIM"
},
"drugadditional": "3",
... |
{
"abstract": "A 20-year-old male patient on oral treatment with ranitidine 300 mg/day in a single bedtime dose was admitted to hospital for a brief episode of syncope which had occurred 20 min earlier. All clinical, laboratory and instrumental examinations yielded negative findings, except for electrocardiographic evidence of first-degree atrioventricular block. Administration of atropine produced transient disappearance of the block, which disappeared altogether after discontinuing ranitidine treatment. Two separate rechallenges with ranitidine each produced recurrence of (asymptomatic) first-degree atrioventricular block at electrocardiographic examination, but oral treatment with cimetidine (400-800 mg/day) and famotidine (40-80 mg/day) induced no electrocardiographic abnormalities. The hypothesis that this patient may be abnormally susceptible to the cholinergic or cholinergic-like effect of ranitidine, a side effect unrelated to the drug's primary H2-blocking action, would appear to be consistent with evidence of an increased vagal tone of the atrioventricular node as revealed by atrial pacing. However, the ability of ranitidine to release histamine in man and the potential dysrhythmia-inducing effect of histamine should also be taken into consideration.",
"affiliations": "Emergency Department, General Regional Hospital, Bolzano, Italy.",
"authors": "Allegri|G|G|;Pellegrini|K|K|;Dobrilla|G|G|",
"chemical_list": "D001285:Atropine; D011899:Ranitidine",
"country": "Switzerland",
"delete": false,
"doi": "10.1007/BF02028277",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0065-4299",
"issue": "24(3-4)",
"journal": "Agents and actions",
"keywords": null,
"medline_ta": "Agents Actions",
"mesh_terms": "D000284:Administration, Oral; D000328:Adult; D001285:Atropine; D004381:Duodenal Ulcer; D004562:Electrocardiography; D006327:Heart Block; D006801:Humans; D008297:Male; D011899:Ranitidine",
"nlm_unique_id": "0213341",
"other_id": null,
"pages": "237-42",
"pmc": null,
"pmid": "3177090",
"pubdate": "1988-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "6127091;6307923;6136992;6182352;2444844;2880057;7053892;6123873;6123238;6182358;6314960;6181367;6096071;6127573;2878343;6469082;6128580",
"title": "First-degree atrioventricular block in a young duodenal ulcer patient treated with a standard oral dose of ranitidine.",
"title_normalized": "first degree atrioventricular block in a young duodenal ulcer patient treated with a standard oral dose of ranitidine"
} | [
{
"companynumb": "IT-GLAXOSMITHKLINE-IT2017GSK130564",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "RANITIDINE HYDROCHLORIDE"
},
"drugad... |
{
"abstract": "Drug-induced thrombocytopenia occurs through immune-mediated platelet destruction, and its management is challenging during tuberculosis treatment. Although rifampicin is the most common drug causing thrombocytopenia, isoniazid can also cause thrombocytopenia. We herein report a 75-year-old man who developed thrombocytopenia during tuberculosis treatment. Platelet-associated immunoglobulin G and a drug-induced lymphocyte stimulation test for isoniazid were positive; no other causes of thrombocytopenia were identified. The patient was diagnosed with isoniazid-induced immune thrombocytopenia, and the platelet count normalized after isoniazid discontinuation. We describe the immunological mechanism of thrombocytosis due to isoniazid, an uncommon cause of thrombocytopenia that physicians should be aware exists.",
"affiliations": "Department of Infection Control Science, Graduate School of Medicine, Osaka City University, Japan.;Department of Hematology, Graduate School of Medicine, Osaka City University, Japan.;Department of Infection Control Science, Graduate School of Medicine, Osaka City University, Japan.;Department of Infection Control Science, Graduate School of Medicine, Osaka City University, Japan.;Department of Infection Control Science, Graduate School of Medicine, Osaka City University, Japan.;Department of Infection Control Science, Graduate School of Medicine, Osaka City University, Japan.;Department of Infection Control Science, Graduate School of Medicine, Osaka City University, Japan.;Department of Respiratory Medicine, Osaka City Juso Hospital, Japan.;Department of Respiratory Medicine, Osaka City Juso Hospital, Japan.;Department of Hematology, Graduate School of Medicine, Osaka City University, Japan.;Department of Respiratory Medicine, Graduate School of Medicine, Osaka City University, Japan.;Department of Infection Control Science, Graduate School of Medicine, Osaka City University, Japan.",
"authors": "Kuwabara|Gaku|G|;Tazoe|Kumiyo|K|;Imoto|Waki|W|;Yamairi|Kazushi|K|;Shibata|Wataru|W|;Oshima|Kazuhiro|K|;Yamada|Koichi|K|;Takagi|Yasuhiro|Y|;Shiraishi|Satoshi|S|;Hino|Masayuki|M|;Kawaguchi|Tomoya|T|;Kakeya|Hiroshi|H|",
"chemical_list": "D007538:Isoniazid; D012293:Rifampin",
"country": "Japan",
"delete": false,
"doi": "10.2169/internalmedicine.6520-20",
"fulltext": "\n==== Front\nIntern Med\nIntern Med\nInternal Medicine\n0918-2918\n1349-7235\nThe Japanese Society of Internal Medicine\n\n34053983\n10.2169/internalmedicine.6520-20\nCase Report\nIsoniazid-induced Immune Thrombocytopenia\nKuwabara Gaku 12\nTazoe Kumiyo 3\nImoto Waki 12\nYamairi Kazushi 1\nShibata Wataru 1\nOshima Kazuhiro 1\nYamada Koichi 1\nTakagi Yasuhiro 4\nShiraishi Satoshi 4\nHino Masayuki 3\nKawaguchi Tomoya 2\nKakeya Hiroshi 1\n1 Department of Infection Control Science, Graduate School of Medicine, Osaka City University, Japan\n2 Department of Respiratory Medicine, Graduate School of Medicine, Osaka City University, Japan\n3 Department of Hematology, Graduate School of Medicine, Osaka City University, Japan\n4 Department of Respiratory Medicine, Osaka City Juso Hospital, Japan\nCorrespondence to Dr. Hiroshi Kakeya, kakeya@med.osaka-cu.ac.jp\n\n29 5 2021\n15 11 2021\n60 22 36393643\n15 10 2020\n13 4 2021\nCopyright © 2021 by The Japanese Society of Internal Medicine\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ The Internal Medicine is an Open Access journal distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (https://creativecommons.org/licenses/by-nc-nd/4.0/).\nDrug-induced thrombocytopenia occurs through immune-mediated platelet destruction, and its management is challenging during tuberculosis treatment. Although rifampicin is the most common drug causing thrombocytopenia, isoniazid can also cause thrombocytopenia. We herein report a 75-year-old man who developed thrombocytopenia during tuberculosis treatment. Platelet-associated immunoglobulin G and a drug-induced lymphocyte stimulation test for isoniazid were positive; no other causes of thrombocytopenia were identified. The patient was diagnosed with isoniazid-induced immune thrombocytopenia, and the platelet count normalized after isoniazid discontinuation. We describe the immunological mechanism of thrombocytosis due to isoniazid, an uncommon cause of thrombocytopenia that physicians should be aware exists.\n\ndrug-induced immune thrombocytopenia\nisoniazid\ntuberculosis\n==== Body\npmcIntroduction\n\nTuberculosis is a chronic granulomatous infection that has caused epidemiological problems for over a century and requires long-term antimicrobial treatment, which can have various side effects. Skin rashes, hepatotoxicity and digestive symptoms, such as diarrhea and loss of appetite, are among the common side effects of anti-tuberculosis drugs. Although tuberculosis treatment is challenging because of these side effects, serious side effects are rare.\n\nThrombocytopenia is an uncommon but possible side effect caused by anti-tuberculosis drugs that can be life-threatening. Rifampicin (RFP) is the most common causative drug among anti-tuberculosis drugs (1-5). However, studies have reported only a few cases of isoniazid (INH)-induced thrombocytopenia (5-10).\n\nWe herein report a case of severe drug-induced immune thrombocytopenia caused by INH.\n\nCase Report\n\nWe herein report a 75-year-old Japanese man with a medical history of spondylitis at 72 years and no medical history of tuberculosis. He was diagnosed with tuberculosis and tuberculous spondylitis. Chest radiography showed bilateral nodular shadow and an infiltrative shadow of the left lung (Fig. 1), and treatment was initiated with RFP (600 mg/day), INH (300 mg/day), ethambutol (EB, 500 mg/day) and pyrazinamide (PZA, 1.2 g/day) at another hospital. Posterior lumbar spinal fusion was performed subsequently.\n\nFigure 1. Chest radiography at the diagnosis showed bilateral nodular shadow and infiltrative shadow of the left lung.\n\nAs hepatic toxicity occurred after 1 month [aspartate transaminase (AST), 164 U/L; alanine transaminase (ALT), 186 U/L], drugs were discontinued for 4 weeks until hepatotoxicity improved. During this period, the platelet count dropped to 9.0×104/μL at 11 days after drug discontinuation and thereafter increased to 13.6×104/μL. Although the patient was desensitized with and INH and RFP after the hepatic function improved (INH and RFP doses started at 50 and 75 mg/day, respectively, and increased 2-fold every 3 days, finally reaching 300 and 600 mg/day, respectively), hepatotoxicity occurred again (AST, 94 U/L; ALT, 76 U/L). Therefore, RFP was discontinued, and treatment with INH and EB was continued. The patient was transferred to our hospital 3 months after the initiation of the treatment (10 days after discontinuation of RFP) because continuing the treatment at that hospital was deemed difficult.\n\nLaboratory investigations on admission showed a low platelet count of 1.5×104/μL (Table 1). Therefore, platelet transfusion of 10 and 20 units was done on days 1 and 2, respectively. Red blood cell transfusion of two units was also performed for anemia on day one. According to laboratory investigations, secondary anemia was diagnosed because of tuberculosis. The decrease in the platelet count was associated with the administration of INH, after reviewing the course and medications (Fig. 2A). Therefore, INH was discontinued on the third day, and levofloxacin (500 mg/day) and streptomycin (0.3 g/day) were added. No bacteria were detected from cultures of blood, sputum or urine, excluding the Mycobacterium tuberculosis detected from sputum culture. An elevated immature platelet fraction of 24.7% (normal range, 2-10%) implied accelerated platelet destruction. Platelet-associated immunoglobulin G (PA-IgG) was positive, and INH was positive using the drug-induced lymphocyte stimulation test (DLST), while RFP was negative. No rash or bleeding symptoms were noted.\n\nTable 1. Laboratory Findings of the Patient on Admission to Our Hospital.\n\nWBC (/μL)\t4,900 (4,300-8,000)\tTP (g/dL)\t6 (6.6-8.1)\t\nNeutrophils (%)\t70.7 (49.5-71.0)\tT-Bil (mg/dL)\t1.4 (0.2-1.4)\t\nEosinophils (%)\t8 (0.2-6.8)\tAST (U/L)\t39 (13-30)\t\nBasophils (%)\t0 (0.0-1.8)\tALT (U/L)\t58 (8-42)\t\nLymphocytes (%)\t15 (26.6-46.6)\tLDH (U/L)\t290 (124-222)\t\nMonocytes (%)\t8(2.3-7.7)\tγ-GTP (U/L)\t107 (13-64)\t\nRBC (×104/μL)\t459(450-510)\tBUN (mg/dL)\t22 (8-20)\t\nHemoglobin (g/dL)\t6.4(12.4-17.2)\tCre (mg/dL)\t1.3 (0.50-1.10)\t\nHematocrit (%)\t18.4 (38.0-54.0)\tNa (mEq/L)\t130 (138-145)\t\nPlt (×104/μL)*\t1.5 (18.0-34.0)\tK (mEq/L)\t3.7 (3.6-4.8)\t\nIPF (%)\t24.7 (2.0-10.0)\tCl (mEq/L)\t103 (101-108)\t\nPT-INR\t1.24\tCRP (mg/dL)\t2.05 (0-0.40)\t\nAPTT (sec)\t55.7 (25.0-40.0)\tHbA1c (%)\t5.3 (4.6-6.2)\t\nFib (mg/mL)\t76 (200-400)\tPA-IgG (ng/107cells)\t1,040\t\nFDP (μg/mL)\t7.8 (0-10.0)\tHP-antibody\tnegative\t\nD-dimer (μg/mL)\t4 (0-1.0)\tDLST\t\t\nFe (μg/dL)\t60 (40-188)\tRFP\tnegative\t\nFerritin (ng/mL)\t814.8 (39.9-465.0)\tINH\tpositive\t\nTIBC (μg/dL)\t62 (250-410)\t\t\t\nWBC: white blood cells, RBC: red blood cells, Plt: platelets, IPF: immature platelet fraction, TP: total protein, T-Bil: total bilirubin, AST: aspartate transaminase, ALT: alanine transaminase, LDH: lactate dehydrogenase, γ-GTP: γ-glutamyl transpeptidase, BUN: blood urine nitrogen, Cre: creatinine, CRP: C-reactive protein, HbA1c: hemoglobin A1c, PT-INR: prothrombin time-international normalized ratio, APTT: activated partial thromboplastin time, Fib: fibrinogen, FDP: fibrin/fibrinogen degradation products, Fe: ferrum, TIBC: total iron binding capacity, PA-IgG: platelet-associated immunoglobulin G, HP-antibody: Helicobacter pylori antibody, DLST: drug-induced lymphocyte stimulation test\n\n*Presence of aggregated platelets was not confirmed.\n\nFigure 2. Clinical course showing the association between the administered drugs and platelet count (A) before and (B) after the transfer to our hospital. INH: isoniazid, RFP: rifampicin, EB: ethambutol, PZA: pyrazinamide, LVFX: levofloxacin, SM: streptomycin, RBT: rifabutin, Plt: platelet\n\nBone marrow aspiration was performed to exclude hematological malignancies and bone marrow tuberculosis, and no specific findings, including malignant and granulomatous findings, were revealed by the histopathological analysis (Fig. 3). Although the platelet count decreased again after platelet transfusion, which implied the continuation of the antibody-mediated destruction of platelets, the decrease stopped five days after INH was discontinued, and the platelet count gradually improved (Fig. 2B). Based on these findings and the interval between drug discontinuation and the cessation of the decrease in the platelet count, INH-induced immune thrombocytopenia was suggested. Rifabutin (RBT) was added to the RFP regimen as an alternative drug, as RFP was considered a causative agent of liver toxicity. Thrombocytopenia did not occur after the addition of RBT. Although a sputum smear for acid-fast bacilli remained positive, the general condition of the patient was stable, and chest radiography showed no significant changes after admission to our hospital. Subsequently, the patient was transferred to another hospital eight weeks after his transfer to our hospital for the continuation of treatment.\n\nFigure 3. A histopathological examination of bone marrow showed the partial collection of hematopoietic cells and hypocellularity. No malignant or granulomatous findings were confirmed (Hematoxylin and Eosin staining, ×100).\n\nDiscussion\n\nAlthough anti-tuberculosis drugs can cause various side effects, it is rare to experience severe thrombocytopenia that necessitates drug discontinuation. Among anti-tuberculosis drugs, RFP is most commonly associated with thrombocytopenia (1-4,10), whereas INH-induced thrombocytopenia is relatively uncommon (5-10). In this case, we observed severe INH-induced immune thrombocytopenia that necessitated discontinuation of INH during the treatment of tuberculosis.\n\nAntiplatelet antibodies are reportedly produced in the presence of the causative drug and bind to the platelet glycoprotein Ib/IX in RFP-induced immune thrombocytopenia (11). Although the mechanism underlying INH-induced immune thrombocytopenia remains unclear, a similar mechanism has been suggested.\n\nTypically, symptoms occur when the platelet count drops below 20,000/mm3. Thrombocytopenia-related findings include ecchymoses, purpura, mucosal bleeding, and more serious hemorrhaging. In a review of 247 cases of drug-induced thrombocytopenia, 23 patients experienced major bleeding, including 2 who died of bleeding, while 60 patients were asymptomatic (12). A report showed that drug-induced thrombocytopenia can occur more rapidly in patients with a history of causative drug administration than in those without such a history (13). This is presumably because patients sensitized by prior medication produce antibodies rapidly. For instance, severe RFP-induced thrombocytopenia occurs more quickly in patients with RFP re-administration or intermittent administration than in patients without RFP re-administration or intermittent administration (14,15). In all cases of INH-induced thrombocytopenia, re-administration of INH was initiated after the discontinuation of anti-tuberculosis drugs (5-9), and the platelet count in 2 cases dropped below 1×104/μL (6,7). Furthermore, in 1 of these 2 cases, re-administration commenced after an interval of 2 weeks, and the platelet count decreased to 0.4×104/μL within 2 days (7).\n\nIn patients administered multiple drugs, such as anti-tuberculosis, the identification of the causative drug is difficult. Furthermore, the exclusion of other etiologies is necessary for the diagnosis. George et al. suggested the criteria for evaluating the association of drugs with thrombocytopenia (Table 2) (12). INH in the present case met criteria 1, 3, and 4, as pyrazinamide was discontinued before the discontinuation of INH. Therefore, the level of evidence set at “possible.”\n\nTable 2. Criteria to Evaluate the Association between the Drugs and Thrombocytopenia (12).\n\nCriterion\t\t\n1\t1) Therapy with the candidate drug preceded thrombocytopenia and\t\n\t2) recovery from thrombocytopenia was complete and sustained after therapy with the drug was discontinued.\t\n2\t1) The candidate drug was the only drug used before the onset or\t\n\t2) other drugs were continued or reintroduced after discontinuation of therapy with the candidate drug with a sustained normal platelet count.\t\n3\tOther causes for thrombocytopenia were excluded.\t\n4\tRe-exposure to the candidate drug resulted in recurrent thrombocytopenia.\t\nLevel of\nevidence\t\t\nDefinite\tCriteria 1, 2, 3, and 4 met\t\nProbable\tCriteria 1, 2, and 3 met\t\nPossible\tCriterion 1 met\t\nUnlikely\tCriterion 1 not met\t\n\nA DLST can detect the proliferation of sensitized T-cells and is generally used for cases of type IV allergy, which results from T-cell-mediated immune responses. Antibody production in immune thrombocytopenia (previously known as idiopathic thrombocytopenia) is accelerated by CD4-positive helper T-cells (16). Therefore, a positive result on the DLST suggests that the mechanism of thrombocytopenia involves T-cell-mediated immune reaction. PA-IgG is a nonspecific antibody, and its titer does not correlate with thrombocytopenia severity (17). However, because its production is driven by helper T-cells, as mentioned above, it may have significance in cases with a positive result for the DLST. In two previous case reports of RFP- or INH-induced immune thrombocytopenia in which DLST and PA-IgG were tested, PA-IgG was positive in both cases (6,18), while the DLST was positive in one case (6). Although no studies have reported the significance of the DLST and PA-IgG in the diagnosis of drug-induced thrombocytopenia, these cases suggest the usefulness of DLST and PA-IgG.\n\nThe mainstay of treatment is the discontinuation of the suspected drug. For patients with severe thrombocytopenia or bleeding symptoms, platelet transfusions should be undertaken without delay. In such cases, it is critical to observe the effects of platelet transfusion, as the effect of transfusion is transient owing to the persistent destruction of donor platelets (19). Drug-induced thrombocytopenia is reversible. In most cases, the platelet count normalizes within approximately one week (16,17,20), while in this case it took over a week to improve because, as noted above, re-administration of the causative drug can cause severe thrombocytopenia. Furthermore, a case of long-term thrombocytopenia caused by re-administration of INH has been reported (6). Although corticosteroids are recommended for treating immune thrombocytopenia (21), their effects on drug-induced thrombocytopenia are controversial (20). However, corticosteroid use is permitted in drug-induced thrombocytopenia, as initially it is difficult to distinguish it from immune thrombocytopenia. Intravenous immunoglobulin infusion may be considered as an alternative therapy, although there are only a few such case reports (7,22).\n\nIn conclusion, we experienced a case of INH-induced immune thrombocytopenia improved by the discontinuation of the drug. INH is an uncommon cause of thrombocytopenia; however, physicians should be aware that thrombocytopenia can be caused by INH.\n\nThe authors state that they have no Conflict of Interest (COI).\n==== Refs\n1. Hadfield JW . Rifampicin-induced thrombocytopenia. Postgrad Med J 56 : 59-60, 1980.7383953\n2. Mehta YS , Jijin EE , Badakere SS , Pathare AV , Mohanty D . Rifampicin-induced immune thrombocytopenia. Tuber Lung Dis 77 : 558-562, 1996.9039451\n3. Verma AK , Singh A , Chandra A , Kumar S , Gupta RK . Rifampicin-induced thrombocytopenia.. Indian J Pharmacol 42 : 240-242, 2010.20927251\n4. Dixit R , George J , Sharma AK . Thrombocytopenia due to rifampicin. Lung India 29 : 90-92, 2012.\n5. George JN . Platelets on the Web [Internet]. [cited 2020 Sep 20]. Available from: https://www.ouhsc.edu/platelets/\n6. Hansen JE . Hypersensitivity to isoniazid with neutropenia and thrombocytopenia. Am Rev Respir Dis 83 : 744-747, 1961.13711337\n7. Hashiguchi N , Furuyama K , Kim M , Hirose N . A case of pulmonary tuberculosis complicated with severe thrombocytopenia during treatment. Kekkaku 87 : 345-349, 2012 (in Japanese, Abstract in English).22702083\n8. Lee EJ , Lee SH , Kim YE , et al . A case of isoniazid-induced thrombocytopenia: recovery with immunoglobulin therapy. Intern Med 51 : 745-748, 2012.22466831\n9. Yakar F , Yildiz N , Yakar A , Kılıçaslan Z . Isoniazid- and rifampicin-induced thrombocytopenia. Multidiscip Respir Med 8 : 13, 2013.23406847\n10. Gupta P , Kumar H , Singh A , Srivastava UK , Verma AK , Chaudhary R . Isoniazid-induced thrombocytopenia in a patient with ocular tuberculosis. Indian J Respir Care 8 : 121-123, 2019.\n11. Pereira J , Hidalgo P , Ocqueteau M , et al . Glycoprotein Ib/IX complex is the target in rifampicin-induced immune thrombocytopenia. Br J Haematol 110 : 907-910, 2000.11054081\n12. George JN , Raskob GE , Shah SR , Rizvi MA , Hamilton SA , Osborne S . Drug-induced thrombocytopenia: a systematic review of published case reports. Ann Intern Med 129 : 886-890, 1998.9867731\n13. Aster RH , Bougie DW . Drug-induced immune thrombocytopenia. N Engl J Med 357 : 580-587, 2007.17687133\n14. Lee CH , Lee CJ . Thrombocytopenia - a rare but potentially serious side effect of initial daily and interrupted use of rifampicin. Chest 96 : 202-203, 1989.2736979\n15. Mori M , Izawa K , Fujikawa T , et al . A case of acute and severe thrombocytopenia due to readministration of rifampicin. J Infect Chemother 17 : 288-290, 2011.20827562\n16. Chong BH . Primary immune thrombocytopenia: understanding pathogenesis is the key to better treatments. J Thromb Haemost 7 : 319-321, 2009.19077111\n17. Rousan TA , Aldoss IT , Cowley BD Jr , et al . Recurrent acute thrombocytopenia in the hospitalized patient: sepsis, DIC, HIT, or antibiotic-induced thrombocytopenia. Am J Hematol 85 : 71-74, 2010.19802882\n18. Onoda T , Murakami K , Eda R , et al . Rifampicin-induced thrombocytopenia in a patient with miliary tuberculosis. Kekkaku 78 : 491-496, 2003.12931647\n19. George JN , el-Harake MA , Raskob GE . Chronic idiopathic thrombocytopenic purpura. N Engl J Med 331 : 1207-1211, 1994.7935660\n20. Pederson-Bjergaard U , Andersen M , Hansen PB . Drug-induced thrombocytopenia: clinical data on 309 cases and the effect of corticosteroid therapy. Eur J Clin Pharmacol 52 : 183-189, 1997.9218924\n21. Neunert C , Terrell DR , Arnold DM , et al . American Society of Hematology 2019 guidelines for immune thrombocytopenia. Blood Adv 3 : 3829-3866, 2019.31794604\n22. Redall MA , Moore BR , Fass L . Use of i.v. immune globulin for presumed quinidine-induced thrombocytopenia. Clin Pharm 8 : 89, 1989.2917452\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0918-2918",
"issue": "60(22)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": "drug-induced immune thrombocytopenia; isoniazid; tuberculosis",
"medline_ta": "Intern Med",
"mesh_terms": "D000368:Aged; D006801:Humans; D007538:Isoniazid; D008297:Male; D010976:Platelet Count; D016553:Purpura, Thrombocytopenic, Idiopathic; D012293:Rifampin; D013921:Thrombocytopenia",
"nlm_unique_id": "9204241",
"other_id": null,
"pages": "3639-3643",
"pmc": null,
"pmid": "34053983",
"pubdate": "2021-11-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Isoniazid-induced Immune Thrombocytopenia.",
"title_normalized": "isoniazid induced immune thrombocytopenia"
} | [
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"companynumb": "JP-NOVARTISPH-NVSC2021JP273284",
"fulfillexpeditecriteria": "1",
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{
"abstract": "OBJECTIVE: To report a possible pharmacogenomics (PGx)-related, cognitive dysfunction, adverse drug reaction from methotrexate (MTX) that may be multifactorial in origin. SUMMARY: The patient subject is a 76-year-old Caucasian female of Russian ancestry suffering from rheumatoid arthritis and treated with MTX who presented to the diagnostic and consultative physician service in a medical clinic with advancing cognitive dysfunction, manifesting as memory loss, dizziness, and confusion. Components of this possible adverse drug reaction (ADR) may include ancestry, pharmacogenomics (PGx) characteristics of the patient, and a change in route of administration, among others. The case demonstrates how patients referred to a pharmacist consult service for a suspected ADR with possible PGx implications may uncover other contributory factors to the ADR. CONCLUSION: PGx testing may increase clinical pharmacist referrals to identify a PGx etiology to an ADR. However, they may also identify other non-PGx contributory factors to an ADR.",
"affiliations": null,
"authors": "Schuh|Michael J|MJ|;Crosby|Sheena|S|",
"chemical_list": "D008727:Methotrexate",
"country": "United States",
"delete": false,
"doi": "10.4140/TCP.n.2019.595",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2639-9636",
"issue": "34(9)",
"journal": "The Senior care pharmacist",
"keywords": null,
"medline_ta": "Sr Care Pharm",
"mesh_terms": "D000368:Aged; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D006801:Humans; D008727:Methotrexate; D009420:Nervous System; D010595:Pharmacists; D010597:Pharmacogenetics; D012017:Referral and Consultation; D012426:Russia",
"nlm_unique_id": "101737969",
"other_id": null,
"pages": "595-599",
"pmc": null,
"pmid": "31601292",
"pubdate": "2019-10-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Methotrexate Central Nervous System Toxicity Identified in a Pharmacogenomics Pharmacist Consult Patient.",
"title_normalized": "methotrexate central nervous system toxicity identified in a pharmacogenomics pharmacist consult patient"
} | [
{
"companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2019R1-228792",
"fulfillexpeditecriteria": "1",
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{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "METHOTREXATE"
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"dr... |
{
"abstract": "BACKGROUND\nThe epidemic of prescription opioid overdose and mortality parallels the dispensing rates of prescription opioids, and the availability of increasingly potent opioid analgesics.\n\n\nOBJECTIVE\nThe common assumption that more potent opioid analgesics are associated with higher rates of adverse outcomes has not been adequately substantiated. We compared the rate of serious adverse events among commonly prescribed opioid analgesics of varying potency.\n\n\nMETHODS\nSerious adverse events (SAEs; defined as death, major medical effect, or hospitalization) resulting from exposure to tablets containing seven opioid analgesics (oxycodone, hydrocodone, morphine, hydromorphone, oxymorphone, tapentadol, and tramadol) captured by the Researched Abuse, Diversion and Addiction-Related Surveillance (RADARS®) System Poison Center Program were evaluated from 2010 through 2016. Rates of SAEs were adjusted for availability through outpatient dispensing data and regressed on morphine milligram equivalents (MME).\n\n\nRESULTS\nThere were 19,480 cases of SAE during the 7-year study period. Hydrocodone and oxycodone contributed to 77% of SAE cases. Comparing rates of outcome by relative potency, a hierarchy was observed with hydromorphone (8.02 SAEs/100 kg) and tapentadol (0.27 SAE/100 kg) as the highest and lowest rates, reflecting a 30-fold difference among individual opioid products. SAE rate and potency were related linearly-SAEs increased 2.04 per 100 kg drug dispensed for each 1-unit rise in MME (p = 0.004). Linear regression of SAE/100 kg drug dispensed and drug potency identified that MME comprised 96% of the variation observed. In contrast, potency did not explain variation seen using other study denominators (prescriptions dispensed, dosage units dispensed, and the number of individuals filling a prescription).\n\n\nCONCLUSIONS\nPotency of a prescription opioid analgesic demonstrates a significant, highly positive linear relationship with exposures resulting in SAEs per 100 kg drug dispensed reported to poison centers. Potency should be carefully considered from both individual provider and public health perspectives.",
"affiliations": "University of Colorado School of Medicine, Aurora, CO, USA. dlmurphy@uw.edu.;University of Colorado School of Medicine, Aurora, CO, USA.;Denver Health and Hospital Authority, Rocky Mountain Poison and Drug Center, Denver, CO, USA.;Denver Health and Hospital Authority, Rocky Mountain Poison and Drug Center, Denver, CO, USA.;Denver Health and Hospital Authority, Rocky Mountain Poison and Drug Center, Denver, CO, USA.;Denver Health and Hospital Authority, Rocky Mountain Poison and Drug Center, Denver, CO, USA.",
"authors": "Murphy|David L|DL|;Lebin|Jacob A|JA|;Severtson|Stevan G|SG|;Olsen|Heather A|HA|;Dasgupta|Nabarun|N|;Dart|Richard C|RC|",
"chemical_list": "D000701:Analgesics, Opioid",
"country": "New Zealand",
"delete": false,
"doi": "10.1007/s40264-018-0660-4",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0114-5916",
"issue": "41(8)",
"journal": "Drug safety",
"keywords": null,
"medline_ta": "Drug Saf",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000701:Analgesics, Opioid; D002648:Child; D002675:Child, Preschool; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009026:Mortality; D009293:Opioid-Related Disorders; D063487:Prescription Drug Misuse; D012189:Retrospective Studies; D055815:Young Adult",
"nlm_unique_id": "9002928",
"other_id": null,
"pages": "787-795",
"pmc": null,
"pmid": "29582394",
"pubdate": "2018-08",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D064888:Observational Study",
"references": "18574361;16023304;28414990;28755832;21482846;25202775;21332934;25714043;21467282;22992943;19066381;25901965;21517709;27428008;27623005;28000295;26987082;20083827;17169712;10783406;24359283;24261474;26720857;16236466;27936038;27764078;22829925;26809459;25587948;16864474;29185815",
"title": "Comparative Rates of Mortality and Serious Adverse Effects Among Commonly Prescribed Opioid Analgesics.",
"title_normalized": "comparative rates of mortality and serious adverse effects among commonly prescribed opioid analgesics"
} | [
{
"companynumb": "US-JNJFOC-20180802129",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TRAMADOL HYDROCHLORIDE"
},
"drugadditional": "3",... |
{
"abstract": "Bone disease remains a major cause of morbidity after renal transplantation. Post-transplant osseous complications include osteoporosis and osteonecrosis, both historically associated with glucocorticoids, and a newer syndrome of bone pain associated with calcineurin inhibitors. Calcineurin inhibitor-induced pain syndrome (CIPS) is a reversible etiology of lower extremity bone pain and bone marrow edema reported in patients receiving cyclosporine or tacrolimus after solid organ or bone marrow transplantation. While the syndrome's pathophysiology is unclear, bone insufficiency and epiphyseal impaction may play a role. We review the literature on this increasingly important post-transplant entity and describe a case illustrating the syndrome's key features.",
"affiliations": "Departments of Neurology and Psychiatry, New York University School of Medicine, New York, NY.;Division of Hypertension and Renal Disease, Department of Medicine, Alpert Medical School of Brown University, Providence, RI, USA.;Division of Musculoskeletal Radiology, Department of Diagnostic Imaging, Alpert Medical School of Brown University, Providence, RI, USA.",
"authors": "Gurin|Lindsey|L|;Gohh|Reginald|R|;Evangelista|Peter|P|",
"chemical_list": null,
"country": "England",
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"doi": "10.1093/ndtplus/sfr156",
"fulltext": "\n==== Front\nClin Kidney JClin Kidney JndtplusckjClinical Kidney Journal2048-85052048-8513Oxford University Press 10.1093/ndtplus/sfr156Original Contributionsin-Depth ReviewsPain syndrome with stress fractures in transplanted patients treated with calcineurin inhibitors Gurin Lindsey 1Gohh Reginald 2Evangelista Peter 31 Departments of Neurology and Psychiatry, New York University School of Medicine, New York, NY2 Division of Hypertension and Renal Disease, Department of Medicine, Alpert Medical School of Brown University, Providence, RI, USA3 Division of Musculoskeletal Radiology, Department of Diagnostic Imaging, Alpert Medical School of Brown University, Providence, RI, USACorrespondence and offprint requests to: Lindsey Gurin; E-mail: lindsey.gurin@nyumc.org2 2012 28 1 2012 28 1 2012 5 1 13 16 04 7 2011 13 10 2011 © The Author 2012. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com2012This 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 non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.comBone disease remains a major cause of morbidity after renal transplantation. Post-transplant osseous complications include osteoporosis and osteonecrosis, both historically associated with glucocorticoids, and a newer syndrome of bone pain associated with calcineurin inhibitors. Calcineurin inhibitor-induced pain syndrome (CIPS) is a reversible etiology of lower extremity bone pain and bone marrow edema reported in patients receiving cyclosporine or tacrolimus after solid organ or bone marrow transplantation. While the syndrome’s pathophysiology is unclear, bone insufficiency and epiphyseal impaction may play a role. We review the literature on this increasingly important post-transplant entity and describe a case illustrating the syndrome’s key features.\n\nbone paincalcineurin inhibitor-induced pain syndromerenal transplantationtacrolimus\n==== Body\nIntroduction\nBone disease, a frequent complication of all solid organ and bone marrow transplants, is of particular concern in renal transplant recipients due to the high prevalence of pre-transplant renal osteodystrophy and the difficulty of predicting this disease’s course in the face of restored renal function and aggressive immunosuppressive therapy. Osteoporosis and osteonecrosis have long been the two major contributors to post-transplant bone complications and are thought to be due in large part to glucocorticoid therapy [1–4]. With the advent of newer immunosuppressive regimens offsetting decreased steroid doses with calcineurin inhibitors (CNIs), calcineurin inhibitor-induced pain syndrome (CIPS) has emerged as a third distinct etiology of post-transplant bone disease [1].\n\nThought to affect between 1 and 5% of solid organ and bone marrow transplant recipients, CIPS is characterized by severe symmetric lower extremity pain in the setting of cyclosporine A or tacrolimus therapy [1, 5, 6]. It generally has a sudden onset in the first 3 weeks to 14 months after transplant and resolves after a period of 3–18 months [1]. Pain is worse with walking and standing and is lessened with rest and elevation of the legs. Magnetic resonance (MR) imaging demonstrates bone marrow edema.\n\nThe pathophysiology of CIPS is not clear, but there is increasing support in the literature for a model in which a CNI-driven disturbance of bone metabolism contributes to epiphyseal impaction and stress fracture with subsequent marrow edema and pain [7–9]. Cyclosporine has for years been believed to affect bone metabolism; a similar linkage between tacrolimus and bone metabolism is suspected but less well documented [10]. We report a case of tacrolimus-related CIPS presenting with bilateral calcaneal stress fractures in a renal transplant recipient, adding to the body of literature supporting CIPS as a disease of bone insufficiency that can be linked to CNIs as a class.\n\nCase report\nThe patient is a 59-year-old woman with a history of end-stage renal disease of unclear etiology who underwent a second living donor kidney transplant on 7 December 2009. Approximately 6 weeks after transplantation, the patient complained of bilateral ankle and knee pain that had progressively worsened over the course of 2 weeks. She also reported lower extremity weakness that impaired her ability to climb stairs. Clinical examination revealed local tenderness over the lateral malleolus of the left ankle, the lateral aspect of the right knee and the medial aspect of the left knee with no associated erythema or swelling. The patient’s immunosuppressive therapy included tacrolimus 1 mg twice daily, prednisone 10 mg daily and mycophenolic acid 720 mg twice daily, with a tacrolimus level of 5.6 ng/mL.\n\nThe etiology of the patient’s joint pain was unclear and was managed conservatively. Her lower extremity weakness was suspected to be prednisone-related, and prednisone was decreased to 5 mg daily. Her tacrolimus dose was raised to 2 mg twice daily, with a goal of maintaining serum levels of 7–8 ng/mL.\n\nThe patient returned 1 week later complaining of a severe increase in her bilateral foot pain that occurred following the increase in her tacrolimus dose. She also reported increasing difficulty walking and presented to clinic in tears due to pain. Clinical exam showed tenderness to palpation of the right heel and the lateral aspect of the right knee and minimal tenderness of the left heel. There was no erythema or swelling. Her tacrolimus level at this time was 4.0 ng/mL; her labs were otherwise remarkable for hematuria and for elevated calcium and parathyroid hormone levels of 2.8 mmol/L (11.2 mg/dL) and 833 ng/L (833 pg/mL), respectively.\n\nThe patient’s lower limb pain was suspected to be due to tacrolimus and the decision was made to convert to sirolimus.\n\nMR imaging of the patient’s ankles 2 weeks later revealed bilateral calcaneal incomplete stress fractures, in addition to patchy areas of bone marrow edema in the medial talar head and posterolateral tibia (Figure 1A–C). MR imaging of the patient’s knees also revealed patchy areas of marrow edema involving the bilateral distal femoral and proximal tibial metaphyseal regions (Figure 1D and E). These findings, in the setting of tacrolimus therapy, were consistent with a diagnosis of CIPS.\n\nFig. 1. A 59-year-old woman post-renal transplant with bilateral knee and ankle pain. Sagittal T1 (A) and sagittal STIR (B) of the left ankle, sagittal STIR of the right ankle (C), coronal T1 (D) and STIR (E) of the bilateral knees demonstrates patchy marrow edema in the bilateral calcanei, talus, distal femora and proximal/distal tibia. In addition, an incomplete left calcaneal stress fracture is demonstrated (arrow in A, B). A normal MR imaging of the knee (F) is shown for comparison.\n\nThe patient showed that initial clinical improvement after tacrolimus was discontinued and sirolimus initiated for immunosuppression. Unfortunately, she suffered a massive intracerebral hemorrhage several weeks later while receiving warfarin therapy for a history of hypercoagulablility and passed away soon thereafter. No further imaging was obtained.\n\nDiscussion\nCyclosporine as a possible etiology of post-transplant bone pain distinct from osteoporosis and osteonecrosis was first described in 1989 [11]. Cases of distal limb pain in organ transplant recipients treated with cyclosporine were reported throughout the 1990s [9, 12, 13], and the first case linked to tacrolimus was reported in 1999 [6, 14–18]. The syndrome has since been documented in patients receiving cyclosporine or tacrolimus for bone marrow and stem cell transplants, in addition to solid organ recipients [5, 19–21]. Several cases have also been reported in patients receiving CNI therapy for reasons other than allograft transplantation including psoriatic arthritis [22], Crohn’s disease [23] and ulcerative colitis [24].\n\nThe syndrome is so named for its apparent association with cyclosporine and tacrolimus, but not with azathioprine or mycophenolate [8]. CNI trough levels may be high or normal, and pain was correlated to elevated trough levels in some studies [8, 14] but not in others [10, 25]. Most patients experience symptomatic improvement with reduction of CNI levels [6]. Some authors have reported success alleviating CIPS pain with dihydropyridine calcium channel blockers [3, 8], though other studies have failed to confirm this effect [10].\n\nThe classic radiologic signs of CIPS include patchy osteoporosis on radiographs (though they are often normal); patchy bone marrow edema on MR imaging and increased uptake on radionuclide bone scintigraphy, particularly involving the knees, ankles and feet [3, 6, 8]. While the pathophysiology of CIPS is not yet entirely known, some authors have posited bone insufficiency and impaction of epiphyseal cortical bone as an etiology of these reversible radiologic findings [7, 9]. In this model, high bone turnover induced by CNI therapy leads to impaction or fracture with accompanying marrow edema [16].\n\nThe issue of whether or not CNIs truly play a significant role in bone remodeling is somewhat controversial, though it is generally accepted that cyclosporine does have some direct effect on bone metabolism [10]. Gain- and loss-of-function experiments in gene-modified mice and rats suggest a critical role for calcineurin in osteoblast and osteoclast formation [26]. Early studies showed an association between elevated blood alkaline phosphatase levels and cyclosporine-based, but not azathioprine-based, immunosuppressive regimens, and a more recent study demonstrated a correlation between elevated alkaline phosphatase and likelihood of developing CIPS [25]. These data are supported by animal models demonstrating a link between CNIs and high-turnover bone disease. Other studies, however, have not shown a link between CNIs and increased bone turnover, and the relationship remains to be further defined [25].\n\nA second proposed hypothesis implicates CNIs in a disturbance of the vascular supply to bones, with changes in perfusion and permeability leading to marrow edema [8, 27]. In this explanation, lower limbs and feet are preferentially affected due to the increased venous pressure resulting from standing upright; elevation of the legs relieves this pressure and subsequently lessens pain [8].\n\nWhile some of the radiologic features of CIPS are also shared by osteonecrosis and reflex sympathetic dystrophy syndrome (RSDS), these latter post-transplant bone pain syndromes differ significantly in clinical course. Osteonecrosis pain is permanent, weight-dependent and usually localized to the hips; CIPS, on the other hand, is typically reversible and preferentially affects feet and knees [8]. RSDS is distinguished clinically from CIPS by its asymmetric pain distribution, its upper limb predominance and its characteristic association with extremity edema, vasomotor instability and trophic skin changes [6, 8].\n\nOur patient’s clinical presentation of lower extremity pain that worsened after increase of her tacrolimus dose and that was accompanied by bone marrow edema on MR imaging, strongly suggests CIPS. Her bilateral calcaneal insufficiency-type stress fractures further suggest a derangement of bone metabolism.\n\nTreatment for CIPS currently involves reducing CNI doses, even when trough levels are within the normal range [6]. Exchanging cyclosporine for tacrolimus (or vice versa) was not effective in one study [25]. Dihydropyridine calcium channel blockers have alleviated symptoms in some patients [8]. Many patients report improved symptoms at rest and with elevation of the legs, and some authors have advocated strict avoidance of physical strain as a way to avoid trauma and subsequent impaction or insufficiency fracture of fragile bone [10]; our experience corroborates this.\n\nConclusions\nThere are numerous contributors to abnormal bone metabolism in end-stage renal disease and transplant, and kidney recipients are more prone than recipients of other solid organ transplants to fractures of the appendicular skeleton and feet [28]. CIPS, however, represents a potentially reversible etiology of lower extremity bone disease in transplant recipients and as such deserves greater recognition. Our patient’s experience provides further support for CIPS as a distinct post-transplant bone disease entity that may be induced by either cyclosporine or tacrolimus.\n\n\nConflict of interest statement. None declared.\n==== Refs\n1. Grotz W Breitenfeldt K Cybulla M Immunosuppression and skeletal disorders Transplantat Proc 2001 33 992 993 \n2. Morales E Gutierrez E Andres A Treatment with calcimimetics in kidney transplantation Transplant Rev 2010 24 79 88 \n3. Elder GJ From marrow oedema to osteonecrosis: common paths in the development of post-transplant bone pain Nephrology 2006 11 560 567 17199798 \n4. Casez JP Lippuner K Horber FF Changes in bone mineral density over 18 months following kidney transplantation: the respective roles of prednisone and parathyroid hormone Nephrol Dial Transplant 2002 17 1318 1326 12105258 \n5. Nishikawa T Okamoto Y Tanabe T Calcineurin-inhibitor-induced pain syndrome after a second allogeneic bone marrow transplantation for a child with aplastic anemia Pediatr Transplant 2009 13 641 644 18785910 \n6. Collini A De Bartolomeis C Barni R Calcineurin-inhibitor induced pain syndrome after organ transplantation Kidney Int 2006 70 1367 1370 16955101 \n7. VandeBerg BC Malghem J Goffin EJ Transient epiphyseal lesions in renal transplant recipients: presumed insufficiency stress fractures Radiology 1994 191 403 407 8153313 \n8. Grotz WH Breitenfeldt MK Braune SW Calcineurin-inhibitor induced pain syndrome (CIPS): a severe disabling complication after organ transplantation Transpl Int 2001 14 16 23 11263551 \n9. Goffin E vande Berg B Pirson Y Epiphyseal impaction as a cause of severe osteoarticular pain of lower limbs after renal transplant Kidney Int 1993 44 98 106 8355472 \n10. Hetzel G Malms J May P Post-transplant distal-limb bone-marrow oedema: MR imaging and therapeutic considerations Nephrol Dial Transplant 2000 15 1859 1864 11071978 \n11. Bouteiller G Lloveras J Condouret J Painful polyarticular syndrome probably induced by cyclosporin in three patients with a kidney transplant and one with a heart transplant Rev Rhum Mal Osteoartic 1989 56 753 755 2609088 \n12. Naredo Sánchez E Balsa Criado A Sanz Guajardo A Leg bone pain syndrome due to cyclosporine in a renal transplant patient Clin Exp Rheumatol 1994 12 653 656 7895401 \n13. Jagose J Bailey R Hughes T Acute bone-marrow oedema in cyclosporin-treated renal transplant recipients QJM 1997 90 359 366 9205672 \n14. Villaverde V Cantalejo M Balsa A Leg bone pain syndrome in a kidney transplant patient treated with tacrolimus (FK506) Ann Rheum Dis 1999 58 653 654 10577370 \n15. Malat G Dupuis R Kassman B Tacrolimus-induced pain syndrome in a pediatric orthotopic liver transplant patient Pediatr Transplant 2002 6 435 438 12390434 \n16. Franco M Blaimont A Albano L Tacrolimus pain syndrome in renal transplant patients: report of two cases Joint Bone Spine 2003 71 157 159 15050204 \n17. Goffin E vande Berg B Devogelaer J Post-renal transplant syndrome of transient lower limb joint pain: description under a tacrolimus-based immunosuppression Clin Nephrol 2003 59 98 105 12608552 \n18. Puig I Marí JM Martinez-Miralles E Perich X Reflex sympathetic dystrophy syndrome of the lower limbs in a renal transplant patient treated with tacrolimus Tranplantation 2000 70 210 211 \n19. Kida A Ohashi K Kobayashii T Incapacitating lower limb pain syndrome in cord blood stem cell transplant recipients with calcineurin inhibitor Pathol Oncol Res 2004 10 204 206 15619640 \n20. Noda Y Kodama K Yasuda T Calcineurin-inhibitor-induced pain syndrome after bone marrow transplantation J Anesth 2008 22 61 63 18306017 \n21. Lavoratore S Navarro O Grunebaum E Cyclosporine-induced pain syndrome in a child undergoing hematopoietic stem cell transplant Ann Pharmacother 2009 43 767 771 19318596 \n22. Lawson C Fraser A Veale D Cyclosporin treatment in psoriatic arthritis: a cause of severe leg pain Ann Rheum Dis 2003 62 489 12695169 \n23. Isaacs K Severe bone pain as an adverse effect of cyclosporin therapy for Crohn's disease Inflamm Bowel Dis 1998 4 95 97 9589296 \n24. Rahman A O'Brien C Patchett S Leg bone pain syndrome in a patient with ulcerative colitis treated with cyclosporin Ir J Med Sci 2007 176 129 131 17431732 \n25. Tillmann F Jäger M Blondin D Post-transplant distal limb syndrome: clinical diagnosis and long-term outcome in 37 renal transplant recipients Transpl Int 2008 21 547 553 18373640 \n26. Tamler R Epstein S Nonsteroid immune modulators and bone disease Ann N Y Acad Sci 2006 1068 284 296 16831929 \n27. Breitenstein A Stumpe K Gnannt R Calcineurin inhibitor-induced pain syndrome after kidney transplantation—a rare but disabling condition NDT Plus 2010 4 63 66 25984107 \n28. Bia M Evaluation and management of bone disease and fractures post transplant Transplant Rev 2008 22 52 61\n\n",
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"abstract": "Ictal asystole (IA) is uncommonly diagnosed and has been implicated as a potential cause of sudden unexpected death in epilepsy. Sudden unexpected death in epilepsy is an increasingly recognizable condition and is more likely to occur in patients with medically intractable epilepsy and those suffering from convulsive epilepsy. We report 2 cases of recent onset of prolonged syncope and unrevealing cardiac work up. The inpatient video-EEG monitoring recorded left temporal ictal discharges followed by IA. Although the role of cardiac pacing is controversial in these patients, both patients had favorable outcome following cardiac pacemaker insertion. This report demonstrates the variability in IA pathophysiology and clinical manifestations. It also advocates that cardiac pacing might have a role in the management of IA.",
"affiliations": "Department of Neurology, University of Arkansas for Medical Sciences, 4301 West Markham St., Slot 500, Little Rock, Arkansas 72205, United States of America. Fax. +1 (501) 6868689. E-mail: shihabuddinbashirs@uams.edu.",
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"fulltext": "\n==== Front\nNeurosciences (Riyadh)\nNeurosciences\nnsj\nnsj\nNeurosciences\nNeurosciences\n1319-6138\n1319-6138\nRiyadh : Armed Forces Hospital\n\n25274593\nNeurosciences-19-317\nCase Report\nIctal asystole in epilepsy patients undergoing inpatient video-EEG monitoring\nShihabuddin Bashir S. MD\nHerlopian Aline S. MD\nGreenfield L. John Jr MD, PhD\nFrom the Department of Neurology, University of Arkansas for Medical Sciences, Arkansas, United States of America\nAddress correspondence and re-print request to: Dr. Bashir S. Shihabuddin, Department of Neurology, University of Arkansas for Medical Sciences, 4301 West Markham St., Slot 500, Little Rock, Arkansas 72205, United States of America. Fax. +1 (501) 6868689. E-mail: shihabuddinbashirs@uams.edu\n10 2014\n19 4 317321\n17 4 2014\n08 7 2014\nCopyright: © Neurosciences\n2014\nhttps://creativecommons.org/licenses/by/3.0/ Neurosciences is an Open Access journal and articles published are distributed under the terms of the Creative Commons Attribution-NonCommercial License (CC BY-NC). Readers may copy, distribute, and display the work for non-commercial purposes with the proper citation of the original work.\nThe value of seizure semiology in lateralizing and localizing partially originating seizuresSemiology of temporal lobe epilepsiesInterictal and ictal electroencephalogram features of temporal lobe epilepsyIctal asystole (IA) is uncommonly diagnosed and has been implicated as a potential cause of sudden unexpected death in epilepsy. Sudden unexpected death in epilepsy is an increasingly recognizable condition and is more likely to occur in patients with medically intractable epilepsy and those suffering from convulsive epilepsy. We report 2 cases of recent onset of prolonged syncope and unrevealing cardiac work up. The inpatient video-EEG monitoring recorded left temporal ictal discharges followed by IA. Although the role of cardiac pacing is controversial in these patients, both patients had favorable outcome following cardiac pacemaker insertion. This report demonstrates the variability in IA pathophysiology and clinical manifestations. It also advocates that cardiac pacing might have a role in the management of IA.\n==== Body\nIctal asystole (IA) is an uncommon event that occurs in 0.1-0.4% of patients experiencing seizures during inpatient video-electroencephalography monitoring (VEEG).1 Ictal asystole is more likely to occur in patients with focal seizures originating from the temporal region.2 It has been implicated as a potential cause for sudden unexpected death in epilepsy patients (SUDEP) that carry an incidence of 0.09-9.3 per 1000 patient-years.1 Although controversial, cardiac pacing has been suggested as a possible preventive measure against IA and SUDEP.3 We report 2 cases of IA encountered at our epilepsy monitoring unit between June 2010 and October 2011, and their clinical outcomes after cardiac pacemaker insertions. These 2 cases highlight the importance in considering IA as a potentially fatal complication of epileptic seizures that might be circumvented by good seizure control, and in some cases cardiac pacing.\n\nCase Report\n\nPatient one\n\nA 65-year-old woman presented with a history of convulsive seizures 20 years earlier that were fully controlled by phenytoin. One year prior to presentation she started experiencing recurrent syncope with lightheadedness rapidly progressing to loss of awareness and collapse. Afterwards, she was unresponsive and completely flaccid for approximately one minute. An extensive cardiac workup including tilt table test, Holter monitor, carotid Doppler’s and echocardiography were unrevealing. An MRI of the brain with and without contrast showed age related mild global cerebral atrophy. Phenytoin was changed to levetiracetam due to the concern that the syncope events might be related to epileptic seizures and she was referred for inpatient VEEG. Levetiracetam was discontinued during VEEG and 2 syncopal events were recorded. Both were associated with left mid temporal ictal discharges that were initially associated with bradycardia and progressed to asystole within 5 and 9 seconds after the ictal onset and lasted 22 and 29 seconds (Figures 1A & 1B). During the cardiac asystole she was unresponsive and the EEG showed a severe voltage attenuation followed by diffuse delta activity, which transitioned to faster frequencies as the cardiac rhythm recovered and she regained consciousness. In addition, the prolonged EEG recorded a localized subclinical ictal discharge of left mid temporal onset that was not associated with any ECG abnormalities (Figure 1C). The following day she underwent a cardiac pacemaker insertion. She was discharged on levetiracetam. Twenty-one months later she remained free of syncopal events, but reported rare and brief sensations of lightheadedness lasting for few seconds.\n\nFigure 1 Ictal asystole and subclinical ictal discharge in patient one showing: A) Subtle left mid temporal ictal discharge onset (up arrows) followed by bradycardia and ictal asystole (down arrow). B) Termination of ictal asystole (arrow) followed by recovery of EEG activity. C) A subclinical ictal discharge of left mid temporal onset (arrows).\n\nPatient two\n\nA 64-year-old woman presented with a 3-year history of syncopal episodes occurring every 1-2 months. The clinical events were stereotypical. She would collapse to the ground without any warning and be flaccid and unresponsive for up to 20 minutes. She underwent an unrevealing cardiac work up, and an MRI of the brain showed mild cerebral atrophy. She was initially placed on levetiracetam for presumed seizures. Valproic acid was added when syncope recurred, and she was referred for inpatient VEEG. After both levetiracetam and valproic acid were discontinued. an ictal discharge was recorded from the left mid temporal area during sleep. Twelve seconds after the ictal onset she developed sinus bradycardia and 28 seconds later cardiac asystole occurred lasting for 9 seconds (Figure 2). The EEG during that period showed diffuse slowing and voltage attenuation. As the cardiac rhythm recovered, the EEG activity normalized. Following a Persantine nuclear imaging test and cardiac catheterization, cardiology opted against cardiac pacing and recommended good seizure control as a means to prevent cardiac arrhythmia. She was discharged on levetiracetam and valproic acid. However, 4 months later she experienced another prolonged syncope and a cardiac pacemaker was inserted. Four months following the procedure she had not experienced any further events suggestive of seizures or syncope.\n\nFigure 2 Ictal asystole in patient 2 showing: A) Left mid temporal ictal discharge onset (up arrow) followed by bradycardia and ictal asystole (down arrow). B) Ictal asystole (arrows) associated with EEG voltage attenuation. C) Termination of ictal asystole followed by recovery of the EEG activity (arrow).\n\nDiscussion\n\nAlong with postictal cerebral suppression and respiratory compromise IA is implicated as a potential cause of SUDEP.1 It is very likely that all 3 causes are contributory during a seizure culminating in SUDEP. The Mortality in Epilepsy Monitoring Units Study (MORTEMUS)4 reported 16 SUDEP cases during inpatient VEEG. Fourteen of these deaths occurred at night. In all cases, SUDEP was triggered by a generalized tonic-clonic seizure followed by EEG suppression then central apnea and eventually severe bradycardia and asystole.4 Scheule et al5 proposed that IA is a self-limiting phenomenon as it results in cerebral hypoxia/anoxia, which hastens seizure termination while SUDEP is a consequence of complete cardiopulmonary arrest due to post-ictal suppression of cerebral activity. Moreover, SUDEP occurs primarily in patients with a long history of intractable symptomatic generalized epilepsy.1\n\nOur 2 patients were of interest as both did not suffer from intractable epilepsy and both had focal seizures without secondary generalization. One patient had well controlled epilepsy for over 20 years before she started having focal seizures manifesting with ictal bradycardia and syncope. The other had a recent onset of focal seizures associated with ictal bradycardia and asystole. In both, the bradycardia and subsequent asystole was preceded by a left temporal focal ictal discharge. The insular cortex is essential in cardiovascular autonomic control. Seizure-induced activity in these autonomic centers may lead to excessive vagal tone and suppression of sympathetic tone resulting in ictal bradycardia and subsequent asystole.1 Although temporal lobe epilepsy is more frequently associated with ictal bradycardia and IA,2 there has been limited association between focal seizures and SUDEP. The authors could not find a documented case of SUDEP related exclusively to IA. In the MORTEMUS, all the 16 SUDEP cases and 7 out of the 9 near SUDEP cases had generalized tonic-clonic seizures.4 Both of our patients had left mid temporal ictal discharge onset that did not progress to generalization. This suggests a completely different physiological mechanism leading to IA in patients who experience generalized tonic-clonic seizures and those with IA starting shortly after a focal ictal onset. The poor understanding of this phenomenon translates into uncertainty regarding the management of IA. Is it better to implant a cardiac pacemaker or to optimize seizure control using anti-epileptic drugs (AEDs)? This question remains a topic of debate. The inability of AEDs to guarantee perfect control of seizures and the potential physical injury and potentially fatal outcome associated with prolonged asystole, argue for the use of an internal cardiac pacemaker. One of our patients had 21 months follow up post-pacemaker insertion, and she was free of any syncope events. Our second patient did not experience any syncope events following the cardiac pacemaker insertion, although had only 4 months of follow up. Similarly, Mosely et al3 reported a decrease in the number of falls following pacemaker insertion in patients with IA. A similar observation was also recently reported by Duplyakov et al.6 These data suggests that cardiac pacemaker insertion might reduce the risk of physical injury and possibly death in patients with IA. Another issue illustrated by these 2 cases is their atypical presentation for seizures. Both patients had events of collapse followed by flaccid unresponsiveness. They did not present with the typical clinical manifestations of temporal lobe epilepsy, and thus distinction between epilepsy and syncope was not feasible based on clinical semiology. This emphasizes the importance of VEEG in making an accurate diagnosis in patients with unexplained episodes of unresponsiveness and decreased muscle tone. It also suggests that ictal bradycardia or asystole should be considered if a patient is experiencing epileptic seizures accompanied by unresponsiveness and decreased muscle tone. This report and previous reports of IA and SUDEP during VEEG underscore the need for the continued presence of well-trained VEEG technicians in epilepsy monitoring units. If continuous visual monitoring is not possible, adjunctive use of cardiac telemetry maybe appropriate to ensure immediate detection of such arrhythmias. An additional safety measure during these studies is the possible use of dedicated respiratory monitoring equipment. Using all these safety measures in combination will ensure the immediate attention of the medical staff to such life threatening occurrences.\n\nIn conclusion, IA is an under recognized entity in patients with epilepsy. It should be included in the differential diagnosis of unexplained syncope, and should be suspected in epilepsy patients experiencing ictal bradycardia or flaccid unresponsiveness. Although IA is not uniformly fatal, cardiac pacemaker insertion in addition to AEDs, might diminish the severity of the clinical manifestation of seizures in certain patients with epilepsy and in some patients might safeguard against SUDEP.\n==== Refs\n1 Devinsky O Sudden, unexpected death in epilepsy N Engl J Med 2011 365 1801 1811 22070477\n2 Lanz M Oehl B Brandt A Schulze-Bonhage A Seizure induced cardiac asystole in epilepsy patients undergoing long term video-EEG monitoring Seizure 2011 20 167 172 21183363\n3 Moseley BD Ghearing GR Munger TM Britton JW The treatment of ictal asystole with cardiac pacing Epilepsia 2011 52 e16 e19 21463267\n4 Ryvlin P Nashef L Lhatoo SD Bateman LM Bird J Bleasel A Incidence and mechanisms of cardiorespiratory arrests in epilepsy monitoring units (MORTEMUS): a retrospective study Lancet Neurol 2013 12 966 977 24012372\n5 Schuele SU Bermeo AC Alexopoulos AV Burgess RC Anoxia-ischemia: A mechanism of seizure termination in ictal asystole Epilepsia 2010 51 170 173 19490047\n6 Duplyakov D Golovina G Lyukshina N Surkova E Elger CE Surges R Syncope, seizure-induced bradycardia and asystole: Two cases and review of clinical and pathophysiological features Seizure 2014 23 506 511 24680552\n\n",
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"mesh_terms": "D000368:Aged; D000927:Anticonvulsants; D001919:Bradycardia; D004569:Electroencephalography; D004833:Epilepsy, Temporal Lobe; D005260:Female; D006323:Heart Arrest; D006801:Humans; D007297:Inpatients; D000077287:Levetiracetam; D008875:Middle Aged; D008991:Monitoring, Physiologic; D010138:Pacemaker, Artificial; D010672:Phenytoin; D010889:Piracetam; D013575:Syncope; D014741:Video Recording",
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"title": "Ictal asystole in epilepsy patients undergoing inpatient video-EEG monitoring.",
"title_normalized": "ictal asystole in epilepsy patients undergoing inpatient video eeg monitoring"
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"abstract": "<p>Extravasation of medications can manifest as tenderness, pain, tissue necrosis, and thrombophlebitis and lead to infection and severe long-term complications. Risk factors for leakage of medications include mechanical and pharmacologic mechanisms such as cannulation technique, vasoconstriction, and cytotoxicity. Well-known vesicants like anthracyclines, vinca alkaloids, and vasopressors are usually administered with proper caution. Often overlooked are many antimicrobial agents, which typically act via differences in osmolality and pH. Vancomycin harms the vascular wall by the latter (pH 2.5-4.5). Although similar in appearance to vancomycin hypersensitivity reactions (eg, linear immunoglobulin A bullous dermatosis), we present a patient whose dermatitis and subsequent cellulitis likely originated due to extravasation of the drug from the peripheral intravenous catheter. The visible dermatitis mimicked bullous cellulitis from toxin-producing Staphylococcus aureus, Group A Streptococcus, and gram-negative rods or anaerobes in the setting of neutropenia. Our case illustrates the importance of getting an appropriate history and recognizing non-infectious causes of rashes that mimic chronic infections.</p> <p><em<J Drugs Dermatol. 2017;16(11):1160-1163.</em></p>.",
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"authors": "Nanjappa|Sowmya|S|;Snyder|Matthew|M|;Greene|John N|JN|",
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"journal": "Journal of drugs in dermatology : JDD",
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"mesh_terms": "D000368:Aged; D000900:Anti-Bacterial Agents; D002481:Cellulitis; D003872:Dermatitis; D003937:Diagnosis, Differential; D005119:Extravasation of Diagnostic and Therapeutic Materials; D006801:Humans; D008297:Male; D011014:Pneumonia; D014640:Vancomycin",
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"title": "Vancomycin Infiltrate-Induced Dermatitis Mimicking Bullous Cellulitis.",
"title_normalized": "vancomycin infiltrate induced dermatitis mimicking bullous cellulitis"
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"abstract": "OBJECTIVE\nWe evaluated the efficacy of a 12-week oral treatment with azithromycin in adult patients with bronchiectasis. The objectives were to demonstrate that this treatment reduces sputum volume, improves quality of life and to assess the lengths of effects after cessation of therapy.\n\n\nMETHODS\nSeventy-eight patients with bronchiectasis confirmed by high-resolution computed tomography were included in this study. Subjects received oral azithromycin or placebo in a randomized manner for 12 weeks followed by placebo for another 12 weeks. Sputum volume, St George's Respiratory Questionnaire (SGRQ) score and spirometry were recorded at baseline, 12 weeks and 24 weeks, respectively. End-point measurements were compared from baseline to the end of each study phase.\n\n\nRESULTS\nSixty-eight subjects were included in the analysis. Mean 24-h sputum volume significantly decreased (P < 0.01) during the active treatment phase and remained low during the control phase (P < 0.01). The mean SGRQ total score with azithromycin decreased (i.e. improved health status) from baseline by more than the 4 points at the end of 12 and 24 weeks. Lung functions remained stable during oral azithromycin therapy and the subsequent control phase.\n\n\nCONCLUSIONS\nTwelve weeks administration of azithromycin in bronchiectasis produces significant reductions in mean sputum volume, health status and stabilization of lung function values. Sputum volume reduction and the improvement of quality of life were sustained for 12 weeks after cessation of azithromycin. (Clinicaltrials.gov number NCT02107274).",
"affiliations": "Respiratory Unit, Hospital Taiping, Taiping, Perak, Malaysia.",
"authors": "Lourdesamy Anthony|Albert I|AI|;Muthukumaru|Umadevi|U|",
"chemical_list": "D000900:Anti-Bacterial Agents; D017963:Azithromycin",
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"keywords": "azithromycin; bronchiectasis; inflammation; macrolide; pulmonary",
"medline_ta": "Respirology",
"mesh_terms": "D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000900:Anti-Bacterial Agents; D017963:Azithromycin; D001987:Bronchiectasis; D016903:Drug Monitoring; D005260:Female; D006304:Health Status; D006801:Humans; D007249:Inflammation; D008168:Lung; D008297:Male; D008875:Middle Aged; D011788:Quality of Life; D012129:Respiratory Function Tests; D013183:Sputum; D016896:Treatment Outcome",
"nlm_unique_id": "9616368",
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"references": null,
"title": "Efficacy of azithromycin in the treatment of bronchiectasis.",
"title_normalized": "efficacy of azithromycin in the treatment of bronchiectasis"
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"abstract": "Mycophenolate mofetil (MM), an immunosuppressant used after organ transplantation, is also used for treatment of autoimmune myasthenia gravis (MG). A patient with generalized MG was effectively managed with MM but developed CNS lymphoma after 3 years of treatment. Primary CNS lymphoma regressed on withdrawal of MM. Despite minimal short-term side effects and apparent efficacy, chronic treatment of MG with MM may be associated with increased risk of lymphoproliferative disorders.",
"affiliations": "Department of Neurology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9036, USA. steven.vernino@utsouthwestern.edu",
"authors": "Vernino|Steven|S|;Salomao|Diva R|DR|;Habermann|Thomas M|TM|;O'Neill|Brian P|BP|",
"chemical_list": "D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents; D007166:Immunosuppressive Agents; D000069283:Rituximab; D009173:Mycophenolic Acid; D011729:Pyridostigmine Bromide; D011241:Prednisone",
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"mesh_terms": "D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents; D001932:Brain Neoplasms; D002471:Cell Transformation, Neoplastic; D004359:Drug Therapy, Combination; D005260:Female; D005625:Frontal Lobe; D006801:Humans; D007111:Immunity, Cellular; D007166:Immunosuppressive Agents; D016393:Lymphoma, B-Cell; D008279:Magnetic Resonance Imaging; D009157:Myasthenia Gravis; D009173:Mycophenolic Acid; D010296:Parietal Lobe; D011241:Prednisone; D011729:Pyridostigmine Bromide; D000069283:Rituximab; D013601:T-Lymphocytes; D016896:Treatment Outcome",
"nlm_unique_id": "0401060",
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"publication_types": "D002363:Case Reports; D016428:Journal Article",
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"title": "Primary CNS lymphoma complicating treatment of myasthenia gravis with mycophenolate mofetil.",
"title_normalized": "primary cns lymphoma complicating treatment of myasthenia gravis with mycophenolate mofetil"
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"abstract": "Thrombotic thrombocytopenic purpura (TTP) is a rare hematologic disorder characterized by thrombotic microangiopathy. Neurologic symptoms are frequently seen in its presentation and the most common finding on neuroimaging of TTP is posterior reversible encephalopathy syndrome (PRES). Acute strokes, hemorrhages and atypical PRES are uncommonly seen. Our case reports the clinical and imaging details of a young male patient with TTP and Sjogren's syndrome, who made a complete recovery after aggressive plasmapheresis and immunosuppressive therapy with resolution of the imaging findings of PRES on follow up brain MR imaging. We briefly review the literature for the spectrum of imaging findings that can be seen on brain MRI with TTP.",
"affiliations": "Department of Radiology, Yale New Haven Health System, Bridgeport Hospital, Bridgeport, CT.;Department of Radiology, Yale New Haven Health System, Bridgeport Hospital, Bridgeport, CT.;Department of Radiology, Yale New Haven Health System, Bridgeport Hospital, Bridgeport, CT.;Department of Radiology, Yale New Haven Health System, Bridgeport Hospital, Bridgeport, CT.;Department of Radiology, University of Minnesota Medical Center, Minneapolis, MIN.;Department of Radiology, Yale New Haven Health System, Bridgeport Hospital, Bridgeport, CT.",
"authors": "Hegde|Rahul|R|;Ismail|Rasha|R|;Vegunta|Aishwariya|A|;Megahed|Ayah|A|;Sharma|Pranav|P|;Rosovsky|Mark|M|",
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"doi": "10.1016/j.radcr.2021.03.035",
"fulltext": "\n==== Front\nRadiol Case Rep\nRadiol Case Rep\nRadiology Case Reports\n1930-0433\nElsevier\n\nS1930-0433(21)00174-6\n10.1016/j.radcr.2021.03.035\nCase Report\nAtypical posterior reversible encephalopathy syndrome in a case of thrombotic thrombocytopenic purpura with Sjogren's syndrome\nHegde Rahul MD FRCR rahul.hegde@yale.edu\na⁎\nIsmail Rasha MD a\nVegunta Aishwariya MD a\nMegahed Ayah MBBCh a\nSharma Pranav MD b\nRosovsky Mark MD a\na Department of Radiology, Yale New Haven Health System, Bridgeport Hospital, Bridgeport, CT\nb Department of Radiology, University of Minnesota Medical Center, Minneapolis, MIN\n⁎ Corresponding author. rahul.hegde@yale.edu\n19 4 2021\n6 2021\n19 4 2021\n16 6 15521556\n24 2 2021\n19 3 2021\n20 3 2021\n© 2021 The Authors. Published by Elsevier Inc. on behalf of University of Washington.\n2021\n\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).\nThrombotic thrombocytopenic purpura (TTP) is a rare hematologic disorder characterized by thrombotic microangiopathy. Neurologic symptoms are frequently seen in its presentation and the most common finding on neuroimaging of TTP is posterior reversible encephalopathy syndrome (PRES). Acute strokes, hemorrhages and atypical PRES are uncommonly seen. Our case reports the clinical and imaging details of a young male patient with TTP and Sjogren's syndrome, who made a complete recovery after aggressive plasmapheresis and immunosuppressive therapy with resolution of the imaging findings of PRES on follow up brain MR imaging. We briefly review the literature for the spectrum of imaging findings that can be seen on brain MRI with TTP.\n\nKeywords\n\nThrombotic thrombocytopenic purpura\nPosterior reversible encephalopathy syndrome\nAtypical PRES\nMicrohemorrhages\nMRI\nSjogren's syndrome\n==== Body\nIntroduction\n\nThrombotic thrombocytopenic purpura (TTP) is a rare hematologic disorder with a classic pentad of thrombocytopenia, hemolytic anemia, neurologic symptoms, fever and renal failure, characterized pathologically by microvascular thrombosis. Abnormally large Von Willebrand factor multimers in the plasma lead to microvascular thrombosis at multiple organ sites, due to deficiency of ADAMTS13, a cleaving protease. Our case highlights findings of atypical posterior reversible encephalopathy syndrome and multiple microhemorrhages on brain MRI (magnetic resonance imaging) with resolution of the signal abnormalities on follow up after plasmapheresis and immunosuppressive therapy.\n\nCase\n\nA 35-year-old male presented to the ED with acute onset confusion and transient tingling in his left arm which resolved by the time he was brought to the ED. A CT (computed tomography), head and CTA (computed tomographic angiography) of the head and neck was performed which was negative with no brain parenchymal or vascular abnormalities seen. The patient was subsequently discharged, only to represent 2 weeks later with fever, headache and altered mental status with waxing and waning of his attention. On neurologic examination, patient was delirious however rest of the exam was non–focal. There was diffuse petechial rash on his extremities. Laboratory evaluation was remarkable for platelets of 7000/mcl, hemoglobin of 10.6 g/dL, a large drop from baseline of 15.6 g/dL, LDH of 817 U/L, haptoglobin <10 mg/dL, concerning for hemolytic anemia and thrombocytopenic thrombotic microangiopathy. Renal function was normal with serum creatinine of 1.0 mg/dL and calculated GFR > 60 mL/min/1.73 m2. Findings were highly concerning for TTP and patient was admitted to the intensive care unit (ICU) with initiation of high dose steroids and plasmapheresis. ADAMTS13 activity assay was performed which was less than 3%, confirming TTP (a value less than 10% activity is considered severely deficient).\n\nA MRI brain study was performed without and with intravenous contrast on a 1.5T scanner on day 1 of the hospital admission. The brain MRI demonstrated multiple patchy areas of T2 and FlAIR (fluid attenuated inversion recovery) hyperintense signal abnormalities in the right perisylvian white matter, right thalamus, left lentiform and right aspect of midbrain (Fig. 1). On SWI (susceptibility weighted imaging) sequence, there were foci of low signal in these regions consistent with microhemorrhages (Fig. 2). No abnormal enhancement was noted on post contrast sequences. Review of his prior CT imaging demonstrated parotid calcifications and cysts (Fig. 3), and the concern for Sjogren's syndrome was brought forth by the radiologist. Differential considerations based on MRI included atypical PRES related to TTP or viral encephalitis. To rule out possibility of encephalitis, CSF (cerebrospinal fluid) analysis with a lumbar puncture was performed. There was no evidence of infection -CSF was clear, cell count of 2 WBCs/dL, Glucose of 67 mg/dL (normal range of 40-70 mg/dL), Protein of 48 mg/dL (normal range of 15-45 mg/dL). CSF culture had no growth and viral PCR and anti–body panel (for West Nile, HSV, VZV and enteroviruses) were negative. Immunologic lab tests were performed and was positive for Sjogren's syndrome with a positive SS-A anti–body test.Fig. 1 Axial FLAIR MRI (A and B) performed on day 10 of admission demonstrates multifocal hyperintense signal abnormalities in the right perisylvian white matter, right thalamus, left lentiform and right midbrain (white arrows). On follow up MRI, performed 4 weeks later, while patient was on plasmapheresis and immunosuppressive therapy, selected axial FLAIR images (C and D) at the same levels show that there was complete resolution of the previously seen abnormal signal.\n\nFig 1 –\n\nFig. 2 SWI images from the initial MRI brain study demonstrate multiple tiny foci of low signal (white arrows) which corresponded to areas of FLAIR signal abnormality seen in Fig. 1, consistent with microhemorrhages.\n\nFig 2 –\n\nFig. 3 Axial T2 image from patient's brain MRI (A) and Axial CT image (B) from a study at time of presentation demonstrate bilateral parotid tiny cysts (black arrows) and foci of calcification (white arrows), for which concern about Sjogren's syndrome was brought forth and subsequently confirmed with a positive serologic SS-A antibody test.\n\nFig 3 –\n\nSubsequently, the patient had a prolonged hospital course of 5 weeks with multiple courses of plasmapheresis and weekly Rituximab therapy for 4 doses with eventual normalization of his platelet levels and resolution of hemolytic anemia. ADAMTS13 activity normalized after this prolonged immunosuppressive therapy. His mental status also gradually improved over the course of the hospitalization and a follow up MRI performed 4 weeks later demonstrated complete resolution of previously seen FLAIR signal abnormalities (Fig. 1 C and D). Patient was finally discharged on oral steroids with plan for steroid taper. On 3 months follow in the outpatient clinic, the patient was now off oral steroids was doing well symptomatically with normal lab work.\n\nDiscussion\n\nTTP is a rare entity which can be potentially lethal if not recognized and treated early underscoring its clinical significance. Deficiency of ADAMTS13 protease is the central etio-pathologic factor [1]. The 2 major types of TTP are- 1. Congenital TTP, which is due to ADAMTS13 deficiency and 2. Immune mediated TTP, which is due to presence of ADAMTS13 autoantibodies. Immune mediated TTP typically occurs in adulthood, median age of onset of fourth decade and more common in females to male with a ratio of 2 to 3:1. Immune mediated TTP can either be primary or idiopathic or secondary to a predisposing condition. Predisposing conditions include autoimmune diseases, malignancy, infection, drugs and pregnancy. Amongst the autoimmune conditions, SLE (systemic lupus erythematosus) is the commonest, although many others autoimmune disorders including Sjogren's syndrome as seen in our case, have been noted in association with TTP [2,3].\n\nClinical evaluation: The diagnosis of TTP is made primarily based on a combination of clinical and laboratory findings. Although, the classic clinical pentad of thrombocytopenia, hemolytic anemia, neurologic symptoms, fever and renal failure has been described for TTP, the diagnosis remains challenging due to variability in clinical features, overlap with other thrombotic microangiopathies and limited availability of the ADAMTS13 test [4]. The diagnosis of TTP is suspected when there are findings of microangiopathic hemolytic anemia and thrombocytopenia which are universally present in all cases of TTP. Neurologic symptoms and renal failure which are due to end organ damage occur variably. Although not gold standard, the ADAMTS13 activity and ADAMTS13 inhibitor assays have been used for confirmation of diagnosis of TTP in clinically suspected cases. Scoring systems incorporating clinical and laboratory findings like the PLASMIC score have been used in prediction of TTP [5].\n\nImaging evaluation: Up to 90% patients of TTP have been found to display neurologic symptoms [6]. Neuroimaging in TTP can be performed with either CT or MRI brain imaging. CT is less sensitive in detection of ischemia and microhemorrhages compared to MRI. Posterior reversible encephalopathy syndrome (PRES) is the most common imaging manifestation seen in patients with TTP on MR imaging [7]. Typical PRES involves the posterior aspects of the supratentorial brain parenchyma ie the parietal and occipital lobes, with classic appearance of white matter edema on both CT and MR imaging of the brain [8]. PRES is considered atypical when there is involvement of either atypical locations, restricted diffusion or presence of hemorrhage [9]. Atypical locations include frontal or temporal lobes, deep grey matter or the infratentorial brain parenchyma. The most important criteria for calling a signal alteration as PRES is its reversibility which can be confirmed only with follow up imaging.\n\nThe most widely accepted hypothesis for PRES is of vascular dysregulation, with rapid increase in blood pressure that leads to development of edema in the posterior parieto-occipital lobes as the posterior circulation has a sparse sympathetic innervation compared to the anterior carotid circulation. Pathophysiology involving systemic inflammation and endothelial dysfunction have also been considered as PRES occurs in multiple inflammatory conditions such as sepsis, preeclampsia and auto immune disorders [10]. The pathophysiology for PRES and other neuroimaging findings in TTP are not well elucidated but probably relate to microvascular thrombosis with subsequent perfusional disturbances and inflammation that accompanies TTP.\n\nAcute infarcts and hemorrhages are less frequently seen in TTP. In most patients, the brain MRI findings in TTP are completely reversible, although there are isolated reports of persistent small infarcts seen on MRI after clinical recovery [11]. There is also a case report where a large acute infarct was seen from large vessel thrombosis in TTP. Presence of hemorrhage makes PRES more severe, although there are no large studies comparing whether presence of infarcts and hemorrhages are associated with worse outcomes in TTP. In our case, the brain parenchymal signal abnormalities were not in the typical parieto-occipital distribution, with involvement of basal ganglia, midbrain, thalamus and temporal white matter. Presence of microhemorrhages is also uncommonly reported. Both ischemia and hemorrhage are potentially possible in this disorder to manifest in the brain based on the hematologic alterations of thrombocytopenia and microvascular thrombosis seen in this disorder.\n\nConclusion\n\nAtypical PRES and microhemorrhages can be seen on MRI brain imaging in TTP. Prompt diagnosis and treatment of TTP is important to ensure complete recovery and a good prognosis. Imaging findings are typically reversible after successful treatment and can be used for follow-up surveillance. Auto-immune diseases can be associated with TTP and should be suspected both clinically and on imaging. In our case, Sjogren's disease was suspected due to parotid abnormalities on imaging.\n\nPatient consent\n\nThere has been anonymization of any identifiable personal patient information. Patient consent has been obtained.\n\nAcknowledgments: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.\n\nCompeting interest: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.\n==== Refs\nReferences\n\n1 Levy GG Nichols WC Lian EC Foroud T McClintick JN McGee BM Mutations in a member of the ADAMTS gene family cause thrombotic thrombocytopenic purpura Nature 413 6855 2001 488 494 11586351\n2 Swisher KK Lewis QF James JA Hovinga JAK Lämmle B Terrell DR The Frequency of Rheumatic Disease Autoantibodies in Patients with ADAMTS13-Deficient Thrombotic Thrombocytopenia Purpura (TTP) Blood 110 11 2007 2090\n3 Noda M Kitagawa M Tomoda F Iida H. Thrombotic thrombocytopenic purpura as a complicating factor in a case of polymyositis and Sjogren's syndrome Am J Clin Pathol 94 2 1990 217 221 2371975\n4 Chiasakul T Cuker A. Clinical and laboratory diagnosis of TTP: an integrated approach Hematology Am Soc Hematol Educ Program 2018 1 2018 530 538 30504354\n5 Wynick C Britto J Sawler D Parker A Karkhaneh M Goodyear D Validation of the Plasmic Score for Predicting ADAMTS13 Activity < 10% in Patients Admitted to Hospitals in Alberta with Suspected Thrombotic Thrombocytopenic Purpura Blood 134 Supplement_1 2019 2379\n6 Meloni G Proia A Antonini G De Lena C Guerrisi V Capria S Thrombotic thrombocytopenic purpura: prospective neurologic, neuroimaging and neurophysiologic evaluation Haematologica 86 11 2001 1194 1199 11694406\n7 Burrus TM Wijdicks EF Rabinstein AA. Brain lesions are most often reversible in acute thrombotic thrombocytopenic purpura Neurology 73 1 2009 66 70 19564586\n8 Raman R Devaramane R Jagadish GM Chowdaiah S. Various Imaging Manifestations of Posterior Reversible Encephalopathy Syndrome (PRES) on Magnetic Resonance Imaging (MRI) Pol J Radiol 82 2017 64 70 28243339\n9 McKinney AM Short J Truwit CL McKinney ZJ Kozak OS SantaCruz KS Posterior Reversible Encephalopathy Syndrome: Incidence of Atypical Regions of Involvement and Imaging Findings American Journal of Roentgenology 189 4 2007 904 912 17885064\n10 Bartynski WS. Posterior reversible encephalopathy syndrome, part 2: controversies surrounding pathophysiology of vasogenic edema AJNR Am J Neuroradiol 29 6 2008 1043 1049 18403560\n11 Gruber O Wittig L Wiggins CJ von Cramon DY. Thrombotic thrombocytopenic purpura: MRI demonstration of persistent small cerebral infarcts after clinical recovery Neuroradiology 42 8 2000 616 618 10997569\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "1930-0433",
"issue": "16(6)",
"journal": "Radiology case reports",
"keywords": "Atypical PRES; MRI; Microhemorrhages; Posterior reversible encephalopathy syndrome; Sjogren's syndrome; Thrombotic thrombocytopenic purpura",
"medline_ta": "Radiol Case Rep",
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"nlm_unique_id": "101467888",
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"pmid": "33981376",
"pubdate": "2021-06",
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"title": "Atypical posterior reversible encephalopathy syndrome in a case of thrombotic thrombocytopenic purpura with Sjogren's syndrome.",
"title_normalized": "atypical posterior reversible encephalopathy syndrome in a case of thrombotic thrombocytopenic purpura with sjogren s syndrome"
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"abstract": "Midline structural defects in the neural axis can give rise to neuro-ophthalmic symptoms. We report a rare case of keyhole aqueduct syndrome presenting after two years of severe cough due to gastroesophageal reflux disease.\nA 58-year-old woman with a 2-year history of daily, severe cough presented to the neuro-ophthalmology clinic with progressive diplopia and oscillopsia. Examination revealed a 1-2 Hz down-beating nystagmus in primary gaze that worsened with left, right, and down gazes. Gaze evoked nystagmus and mild paresis were also seen with up gaze. There was an incomitant left hypertropia due to skew deviation that worsened with right and up gazes and improved with down gaze. She also had a right-sided ptosis and a 3 mm anisocoria not due to cranial nerve 3 paresis or Horner's syndrome. Brain magnetic resonance imaging showed a 1.5 mm × 11.7 mm × 6 mm midline cleft in the ventral midbrain communicating with the cerebral aqueduct, consistent with keyhole aqueduct syndrome. Her nystagmus and diplopia improved with oral acetazolamide treatment, at high doses of 2500-3000 mg per day.\nWe report the first case of midbrain keyhole aqueduct syndrome with ocular motor and other neuro-ophthalmic manifestations associated with severe cough. Although her cough was effectively treated and intracranial pressure measurement was normal, her ophthalmic symptoms continued to progress, which is common in previous cases reported. Treatment with acetazolamide led to significant improvement, supporting the use of acetazolamide in this rare condition.",
"affiliations": "Department of Ophthalmology, Stanford School of Medicine, 2452 Watson Court, Palo Alto, CA 94303-5353, USA.;Department of Radiology, Neuroradiology Division, Stanford University Medical Center, 300 Pasteur Dr. S031, Stanford, CA 94305, USA.;Department of Ophthalmology, Stanford School of Medicine, 2452 Watson Court, Palo Alto, CA 94303-5353, USA.",
"authors": "Oh|Angela Jinsook|AJ|;Lanzman|Bryan Alexander|BA|;Liao|Yaping Joyce|YJ|",
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"doi": "10.1016/j.ajoc.2018.02.009",
"fulltext": "\n==== Front\nAm J Ophthalmol Case RepAm J Ophthalmol Case RepAmerican Journal of Ophthalmology Case Reports2451-9936Elsevier S2451-9936(17)30315-810.1016/j.ajoc.2018.02.009Case reportVertical diplopia and oscillopsia due to midbrain keyhole aqueduct syndrome associated with severe cough Oh Angela Jinsook aLanzman Bryan Alexander bLiao Yaping Joyce yjliao@stanford.eduac∗a Department of Ophthalmology, Stanford School of Medicine, 2452 Watson Court, Palo Alto, CA 94303-5353, USAb Department of Radiology, Neuroradiology Division, Stanford University Medical Center, 300 Pasteur Dr. S031, Stanford, CA 94305, USAc Department of Neurology, Stanford School of Medicine, 291 Campus Drive, Stanford, CA 94305, USA∗ Corresponding author. Department of Ophthalmology, Stanford University School of Medicine, 2452 Watson Court, Palo Alto, CA 94303-5353, USA. yjliao@stanford.edu15 2 2018 6 2018 15 2 2018 10 128 131 8 1 2018 9 2 2018 9 2 2018 © 2018 The Authors. Published by Elsevier Inc.2018This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Purpose\nMidline structural defects in the neural axis can give rise to neuro-ophthalmic symptoms. We report a rare case of keyhole aqueduct syndrome presenting after two years of severe cough due to gastroesophageal reflux disease.\n\nObservations\nA 58-year-old woman with a 2-year history of daily, severe cough presented to the neuro-ophthalmology clinic with progressive diplopia and oscillopsia. Examination revealed a 1–2 Hz down-beating nystagmus in primary gaze that worsened with left, right, and down gazes. Gaze evoked nystagmus and mild paresis were also seen with up gaze. There was an incomitant left hypertropia due to skew deviation that worsened with right and up gazes and improved with down gaze. She also had a right-sided ptosis and a 3 mm anisocoria not due to cranial nerve 3 paresis or Horner's syndrome. Brain magnetic resonance imaging showed a 1.5 mm × 11.7 mm × 6 mm midline cleft in the ventral midbrain communicating with the cerebral aqueduct, consistent with keyhole aqueduct syndrome. Her nystagmus and diplopia improved with oral acetazolamide treatment, at high doses of 2500–3000 mg per day.\n\nConclusions and importance\nWe report the first case of midbrain keyhole aqueduct syndrome with ocular motor and other neuro-ophthalmic manifestations associated with severe cough. Although her cough was effectively treated and intracranial pressure measurement was normal, her ophthalmic symptoms continued to progress, which is common in previous cases reported. Treatment with acetazolamide led to significant improvement, supporting the use of acetazolamide in this rare condition.\n\nKeywords\nKeyhole aqueduct syndromeMidbrain cleftMesencephalic cleftSyrinxSyringobulbiaDown-beating nystagmusCerebrospinal fluid\n==== Body\n1 Introduction\nEye movement abnormality and vertical nystagmus can arise from midline brainstem abnormalities due to Chiari malformation and rarely, from keyhole aqueduct syndrome or mesencephalic cleft. These latter two conditions have been reported in adults who typically develop progressive diplopia, ocular motor abnormality such as vertical nystagmus and internuclear ophthalmoplegia, balance issues, facial weakness, and sensory abnormality.1 The term keyhole aqueduct syndrome is initially coined in 1986 by de la Monte et al. in two patients who were incorrectly diagnosed with multiple sclerosis and developed progressive gait abnormality, slurred speech, ocular motor abnormality, and ataxia.2 On autopsy, these two patients had a keyhole-shaped syrinx in the midbrain and upper pons with open communication with the cerebral aqueduct and fourth ventricle.2 Cerebellar atrophy and gliosis were also present on imaging. Since then, there have only been 9 published cases1, 2, 3, 4, 5, 6, 7 in the English literature on idiopathic keyhole aqueduct syndrome or mesencephalic cleft. Several theories hypothesize that the mesencephalic cleft may be related to the formation of a midbrain syrinx, cerebellar ischemia, trauma, a congenital anomaly, or a pre-existing abnormality in the upper part of the brainstem.2,3,5 In these cases, damage to the medial longitudinal fasciculus and oculomotor subnuclei can cause ptosis, anisocoria, ophthalmoparesis, and gaze-evoked nystagmus, along with other eye movement abnormalities.4,5\n\n2 Case report\nA 58-year-old Caucasian woman presented to the neuro-ophthalmology clinic with a two-month history of diplopia, oscillopsia, right-sided ptosis, and headache. Her past medical history was significant for a two-year history of severe cough associated with vomiting, headaches, and a hairline fracture in her right 8th rib. At presentation, her cough was already improving following treatment with a proton-pump inhibitor, consistent with gastroesophageal reflux disease. She also had a history of depression, anxiety, right total knee replacement, and osteoarthritis, and her medications included pantoprazole, venlafaxine, aripiprazole, lamotrigine, and clonazepam. There was no family history of craniospinal developmental abnormality, and her mother had idiopathic Parkinson's disease.\n\nOn examination, her uncorrected visual acuity was 20/25 in the right eye and 20/30 in the left eye, and anterior and posterior segment exam were normal with a cup-to-disc (C/D) ratio of 0.2 in both eyes. Her ocular motor exam revealed 1–2 Hz down-beating nystagmus worse on horizontal and down gaze (measured on exam and using 60-Hz three-dimensional binocular infrared video oculography). On down gaze, she also had bilateral alternating dysconjugate gaze-evoked nystagmus (video 1). On up gaze, she had a mild gaze evoked nystagmus and paresis. There was no internuclear ophthalmoplegia or any other eye movement abnormalities. Assessment for ocular alignment showed a skew deviation with an incomitant left hypertropia (14 prism diopter) in primary gaze that worsened with right and up gazes and improved with down gaze and ipsilateral head tilt. When supine, her nystagmus increased in amplitude, and her left hypertropia worsened.\n\nSupplementary video related to this article can be found at https://doi.org/10.1016/j.ajoc.2018.02.009.\n\nThe following is the supplementary data related to this article:Video 1\nDown-beating nystagmus and gaze evoked nystagmus in keyhole aqueduct syndrome.\n\nVideo 1 \n\nPupillary exam showed a 3 mm anisocoria in the dark (3.5 mm, right; 6.5 mm, left), reduced pupillary light response in the right eye, normal pupillary light response in the left eye, and brisk accommodative pupillary response in both eyes. She also had right ptosis. Horner's syndrome was excluded by performing a 0.5% apraclonidine drop test followed by a 1% phenylephrine drop test, both of which showed no change in her ptosis and pupillary responses. Assessment of the parasympathetic pupillary pathway with 0.1% pilocarpine showed hypersensitivity in the left pupil, consistent with a relative dysfunction of the parasympathetic pupillary pathway on the left.\n\nHer systemic exam revealed normal vitals and no evidence of scoliosis or other midline structural abnormalities. Her neurological exam was unremarkable with a normal sensory and motor examination, no extrapyramidal findings, or any evidence of cerebellar ataxia (normal mental status, facial strength and sensation, truncal and extremity strength and sensation, low normal deep tendon reflexes). She had a normal base and was able to ambulate well. A brain magnetic resonance imaging (MRI) from another hospital completed three months ago was read as normal.\n\nExtensive workup to rule out other causes of her nystagmus and diplopia was unrevealing, with normal blood count, metabolites, anti-acetylcholine antibody, and absence of paraneoplastic antibodies in the serum (NeoComplete paraneoplastic antibody profile) and cerebrospinal fluid (CSF) (ANNA-1 to 3, AGNA-1, PCA-1, PCA-2, PCA-Tr, amphipysin, CRMP-5). She had normal CSF assessments including intracranial pressure (17cm H20), cell count, protein, glucose, IgG/albumin index, and IgG profiling by electrophoresis. A high resolution brain MRI revealed a 1.5 mm wide, 11.7 mm long, and 6 mm tall fluid-filled cleft in the midline of the ventral midbrain, which involved the entire ventral tegmentum and communicated with the cerebral aqueduct, consistent with keyhole aqueduct syndrome (Fig. 1). There was also prominent T2 hyperintense lesions in the periventricular and subcortical white matter of both cerebral hemispheres, greater than typical for age, and mild ventricular and sulcal prominence likely related to parenchymal volume loss (not shown). There was no evidence of edema in the parenchyma surrounding the cleft or in the brainstem. Spinal MRI showed no syrinx in the cervical and thoracic spine and revealed multilevel degeneration of the cervical spine (primarily C4-C5) with bilateral neuro-foraminal narrowing and moderate spinal canal stenosis. The initial MRI was reviewed, and in retrospect, revealed the same midline midbrain cleft seen in the second MRI though more difficult to see given thicker sections were obtained.Fig. 1 Brain magnetic resonance imaging demonstrating a 1.5 mm wide by 11.7 mm long by 6 mm tall keyhole aqueduct. A. Images from axial T1–weighted spoiled gradient-recall (SPGR) sequence with gadolinium enhancement of a 55-year-old control (left) and a 58-year-old female with keyhole aqueduct syndrome (right arrow). Images are 1 mm thick. B. Images of sagittal T2–weighted fast imaging employing steady-state acquisition (FIESTA) sequence from 58-year-old control (left) and patient (right arrows). Images are 0.8 mm thick.\n\nFig. 1\n\nOver several months, her symptoms and nystagmus worsened, with a new alternating skew deviation (left hypertropia in primary gaze worse with right gaze, and right hypertropia with left gaze). Her anisocoria decreased by 1 mm in both eyes. Trials of 4-aminopyridine (up to 10 mg twice per day), gabapentin (up to 1800 mg per day), baclofen (up to 10 mg twice per day), and clonazepam (up to 0.5 mg twice per day) either did not improve her ocular motor symptoms or led to significant side effects. She was then started on the carbonic anhydrase inhibitor, acetazolamide (1000mg per day), which led to significant improvement of her symptoms and examination. Her dosage was gradually increased to 3000 mg per day because of further clinical improvement on higher dosage and absence of significant side effects. A trial of dose reduction from 2000 mg to 1500 mg per day led to worsening of her nystagmus and ocular alignment, confirming the benefit of acetazolamide. Repeat brain MRI six months later showed no structural changes despite improvement of her symptoms. Although her nystagmus stabilized, her right eye ptosis did not improve with 2.5% phenylephrine eye drops, oral pyridostigmine (up to 60 mg three times per day), prednisone (up to 60 mg per day), or acetazolamide, and was repaired with levator advancement.\n\n3 Discussion\nWe report a rare case of isolated midbrain keyhole aqueduct syndrome that manifested with down-beating nystagmus, skew deviation, balance issues, and headache, which improved with acetazolamide treatment. There are only 9 reported cases of keyhole aqueduct syndrome or mesencephalic cleft in the English literature, which are associated with eye movement abnormality, ptosis, ataxia, and other neuro-ophthalmic issues.1, 2, 3, 4, 5, 6, 7 The most common ocular motor abnormalities in patients with keyhole aqueduct syndrome include vertical and rotatory nystagmus, ocular misalignment, internuclear ophthalmoplegia, and convergence insufficiency syndrome.1, 2, 3, 4, 5\n\nIn our patient, the keyhole aqueduct may affect the structure of the brainstem including the midbrain, which contains the vertical gaze center. Down-beating nystagmus can be due to dysfunction of connections to the interstitial nucleus of Cajal, leading to an upward drift and compensatory down-beating nystagmus.8 The skew deviation can result from disruption of the vestibular input in the medial longitudinal fasciculus without causing an internuclear ophthalmoplegia, which is frequently seen in other cases of keyhole aqueduct syndrome.1 Her brain MRI also showed significant cerebral white matter disease around the lateral ventricle, which may lead to misdiagnosis of multiple sclerosis, described in previous reports of keyhole aqueduct syndrome.2,6\n\nThe formation of keyhole aqueduct syndrome may be similar to the pathogenesis of syringomyelia, a fluid-filled cavity in the spinal cord. Clinical manifestations of keyhole aqueduct syndrome may be related to a local disturbance of CSF outflow, which contributes to the delayed onset, clinical manifestation at different ages, and slow progression over years.3,5 Histopathological studies of other cases of midbrain clefts show compression and edema of structures in and around the midbrain, suggesting a disruption of CSF flow can lead to formation of an alternate route through a midbrain cleft, which in our case, connects the fourth ventricle to the cerebral aqueduct.2,4 The formation of midbrain syrinx from trauma or increased intracranial pressure is extremely rare.\n\nA case of keyhole aqueduct syndrome associated with severe cough has not previously been reported. Although mechanistically interesting, we do not know how the severe cough contributed to her symptoms. Because Valsalva maneuvers such as coughing can cause spikes in intracranial pressure, this raises the interesting hypothesis that spikes in intracranial pressure may precipitate neuro-ophthalmic manifestations or even cause structural damage to the brainstem over time.9,10 During coughing and other maneuvers that increase intracranial pressure, there is a surge of blood into the epidural venous plexus from the abdominal and thoracic cavities, which squeezes the dura. The venous pulsation is easily transmitted into the CSF pathway11 and causes an upward CSF wave that can potentially cause midline CSF pressure pulsations on the cerebral aqueduct and around brainstem. Healthy controls can typically absorb the abrupt CSF pressure waves after coughing without inducing tissue damage, but patients with syringomyelia or spinal stenosis may have increased CSF pressure gradients and altered fluid dynamics leading to anatomical, compliance, or pressure abnormalities that can exacerbate the effect of coughing, straining, and other maneuvers that impact CSF flow.10,12\n\nThere has been no previously reported effective treatment for keyhole aqueduct syndrome or mesencephalic cleft. Our patient's improvement on high dose acetazolamide provided support for consideration of this medication in other patients with keyhole aqueduct syndrome and mesencephalic cleft and suggested that manipulation of CSF synthesis or dynamics can ameliorate symptoms of keyhole aqueduct syndrome. Acetazolamide, a carbonic anhydrase inhibitor that decreases CSF production and secretion, can help improve symptoms of intracranial hypertension,13 syringomyelia,14 hindbrain herniation headache,15 and Chiari malformation.16 Furthermore, a majority of patients with keyhole aqueduct syndrome exhibit a progressive clinical course, although some have a static course.1 In one patient with a slit-like lesion in the paramedian midbrain, the lesion decreased in size and the patient's eye movement abnormality improved over four months with no reported medication.6 It will be interesting to see whether acetazolamide can impact the progression of disease, especially given some patients progress over years, with severe debilitation of their activities of daily living.1\n\nLimitations to our study include the inherent limitation of a single case report, inability to confirm contribution of coughing to a disturbance in CSF dynamics, and lack of prior imaging.\n\n4 Conclusion\nThe etiology of keyhole aqueduct syndrome is controversial, and our case suggests severe coughing and spikes in intracranial pressure may be associated with its formation. Brain MRI should be performed in patients with abnormal ocular motor behavior, especially in the setting of coughing or possible spikes in intracranial pressure because these symptoms can be associated with significant brainstem lesions. Our patient's eye movement abnormality and symptoms also improved with high dose acetazolamide therapy, suggesting manipulation of CSF flow plays an important role in treating these patients.\n\nPatient consent\nInformed written consent was obtained from patient for publication of personal and medical record details.\n\nFunding\nNo funding or grant support.\n\nConflicts of interest\nNone. The following authors have no financial disclosures: AJO, BAL, YJL.\n\nAuthorship\nAll authors attest that they meet the current ICMJE criteria for Authorship.\n\nAcknowledgements\nNone.\n==== Refs\nReferences\n1 Ahmad O. Reddel S. Lueck C.J. Midbrain cleft as a cause of chronic internuclear ophthalmoplegia, progressive ataxia, and facial weakness J Neuro Ophthalmol 30 2010 145 149 \n2 de la Monte S.M. Horowitz S.A. Larocque A.A. Richardson E.P. Jr. Keyhole aqueduct syndrome Arch Neurol 43 1986 926 929 3741209 \n3 Lagreze W.D. Warner J.E. Zamani A.A. Gouras G.K. Koralnik I.J. Bienfang D.C. Mesencephalic clefts with associated eye movement disorders Arch Ophthalmol 114 1996 429 432 8602780 \n4 Samples J.R. Howard F.M. Jr. Okazaki H. Syringomesencephalia. Report of a case Arch Neurol 40 1983 757 759 6625993 \n5 Burgett R.A. Kawasaki A. Mesencephalic clefts and eye movement disorders Arch Ophthalmol 115 1997 824 9194747 \n6 Chen C.M. Lin S.H. Wall-eyed bilateral internuclear ophthalmoplegia from lesions at different levels in the brainstem J Neuro Ophthalmol 27 2007 9 15 \n7 Fredericks E.J. Van Nuis C. Diverticulum of the rostral cerebral aqueduct with ocular dysfunctions Arch Neurol 16 1967 32 36 5297893 \n8 Glasauer S. Hoshi M. Kempermann U. Eggert T. Buttner U. Three-dimensional eye position and slow phase velocity in humans with downbeat nystagmus J Neurophysiol 89 2003 338 354 12522184 \n9 Williams B. Cerebrospinal fluid pressure changes in response to coughing Brain 99 1976 331 346 990900 \n10 Martin B.A. Loth F. The influence of coughing on cerebrospinal fluid pressure in an in vitro syringomyelia model with spinal subarachnoid space stenosis Cerebrospinal Fluid Res 6 2009 17 20043856 \n11 Bedford T.H. The effect of increased intracranial venous pressure on the pressure of the cerebrospinal fluid Brain 58 1935 427 447 \n12 Levine D.N. The pathogenesis of syringomyelia associated with lesions at the foramen magnum: a critical review of existing theories and proposal of a new hypothesis J Neurol Sci 220 2004 3 21 15140600 \n13 Supuran C.T. Acetazolamide for the treatment of idiopathic intracranial hypertension Expert Rev Neurother 15 2015 851 856 26154918 \n14 Rusbridge C. Greitz D. Iskandar B.J. Syringomyelia: current concepts in pathogenesis, diagnosis, and treatment J Vet Intern Med 20 2006 469 479 16734077 \n15 Chalaupka F.D. Therapeutic effectiveness of acetazolamide in hindbrain hernia headache Neurol Sci 21 2000 117 119 10938192 \n16 Vaphiades M.S. Braswell R. Resolution of Chiari I malformation following acetazolamide therapy Semin Ophthalmol 22 2007 9 11 17366111\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2451-9936",
"issue": "10()",
"journal": "American journal of ophthalmology case reports",
"keywords": "Cerebrospinal fluid; Down-beating nystagmus; Keyhole aqueduct syndrome; Mesencephalic cleft; Midbrain cleft; Syringobulbia; Syrinx",
"medline_ta": "Am J Ophthalmol Case Rep",
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"pages": "128-131",
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"title": "Vertical diplopia and oscillopsia due to midbrain keyhole aqueduct syndrome associated with severe cough.",
"title_normalized": "vertical diplopia and oscillopsia due to midbrain keyhole aqueduct syndrome associated with severe cough"
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"abstract": "In the hospital, antibiotics are widely used to treat infections. We report a case of acute kidney injury (AKI) caused by an antibiotic drug combination. A 30-year-old Japanese male presented with lung metastases, pneumothorax, empyema, and methicillin-resistant Staphylococcus aureus (MRSA) infection. The patient received a combination of vancomycin and piperacillin/tazobactam, which resulted in elevated vancomycin trough concentration and subsequently in AKI. Renal function was restored upon vancomycin and piperacillin/tazobactam cessation. Though this patient had AKI most likely due to the combined use of two agents as has been reported in many cases, vancomycin trough concentration showed an unexpected abnormal increase when halting vancomycin treatment. This is the first report indicating a drug-drug interaction between vancomycin and piperacillin/tazobactam with unexpected abnormal vancomycin trough concentration, leading to AKI, additionally we think that there was a situation that he stressed against the kidney by a history of medications caused renal dysfunction and co-administration. We suggest that when using vancomycin in combination with piperacillin/tazobactam, the trough concentration of vancomycin must be confirmed simultaneously with renal function and evaluation, and that the combination of these two drugs should be minimized.",
"affiliations": "Department of Pharmacy, Kurume University Hospital.;Department of Pharmacy, Kurume University Hospital.;Department of Surgery, Kurume University School of Medicine.;Department of Infection Control and Prevention, Kurume University School of Medicine.",
"authors": "Sakai|Yoshiro|Y|;Miwa|Ryoko|R|;Mitsuoka|Masahiro|M|;Watanabe|Hiroshi|H|",
"chemical_list": "D000900:Anti-Bacterial Agents; D000077725:Piperacillin, Tazobactam Drug Combination; D014640:Vancomycin",
"country": "Japan",
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"doi": "10.1248/yakushi.19-00234",
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"journal": "Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan",
"keywords": "acute kidney injury; piperacillin/tazobactam; vancomycin; vancomycin trough concentration",
"medline_ta": "Yakugaku Zasshi",
"mesh_terms": "D058186:Acute Kidney Injury; D000328:Adult; D000900:Anti-Bacterial Agents; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D006801:Humans; D008297:Male; D055624:Methicillin-Resistant Staphylococcus aureus; D000077725:Piperacillin, Tazobactam Drug Combination; D013203:Staphylococcal Infections; D014640:Vancomycin",
"nlm_unique_id": "0413613",
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"title": "Combinatorial Vancomycin and Piperacillin/Tazobactam Results in Elevated Vancomycin Trough Concentration and Acute Kidney Injury: A Case Report.",
"title_normalized": "combinatorial vancomycin and piperacillin tazobactam results in elevated vancomycin trough concentration and acute kidney injury a case report"
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"abstract": "BACKGROUND\nDRESS (drug reaction with eosinophilia and systemic symptoms) syndrome is a severe adverse drug-induced reaction. It manifests with pyrexia, eosinophilia, and lymphadenopathy, with multiple organ involvement, mainly the skin, liver, and kidneys. The purpose of this article is to demonstrate that DRESS syndrome can be associated with cerebral manifestations, a concept not well known in the neuroradiological literature.\n\n\nMETHODS\nWe describe three cases of DRESS syndrome associated with cerebral vasculitic-like lesions and realize a review of the literature to demonstrate that this association represents a very rare entity.\n\n\nRESULTS\nAcute ischemic lesions were found among two patients. In all cases, perivascular enhancement was present. Magnetic resonance angiography (MRA) sequence was normal. Although no cerebral biopsy was performed, this enhancement pattern is strongly suggestive of a vasculitic process associated with DRESS syndrome.\n\n\nCONCLUSIONS\nDiagnosis of cerebral vasculitic-like associated lesions must be considered in patients with DRESS syndrome since it can be reversed completely by withdrawing the causal medication and instigating corticosteroid treatment in a timely fashion.",
"affiliations": "Department of Neuroradiology, Montreal University Hospital (CHUM), Montreal, Canada. mehdi.gaha@yahoo.fr.;Department of Neuroradiology, Montreal University Hospital (CHUM), Montreal, Canada.;Department of Neuroradiology, Montreal University Hospital (CHUM), Montreal, Canada.;Department of Immunology, Montreal University Hospital (CHUM), Montreal, Canada.;Department of Immunology, Montreal University Hospital (CHUM), Montreal, Canada.;Department of Neuroradiology, Montreal University Hospital (CHUM), Montreal, Canada.",
"authors": "Gaha|Mehdi|M|;Landry|David|D|;Bélair|Manon|M|;Paquet|Brenda|B|;Chapdelaine|Hugo|H|;Bard|Céline|C|",
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"doi": "10.1007/s00234-015-1562-0",
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"issue": "57(10)",
"journal": "Neuroradiology",
"keywords": "Brain; Drug-induced hypersensitivity; Vasculitis",
"medline_ta": "Neuroradiology",
"mesh_terms": "D002536:Cerebral Arteries; D003937:Diagnosis, Differential; D063926:Drug Hypersensitivity Syndrome; D005260:Female; D006801:Humans; D018810:Magnetic Resonance Angiography; D008875:Middle Aged; D020293:Vasculitis, Central Nervous System",
"nlm_unique_id": "1302751",
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"pubdate": "2015-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "23330880;14872278;23045170;8871466;17300272;17854362;10071114;22156692;16943303;21592453;15743917;24117125;23855313;23602182;25836767;23774556",
"title": "DRESS syndrome: cerebral vasculitic-like presentation.",
"title_normalized": "dress syndrome cerebral vasculitic like presentation"
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"abstract": "Objective and importance: Candida auris is a relatively new yeast species and an emerging opportunistic pathogen. It was first reported in 2009 in East Asia, as a difficult-to-identify Candida species of uncertain clinical relevance. In recent years, it has appeared globally as a cause of invasive infections, not infrequently eliciting nosocomial outbreaks. Species identification in clinical laboratories has been challenging, as traditional phenotypic and biochemical methods have been generally unreliable. Clinical management is often complicated by multidrug resistance in many isolates. Additionally, C. auris has demonstrated an unusual ability for persistence in the hospital environment and in asymptomatic patients. We present the first Belgian case of C. auris infection along with a brief review of the literature.Clinical presentation: A patient was referred from Kuwait for surgical treatment after a complicated bariatric procedure. Few days after transferral, she developed a catheter-related blood stream infection with C. auris. We obtained a low-confidence identification of C. auris with the Bruker Biotyper MALDI-TOF MS system (Bruker Corporation, Billerica, MA, U.S.A.), and of Candida haemulonii with the Vitek YST identification system, version 7.01 (bioMérieux, Marcy-L'Etoile, France). Definite identification was obtained using Internal Transcribed Spacer (ITS) sequencing. As most C. auris isolates, our strain was resistant to fluconazole, and the patient was eventually treated with catheter removal and anidulafungin therapy. We documented persistence of C. auris clones with acquired echinocandin resistance in our patient up to 18 months after the infection.Conclusion: Clinicians and microbiologists should be aware of this globally emerging yeast, that poses important challenges in identification, treatment and hospital infection control.",
"affiliations": "Department of Clinical Microbiology, Imelda General Hospital, Bonheiden, Belgium.;Department of Clinical Microbiology, Imelda General Hospital, Bonheiden, Belgium.;Department of Clinical Microbiology, Imelda General Hospital, Bonheiden, Belgium.;Department of Clinical Microbiology, Imelda General Hospital, Bonheiden, Belgium.;Department of Abdominal Surgery, Imelda General Hospital, Bonheiden, Belgium.;Department of Microbiology and Immunology, KU Leuven, Leuven, Belgium.",
"authors": "Dewaele|Klaas|K|https://orcid.org/0000-0002-7029-2470;Frans|Johan|J|https://orcid.org/0000-0002-0440-8383;Smismans|Annick|A|;Ho|Erwin|E|https://orcid.org/0000-0001-5642-5006;Tollens|Tim|T|https://orcid.org/0000-0003-0542-6361;Lagrou|Katrien|K|https://orcid.org/0000-0001-8668-1350",
"chemical_list": "D000935:Antifungal Agents; D000077612:Anidulafungin",
"country": "England",
"delete": false,
"doi": "10.1080/17843286.2018.1555114",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1784-3286",
"issue": "75(3)",
"journal": "Acta clinica Belgica",
"keywords": "Antifungal resistance; Candida auris; Infection control; MALDI-TOF",
"medline_ta": "Acta Clin Belg",
"mesh_terms": "D057868:Anastomotic Leak; D000077612:Anidulafungin; D000935:Antifungal Agents; D001530:Belgium; D002175:Candida; D058365:Candidiasis, Invasive; D055499:Catheter-Related Infections; D062905:Central Venous Catheters; D025141:Drug Resistance, Fungal; D005260:Female; D015390:Gastric Bypass; D006801:Humans; D007082:Ileum; D007412:Intestinal Fistula; D007416:Intestinal Perforation; D007730:Kuwait; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D010360:Patient Transfer; D011183:Postoperative Complications; D013530:Surgical Wound Infection; D014552:Urinary Tract Infections",
"nlm_unique_id": "0370306",
"other_id": null,
"pages": "221-228",
"pmc": null,
"pmid": "30514182",
"pubdate": "2020-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "First case of Candida auris infection in Belgium in a surgical patient from Kuwait.",
"title_normalized": "first case of candida auris infection in belgium in a surgical patient from kuwait"
} | [
{
"companynumb": "BE-TEVA-2020-BE-1802637",
"fulfillexpeditecriteria": "1",
"occurcountry": "BE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LEVOFLOXACIN"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nDue to a shortage of donor kidneys, many centers have utilized graft kidneys from brain-dead donors with expanded criteria. Kidney transplantation (KT) from donors on extracorporeal membrane oxygenation (ECMO) has been identified as a successful way of expanding donor pools. However, there are currently no guidelines or recommendations that guarantee successful KT from donors undergoing ECMO treatment. Therefore, acceptance of appropriate allografts from those donors is solely based on clinician decision.\n\n\nMETHODS\nWe report a case of successful KT from a brain-dead donor supported by ECMO for the longest duration to date. A 69-year-old male received a KT from a 63-year-old brain-dead donor who had been on therapeutic ECMO treatment for the previous three weeks. The recipient experienced slow recovery of graft function after surgery but was discharged home on post-operative day 17 free from hemodialysis. Allograft function gradually improved thereafter and was comparatively acceptable up to the 12 mo follow-up, with serum creatinine level of 1.67 mg/dL.\n\n\nCONCLUSIONS\nThis case suggests that donation even after long-term ECMO treatment could provide successful KT to suitable candidates.",
"affiliations": "Division of Nephrology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, South Korea.;Division of Nephrology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, South Korea.;Division of Nephrology, Department of Internal Medicine, Jeju National University Hospital, Jeju-do 63241, South Korea.;Department of Surgery, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seoul 06591, South Korea.;Division of Nephrology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, South Korea.;Division of Nephrology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, South Korea.;Division of Nephrology, Department of Internal Medicine, Eunpyeong St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Eunpyeong-gu, Seoul 03312, South Korea. deux0123@catholic.ac.kr.",
"authors": "Seo|Hye Won|HW|;Lee|Sua|S|;Lee|Hwa Young|HY|;Park|Sun Cheol|SC|;Chung|Byung Ha|BH|;Yang|Chul Woo|CW|;Ban|Tae Hyun|TH|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.12998/wjcc.v8.i3.540",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2307-8960",
"issue": "8(3)",
"journal": "World journal of clinical cases",
"keywords": "Case report; Delayed graft function; Donor selection; Extracorporeal membrane oxygenation; Kidney transplantation",
"medline_ta": "World J Clin Cases",
"mesh_terms": null,
"nlm_unique_id": "101618806",
"other_id": null,
"pages": "540-545",
"pmc": null,
"pmid": "32110664",
"pubdate": "2020-02-06",
"publication_types": "D002363:Case Reports",
"references": "28104114;20061924;24928419;12694055;28546439;24815128;15877803;27139839;25772854;26031585;28640022;24805948;27109948;30577189;24815130",
"title": "Successful kidney transplantation from an expanded criteria donor with long-term extracorporeal membrane oxygenation treatment: A case report.",
"title_normalized": "successful kidney transplantation from an expanded criteria donor with long term extracorporeal membrane oxygenation treatment a case report"
} | [
{
"companynumb": "KR-ASTELLAS-2020US009572",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "MYCOPHENOLIC ACID"
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"drugadditional": null,... |
{
"abstract": "Abdominal pain may precede the characteristic varicella skin lesions in immunocompromised patients with visceral varicella. The absence of skin lesions may delay timely diagnosis and treatment of varicella for those patients. Furthermore, abdominal imaging findings to provide information to diagnose visceral varicella have rarely been reported. Varicella was diagnosed in a 5-year-old boy with acute lymphoblastic leukemia complaining of fever and abdominal pain followed by papulovesicular skin lesions. Later, the patient was found to have rapidly progressive acute hepatitis, and abdominal computed tomography showed multiple hypodense hepatic nodules. The patient was treated with intravenous acyclovir, intravenous immunoglobulin, and empirical antibiotic and antifungal therapy. However, his fever and abdominal pain persisted, and a laparoscopic liver biopsy was performed to differentiate other causes of the persisting symptoms. Eventually, the patient was diagnosed with visceral varicella based on histopathologic findings. In conclusion, visceral varicella should be considered in immunocompromised patients with abdominal pain and multiple hypodense hepatic nodules on abdominal imaging studies. However, bacteria, fungi, and tuberculosis can produce similar imaging findings; therefore, a biopsy may be necessary in patients not responding to antiviral therapy.",
"affiliations": "Department of Pediatrics, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea; Vaccine Bio Research Institute, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.;Department of Pediatrics, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.;Department of Pediatrics, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea; Catholic Blood and Marrow Transplantation Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.;Department of Pediatrics, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea; Catholic Blood and Marrow Transplantation Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea. Electronic address: dashwood@catholic.ac.kr.;Vaccine Bio Research Institute, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea; Catholic Blood and Marrow Transplantation Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea; Division of Infectious Diseases, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.;Department of Pediatrics, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea; Catholic Blood and Marrow Transplantation Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.;Department of Pediatrics, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea; Catholic Blood and Marrow Transplantation Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.;Department of Pediatrics, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea; Vaccine Bio Research Institute, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.;Department of Pediatrics, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea; Catholic Blood and Marrow Transplantation Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.;Department of Hospital Pathology, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.",
"authors": "Han|Seung Beom|SB|;Seo|Young Eun|YE|;Kim|Seong-Koo|SK|;Lee|Jae Wook|JW|;Lee|Dong-Gun|DG|;Chung|Nack-Gyun|NG|;Cho|Bin|B|;Kang|Jin Han|JH|;Kim|Hack-Ki|HK|;Jung|Eun Sun|ES|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.jiac.2016.07.005",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1341-321X",
"issue": "22(12)",
"journal": "Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy",
"keywords": "Acute lymphoblastic leukemia; Chickenpox; Child; Hepatitis; Varicella-zoster virus",
"medline_ta": "J Infect Chemother",
"mesh_terms": "D015746:Abdominal Pain; D000208:Acute Disease; D002644:Chickenpox; D002675:Child, Preschool; D018450:Disease Progression; D006505:Hepatitis; D006801:Humans; D008099:Liver; D008297:Male; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma",
"nlm_unique_id": "9608375",
"other_id": null,
"pages": "822-825",
"pmc": null,
"pmid": "27496601",
"pubdate": "2016-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Varicella with rapidly progressive hepatitis presenting with multiple hepatic nodules in a child with acute leukemia.",
"title_normalized": "varicella with rapidly progressive hepatitis presenting with multiple hepatic nodules in a child with acute leukemia"
} | [
{
"companynumb": "KR-CONCORDIA PHARMACEUTICALS INC.-E2B_00008420",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VINCRISTINE"
},
"drugadd... |
{
"abstract": "BACKGROUND\nAmeloblastoma is generally characterized as a benign tumor originating in odontogenic epithelium. However, few cases of metastatic malignant ameloblastoma have also been reported. Due to the low incidence of malignant ameloblastoma, there is no established treatment regimen. To explore effective treatment for malignant ameloblastoma, we reported this case study.\nThis report described a case of a 28-year-old malignant ameloblastoma female patient with multiple metastasis (brain and lung).\nThe patient presented ameloblastoma of the left mandible in 2012. Three years later, local recurrence and brain metastasis was observed during a follow-up examination. Five years later, malignant ameloblastoma was detected by imaging and immunohistochemistry in the bilateral multiple pulmonary nodules and mediastinal lymph nodes.\n\n\nMETHODS\nThe patient was initially treated with tumor resection. Three years later after local recurrence and brain metastasis, she was accepted the extensive mandibulectomy supplemented with brain stereotactic body radiotherapy (SBRT). When diagnosed with pulmonary metastasis, the patient received combined chemotherapy regimen of MAID (mesna, adriamycin, ifosfamide and dacarbazine) for 6 cycles.\n\n\nRESULTS\nThe efficacy evaluation was partial remission (PR) after the 6 cycles of MAID. The last patient follow-up was July 24th 2018, and no evidence of progression was observed. The progression-free survival (PFS) of the patient was more than 9 months.\n\n\nCONCLUSIONS\nSurgical resection is the optimal treatment for locally recurrent ameloblastoma. SBRT may be an effective treatment for unresectable oligometastasis of malignant ameloblastoma. Finally, combined chemotherapy of MAID showed encouraging effects in the management of metastatic malignant ameloblastoma.",
"affiliations": "Department of Medical Oncology of Zhengzhou University Affiliated Cancer Hospital.;Department of Medical Oncology of Zhengzhou University Affiliated Cancer Hospital.;Department of Pathology of Zhengzhou University Affiliated Cancer Hospital.;Department of Medical Oncology of Zhengzhou University Affiliated Cancer Hospital.;Department of Imaging of Zhengzhou University Affiliated Cancer Hospital, Henan Cancer Hosptial, Zhengzhou, Henan, China.;Department of Medical Oncology of Zhengzhou University Affiliated Cancer Hospital.",
"authors": "Li|Danyang|D|;Xu|Shuning|S|;Sun|Miaomiao|M|;Qiao|Lei|L|;Wang|Lifeng|L|;Liu|Ying|Y|",
"chemical_list": "D003606:Dacarbazine; D004317:Doxorubicin; D015080:Mesna; D007069:Ifosfamide",
"country": "United States",
"delete": false,
"doi": "10.1097/MD.0000000000015873",
"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 31232921MD-D-18-0926910.1097/MD.0000000000015873158735700Research ArticleClinical Case ReportMAID chemotherapy regimen as a treatment strategy for metastatic malignant ameloblastoma A case reportLi Danyang aXu Shuning aSun Miaomiao bQiao Lei aWang Lifeng cLiu Ying a∗NA. a Department of Medical Oncology of Zhengzhou University Affiliated Cancer Hospitalb Department of Pathology of Zhengzhou University Affiliated Cancer Hospitalc Department of Imaging of Zhengzhou University Affiliated Cancer Hospital, Henan Cancer Hosptial, Zhengzhou, Henan, China.∗ Correspondence: Ying Liu, Department of Medical Oncology of Zhengzhou University Affiliated Cancer Hospital, Henan Cancer Hosptial, 127th Dongming Road, Zhengzhou, Henan, China (e-mail: yaya7207@126.com).6 2019 21 6 2019 98 25 e1587321 12 2018 17 4 2019 9 5 2019 Copyright © 2019 the Author(s). Published by Wolters Kluwer Health, Inc.2019This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0Abstract\nRationale:\nAmeloblastoma is generally characterized as a benign tumor originating in odontogenic epithelium. However, few cases of metastatic malignant ameloblastoma have also been reported. Due to the low incidence of malignant ameloblastoma, there is no established treatment regimen. To explore effective treatment for malignant ameloblastoma, we reported this case study.\n\nPatients concerns:\nThis report described a case of a 28-year-old malignant ameloblastoma female patient with multiple metastasis (brain and lung).\n\nDiagnoses:\nThe patient presented ameloblastoma of the left mandible in 2012. Three years later, local recurrence and brain metastasis was observed during a follow-up examination. Five years later, malignant ameloblastoma was detected by imaging and immunohistochemistry in the bilateral multiple pulmonary nodules and mediastinal lymph nodes.\n\nInterventions:\nThe patient was initially treated with tumor resection. Three years later after local recurrence and brain metastasis, she was accepted the extensive mandibulectomy supplemented with brain stereotactic body radiotherapy (SBRT). When diagnosed with pulmonary metastasis, the patient received combined chemotherapy regimen of MAID (mesna, adriamycin, ifosfamide and dacarbazine) for 6 cycles.\n\nOutcomes:\nThe efficacy evaluation was partial remission (PR) after the 6 cycles of MAID. The last patient follow-up was July 24th 2018, and no evidence of progression was observed. The progression-free survival (PFS) of the patient was more than 9 months.\n\nLessons:\nSurgical resection is the optimal treatment for locally recurrent ameloblastoma. SBRT may be an effective treatment for unresectable oligometastasis of malignant ameloblastoma. Finally, combined chemotherapy of MAID showed encouraging effects in the management of metastatic malignant ameloblastoma.\n\nKeywords\nadriamycinchemotherapydacarbazineifosfamideMAIDmesnametastatic malignant ameloblastomaOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nAmeloblastoma is generally characterized as a benign tumor arising from odontogenic epithelium. The median age of diagnosis is 36 years. More than 80% ameloblastomas originate in the mandible.[1] In 2016, the fourth edition of WHO classified ameloblastoma into 2 types: the unicystic ameloblastoma and the extra osseous/peripheral ameloblastoma.[2] This was simplified compared with the four types of 2005 WHO classification.[3] Ameloblastoma grows slowly with local invasiveness. The highest recurrence type, with a rate between 60% and 80%, is solid/multicystic ameloblastoma according to 2005 WHO classification.[4] The main treatment for ameloblastoma is surgery, including both curettage and radical surgery.[5]\n\nAlthough ameloblastoma has benign biological characteristics, distant metastases can occur in cases of malignant ameloblastoma. The most likely metastatic location of malignant ameloblastoma is the lung.[6] Due to its low incidence rate, there is no standard therapy for metastatic ameloblastoma. Here, we reported a case of malignant ameloblastoma with lung and brain metastases.\n\n2 Case presentation\nA 28-year-old female with a history of ameloblastoma of the left mandible underwent local tumor curettage in 2012. Either local recurrence or distant metastasis had not been found until 2015. Brain metastasis and local recurrence were confirmed by magnetic resonance imaging (MRI) and contrast computer tomography (CT). The patient received left extensive mandibulectomy and brain stereotactic body radiotherapy (SBRT) at the dose of 24.4Gy. The disease was stable until bilateral multiple pulmonary nodules and mediastinal lymph nodes were identified by chest CT in November 2017. After admitting the patient into our hospital, malignant ameloblastoma was detected in the pulmonary nodule biopsy by Hematoxylin and eosin (H&E) staining and immunohistochemistry (Figs. 1 and 2). We performed whole exon detection for metastatic lesion specimens by next generation sequencing (NGS). The detection included somatic mutation, germline mutation, microsatellite instability and tumor mutation load. A total of 7 somatic mutations were revealed including BRAF (c.1799T>A, p.V600E EX15 41.2%), MYCN (c.131>T, p.P44L EX2 40.2%), MLL2(c.3045C[2>1], p.L1016∗fs∗1 EX11 35.9%), ARIDIA(c.3715+1G>A IVS14 34.5%), MLL2(c.6392C[5>6], p.A2133Rfs∗22 EX31 33.5%), RUNX1(c.364G[4>6], p.D123Gf∗11 EX5 31.5%) and ASXL1(c.1927G[8>9], p.G646Wfs∗12 EX13 29.8%). Germline mutations were not detected. Microsatellite status was stable with low tumor mutation load (7.0 Muts/Mb).\n\nFigure 1 (a and b). Hematoxylin and eosin (H&E) staining of ameloblastoma lung metastasis tissues under microscopically (original magnification×200). Microscopic cell morphology was in accordance with ameloblastoma cell.\n\nFigure 2 (a–f). Immunohistochemistry staining of ameloblastoma lung metastasis tissue (original magnification×200). The positive of CK(a), P40(d), P63(e), the weakly focally positive of CK5/6(c), CD56(f) and the negative of TTF-1(b).\n\nThe patient received combined chemotherapy including adriamycin (50 mg/m2), ifosfamide (7500 mg/m2), and dacarbazine (1000 mg/m2), which were administered intravenously for 72 hours every 3 weeks. Mesna (2500 mg/m2) was also administered intravenously for 96 hours every 3 weeks. According to RECIST 1.1 criteria, the objective response was partial remission (PR) after 2 cycles of chemotherapy. The lung metastases reduced over 90% compared with the base line after 6 cycles of chemotherapy (Fig. 3). The most common treatment related adverse events included neutropenia, leukopenia, anemia, acratia and nausea. In addition to grade 3 neutropenia, no other grade 3/4 adverse events were observed during chemotherapy.\n\nFigure 3 (a–d). Contrast computerized tomography (CT) scans show the multiple lung metastases of the initial presentation from November 2017 (a and c) and the 6 cycles of MAID chemotherapy treatment from March 2018 (b and d), the pulmonary metastases have reduced over 90%.\n\n3 Discussion\nAmeloblastoma is a rare odontogenic tumor. There is no significant difference in incidence rate between gender, territory and race.[1] The incidence rate of malignant ameloblastoma is 1.79 per 10 million person/year and the overall survival is 17.6 years from Surveillance, Epidemiology and End-Results (SEER) database.[7] For cases of locoregional ameloblastoma, the advised primary treatment is surgery including radical and conservation surgery.[5] Radical surgery has lower local recurrence rate than conservation surgery.[8] Kunze et al demonstrated that the lung was the organ with the highest metastatic rate of ameloblastoma followed by pleura, lymph nodes, bone, brain, kidney, and liver.[9] When distant metastasis occurred, more aggressive treatments could be applied. Chemotherapy, radiotherapy and surgery are the methods reported in the related literature. Due to the low incidence of ameloblastoma, retrospective and prospective large sample clinical studies have not been conducted. As such, most papers regarding the treatment of ameloblastoma are case reports.[10] Therefore, there is no standard therapy for metastatic ameloblastoma.\n\nA retrospective study confirmed that radiotherapy followed by palliative surgery could control the local recurrence of ameloblastoma.[11] In this study, gene screening revealed that radiotherapy increased the sensitivity to BRAF inhibitors in patients with BRAF gene mutations. As for recurrent ameloblastoma with skull metastasis, radiation therapy also had a better disease control with a disease progression free survival (PFS) of 28 months.[12] However, another study suggested that patients with metastatic ameloblastoma could only benefit from surgery instead of radiation therapy and chemotherapy.[13] Stereotactic body radiotherapy (SBRT) is a technique that has risen in popularity in recent years. Several studies demonstrated that patients of non-small cell lung cancer (NSCLC) who had oligometastasis including brain, bone, lung, lymphatic, or adrenal gland and received SBRT owned the median PFS of 11.2 to 13.7 months and lower local recurrence rate.[14–16] The female patient in our study exhibited local recurrence and a single brain metastasis. She underwent extended maxillary resection combined with SBRT for the brain metastasis with the PFS of 24.0 months.\n\nIf multiple metastases are confirmed, local treatments will not control the disease effectively, thus systemic therapy should be the primary focus. In previous studies, the effects of several combination chemotherapy regimens were reported. Secondary regimens include doxorubicin with cisplatin,[17] or paclitaxel with carboplatin[18,19] and triple combined therapy (doxorubicin combined with cisplatin and cyclophamide)[20] showed encouraging efficacy and safety. However, due to the lack of large sample randomized comparative clinical trials, high grade evidence is not available. MAID (mesna, adriamycin, ifosfamide, and dacarbazine) regimen achieved a better outcome in advanced sarcoma with the PFS of more than one year and the ORR of 27% to 35%.[21,22] The most frequent adverse events were grade 3 or 4 hematological toxicities. Meanwhile, a perspective study conducted with patients diagnosed with advanced pulmonary pleomorphic carcinoma treated with MAID had a median PFS and an OS of 2.8 months and 8.7 months, respectively.[23] Therefore, we tried MAID as the first-line chemotherapy for the patient. Fortunately, she achieved PR after 2 cycles. After 6 cycles of MAID chemotherapy regimen, the lung metastases reduced over 90% compared with the base line. The last patient follow-up was July 24th 2018. At that time, imaging results showed no evidence of disease progression. The progression-free survival (PFS) of the patient was more than 9 month. Thus, it appears that MAID may be an effective regimen with good tolerance in patients with metastatic ameloblastoma and further investigation is deserved.\n\nIn general, the BRAF V600E mutation is the most aberration in ameloblastoma. Vemurafenib, a BRAF inhibitor, showed promising response in ameloblastoma cells in vitro.[24,25] The whole exon gene sequencing result of the present case is consistent with these studies. In addition, the RAS gene mutation rate is 20% in metastatic ameloblastoma.[26] The overexpression of vascular endothelial growth factor (VEGF) occurs in both benign and malignant ameloblastoma.[27] Although ameloblastoma originates from dental epithelium and epidermal growth factor receptor (EGFR) expression is positive in normal oral mucosa, the EGFR mutation rate was extremely low.[28] At present, no data has shown that EGFR could be used as a target for the treatment of ameloblastoma. In summary, VEGF, TIMP-2, MMP-14 mRNA, FGF, and TGF-β may be potential targets for recurrence and metastasis of malignant ameloblastoma in the future.[29]\n\n4 Conclusion\nDue to the low incidence of metastatic malignant ameloblastoma, there is no standard treatment strategy. Surgical resection is the optimal treatment for local recurrence malignant ameloblastoma. According to the literature we reviewed and the case we reported, SBRT may be an effective treatment for unresectable oligometastasis of ameloblastoma, and MAID chemotherapy regimen also showed encouraging efficacy in metastatic malignant ameloblastoma. With further development of methods enabling the detection tumor-specific gene signatures, targeted therapy may be worth further consideration.\n\nAuthor contributions\nDanyang Li drafted the manuscript; Ying Liu designed and critically revised the manuscript, providing language help; Danyang Li, Shuning Xu and Lei Qiao cared the patient and collected the date of the case; Miaomiao Sun and Lifeng Wang selected the figures.\n\nConceptualization: Ying Liu.\n\nData curation: Danyang Li, Shuning Xu, Miaomiao Sun, Lei Qiao, Lifeng Wang.\n\nProject administration: Shuning Xu, Lei Qiao.\n\nValidation: Ying Liu.\n\nWriting – original draft: Danyang Li.\n\nWriting – review & editing: Danyang Li.\n\nAbbreviations: CT = computer tomography, EGFR = epidermal growth factor receptor, H&E = hematoxylin and eosin, MAID = mesna, adriamycin, ifosfamide and dacarbazine, MRI = magnetic resonance imaging, NGS = next generation sequencing, NSCLC = non-small cell lung cancer, ORR = objective response rate, OS = overall survival, PFS = progression free survival, PR = partial remission, RECIST = response evaluation criteria in solid tumors, SBRT = stereotactic body radiotherapy, VEGF = vascular endothelial growth factor.\n\nInformed written consent was obtained from the patient for publication of this case report and accompanying images.\n\nThe authors have no conflicts of interest to disclose.\n==== Refs\nReferences\n[1] Reichart PA Philipsen HP Sonner S \nAmeloblastoma: biological profile of 3677 cases . Eur J Cancer B Oral Oncol \n1995 ;31B :86–99 .7633291 \n[2] Wright JM Vered M \nUpdate from the 4th Edition of the World Health Organization classification of head and neck tumours: odontogenic and maxillofacial bone tumors . Head Neck Pathol \n2017 ;11 :68–77 .28247226 \n[3] Barnes L Eveson J Reichart PA Sidransky D \nWorld Health Organization Classification of Tumours: Head and Neck Tumours . Lyon : IARC Press ; 268–95 .\n[4] Pogrel MA Montes DM \nIs there a role for enucleation in the management of ameloblastoma? \nInt J Oral Maxillofac Surg \n2009 ;38 :807–12 .19297131 \n[5] Sehdev MK Huvos AG Strong EW \nProceedings: Ameloblastoma of maxilla and mandible . Cancer \n1974 ;33 :324–33 .4812754 \n[6] Henderson JM Sonnet JR Schlesinger C \nPulmonary metastasis of ameloblastoma: case report and review of the literature . Oral Surg Oral Med Oral Pathol Oral Radiol Endod \n1999 ;88 :170–6 .10468461 \n[7] Rizzitelli A Smoll NR Chae MP \nIncidence and survival of malignant ameloblastoma . PLoS One \n2015 ;10 :e0117789.25692490 \n[8] Hammarfjord O Roslund J Abrahamsson P \nSurgical treatment of recurring ameloblastoma, are there options? \nBr J Oral Maxillofac Surg \n2013 ;51 :762–6 .24050920 \n[9] Kunze E Donath K Luhr HG \nBiology of metastasizing ameloblastoma . Pathol Res Pract \n1985 ;180 :526–35 .4080638 \n[10] Van Dam SD Unni KK Keller EE \nMetastasizing (malignant) ameloblastoma: review of a unique histopathologic entity and report of Mayo Clinic experience . J Oral Maxillofac Surg \n2010 ;68 :2962–74 .20970910 \n[11] Kennedy WR Werning JW Kaye FJ \nTreatment of ameloblastoma and ameloblastic carcinoma with radiotherapy . Eur Arch Otorhinolaryngol \n2016 ;273 :3293–7 .26796877 \n[12] Huang CM Chen JY Chen CH \nRadiotherapy for a repeatedly recurrent ameloblastoma with malignant transformation . Head Neck \n2014 ;36 :E1–3 .23633444 \n[13] Ricard AS Majoufre-Lefebvre C Siberchicot F \nA multirecurrent ameloblastoma metastatic to the lung . Rev Stomatol Chir Maxillofac \n2010 ;111 :98–100 .20347463 \n[14] Fleckenstein J Petroff A Schäfers HJ \nLong-term outcomes in radically treated synchronous vs. metachronous oligometastatic non-small-cell lung cancer . BMC Cancer \n2016 ;16 :348.27255302 \n[15] Collen C Christian N Schallier D \nPhase II study of stereotactic body radiotherapy to primary tumor and metastatic locations in oligometastatic nonsmall-cell lung cancer patients . Ann Oncol \n2014 ;25 :1954–9 .25114022 \n[16] Buglione M Pedretti S Gipponi S \nThe treatment of patients with 1-3 brain metastases: is there a place for whole brain radiotherapy alone, yet? A retrospective analysis . Radiol Med \n2015 ;120 :1146–52 .25917339 \n[17] Amzerin M Fadoukhair Z Belbaraka R \nMetastatic ameloblastoma responding to combination chemotherapy: case report and review of the literature . J Med Case Rep \n2011 ;5 :491–5 .21968082 \n[18] Grunwald V Le Blanc S Karstens JH \nMetastatic malignant ameloblastoma responding to chemotherapy with paclitaxel and carboplatin . Ann Oncol \n2001 ;12 :1489–91 .11762824 \n[19] Ghiam A Al Zaharani A Feld R \nA case of recurrent metastatic ameloblastoma and hypercalcaemia successfully treated with carboplatin and paclitaxel: long survival and prolonged stable disease . Ecancermedicalscience \n2013 ;7 :323–7 .23781278 \n[20] Ramadas K Jose CC Subhashini J \nPulmonary metastases from ameloblastoma of the mandible treated with cisplatin, adriamycin, and cyclophosphamide . Cancer \n1990 ;66 :1475–9 .2207999 \n[21] Fayette J Penel N Chevreau C \nPhase III trial of standard versus dose-intensified doxorubicin, ifosfamide and dacarbazine (MAID) in the first-line treatment of metastatic and locally advanced soft tissue sarcoma . Invest New Drugs \n2009 ;27 :482–9 .19148579 \n[22] Ogura K Goto T Imanishi J \nNeoadjuvant and adjuvant chemotherapy with modified mesna, adriamycin, ifosfamide, and dacarbazine (MAID) regimen for adult high-grade non-small round cell soft tissue sarcomas . Int J Clin Oncol \n2013 ;18 :170–6 .22179493 \n[23] Lee J Jung HA Kim Y \nEfficacy of mesna, doxorubicin, ifosfamide, and dacarbazine (MAID) in patients with advanced pulmonary pleomorphic carcinoma . Lung Cancer \n2018 ;122 :160–4 .30032825 \n[24] Diniz MG Gomes CC Guimarães BV \nAssessment of BRAFV600E and SMOF412E mutations in epithelial odontogenic tumours . Tumour Biol \n2015 ;36 :5649–53 .25854168 \n[25] Brown NA Rolland D Mchugh JB \nActivating FGFR2-RAS-BRAF mutations in ameloblastoma . Clin Cancer Res \n2014 ;20 :5517–26 .24993163 \n[26] Brown NA Betz BL \nAmeloblastoma: a review of recent molecular pathogenetic discoveries . Biomark Cancer \n2015 ;7 Suppl 2 :19–24 .\n[27] Kumamoto H Ohki K Ooya K \nAssociation between vascular endothelial growth factor (VEGF) expression and tumor angiogenesis in ameloblastomas . J Oral Pathol Med \n2002 ;31 :28–34 .11896820 \n[28] Vered M Shohat I Buchner A \nEpidermal growth factor receptor expression in ameloblastoma . Oral Oncol \n2003 ;39 :138–43 .12509966 \n[29] Zhong Y Guo W Wang L \nMolecular markers of tumor invasiveness in ameloblastoma: an update . Ann Maxillofac Surg \n2011 ;1 :145–9 .23482687\n\n",
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"mesh_terms": "D000328:Adult; D000564:Ameloblastoma; D000971:Antineoplastic Combined Chemotherapy Protocols; D001932:Brain Neoplasms; D003606:Dacarbazine; D018572:Disease-Free Survival; D004317:Doxorubicin; D005260:Female; D006801:Humans; D007069:Ifosfamide; D007573:Jaw Neoplasms; D008175:Lung Neoplasms; D015080:Mesna; D009362:Neoplasm Metastasis; D009364:Neoplasm Recurrence, Local; D016896:Treatment Outcome",
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"title": "MAID chemotherapy regimen as a treatment strategy for metastatic malignant ameloblastoma: A case report.",
"title_normalized": "maid chemotherapy regimen as a treatment strategy for metastatic malignant ameloblastoma a case report"
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"abstract": "The aim of this study is to report the side effects of oral topiramate in two young patients presented with bilateral ocular blurring and discomfort, causing unique development of secondary acute angle closure (AAC) after discontinuation of oral topiramate. Both patients, with a history of seizure and migraine, respectively, were taking oral topiramate to control their mentioned diseases. Both had secondary AAC and high intraocular pressure, after discontinuing topiramate. They were treated with topical medications and underwent initial and subsequent multimodal imaging to track up their response to the management. Ocular side effect, during topiramate use and possibly even after discontinuation, will improve early detection of secondary AAC. Topical management along with multimodal imaging of such cases can give optimal results.",
"affiliations": "King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia.;King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia.;King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia.;King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia.;King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia.",
"authors": "Alzendi|Nouf A|NA|;Badawi|Abdulrahman H|AH|;Alhazzaa|Bader|B|;Alshahrani|Ali|A|;Owaidhah|Ohoud|O|",
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"fulltext": "\n==== Front\nSaudi J Ophthalmol\nSaudi J Ophthalmol\nSJO\nSaudi Journal of Ophthalmology\n1319-4534\n2542-6680\nWolters Kluwer - Medknow India\n\nSJO-34-202\n10.4103/SJOPT.SJOPT_9_20\nCase Report\nTopiramate-induced angle closure glaucoma: Two unique case reports\nAlzendi Nouf A.\nBadawi Abdulrahman H.\nAlhazzaa Bader\nAlshahrani Ali\nOwaidhah Ohoud\nKing Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia\nAddress for correspondence: Dr. Nouf A. Alzendi, King Khaled Eye Specialist Hospital, PO Box 7191, Riyadh 11462, Saudi Arabia. E-mail: nouf.alzendi@gmail.com\nJul-Sep 2020\n27 2 2021\n34 3 202204\n04 9 2020\n31 10 2020\n02 12 2020\nCopyright: © 2021 Saudi Journal of Ophthalmology\n2021\nhttps://creativecommons.org/licenses/by-nc-sa/4.0/ This 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.\nThe aim of this study is to report the side effects of oral topiramate in two young patients presented with bilateral ocular blurring and discomfort, causing unique development of secondary acute angle closure (AAC) after discontinuation of oral topiramate. Both patients, with a history of seizure and migraine, respectively, were taking oral topiramate to control their mentioned diseases. Both had secondary AAC and high intraocular pressure, after discontinuing topiramate. They were treated with topical medications and underwent initial and subsequent multimodal imaging to track up their response to the management. Ocular side effect, during topiramate use and possibly even after discontinuation, will improve early detection of secondary AAC. Topical management along with multimodal imaging of such cases can give optimal results.\n\nAcute angle closure glaucoma\nciliochoroidal effusion\ntopiramate\n==== Body\nINTRODUCTION\n\nTopiramate is an oral drug used in the management of seizures, migraines, and neurogenic pain.[123] It has previously been reported that topiramate and other sulfa-containing drugs are associated with secondary acute angle closure (AAC) and myopic shift.[45] We report two cases of bilateral secondary angle closure glaucoma related to topiramate discontinuation and the use of multimodal imaging for establishing the diagnosis and tracking patients improvements. To the best of our knowledge, there is no report using multimodal imaging to diagnose and follow-up patients presented with topiramate-induced bilateral angle closure glaucoma after discontinuing oral topiramate.\n\nCASE REPORTS\n\nCase 1\n\nA 15-year-old girl presented to the emergency department with a complaint of 1-day blurry vision and ocular discomfort in both eyes, not associated with headache, vomiting, or nausea. Her medical history was notable for seizures. The patient was not on medications on presentation. She used topiramate 25 mg once daily for 4 days and then stopped the medication for 7 days before the presentation. On initial examination, her visual acuity (VA) was 20/400 in both eyes (OU) without correction, reaching 20/80 OU with pinhole (OD: −4.25–1.25 × 15 and OS: −4.50–1.00 × 15). Her intraocular pressure (IOP) measured 45 mmHg in the right eye and 37 mmHg in the left eye. Her pupils were normal. A slit-lamp examination showed conjunctival injections, mild corneal edema, and markedly shallow anterior chamber in both eyes. Gonioscopic examination showed appositional angle closure for 360° in both eyes. Fundus examination of both eyes was unremarkable, with healthy optic discs [Figure 1a]. B-scan ultrasonography showed 360° low-lying choroidal effusions [Figure 1b]. Ultrasound biomicroscopy (UBM) of both eyes revealed total closed angels, due to lens pushing the iris forward, choroidal effusion, and anterior rotation of ciliary body (CB) [Figure 1c and d]. The patient was diagnosed with bilateral AAC glaucoma secondary to topiramate. She was given stat topical atropine 1%, timolol maleate 0.5%, apraclonidine 0.5%, and prednisolone acetate 1% in both eyes for three doses 15 min apart. Once the IOP was deemed appropriate, the patient was discharged with topical combination of brimonidine 0.2%/timolol maleate 0.5% BID, bimatoprost 0.01% QHS, atropine 1% TID, and prednisolone acetate 1% QID in both eyes. One day after the initial examination, the patient comfort level was good and reported an improvement in her vision. VA with pinhole testing was 20/25 OU, and IOP measured 13 mmHg in the right eye and 11 mmHg in the left eye. The anterior chambers were still shallow, with minimal deepening centrally. After 1 week of initial presentation and treatment, the patient VA was 20/20 OU with correction (OD: +2.25–1.25 × 15, and OS: +2.25–1.00 × 15), and the IOP measured 12 mmHg in the right eye and 11 mmHg in the left eye. The anterior chambers were deep and quiet, and UBM and B-scan showed normal findings [Figure 1e and f]. The patient was kept on bimatoprost 0.01% once a daily; other antiglaucoma drops and prednisolone acetate 1% were discontinued; atropine 1% was changed to cyclopentolate TID. On her next follow-up, a week later, the patient's VA was 20/20 OU with the same correction, IOP was 11 mmHg in both eyes, complete recovery has been noted, and all drops were discontinued.\n\nFigure 1 (case 1) (a) Fundus photograph with healthy optic nerve disc in both eye; (b) B-scan ultrasonography of the right eye manifesting 360° low-lying peripheral choroidal effusions; (c and d) an ultrasound biomicroscopy revealed both eyes with total closed angels, choroidal effusion, and anterior rotation of ciliary body at the time of the presentation of the patient (pretreatment) (c, right eye; d, left eye); (e and f) ultrasound biomicroscopy showing resolved choroidal effusion and deepening of the angle after treatment (e, right eye; f, left eye)\n\nCase 2\n\nA 24-year-old female presented with a complaint of bilateral ocular pain, associated with blurriness of vision, headache, and nausea. Her medical history is significant for migraine. She was on oral topiramate 25 mg per day for 1 week and discontinued the topiramate 4 days before her presentation. On initial examination, her uncorrected VA was 3/200 OU. Reaching 20/30 OU with correction of − 6.00 sphere OU, IOP was 35 OU and pupils were normal. A slit-lamp examination showed mild conjunctival injections, clear cornea, and markedly shallow anterior chamber in both eyes. Gonioscopic examination showed appositional angle closure for 360° in both eyes. Fundus examination of both eyes was unremarkable, with healthy optic discs. B-scan ultrasonography showed 360° choroidal effusions [Figure 2a and b]. UBM of both eyes revealed 360° narrow angels and CB detachment [Figure 2c and d]. Again, this patient was diagnosed with bilateral ACC glaucoma secondary to topiramate. She was given topical atropine 1%, timolol maleate 0.5%, apraclonidine 0.5%, and prednisolone acetate 1% in both eyes for three doses 15 min apart. One hour after the medications, her IOP dropped to 21 mmHg OD and 24 mmHg OS. The patient was discharged with topical combination of dorzolamide 2%/timolol maleate 0.5% BID, latanoprost 0.005% once daily, brimonidine tartrate 0.15% BID, atropine 1% TID, and prednisolone acetate 1% QID for both eyes. Two days after the treatment, the patient expressed comfort and reported an improvement in her vision. VA with pinhole testing was 20/30 OU, and IOP measured 08 mmHg in the right eye and 11 mmHg in the left eye. The anterior chambers were still shallow. The patient was kept on brimonidine tartrate 0.15% BID, prednisolone acetate 1%, and atropine 1% TID; other antiglaucoma drops were discontinued. On her next follow-up, a week later, the patient's visual acuity was 20/30 OU with correction (OD: +0.25–0.75 × 180 and OS: PL–1.00 × 180), IOP was 11 mmHg both eyes, B-scan showed complete recovery of choroidal detachment [Figure 2e and f], UBM showed complete recovery of CB detachment [Figure 2g and h], and all drops were stopped.\n\nFigure 2 (case 2) (a and b) B-Scan ultrasonography of both eyes (a, right eye; b, left eye), showing 360° peripheral choroidal effusions at the time of presentation of the patient; (c and d) ultrasound biomicroscopy of both eyes (c, right eye; d, left eye) with closed angels, choroidal effusion, and anterior rotation of ciliary body (pretreatment); (e and f) recovery of choroidal detachment on B-scan after treatment (e, right eye; f, left eye); (g and h) ultrasound biomicroscopy with resolved choroidal effusion and deepening of the angle after treatment (g, right eye; h, left eye)\n\nDISCUSSION\n\nTopiramate, brand name Topamax, is an oral sulfamate medication used for epilepsy, migraine, and neuropathic pain management in adults and children older than 2 years.[1] The exact mechanism of topiramate is unknown. Since both migraine and epilepsy share some pathophysiologic properties, it is believed that topiramate exhibits same mechanism of action in both diseases. Several studies reported that the half-life of Topamax range from 21 h up to 27.2 days.[23]\n\nThe incidence of bilateral angle closure glaucoma secondary to topiramate use is rare.[4] Lan et al. reported two cases of bilateral AAC glaucoma while using topiramate for 3 weeks period.[5] Grewal et al. described one case with similar attack of bilateral angle closure glaucoma after using combination agent containing topiramate for weight loss for 1-week duration with complete recovery after medical treatment.[6] Moreover, Senthil et al. published a case series in which one of the cases had 4 days duration of topiramate usage.[7]\n\nWe report the third case report of topiramate-induced bilateral angle closure glaucoma after discontinuing the medication; both cases developed the symptoms 7 and 4 days, respectively, of stopping the topiramate medication. Two other published reports mentioned similar findings after disusing topiramate 14 and 7 days, respectively.[89] To the best of our knowledge, this is the first case report using multimodal imaging in diagnosing and following up patients utilizing different modalities. We believe that the persistent effect of topiramate after few days of discontinuation in our reported cases resulted in the presentation of bilateral angle closure glaucoma. This was supported by one third-level evidence trial that examined migraine frequency after the end of prophylaxis topiramate treatment, investigators noticed that topiramate treatment had persistent benefit, because the number of migraine days did not return to pretreatment values.[10]\n\nOral carbonic anhydrase inhibitors as well as hyperosmolar agents are frequently used in acute cases with marked elevation of IOPs.[11] Nevertheless, other reports recommend caution over the use of acetazolamide as this agent is also a sulfa-derived drug and may exacerbate the problem.[12]\n\nIn conclusion, the incidence of ocular complications appears to be rare. However, with increasing use of topiramate, it is necessary to inform and educate the patients about the possible complications, to seek assistance from healthcare providers at an early stage for appropriate management. Further studies needed to prove the persistent effect of topiramate after discontinuation. Topical treatment with antiglaucoma, steroid, and atropine only can help fasten the recovery and restore patients vision with optimal IOP. Finally, we encourage ophthalmologists to use multimodal imaging to diagnose and follow-up patients improvement.\n\nDeclaration of patient consent\n\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 initial s will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.\n\nFinancial support and sponsorship\n\nNil.\n\nConflicts of interest\n\nThere are no conflicts of interest.\n==== Refs\nREFERENCES\n\n1 Nickel C Lahmann C Tritt K Muehlbacher M Kaplan P Kettler C Topiramate in treatment of depressive and anger symptoms in female depressive patients: A randomized, double-blind, placebo-controlled study J Affect Disord 2005 87 243 52 15985295\n2 Minton GC Miller AD Bookstaver PB Love BL Topiramate: Safety and efficacy of its use in the prevention and treatment of migraine J Cent Nerv Syst Dis 2011 3 155 68 23861645\n3 Gidal BE Clark AM Anders B Gilliam F The application of half-life in clinical decision making: Comparison of the pharmacokinetics of extended-release topiramate (USL255) and immediate-release topiramate Epilepsy Res 2017 129 26 32 27883934\n4 Quagliato LB Barella K Abreu Neto JM Quagliato EM Topiramate-associated acute, bilateral, angle-closure glaucoma: Case report Arq Bras Oftalmol 2013 76 48 9 23812529\n5 Lan YW Hsieh JW Bilateral acute angle closure glaucoma and myopic shift by topiramate-induced ciliochoroidal effusion: Case report and literature review Int Ophthalmol 2018 38 2639 48 29063980\n6 Grewal DS Goldstein DA Khatana AK Tanna AP Bilateral angle closure following use of a weight loss combination agent containing topiramate J Glaucoma 2015 24 e132 6 25304279\n7 Senthil S Garudadri C Rao HB Maheshwari R Bilateral simultaneous acute angle closure caused by sulphonamide derivatives: A case series Indian J Ophthalmol 2010 58 248 52 20413935\n8 Tambe V Goodman A Tambe A Hess M Topiramate-associated acute angle closure glaucoma with myopic shift Am J Ther 2020 27 e537 e538 32039989\n9 Mazumdar S Tripathy K Sarma B Agarwal N Acquired myopia followed by acquired hyperopia due to serous neurosensory retinal detachment following topiramate intake Eur J Ophthalmol 2019 29 NP21 NP24 30175623\n10 Diener HC Agosti R Allais G Bergmans P Bussone G Davies B Cessation versus continuation of 6-month migraine preventive therapy with topiramate (PROMPT): A randomised, double-blind, placebo-controlled trial Lancet Neurol 2007 6 1054 62 17988947\n11 Medeiros FA Zhang XY Bernd AS Weinreb RN Angle-closure glaucoma associated with ciliary body detachment in patients using topiramate Arch Ophthalmol 2003 121 282 5 12583802\n12 Gawley SD Topiramate induced acute transient myopia: A case report Cases J 2009 2 7430 19829963\n\n",
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"issn_linking": "1319-4534",
"issue": "34(3)",
"journal": "Saudi journal of ophthalmology : official journal of the Saudi Ophthalmological Society",
"keywords": "Acute angle closure glaucoma; ciliochoroidal effusion; topiramate",
"medline_ta": "Saudi J Ophthalmol",
"mesh_terms": null,
"nlm_unique_id": "9425601",
"other_id": null,
"pages": "202-204",
"pmc": null,
"pmid": "34085015",
"pubdate": "2020",
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"title": "Topiramate-induced angle closure glaucoma: Two unique case reports.",
"title_normalized": "topiramate induced angle closure glaucoma two unique case reports"
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"abstract": "To date, no randomized clinical trials have investigated perioperative systemic therapy relative to cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) alone for resectable colorectal peritoneal metastases (CPM).\nTo assess the feasibility and safety of perioperative systemic therapy in patients with resectable CPM and the response of CPM to neoadjuvant treatment.\nAn open-label, parallel-group phase 2 randomized clinical trial in all 9 Dutch tertiary centers for the surgical treatment of CPM enrolled participants between June 15, 2017, and January 9, 2019. Participants were patients with pathologically proven isolated resectable CPM who did not receive systemic therapy within 6 months before enrollment.\nRandomization to perioperative systemic therapy or CRS-HIPEC alone. Perioperative systemic therapy comprised either four 3-week neoadjuvant and adjuvant cycles of CAPOX (capecitabine and oxaliplatin), six 2-week neoadjuvant and adjuvant cycles of FOLFOX (fluorouracil, leucovorin, and oxaliplatin), or six 2-week neoadjuvant cycles of FOLFIRI (fluorouracil, leucovorin, and irinotecan) and either four 3-week adjuvant cycles of capecitabine or six 2-week adjuvant cycles of fluorouracil with leucovorin. Bevacizumab was added to the first 3 (CAPOX) or 4 (FOLFOX/FOLFIRI) neoadjuvant cycles.\nProportions of macroscopic complete CRS-HIPEC and Clavien-Dindo grade 3 or higher postoperative morbidity. Key secondary outcomes were centrally assessed rates of objective radiologic and major pathologic response of CPM to neoadjuvant treatment. Analyses were done modified intention-to-treat in patients starting neoadjuvant treatment (experimental arm) or undergoing upfront surgery (control arm).\nIn 79 patients included in the analysis (43 [54%] men; mean [SD] age, 62 [10] years), experimental (n = 37) and control (n = 42) arms did not differ significantly regarding the proportions of macroscopic complete CRS-HIPEC (33 of 37 [89%] vs 36 of 42 [86%] patients; risk ratio, 1.04; 95% CI, 0.88-1.23; P = .74) and Clavien-Dindo grade 3 or higher postoperative morbidity (8 of 37 [22%] vs 14 of 42 [33%] patients; risk ratio, 0.65; 95% CI, 0.31-1.37; P = .25). No treatment-related deaths occurred. Objective radiologic and major pathologic response rates of CPM to neoadjuvant treatment were 28% (9 of 32 evaluable patients) and 38% (13 of 34 evaluable patients), respectively.\nIn this randomized phase 2 trial in patients diagnosed with resectable CPM, perioperative systemic therapy seemed feasible, safe, and able to induce response of CPM, justifying a phase 3 trial.\nClinicalTrials.gov Identifier: NCT02758951.",
"affiliations": "Department of Surgery, Catharina Cancer Institute, Eindhoven, the Netherlands.;Department of Surgery, Catharina Cancer Institute, Eindhoven, the Netherlands.;Department of Surgery, Catharina Cancer Institute, Eindhoven, the Netherlands.;Department of Surgery, Catharina Cancer Institute, Eindhoven, the Netherlands.;Department of Medical Oncology, Catharina Cancer Institute, Eindhoven, the Netherlands.;Department of Medical Oncology, Catharina Cancer Institute, Eindhoven, the Netherlands.;Department of Surgery, Erasmus MC Cancer Institute, Rotterdam, the Netherlands.;Department of Surgery, Erasmus MC Cancer Institute, Rotterdam, the Netherlands.;Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands.;Department of Surgery, Amsterdam University Medical Centers, location VUMC, Amsterdam, the Netherlands.;Department of Surgery, Amsterdam University Medical Centers, location VUMC, Amsterdam, the Netherlands.;Department of Medical Oncology, Amsterdam University Medical Centers, location VUMC, Amsterdam, the Netherlands.;Department of Surgery, Netherlands Cancer Institute, Amsterdam, the Netherlands.;Department of Surgery, Netherlands Cancer Institute, Amsterdam, the Netherlands.;Department of Gastrointestinal Oncology, Netherlands Cancer Institute, Amsterdam, the Netherlands.;Department of Surgery, Sint Antonius Hospital, Nieuwegein, the Netherlands.;Department of Surgery, Sint Antonius Hospital, Nieuwegein, the Netherlands.;Department of Medical Oncology, Sint Antonius Hospital, Nieuwegein, the Netherlands.;Department of Surgery, Radboud University Medical Center, Nijmegen, the Netherlands.;Department of Surgery, Radboud University Medical Center, Nijmegen, the Netherlands.;Department of Medical Oncology, Radboud University Medical Center, Nijmegen, the Netherlands.;Department of Surgery, University Medical Center Groningen, Groningen, the Netherlands.;Department of Medical Oncology, University Medical Center Groningen, Groningen, the Netherlands.;Department of Surgery, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.;Department of Surgery, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.;Department of Medical Oncology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.;Department of Radiology, Catharina Cancer Institute, Eindhoven, the Netherlands.;Department of Radiology, Netherlands Cancer Institute, Amsterdam, the Netherlands.;Cancer Center, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.;Department of Pathology, Netherlands Cancer Institute, Amsterdam, the Netherlands.;Department of Pathology, Netherlands Cancer Institute, Amsterdam, the Netherlands.;Department of Pathology, Netherlands Cancer Institute, Amsterdam, the Netherlands.;Department of Surgery, University Medical Center Groningen, Groningen, the Netherlands.;Department of Epidemiology and Data Science, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands.;Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands.;Department of Surgery, Amsterdam University Medical Centers, University of Amsterdam, Cancer Center Amsterdam, Amsterdam, the Netherlands.;Department of Surgery, Catharina Cancer Institute, Eindhoven, the Netherlands.",
"authors": "Rovers|Koen P|KP|;Bakkers|Checca|C|;Nienhuijs|Simon W|SW|;Burger|Jacobus W A|JWA|;Creemers|Geert-Jan M|GM|;Thijs|Anna M J|AMJ|;Brandt-Kerkhof|Alexandra R M|ARM|;Madsen|Eva V E|EVE|;van Meerten|Esther|E|;Tuynman|Jurriaan B|JB|;Kusters|Miranda|M|;Versteeg|Kathelijn S|KS|;Aalbers|Arend G J|AGJ|;Kok|Niels F M|NFM|;Buffart|Tineke E|TE|;Wiezer|Marinus J|MJ|;Boerma|Djamila|D|;Los|Maartje|M|;de Reuver|Philip R|PR|;Bremers|Andreas J A|AJA|;Verheul|Henk M W|HMW|;Kruijff|Schelto|S|;de Groot|Derk Jan A|DJA|;Witkamp|Arjen J|AJ|;van Grevenstein|Wilhelmina M U|WMU|;Koopman|Miriam|M|;Nederend|Joost|J|;Lahaye|Max J|MJ|;Kranenburg|Onno|O|;Fijneman|Remond J A|RJA|;van 't Erve|Iris|I|;Snaebjornsson|Petur|P|;Hemmer|Patrick H J|PHJ|;Dijkgraaf|Marcel G W|MGW|;Punt|Cornelis J A|CJA|;Tanis|Pieter J|PJ|;de Hingh|Ignace H J T|IHJT|;|||",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1001/jamasurg.2021.1642",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2168-6254",
"issue": "156(8)",
"journal": "JAMA surgery",
"keywords": null,
"medline_ta": "JAMA Surg",
"mesh_terms": null,
"nlm_unique_id": "101589553",
"other_id": null,
"pages": "710-720",
"pmc": null,
"pmid": "34009291",
"pubdate": "2021-08-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Perioperative Systemic Therapy vs Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy Alone for Resectable Colorectal Peritoneal Metastases: A Phase 2 Randomized Clinical Trial.",
"title_normalized": "perioperative systemic therapy vs cytoreductive surgery and hyperthermic intraperitoneal chemotherapy alone for resectable colorectal peritoneal metastases a phase 2 randomized clinical trial"
} | [
{
"companynumb": "NL-MYLANLABS-2022M1018781",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "FLUOROURACIL"
},
"drugadditional": null,
... |
{
"abstract": "We assessed the virological efficacy of a 6 month maraviroc/raltegravir simplification strategy following 6 months of quadruple therapy combining tenofovir disoproxil fumarate/emtricitabine with maraviroc/raltegravir.\n\n\n\nHIV-1-infected naive patients were enrolled in an open label, single-arm, Phase 2 trial. All patients received maraviroc 300 mg twice daily, raltegravir 400 mg twice daily and tenofovir/emtricitabine for 24 weeks. Patients with stable HIV-RNA <50 copies/mL stopped tenofovir/emtricitabine at week (W) 24 and pursued maraviroc/raltegravir until W48. The primary endpoint was the virological response defined by HIV-RNA <50 copies/mL at W48.\n\n\n\nThirty-three patients were analysed. Patients were mostly male (94%), Caucasians (91%), MSM (82%); their median age was 42 years. At baseline, median CD4 cell count was 453 cells/mm3 and HIV-RNA was 4.3 log copies/mL. All patients had CCR5-tropic viruses by genotropism and phenotropism assays. All but one patient had an HIV-RNA < 50 copies/mL at W24 and entered the simplification phase. Virological success was maintained at W48 in 88% (90% CI 79%-97%) of patients. N155H mutation was detected at failure in one patient. No tropism switch was observed. Raltegravir and maraviroc plasma exposure were satisfactory in 92% and 79% of 41 samples from 21 patients. Five severe adverse events (SAEs) were observed up to W48; none was related to the study drugs. Four patients presented grade 3 AEs; none was related to the study. No grade 4 AE was observed. No patient died.\n\n\n\nMaraviroc/raltegravir maintenance therapy following a 6 month induction phase with maraviroc/raltegravir/tenofovir/emtricitabine was well tolerated and maintained virological efficacy in these carefully selected patients.",
"affiliations": "Centre for Clinical Research, Department of Hepatology, Croix-Rousse Hospital, Hospices Civils de Lyon, Lyon, France.;Department of Infectious Diseases, Hôpital de l'Archet, Nice, France.;Centre for Clinical Research, Department of Hepatology, Croix-Rousse Hospital, Hospices Civils de Lyon, Lyon, France.;Department of Virology, Croix-Rousse Hospital, Hospices Civils de Lyon, Lyon, France.;Department of Virology, Hôpital de l'Archet, Nice, France.;INSERM U1043, Toulouse, France.;Department of Infectious Diseases, Nantes University Hospital, Nantes, France.;Department of Infectious Diseases, Hôpital Nord, Saint Etienne, France.;Department of Pharmacology, Hôpital E. Herriot, Hospices Civils de Lyon, Lyon, France.;Department of Infectious Diseases, Saint-Louis Hospital, Paris, France.;Department of Infectious Diseases, CHU Gabriel Montpied, Clermont-Ferrand, France.;Department of Internal Medicine, Centre Hospitalier de Cannes, Cannes, France.;Department of Infectious Diseases, Hôpital de l'Archet, Nice, France.;Department of Infectious Diseases and Tropical Medicine, Croix-Rousse Hospital, Hospices Civils de Lyon, Lyon, France laurent.cotte@chu-lyon.fr.",
"authors": "Pradat|Pierre|P|;Durant|Jacques|J|;Brochier|Corinne|C|;Trabaud|Mary-Anne|MA|;Cottalorda-Dufayard|Jacqueline|J|;Izopet|Jacques|J|;Raffi|François|F|;Lucht|Frédéric|F|;Gagnieu|Marie-Claude|MC|;Gatey|Caroline|C|;Jacomet|Christine|C|;Vassallo|Matteo|M|;Dellamonica|Pierre|P|;Cotte|Laurent|L|;|||",
"chemical_list": "D019380:Anti-HIV Agents; D003510:Cyclohexanes; D014230:Triazoles; D000068898:Raltegravir Potassium; D000068698:Tenofovir; D000068679:Emtricitabine; D000077592:Maraviroc",
"country": "England",
"delete": false,
"doi": "10.1093/jac/dkw273",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0305-7453",
"issue": "71(11)",
"journal": "The Journal of antimicrobial chemotherapy",
"keywords": null,
"medline_ta": "J Antimicrob Chemother",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D019380:Anti-HIV Agents; D023241:Antiretroviral Therapy, Highly Active; D003510:Cyclohexanes; D000068679:Emtricitabine; D005260:Female; D015658:HIV Infections; D015497:HIV-1; D006801:Humans; D060046:Maintenance Chemotherapy; D008297:Male; D000077592:Maraviroc; D008875:Middle Aged; D000068898:Raltegravir Potassium; D000068698:Tenofovir; D016896:Treatment Outcome; D014230:Triazoles; D019562:Viral Load; D055815:Young Adult",
"nlm_unique_id": "7513617",
"other_id": null,
"pages": "3235-3241",
"pmc": null,
"pmid": "27432606",
"pubdate": "2016-11",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Maraviroc/raltegravir simplification strategy following 6 months of quadruple therapy with tenofovir/emtricitabine/maraviroc/raltegravir in treatment-naive HIV patients.",
"title_normalized": "maraviroc raltegravir simplification strategy following 6 months of quadruple therapy with tenofovir emtricitabine maraviroc raltegravir in treatment naive hiv patients"
} | [
{
"companynumb": "FR-VIIV HEALTHCARE LIMITED-FR2017133551",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MARAVIROC"
},
"drugadditional":... |
{
"abstract": "Immunoglobulin light chain amyloidosis remains incurable despite recent therapeutic advances, and is particularly difficult to treat in patients with amyloid cardiomyopathy. Based on evidence of activity in multiple myeloma, we designed a pilot study of an oral regimen of lenalidomide in combination with dexamethasone and low-dose melphalan in order to evaluate its safety and efficacy in patients with amyloidosis, including those with advanced cardiac involvement. Twenty-five patients were enrolled. Ninety-two percent of patients had cardiac involvement by amyloidosis, and 36% of patients met the criteria for Mayo Clinic cardiac stage III disease. Patients received up to nine cycles of treatment, consisting of lenalidomide 10 mg/day orally on days 1 - 21 (28-day cycle); melphalan 0.18 mg/kg orally on days 1-4; and dexamethasone 40 mg orally on days 1, 8, 15, and 22. High rates (33%) of cardiac arrhythmias and low rates of treatment completion (12.5%) were observed. Ten patients died during the study, all within the first several months of treatment due to acute cardiac events. The overall hematologic response rate was 58%, however organ responses were seen in only 8% of patients. The overall survival rate at 1 year was 58%. While we confirmed the hematologic response rates observed with similar regimens, front-line treatment with melphalan, lenalidomide and dexamethasone was toxic, ineffective, and did not alter survival outcomes for patients with high-risk cardiac disease. Our data highlight the importance of developing novel treatment approaches for amyloid cardiomyopathy. This trial was registered at www.clinicaltrials.gov (NCT00890552).",
"affiliations": "mliedtke@stanford.edu.",
"authors": "Dinner|Shira|S|;Witteles|Wesley|W|;Afghahi|Anosheh|A|;Witteles|Ronald|R|;Arai|Sally|S|;Lafayette|Richard|R|;Schrier|Stanley L|SL|;Liedtke|Michaela|M|",
"chemical_list": "D007147:Immunoglobulin Light Chains; D013792:Thalidomide; D003907:Dexamethasone; D000077269:Lenalidomide; D008558:Melphalan",
"country": "Italy",
"delete": false,
"doi": "10.3324/haematol.2013.084574",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0390-6078",
"issue": "98(10)",
"journal": "Haematologica",
"keywords": null,
"medline_ta": "Haematologica",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000686:Amyloidosis; D015331:Cohort Studies; D003907:Dexamethasone; D004359:Drug Therapy, Combination; D005260:Female; D006331:Heart Diseases; D006801:Humans; D007147:Immunoglobulin Light Chains; D000077269:Lenalidomide; D008297:Male; D008558:Melphalan; D008875:Middle Aged; D010865:Pilot Projects; D015996:Survival Rate; D013792:Thalidomide",
"nlm_unique_id": "0417435",
"other_id": null,
"pages": "1593-9",
"pmc": null,
"pmid": "23716538",
"pubdate": "2013-10",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "22331187;22517904;18691169;17855669;20375312;16044444;22475872;18779964;17008538;12904524;21127185;21193650;21630308;17785703;8629674;14986485;23091105;15070667;16960148;15057291;22331188;16530576;21562045;20872958;22983583;20085941;16990593;22504925;23144200;20724537;17673601;17920916;20821326;9110907",
"title": "Lenalidomide, melphalan and dexamethasone in a population of patients with immunoglobulin light chain amyloidosis with high rates of advanced cardiac involvement.",
"title_normalized": "lenalidomide melphalan and dexamethasone in a population of patients with immunoglobulin light chain amyloidosis with high rates of advanced cardiac involvement"
} | [
{
"companynumb": "US-MYLANLABS-2017M1011162",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "DEXAMETHASONE"
},
"drugadditional": null,
... |
{
"abstract": "Drug-induced liver injury is the fourth most common cause of liver disease in industrialised countries. Methylprednisolone is often considered to be a treatment with a low hepatotoxicity. We report a case of methylprednisolone-induced liver injury in a 35-year-old woman. She was admitted to our department for acute liver injury 2 months after a treatment with high dose of methylprednisolone (1 g/day) for a multiple sclerosis relapse. No other cause of liver injury could be found (screening for hepatotropic viruses, autoimmune antibodies, ceruloplasmin, abdominal ultrasonography and liver biopsy). Liver function tests spontaneously improved and returned to normal range within 6 weeks. We also performed a brief review of the literature and identified 12 other cases of methylprednisolone-induced liver injury in patients treated for multiple sclerosis relapse. An immune rebound phenomenon could be responsible for rare but true hepatotoxicity of high-dose methylprednisolone therapy.",
"affiliations": "Department of Hepato Gastroenterology and Nutirtion, Hopital Antoine-Beclere, Clamart, France.;Department of Pathology, Hopital Antoine-Beclere, Clamart, France.;Department of Hepato Gastroenterology and Nutirtion, Hopital Antoine-Beclere, Clamart, France.;Department of Hepato Gastroenterology and Nutirtion, Hopital Antoine-Beclere, Clamart, France.",
"authors": "Bresteau|Clement|C|;Prevot|Sophie|S|;Perlemuter|Gabriel|G|;Voican|Cosmin|C|",
"chemical_list": "D005938:Glucocorticoids; D008775:Methylprednisolone",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2017-223670",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2018()",
"journal": "BMJ case reports",
"keywords": "contraindications and precautions; hepatitis other; multiple sclerosis; safety",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000328:Adult; D001706:Biopsy; D056486:Chemical and Drug Induced Liver Injury; D002908:Chronic Disease; D005938:Glucocorticoids; D006801:Humans; D008099:Liver; D008775:Methylprednisolone; D020529:Multiple Sclerosis, Relapsing-Remitting",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "29507031",
"pubdate": "2018-03-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "15967341;21455003;17264438;19931994;16083708;26676833;24935270;23318289;22140391;23723114;19159178;24906135;12143055;18803363;8229110;11805241;28438569;15186621",
"title": "Methylprednisolone-induced acute liver injury in a patient treated for multiple sclerosis relapse.",
"title_normalized": "methylprednisolone induced acute liver injury in a patient treated for multiple sclerosis relapse"
} | [
{
"companynumb": "FR-JUBILANT CADISTA PHARMACEUTICALS-2018JUB00164",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE"
},
... |
{
"abstract": "We describe a rare case of recurrent pulmonary nocardiosis (PN) in a hematopoietic stem cell transplant recipient. The patient developed Nocardia farcinica infection while receiving corticosteroid and cyclosporine for the treatment of bronchiolitis obliterans, probably due to chronic graft-versus-host disease (cGVHD). The patient responded well to the initial treatment with meropenem, but PN recurred 3 times during oral maintenance therapies using different antibiotics, which were chosen on the basis of the results of in vitro susceptibility testing against N farcinica Minocycline, amoxicillin/clavulanate, and levofloxacin were not effective as oral maintenance therapies. Frequent exacerbation of PN was considered to have resulted from the low blood concentration of these antibiotics, and decreased gastrointestinal absorption, probably due to cGVHD, might have been the underlying problem.",
"affiliations": "Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, 3-18-22 Honkomagome, Bunkyo-ku, Tokyo, Japan.",
"authors": "Kakihana|Kazuhiko|K|;Ohashi|Kazuteru|K|;Iguchi|Mari|M|;Negishi|Kumiko|K|;Suzuki|Tomokazu|T|;Shitara|Minori|M|;Honma|Misao|M|;Akiyama|Hideki|H|;Sakamaki|Hisashi|H|",
"chemical_list": "D000305:Adrenal Cortex Hormones; D000900:Anti-Bacterial Agents",
"country": "Japan",
"delete": false,
"doi": "10.1532/IJH97.07015",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0925-5710",
"issue": "86(5)",
"journal": "International journal of hematology",
"keywords": null,
"medline_ta": "Int J Hematol",
"mesh_terms": "D000293:Adolescent; D000305:Adrenal Cortex Hormones; D000900:Anti-Bacterial Agents; D001989:Bronchiolitis Obliterans; D002908:Chronic Disease; D006086:Graft vs Host Disease; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008297:Male; D009615:Nocardia; D009617:Nocardia Infections; D018410:Pneumonia, Bacterial; D014057:Tomography, X-Ray Computed; D014184:Transplantation, Homologous",
"nlm_unique_id": "9111627",
"other_id": null,
"pages": "455-8",
"pmc": null,
"pmid": "18192116",
"pubdate": "2007-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "7728120;11464085;6340623;12352633;8449101;8922795;15352978;16101725;16614249;8434299;7599576;9195074;8635332;2188320",
"title": "Frequent exacerbation of pulmonary nocardiosis during maintenance antibiotic therapies in a hematopoietic stem cell transplant recipient.",
"title_normalized": "frequent exacerbation of pulmonary nocardiosis during maintenance antibiotic therapies in a hematopoietic stem cell transplant recipient"
} | [
{
"companynumb": "JP-BAUSCH-BL-2019-064252",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "CYCLOSPORINE"
},
"drugadditional": null,
... |
{
"abstract": "Compared to morphine and morphine-6-glucuronide (M6G), codeine and its other major metabolites codeine-6-glucuronide and norcodeine have weak affinity to opioid μ-receptors. Analgesic effects of codeine are thus largely dependent on metabolic conversion to morphine by the polymorphic cytochrome P450 isoenzyme 2D6 (CYP2D6). How this relates to toxicity and post-mortem whole blood levels is not known. This paper presents a case series of codeine-related deaths where concentrations of morphine, M6G and morphine-3-glucuronide (M3G), as well as CYP2D6 genotype, are taken into account. Post-mortem toxicological specimens from a total of 1444 consecutive forensic autopsy cases in Central Norway were analyzed. Among these, 111 cases with detectable amounts of codeine in femoral blood were identified, of which 34 had femoral blood concentrations exceeding the TIAFT toxicity threshold of 0.3mg/L. Autopsy records of these 34 cases were retrieved and reviewed. In the 34 reviewed cases, there was a large variability in individual morphine to codeine concentration ratios (M/C ratios), and morphine levels could not be predicted from codeine concentrations, even when CYP2D6 genotype was known. 13 cases had codeine concentrations exceeding the TIAFT threshold for possibly lethal serum concentrations (1.6 mg/L). Among these, 8 individuals had morphine concentrations below the toxic threshold according to TIAFT (0.15 mg/L). In one case, morphine as well as M6G and M3G concentrations were below the limit of detection. A comprehensive investigation of codeine-related fatalities should, in addition to a detailed case history, include quantification of morphine and morphine metabolites. CYP2D6 genotyping may be of interest in cases with unexpectedly high or low M/C ratios.",
"affiliations": "Department of Laboratory Medicine, Children's and Women's Health, Norwegian University of Science and Technology (NTNU), Trondheim, Norway. joachim.frost@stolav.no",
"authors": "Frost|Joachim|J|;Helland|Arne|A|;Nordrum|Ivar S|IS|;Slørdal|Lars|L|",
"chemical_list": "D007527:Isoenzymes; D009022:Morphine Derivatives; D009294:Narcotics; C010414:norcodeine; C035349:morphine-6-glucuronide; D009020:Morphine; D003577:Cytochrome P-450 Enzyme System; C061773:codeine-6-glucuronide; D003061:Codeine",
"country": "Ireland",
"delete": false,
"doi": "10.1016/j.forsciint.2012.01.019",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0379-0738",
"issue": "220(1-3)",
"journal": "Forensic science international",
"keywords": null,
"medline_ta": "Forensic Sci Int",
"mesh_terms": "D000328:Adult; D000368:Aged; D003061:Codeine; D003577:Cytochrome P-450 Enzyme System; D005260:Female; D053593:Forensic Toxicology; D008401:Gas Chromatography-Mass Spectrometry; D005838:Genotype; D006801:Humans; D007527:Isoenzymes; D008297:Male; D008875:Middle Aged; D009020:Morphine; D009022:Morphine Derivatives; D009294:Narcotics; D016133:Polymerase Chain Reaction",
"nlm_unique_id": "7902034",
"other_id": null,
"pages": "6-11",
"pmc": null,
"pmid": "22285504",
"pubdate": "2012-07-10",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Investigation of morphine and morphine glucuronide levels and cytochrome P450 isoenzyme 2D6 genotype in codeine-related deaths.",
"title_normalized": "investigation of morphine and morphine glucuronide levels and cytochrome p450 isoenzyme 2d6 genotype in codeine related deaths"
} | [
{
"companynumb": "NO-RANBAXY-2014R1-84749",
"fulfillexpeditecriteria": "1",
"occurcountry": "NO",
"patient": {
"drug": [
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"abstract": "Patients with Human Immunodeficiency Virus (HIV) infection and Acquired Immunodeficiency Syndrome (AIDS) are at risk for multiple infectious and oncologic complications. In such cases, Occam's razor need not apply: multiple infections and malignancies are often present concurrently upon presentation to care. A patient off anti-retroviral therapy (ART) for several years developed advanced HIV infection (CD4 count 19 cells/uL) and presented with five simultaneous opportunistic infections including Pneumocystis jiroveci pneumonia (PJP), cytomegalovirus (CMV) retinitis, Mycobacterium avium complex (MAC) bloodstream infection, chronic hepatitis B virus (HBV), and Epstein-Barr virus (EBV) viremia. Simultaneously, he was found to have primary central nervous system (CNS) B-cell lymphoma. Treatment decisions for such patients are often complex, as ideal therapy for one disease may directly counter or interact with therapy for another. For instance, methotrexate for primary CNS lymphoma and trimethoprim/sulfamethoxazole for PJP is a strictly contraindicated medication combination. It is important to understand not just the management of any single opportunistic disease in patients with advanced HIV, but how to balance management for patients with a variety of concurrent processes. In an era when HIV care is becoming increasingly simplified, patients presenting with advanced infection highlight the lack of data on how best to manage patients with multiple concurrent disease processes. Significant further research is needed to clarify ideal comparative therapy.",
"affiliations": "The University of Vermont Medical Center, United States.;The University of Vermont Medical Center, United States.;The University of Vermont Medical Center, Larner College of Medicine at the University of Vermont, Burlington, VT, United States.;Beth Israel Deaconess Medical Center, Boston, MA, United States.;The University of Vermont Medical Center, Larner College of Medicine at the University of Vermont, Burlington, VT, United States.",
"authors": "Porter|Louis-Bassett|LB|;Kozakewich|Elena|E|;Clouser|Ryan|R|;Kershaw|Colleen|C|;Hale|Andrew J|AJ|",
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"fulltext": "\n==== Front\nIDCasesIDCasesIDCases2214-2509Elsevier S2214-2509(18)30119-710.1016/j.idcr.2018.e00437e00437ArticleOccam’s razor need not apply: Advanced HIV infection presenting with five simultaneous opportunistic infections and central nervous system lymphoma Porter Louis-Bassett a1Kozakewich Elena a1Clouser Ryan bKershaw Colleen cHale Andrew J. Andrew.Hale@UVMhealth.orgb⁎a The University of Vermont Medical Center, United Statesb The University of Vermont Medical Center, Larner College of Medicine at the University of Vermont, Burlington, VT, United Statesc Beth Israel Deaconess Medical Center, Boston, MA, United States⁎ Corresponding author at: University of Vermont Medical Center, Infectious Disease Unit. 111 Colchester Avenue, Mailstop 115 SM2., Burlington, VT, 05401, United States. Andrew.Hale@UVMhealth.org1 Dr. Porter and Dr. Kozakewich contributed equally to this manuscript.\n\n08 8 2018 2018 08 8 2018 13 4 4 18 6 2018 6 8 2018 6 8 2018 © 2018 The Authors2018This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Patients with Human Immunodeficiency Virus (HIV) infection and Acquired Immunodeficiency Syndrome (AIDS) are at risk for multiple infectious and oncologic complications. In such cases, Occam’s razor need not apply: multiple infections and malignancies are often present concurrently upon presentation to care. A patient off anti-retroviral therapy (ART) for several years developed advanced HIV infection (CD4 count 19 cells/uL) and presented with five simultaneous opportunistic infections including Pneumocystis jiroveci pneumonia (PJP), cytomegalovirus (CMV) retinitis, Mycobacterium avium complex (MAC) bloodstream infection, chronic hepatitis B virus (HBV), and Epstein-Barr virus (EBV) viremia. Simultaneously, he was found to have primary central nervous system (CNS) B-cell lymphoma.\n\nTreatment decisions for such patients are often complex, as ideal therapy for one disease may directly counter or interact with therapy for another. For instance, methotrexate for primary CNS lymphoma and trimethoprim/sulfamethoxazole for PJP is a strictly contraindicated medication combination. It is important to understand not just the management of any single opportunistic disease in patients with advanced HIV, but how to balance management for patients with a variety of concurrent processes. In an era when HIV care is becoming increasingly simplified, patients presenting with advanced infection highlight the lack of data on how best to manage patients with multiple concurrent disease processes. Significant further research is needed to clarify ideal comparative therapy.\n\nKeywords\nHuman Immunodeficiency VirusAcquired Immunodeficiency DisorderOpportunistic infection\n==== Body\nIntroduction\nFor many clinicians practicing in the United States, especially young clinicians, treatment of the manifestations of untreated HIV with progression to AIDS may be evocative of a past era of medicine that seems disconnected from the present-day. While HIV and AIDS are recognized as major issues pertaining to global health, prevalence in the United States is perceived to be much lower. However, the Centers for Disease Control and Prevention (CDC) estimate that in 2014 over 1.1 million people in the United States were living with HIV, with 15% of those patients (approximately 165,000) unaware of their HIV-positive status. Furthermore, in 2014 HIV was the eighth leading cause of death in 25–34 year-olds and ninth in 35–44 year-olds in the United States [1]. The reality is that despite significant strides in HIV prevention and antiretroviral therapy, HIV, AIDS and associated opportunistic infections remain fundamentally important topics in clinical practice in the United States.\n\nCase description\nA 56-year-old man was found by his spouse unresponsive and demonstrating generalized tonic-clonic movements with bowel and bladder incontinence. Emergency medical services were called and he was intubated for airway protection. Preceding this event, the patient had reported upper respiratory illness symptoms for several weeks with intermittent fevers, as well as altered mental status described as slowed cognition and unusual affect. He took no medications prior to admission, though did have a history of chronic HBV and HIV acquired in the 1980s, thought to be from MSM exposure. He had previously taken HIV and HBV medications for nearly 20 years, but had discontinued all medical therapy three years prior to admission due to side effects. His CD4 T-cell count at the time of discontinuation was 250 cells/μL.\n\nOn admission the patient’s temperature was 38 °C, heart rate was 127 beats per minute, respiratory rate was 12 breaths per minute, blood pressure was 122/83 mmHg, and blood oxygen saturation was 100% on FiO2 30%. He was cachectic on examination. Lungs were clear to auscultation bilaterally. Notable initial laboratory values included a serum sodium of 114 mEq/L, lactic acid of 7.5 mmol/L, creatinine kinase of 1292 U/L, hemoglobin of 12.0 gm/dl, white blood cell count of 5.8 K/μL, and platelets of 143 K/μL. Absolute CD4 T-cell count was 19 cells/uL and HIV viral load was 468,999 copies/mL. A computed tomography scan of the head revealed a right basal ganglia edematous area measuring 20 × 24 mm, with mild mass effect. A brain magnetic resonance imaging study with gadolinium showed a rim-enhancing lesion involving the right caudate and basal ganglia with mass effect indenting the right lateral ventricle (Fig. 1). Lumbar puncture revealed atypical lymphocytes with cytopathology consistent with B-cell lymphoma. The patient’s respiratory status improved and he was liberated from mechanical ventilation the day following admission, though remained somnolent afterwards.Fig. 1 Brain magnetic resonance imaging study with contrast demonstrates a single rim-enhancing lesion (green arrow) involving the right caudate and basal ganglia with mass effect indenting the right lateral ventricle. Lumbar puncture cytology demonstrated B-cell lymphoma.\n\nFig. 1\n\nFurther work-up revealed positive hepatitis B surface antigen with HBV viral load 8.23 log IU/mL, Mycobacterium avium complex (MAC) growth in blood cultures, positive Epstein-Barr virus (EBV) polymerase chain reaction (PCR) in cerebrospinal fluid, and serum cytomegalovirus (CMV) viral load of 2770 IU/mL with findings on funduscopic exam of creamy exudates with associated dot-blot hemorrhages, consistent with CMV retinitis. Video electroencephalogram monitoring did not record further seizure activity. Positron emission tomography (PET) showed strong fludeoxyglucose (FDG) avidity primarily within the CNS lesion, consistent with HIV-associated primary CNS B-cell lymphoma (Fig. 2). Diffuse, though weak, FDG avidity was also noted in the lungs which prompted a subsequent bronchoalveolar lavage, which demonstrated Pneumocystis jiroveci pneumonia (PJP) via PCR. Thus, this patient’s presentation was ultimately consistent with advanced HIV infection with CD4 count of 19 cells/uL, chronic HBV, HIV and EBV-associated primary CNS B-cell lymphoma, PJP, CMV retinitis, and MAC bloodstream infection.Fig. 2 Positron emission tomography study. Note the high fludeoxyglucose (FDG) avidity within the central nervous system lesion as well as uptake within lungs bilaterally (green arrows). Lumbar puncture cytology confirmed the solitary CNS lesion as HIV-associated primary CNS B-cell lymphoma, and bronchoscopy confirmed the pulmonary findings as Pneumocystis jirovecii pneumonia (PJP).\n\nFig. 2\n\nInitially, trimethoprim/sulfamethoxazole was started for treatment of PJP and was transitioned to atovaquone due to concern for interaction with methotrexate (planned therapy for primary B-cell lymphoma), unknown glucose-6-dehydrogenase deficiency (G6PD) status, and minimal hypoxia post-extubation. However, methotrexate was later deferred due to the patient's multiple comorbidities. CMV retinitis was initially treated with intravenous ganciclovir, though with developing marrow suppression he was transitioned to intravitreal ganciclovir injection. Anti-retroviral therapy and anti-HBV medications were initiated after seven days of CMV therapy, including tenofovir alafenamide, emtricitabine, dolutegravir, and rilpivirine, based on prior genotype data. Clarithromycin, ethambutol, and rifabutin were recommended for MAC bloodstream infection. Dexamethasone was started for cerebral edema, after detection of primary CNS lymphoma.\n\nThe patient had ongoing encephalopathy that required the patient’s family to provide direction regarding goals of care. By hospital day 36, the patient’s encephalopathy had not significantly improved and the family requested that most anti-infective medications, including ART, be stopped, as this was felt to be what the patient would have wanted. At the request of the patient’s spouse he was discharged home with palliative care, and passed away at home several weeks later.\n\nDiscussion\nThis case illuminates that despite many advances made in the fight against HIV, treatment of advanced HIV and associated opportunistic infections can be highly complex. Therapeutic conflicts present clinicians with significant treatment dilemmas. Here, numerous first-line therapies presented conflicts with the treatment of other concurrent disease processes (Fig. 3). These conflicts were two-fold: 1) First line therapies could exacerbate concurrent disease processes; 2) adverse effects of interventions including drug toxicities and drug-drug interactions.Fig. 3 Treatment algorithm and potential interactions for the case presented. Green demonstrates the disease processes that were diagnosed. Blue demonstrates first-line, guidelines-based therapy for each of these processes. Dotted red lines show potentially serious interactions of using these first-line regimens concurrently. In order from top-down and left to right: 1) ARV therapy in the setting of CMV retinitis can precipitate vision-threatening IRIS. 2) Both steroids and rituximab for CNS lymphoma can precipitate acute hepatitis from chronic HBV infection. 3) Methotrexate for CNS lymphoma and trimethroprim/sulfamethoxazole for PJP can cause critically low blood counts and are contraindicated together. 4) Ganciclovir for CMV retinitis and tenofovir for HIV and HBV, combined with trimethroprim/sulfamethoxazole, can additionally cause significant bone-marrow suppression. 5) Ethambutol for MAC can cause optic neuritis, which is concerning in a patient already with significant CMV retinitis. 6) Rifampin is a potent inducer of the cytochrome P450 CYP3A system and has many drug-drug interactions, particularly with many HIV medications. 7) Clarithromycin should be avoided with concomitant steroids as this can elevated steroid levels and cause adrenal suppression. In red at the bottom is the regimen recommended for this patient to balance these interactions.\n\nFig. 3\n\nFirst, treatment of certain diseases can lead to worsening of others. While initiation of ART leads to improvements in cellular immunity and overall mortality [2], this patient’s multiple infections represented substantial risk of immune reconstitution inflammatory syndrome (IRIS). IRIS is defined as a paradoxical worsening of a known condition (or the new manifestation of a previously unknown condition), most commonly infection, after initiation of ART in a patient with HIV/AIDS [3]. Up to 13% of patients with HIV/AIDS may develop IRIS after initiation of ART [4]. PJP, mycobacterial infections, and CMV retinitis are commonly reported opportunistic infections associated with IRIS [5]. A recent meta-analysis reported that in patients with advanced HIV and concurrent CMV, IRIS developed in 37.7% of patients after initiation of ART [4]. IRIS occurring within a confined anatomical space, such as the eye or brain, can significantly increase morbidity and mortality [6]. In our patient there was concern that early initiation of ART carried a substantial risk of an adverse retinal outcome, potentially blindness related to ocular IRIS, and thus delay of ART would potentially be beneficial. However,compelling data exists that ART should not be delayed in HIV-infected patients presenting with PJP [7]. This presented a conflict in our patient with both CMV retinitis and PJP regarding when ART should be initiated. At present, Health and Human Services Opportunistic Infection guidelines suggest initiation of ART begin no later than two weeks after diagnosis of opportunistic infection, unless there is cryptococcal or tubercular meningitis, in which case a delay of ART initiation of several weeks is recommended [8,9]. For this patient, ART was initiated after seven days of CMV therapy. Because of his encephalopathy, it is unknown what effect this had on his vision.\n\nThe second challenge in caring for this patient’s multiple infections and CNS lymphoma involved drug toxicities and drug-drug interactions. For example, with the risk for vision loss from CMV retinitis and IRIS, the use of ethambutol for MAC was problematic, as ethambutol has a well-documented toxicity of optic neuropathy [10]. For the treatment of MAC, intermittent dosing (three days a week versus every day) of ethambutol may reduce the risk of ocular toxicity [11]. Alternatively, a regimen without ethambutol can be used, though likely is inferior therapy for invasive MAC disease [12]. This patient was never initiated on MAC therapy as the direction of care moved to a comfort-focus. Furthermore, ganciclovir is the drug of choice for CMV retinitis, but its use was complicated by bone marrow suppression in a patient already with HIV-related pancytopenia [13]. This prompted the decision to use intravitreal ganciclovir for this patient, which is supported by CDC guidelines [8]. Additionally, there was concern regarding treatment of the patient’s CNS lymphoma with rituximab and steroids in the setting of his chronic surface-antigen positive HBV. Although the patient presented with immune-tolerant chronic HBV, treatment with anti-CD20 or steroid therapy can precipitate acute hepatitis in up to 50% of cases [14]. Typically, HBV viral load suppressive therapy is recommended before steroid treatment is initiated [15]. Although HBV suppressive therapy was started on day seven (tenofovir alafenamide), full HBV suppression can take months, which was not an option in this case as it was vital to urgently address cerebral edema from the CNS lymphoma. Lastly, another drug-drug interaction that complicated this case was the use of trimethoprim/sulfamethoxazole (first-line therapy for PJP) in conjunction with methotrexate (first-line therapy for primary CNS lymphoma). Although the evidence is largely from case reports, trimethoprim/sulfamethoxazole may enhance the bone marrow toxicity of methotrexate and result in critical bone marrow suppression and neutropenia [16].\n\nIn an era when HIV care is generally becoming increasingly simplified, patients with advanced infection highlight the lack of data on how best to manage patients with multiple concurrent disease processes. Significant further research is needed to clarify ideal comparative therapy.\n\nFunding\nNone.\n\nConflict of interests statement\nNone of the authors report any conflicts of interest.\n\nAuthorship verification\nAll co-authors have seen and agree with the contents of the manuscript and have contributed significantly to the work.\n\nConsent\nInformed consent was obtained for publication of this case report and accompanying images. A copy of the consent is available for review by the Editor-in-Chief of this journal on request.\n\nAuthor contributions statement\nLouis-Bassett Porter, MD: conceptualization, writing original draft, review and editing.\n\nElena Kozakewich, MD: conceptualization, writing original draft, review and editing.\n\nRyan Clouser, DO: conceptualization, writing original draft, review and editing.\n\nColleen Kershaw, MD: conceptualization, writing original draft, review and editing.\n\nAndrew J. Hale, MD: conceptualization, writing original draft, review and editing.\n\nAcknowledgements\nNone.\n==== Refs\nReferences\n1 HIV/AIDS basic statistics 2018 Centers for Disease Control and Prevention Available at https://www.cdc.gov/hiv/basics/statistics.html (Accessed 18 March 2018) \n2 Palella F.J. Jr Delaney K.M. Moorman A.C. Loveless M.O. Fuhrer J. Satten G.A. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection N Engl J Med 338 13 1998 853 860 9516219 \n3 Singh N. Perfect J.R. Immune reconstitution syndrome associated with opportunistic mycoses Lancet Infect Dis 7 6 2007 395 401 17521592 \n4 Müller M. Wandel S. Colebunders R. Attia S. Furrer H. Egger M. Immune reconstitution inflammatory syndrome in patients starting antiretroviral therapy for HIV infection: a systematic review and meta-analysis Lancet Infect Dis 10 4 2010 251 20334848 \n5 Murdoch D.M. Venter W.D. Van Rie A. Feldman C. Immune reconstitution inflammatory syndrome (IRIS): review of common infectious manifestations and treatment options AIDS Res Ther 4 2007 9 17488505 \n6 Franco-Paredes C. Chastain D.B. Rodriguez-Morales A.J. Marcos L.A. Cryptococcal meningoencephalitis in HIV/AIDS: when to start antiretroviral therapy? Ann Clin Microbiol Antimicrob 16 2017 9 28264683 \n7 Zolopa A.R. Andersen J. Komarow L. Sanne I. Sanchez A. Hogg E. Early antiretroviral therapy reduces AIDS Progression/Death in individuals with acute opportunistic infections: a multicenter randomized strategy trial Carr A ed. PLoS One 4 5 2009 e5575 19440326 \n8 Guidelines for the prevention and treatment of opportunistic infections in HIV-infected adults and adolescents 2018 Recommendations from the Centers for Disease Control and Prevention, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America Available at http://aidsinfo.nih.gov/contentfiles/lvguidelines/adult_oi.pdf (Accessed 18 March 2018) \n9 Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents 2018 US Department of Health and Human Services Available at: https://aidsinfo.nih.gov/guidelines (Accessed 19 March 2018) \n10 Leibold J.E. The ocular toxicity of ethambutol and its relation to dose Ann N Y Acad Sci 135 2 1966 904 5220245 \n11 Griffith D.E. Brown-Elliott B.A. Shepherd S. McLarty J. Griffith L. Wallace R.J. Jr. Ethambutol ocular toxicity in treatment regimens for Mycobacterium avium complex lung disease Am J Respir Crit Care Med 172 2 2005 250 15860751 \n12 May T. Brel F. Beuscart C. Vincent V. Perronne C. Doco-Lecompte T. Comparison of combination therapy regimens for treatment of human immunodeficiency virus-infected patients with disseminated bacteremia due to Mycobacterium avium Clin Infect Dis 25 3 1996 621 629 \n13 Feola D.J.1 Thornton A.C. Garvy B.A.D. Effects of antiretroviral therapy on immunity in patients infected with HIV Curr Pharm Des 12 9 2006 1015 1022 16515483 \n14 Tsutsumi Y. Yamamoto Y. Ito S. Ohigashi H. Shiratori S. Naruse H. Hepatitis B virus reactivation with a rituximab-containing regimen World J Hepatol 7 21 2015 2344 2351 26413224 \n15 Marzano A. Angelucci E. Andreone P. Brunetto M. Bruno R. Burra P. Prophylaxis and treatment of hepatitis B in immunocompromised patients Dig Liver Dis 39 5 2007 397 408 17382608 \n16 Al-Quteimat O.M. Al-Badaineh M.A. Methotrexate and trimethoprim-sulphamethoxazole: extremely serious and life-threatening combination J Clin Pharm Ther 38 3 2013 203 205 23521709\n\n",
"fulltext_license": "CC BY-NC-ND",
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"keywords": "Acquired Immunodeficiency Disorder; Human Immunodeficiency Virus; Opportunistic infection",
"medline_ta": "IDCases",
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"nlm_unique_id": "101634540",
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"pages": "e00437",
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"pubdate": "2018",
"publication_types": "D016428:Journal Article; D002363:Case Reports",
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"title": "Occam's razor need not apply: Advanced HIV infection presenting with five simultaneous opportunistic infections and central nervous system lymphoma.",
"title_normalized": "occam s razor need not apply advanced hiv infection presenting with five simultaneous opportunistic infections and central nervous system lymphoma"
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"abstract": "Acute myelogenous leukemia (AML) is a malignant disease of the hematopoietic system, characterized by features of bone marrow insufficiency and organ infiltration by leukemic cells. Venous thrombosis in AML patients is uncommon, compared to bleeding; therefore in patients with AML, simultaneous occurrence of venous and arterial thrombosis is a rather rare presentation. We reported an unusual case of anti-phospholipid antibody syndrome secondary to AML characterized by venous and arterial thrombosis. A 70-year-old man with deep venous thrombosis (DVT) of the left leg confirmed by Doppler was seen in our clinic. During treatment with a Vitamin K antagonist (3 mg daily of Warfarin) and a low molecular weight heparin (LMWH), he developed an acute pulmonary embolism and an acute inferior wall ST elevation myocardial infarction (STEMI), a result of right coronary artery embolism. His full blood count showed leukocytosis and thrombocytopenia. Lupus anticoagulant and anti-cardiolipin antibodies were positive. A bone marrow aspirate test showed results consistent with AML (FAB class M1). A diagnosis of antiphospholipid antibody syndrome secondary to AML characterized by coronary artery embolism, pulmonary embolism and left leg DVT was eventually established. He received anticoagulation with a low dose of warfarin after refusing chemotherapy. He however died of cerebral hemorrhage despite the fact that the INR was in the normal therapeutic range. It is challenging to anticoagulated AML patients complicated by multiple vascular thromboses and thrombocytopenia.",
"affiliations": "Department of Cardiology, Guangdong Provincial People's Hospital's Nanhai Hospital, Foshan, China.;Department of Cardiology, Guangdong Provincial People's Hospital's Nanhai Hospital, Foshan, China.;Department of Cardiology, Guangdong Provincial People's Hospital's Nanhai Hospital, Foshan, China.;Department of Cardiology, Guangdong Provincial People's Hospital's Nanhai Hospital, Foshan, China.;Department of Cardiology, Guangdong Provincial People's Hospital's Nanhai Hospital, Foshan, China.;Department of Cardiology, Guangdong Provincial People's Hospital's Nanhai Hospital, Foshan, China.;Department of Cardiology, Guangdong Provincial People's Hospital's Nanhai Hospital, Foshan, China.",
"authors": "Liang|Huasheng|H|;Ba|Mingchuan|M|;Li|Chen|C|;Li|Haoping|H|;Guo|Zhiqiang|Z|;He|Pengcheng|P|;Lin|Chunying|C|",
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"issue": "10(5)",
"journal": "Cardiovascular diagnosis and therapy",
"keywords": "Acute myelogenous leukemia (AML); acute myocardial infarction; antiphospholipid antibody syndrome; deep venous thrombosis (DVT); pulmonary embolism",
"medline_ta": "Cardiovasc Diagn Ther",
"mesh_terms": null,
"nlm_unique_id": "101601613",
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"pages": "1332-1340",
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"title": "A case of acute myelogenous leukemia characterized by arterial and venous thrombosis.",
"title_normalized": "a case of acute myelogenous leukemia characterized by arterial and venous thrombosis"
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"abstract": "OBJECTIVE\nTo improve the clinical understanding of fungal esophagitis in patients with hematologic malignancies.\n\n\nMETHODS\nThe clinical data of a cohort of 279 patients with hematologic malignancies who underwent gastroscopy between 2012 and 2015 in the Endoscopy Center of Henan Tumor Hospital were retrospectively analyzed. To investigate the clinical characteristics and prognosis of fungal esophagitis in patients with heratologic malignancies.\n\n\nRESULTS\n13 of the 279 patients were diagnosed as fungal esophagitis (4.66% ). C. albicans was prevalent (12/13), and only 1 case was cryptococcus. All of the 13 patients had lymphatic systemic diseases (8 cases with diffuse large B cell lymphoma, 1 with peripheral T-cell lymphoma, 2 with acute lymphoblastic leukemia, and 1 with multiple myeloma). 6 patients had gastrointestinal symptoms (3 cases with nausea and anorexia as well as the sentation of having a foreign body in pharyngeal, 2 cases with pain or a burning sensation behind the sternum, and 1 case having difficulty or pain when swallowing), while 7 patients had no obvious manifestations. 6 patients accepted fluconazole 400 mg/d for 2 weeks and achieved satisfactory results; Meanwhile 7 cases were given nystatin 1 million uint 3 times a day for 2 weeks, of which 6 cases responded well, and 1 case was not relieved until he was given fluconazole 400 mg/d for 1 week. Treatmentassociated adverse events included mildly elevated aminotransferase (1 case) and mild gastrointestinal adverse reaction (1 case).\n\n\nCONCLUSIONS\nThe fungal esophagitis in patients with hematologic malignancies was not rare. Most of those patients had lymphatic systemic diseases and the main pathogen was candida albicans. The clinical manifestations of fungal esophagitis were quite atypical and about more than half of those patients had no gastrointestinal symptoms. Either fluconazole or nystatin was safe and effective treatment with slight adverse reactions.",
"affiliations": "Department of Hematology, the Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou 450008, China.",
"authors": "Zhou|Y L|YL|;Wei|X D|XD|;Mi|R H|RH|;Ai|H|H|;Zhang|L N|LN|;Liu|Y Y|YY|;Li|Y F|YF|;Song|Y P|YP|",
"chemical_list": "D015725:Fluconazole",
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"delete": false,
"doi": "10.3760/cma.j.issn.0253-2727.2016.06.013",
"fulltext": "\n==== Front\nZhonghua Xue Ye Xue Za Zhi\nZhonghua Xue Ye Xue Za Zhi\nCJH\nChinese Journal of Hematology\n0253-2727 2707-9740 Editorial office of Chinese Journal of Hematology No. 288, Nanjing road, Heping district, Tianjin \n\n27431077\ncjh-37-06-507\n10.3760/cma.j.issn.0253-2727.2016.06.013\n论著\n13例恶性血液病并发真菌性食管炎患者的临床分析\nA clinical study of fungal esophagitis in 13 patients with hematologic malignancies 周 亚兰 Zhou Yalan 魏 旭东 Wei Xudong 米 瑞华 Mi Ruihua 艾 昊 Ai Hao 张 丽娜 Zhang Li'na 刘 艳艳 Liu Yanyan 李 玉富 Li Yufu 宋 永平 Song Yongping 450008 郑州大学附属肿瘤医院（河南省肿瘤医院）血液科Department of Hematology, the Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou 450008, China\n刘 爽 通信作者：魏旭东(Wei Xudong)，Email：weixudong63@126.com\n6 2016 \n37 6 507 511\n9 1 2016 2016年版权归中华医学会所有Copyright © 2016 by Chinese Medical Association2016This work is licensed under a Creative Commons Attribution 3.0 License (CC-BY-NC). The Copyright own by Publisher. Without authorization, shall not reprint, except this publication article, shall not use this publication format design. Unless otherwise stated, all articles published in this journal do not represent the views of the Chinese Medical Association or the editorial board of this journal.目的\n提高对血液系统恶性疾病并发真菌性食管炎的认识。\n\n方法\n回顾性分析2012年1月至2015年11月河南省肿瘤医院血液科收治的279例行胃镜检查的恶性血液病患者临床资料，观察恶性血液病并发真菌性食管炎的临床特征及转归。\n\n结果\n279例患者中真菌性食管炎13例（4.66%），刷片镜检5例可见真菌孢子，3例可见真菌孢子及菌丝，5例仅见真菌菌丝。12例致病菌为白色念珠菌，1例为隐球菌。13例患者中弥漫大B细胞淋巴瘤8例，外周T细胞淋巴瘤1例，急性淋巴细胞白血病2例，多发性骨髓瘤1例；6例患者伴消化道症状（咽部异物感、恶心、纳差3例，胸骨后疼痛或烧灼感2例，吞咽困难伴疼痛1例），7例患者无明显症状体征。6例患者予氟康唑注射液400 mg/d治疗14 d，均有效；7例患者予制霉菌素片（100万U，每天3次）治疗14 d, 6例有效，1例持续不缓解，调整为氟康唑注射液400 mg/d治疗7 d后症状消失。治疗相关不良反应为一过性转氨酶升高及轻度消化道不良反应。\n\n结论\n恶性血液病并发真菌性食管炎并非少见，以淋巴系统疾病患者居多，致病菌主要为白色念珠菌；其临床症状不典型，约半数以上患者无明显临床表现；氟康唑及制霉菌素单药治疗安全有效。\n\nObjective\nTo improve the clinical understanding of fungal esophagitis in patients with hematologic malignancies.\n\nMethods\nThe clinical data of a cohort of 279 patients with hematologic malignancies who underwent gastroscopy between 2012 and 2015 in the Endoscopy Center of Henan Tumor Hospital were retrospectively analyzed. To investigate the clinical characteristics and prognosis of fungal esophagitis in patients with heratologic malignancies.\n\nResults\n13 of the 279 patients were diagnosed as fungal esophagitis (4.66%). C. albicans was prevalent (12/13), and only 1 case was cryptococcus. All of the 13 patients had lymphatic systemic diseases (8 cases with diffuse large B cell lymphoma, 1 with peripheral T-cell lymphoma, 2 with acute lymphoblastic leukemia, and 1 with multiple myeloma). 6 patients had gastrointestinal symptoms (3 cases with nausea and anorexia as well as the sentation of having a foreign body in pharyngeal, 2 cases with pain or a burning sensation behind the sternum, and 1 case having difficulty or pain when swallowing), while 7 patients had no obvious manifestations. 6 patients accepted fluconazole 400 mg/d for 2 weeks and achieved satisfactory results; Meanwhile 7 cases were given nystatin 1 million uint 3 times a day for 2 weeks, of which 6 cases responded well, and 1 case was not relieved until he was given fluconazole 400 mg/d for 1 week. Treatmentassociated adverse events included mildly elevated aminotransferase (1 case) and mild gastrointestinal adverse reaction (1 case).\n\nConclusion\nThe fungal esophagitis in patients with hematologic malignancies was not rare. Most of those patients had lymphatic systemic diseases and the main pathogen was candida albicans. The clinical manifestations of fungal esophagitis were quite atypical and about more than half of those patients had no gastrointestinal symptoms. Either fluconazole or nystatin was safe and effective treatment with slight adverse reactions.\n\n血液肿瘤食管炎真菌病Hematologic neoplasmsEsophagitisMycoses基金项目：国家自然科学基金（81170520）Fund program: National Natural Science Foundation of China（81170520）\n==== Body\n疾病本身造成的免疫力低下、放化疗所引起的免疫抑制状态及黏膜屏障的破坏、广谱抗生素的大量应用等诸多因素使侵袭性真菌感染逐渐成为恶性血液病的主要并发症。消化道为系统性真菌感染的主要侵入途径之一，食管介于口咽与深部组织之间，念珠菌是其常见的条件致病菌。恶性血液病并发真菌性食管炎国内外仅有散在报道[1]–[2]。近年来，我中心诊治了13例恶性血液病并发真菌性食管炎患者，现报道如下并进行文献复习，旨在提高对其的认识。\n\n病例与方法\n1．病例资料：2012年1月至2015年11月期间于我院行电子胃镜检查的恶性血液病患者共279例，恶性血液病诊断参照文献[3]–[4]标准，粒细胞缺乏定义为外周血中性粒细胞绝对计数<0.5×109/L或预计48 h内<0.5×109/L。279例患者中非霍奇金淋巴瘤（NHL）202例（72.4%），霍奇金淋巴瘤（HL）11例（3.9%），多发性骨髓瘤（MM) 26例（9.3%），急性髓系白血病（AML）23例（8.2%），急性淋巴细胞白血病（ALL) 17例（6.1%）。\n\n2．真菌性食管炎的诊断及治疗：采用PEN-TAX3.2 EG29-i10N型电子胃镜进行检查，于食管黏膜白苔较明显处刷取黏膜表面白色黏附物，直接涂片显微镜下寻找真菌孢子、菌丝并进行常规真菌培养。真菌性食管炎诊断标准参照Kodsi内镜分级标准[5]分为4级：Ⅰ级：少数隆起白斑，直径<2 mm，伴充血，无水肿或溃疡；Ⅱ级：多数隆起白斑，直径≥2 mm，伴充血，无水肿或溃疡；Ⅲ级：融合的线状或结节样隆起斑块，伴充血和溃疡；Ⅳ级：Ⅲ级的镜下表现加黏膜松脆，有时伴管腔狭窄。确诊真菌性食管炎后立即予氟康唑注射液（400 mg/d，连用14 d）或制霉菌素片（100万U，每天3次，连用14 d）进行治疗。\n\n3．随访：采用电话回访结合门诊及住院复查方式进行随访，截止日期为2016年1月31日，中位随访时间为17(9~47）个月。随访内容包括原发病状态、真菌性食管炎转归及抗真菌治疗相关不良反应等。\n\n结果\n1．临床特征：279例行胃镜检查的恶性血液病患者中13例（4.66%）确诊并发真菌性食管炎。男7例，女6例，中位年龄51(19~71）岁。弥漫大B细胞淋巴瘤（DLBCL）8例，ALL 2例，外周T细胞淋巴瘤（PTCL）、T淋巴母细胞性淋巴瘤（TLBL）、MM各1例。其中3例合并2型糖尿病，1例合并慢性肾功能不全，1例伴皮肤朗格汉斯细胞组织细胞增生症。6例患者因消化道症状而行胃镜检查，主要症状包括：咽部异物感、恶心、纳差3例，胸骨后疼痛或烧灼感2例，吞咽困难伴疼痛1例；7例患者无明显症状，其中2例因反复大便潜血阳性而行胃镜检查，5例因原发病治疗过程中复查胃镜而发现。诊断真菌性食管炎时10例患者处于化疗后粒细胞恢复期，2例处于粒细胞缺乏期（中性粒细胞绝对计数分别为0.37×109/L及0.41×109/L，分别为粒细胞缺乏第11、17天），1例因反复咽部异物感、恶心而行胃镜检查，另1例因多次大便潜血阳性而行胃镜检查。除1例新诊断患者外，余12例患者均发生于化疗后。13例患者一般临床特征见表1。\n\n表1 13例患者的基本资料及真菌性食管炎的治疗情况\n例号\t性别\t年龄（岁）\t原发病类型\t原发病治疗方案\t消化道症状\t真菌类型\t抗真菌治疗方案\t疗效\t不良反应\t\n1\t女\t65\tDLBCL\t无\t无\t白色念珠菌\t制霉菌素\t黏膜病变消失\t恶心\t\n2\t男\t58\tDLBCL\t2R-CHOP、1R-EPOCH\t无\t白色念珠菌\t氟康唑\t黏膜病变消失\t无\t\n3\t女\t64\tDLBCL\t2R-CHOP、1R-EPOCH\t吞咽困难伴疼痛\t白色念珠菌\t氟康唑\t临床症状消失\t一过性转氨酶升高\t\n4\t男\t51\tDLBCL\t3R-CHOP、1EPOCH\t无\t白色念珠菌\t制霉菌素\t黏膜病变消失\t无\t\n5\t女\t46\tDLBCL\t1CHOP、2EPOCH\t无\t白色念珠菌\t制霉菌素\t黏膜病变消失\t无\t\n6\t男\t67\tDLBCL\t2R-CHOP、2R-EPOCH\t无\t白色念珠菌\t制霉菌素\t黏膜病变减轻\t无\t\n7\t女\t61\tDLBCL\t1CHOP、2EPOCH\t无\t白色念珠菌\t制霉菌素\t黏膜病变消失\t无\t\n8\t男\t71\tDLBCL\t5CHOP、1CVP\t无\t白色念珠菌\t制霉菌素\t/\t轻度恶心\t\n9\t男\t48\tPTCL\t1R-CHOP\t胸骨后烧灼感\t白色念珠菌\t氟康唑\t临床症状消失\t无\t\n10\t男\t19\tTLBL\t1VTCLP\t胸骨后烧灼感\t白色念珠菌\t氟康唑\t临床症状消失\t无\t\n11\t女\t33\tALL\t2VDCP、2CA、3HD-MTX，持续应用达沙替尼\t咽部异物感、恶心\t白色念珠菌\t氟康唑\t临床症状消失\t无\t\n12\t女\t24\tALL\t1VDCLP\t咽部异物感、恶心\t白色念珠菌\t氟康唑\t临床症状消失\t无\t\n13\t男\t64\tMM\t4VMCP\t咽部异物感、恶心\t隐球菌\t制霉菌素、氟康唑\t临床症状消失\t无\t\n注：DLBCL：弥漫大B细胞淋巴瘤；PTCL：外周T细胞淋巴瘤；TLBL: T淋巴母细胞性淋巴瘤；ALL：急性淋巴细胞白血病；MM：多发性骨髓瘤；R：利妥昔单抗；CHOP：环磷酰胺、阿霉素、长春新碱、泼尼松；EPOCH：依托泊苷、表柔比星、阿霉素、环磷酰胺、泼尼松；VTCLP：长春新碱、吡柔比星、环磷酰胺、左旋门冬酰胺酶、泼尼松；CVP：环磷酰胺、长春新碱、泼尼松；VDCP：长春新碱、柔红霉素、环磷酰胺、泼尼松；CA：环磷酰胺、阿糖胞苷；HD-MTX：大剂量甲氨蝶呤；VDCLP: VDCP＋左旋门冬酰胺酶；VMCP：长春地辛、环磷酰胺、表柔比星、地塞米松；/：例8治疗前无明显临床表现，治疗后拒绝复查胃镜，无法评估治疗结果\n\n2．真菌性食管炎内镜表现：13患者均经胃镜检查细胞涂片而确诊为真菌性食管炎。刷片镜检5例可见真菌孢子，3例见真菌孢子及菌丝，5例仅可查见真菌菌丝；其中12例为白色念珠菌，1例为隐球菌。内镜下表现主要为食管黏膜散在乳白色点状、斑片状附着物，部分融合成条、甚至大片状膜状物，难以冲洗或刷去，刷掉后可见黏膜糜烂及出血（图1）。病变部位：食管中下段9例、上段1例、全程食管3例；其中2例同时侵犯全程食管及胃。按Kodsi分级标准，其中Ⅰ级3例、Ⅱ级6例、Ⅲ级3例、Ⅳ级1例。\n\n图1 真菌性食管炎的胃镜下表现（可见融合的线状或结节样隆起斑块，伴轻度充血和溃疡，侵及食管中下段，Kodsi分级Ⅲ级）\n3．治疗及转归：13例真菌性食管炎患者中，6例初始接受氟康唑治疗，均有效；7例初始治疗为制霉菌素片，6例有效，1例未缓解。初始接受制霉菌素片治疗的1例（例13）因症状持续不缓解调整为氟康唑400 mg/d治疗，7 d后症状消失，复查胃镜刷片镜检未见真菌孢子及菌丝。13例患者中，6例复查胃镜，其中5例食管黏膜病变恢复正常，1例患者黏膜病变减轻；余7例未复查胃镜，但其上消化道症状或大便潜血均未再出现。治疗相关不良反应仅为一过性的转氨酶升高及轻度胃肠反应，停药后短时间内恢复正常，所有患者均未出现明显不耐受，未出现严重心、肝、肾等重要脏器功能损伤（表1）。患者在真菌性食管炎治疗的同时，均继续接受原发病的治疗，治疗期间均未出现真菌性食管炎反复。至随访结束，13例患者中10例存活，生存状况良好，3例死于原发病进展或其并发症。\n\n讨论\n消化道黏膜是机体系统性真菌感染的主要入侵途径之一，而食管是常见的受侵犯部位之一。念珠菌是常见条件致病菌，35%~50％的正常人及70%的住院患者口咽部可培养出白色念珠菌，但一般不致病[6]。血液系统恶性疾病患者由于疾病本身及长期大剂量抗肿瘤药物与免疫抑制药物的应用，机体免疫功能低下，消化道黏膜屏障破坏，加之粒细胞缺乏期间因细菌感染而应用大量广谱抗生素所导致的菌群失调等诸多因素使血液系统恶性肿瘤患者免疫功能极度低下，侵袭性真菌感染的风险显著增加[7]–[8]。Takahashi等[9]报道真菌性食管炎在免疫力正常人群中检出率为0.32%，本组资料中真菌性食管炎的检出率为4.66%，提示血液恶性疾病患者更易并发真菌性食管炎。\n\n参照血液病／恶性肿瘤患者侵袭性真菌感染的诊断标准与治疗原则[10]及美国感染疾病学会（IDSA）提出的念珠菌病治疗指南[11]，真菌性食管炎介于口咽念珠菌病等浅表真菌感染与肝脾念珠菌病等深部感染之间，属侵袭性真菌疾病。食管真菌感染可局限于食管本身亦可能播散入血导致播散性真菌病，而食管黏膜血供极其丰富，加之放化疗对黏膜屏障的损伤，提示血液系统恶性疾病并发真菌性食管炎的患者存在发展为播散性真菌病的风险。真菌性食管炎的感染源主要为定植在胃肠道的念珠菌，且可以与口咽念珠菌病并存[12]。\n\n根据文献[13]–[14]报道，真菌性食管炎的常见危险因素有：①基础疾病，如获得性免疫缺陷综合征、恶性肿瘤、糖尿病、肺结核等；②长期大量联合使用广谱抗生素；③大量应用糖皮质激素、免疫抑制剂；④放疗或化疗后。Takahashi等[9]统计80 219名接受内镜检查的人群，单因素分析提示年龄、HIV感染及大剂量糖皮质激素应用与真菌性食管炎的发生显著相关。王晓虎等[15]采用流式细胞术检测154例真菌性食管炎患者外周血T细胞亚群CD3、CD4、CD4/CD8及血清IgA、IgM、IgG，并与正常对照组相比，发现真菌性食管炎组上述指标均低于正常对照组（P<0.01），也提示真菌性食管炎患者的细胞及体液免疫功能均明显低下。综合分析本组资料可以发现，确诊的真菌性食管炎患者血液系统原发病以ALL及NHL等淋巴系统增殖疾病为主（13例中12例），这除了与疾病本身流行病学相关之外，或许与上述病种化疗方案中包含大剂量激素及疾病本身造成的免疫缺陷相关，但由于本研究病例数较少，尚需大样本临床分析来确定上述因素是否具有统计学意义。\n\n真菌性食管炎的临床表现极其不典型，轻者可表现为咽部异物感、恶心、呕吐、烧心、胸骨后不适，重者可表现为吞咽困难等，穿孔、出血和狭窄是罕见的并发症[13]。Choi等[8]研究发现58%（163/281）的真菌性食管炎患者无胃肠道症状，仅有11.7％的患者有较明显的消化道症状，包括吞咽困难、吞咽疼痛、胸骨后不适等，然而具有典型症状的真菌性食管炎患者并非常见。老年患者敏感性较差，症状更为不典型，部分患者甚至可无任何症状，导致诊断困难，极易漏诊或误诊[1]。另外，食管位置隐蔽，加之血液科医师对食管感染的关注远低于肺部及肝脏等器官，也进一步增加了该病诊断的难度。本组资料中4例DLBCL患者均无任何临床表现，因原发病侵及胃肠道而行胃镜复查原发病治疗效果时发现真菌性食管炎。但是真菌性食管炎的内镜下表现较为典型，内镜下刷检细胞涂片法诊断该病简便易行，因此我们认为对具有高危因素或可疑的症状体征（如恶心、呕吐、烧心、胸骨后异物感、吞咽困难、大便潜血阳性、反复低热、影像学发现胃食管黏膜异常等）的患者，及时行胃镜检查是减少真菌性食管炎漏诊的可靠途径。\n\n尽管多数真菌性食管炎患者无明显症状和体征，且病原菌对食管壁的侵犯多数仅局限在上皮层浅表处，在免疫功能正常的患者中，该病多为自限性疾病，去除诱因后多可自愈，然而该病仍然具有潜在的导致食管组织大范围坏死进而导致食管穿孔的风险，且在免疫力低下的患者中其侵袭性更强，病灶更不易局灶化[1],[8]。Tran等[16]曾报道1例造血干细胞移植术后并发真菌性食管炎最终导致食管穿孔的病例，并认为食管穿孔之后继发的最严重的并发症为纵隔感染。恶性血液病并发真菌性食管炎患者免疫力极度低下，黏膜屏障受损，局部组织菌群失调等因素，导致病情难以呈自限性进程。一旦出现相关的症状体征，应及时行胃镜检查并刷检细胞涂片，诊断明确后应及时予抗真菌治疗[17]–[18]。\n\n真菌性食管炎的致病菌多为白色念珠菌，南里奥格兰德联邦大学统计结果显示白色念珠菌占所有真菌性食管炎的96.2%[9]。IDSA发表的念珠菌病治疗指南中将氟康唑作为多种类型念珠菌感染的推荐用药，强调氟康唑和棘白菌素作为治疗确诊和疑诊念珠菌病的优选药物，淡化两性霉素B及其脂质体的地位[11]。氟康唑高度特异性结合真菌细胞色素P450酶，广泛用于防治免疫力低下患者的继发性真菌感染，显示了良好的有效性及安全性，但随着疾病谱及治疗模式的变化，感染菌种也逐渐发生变化，氟康唑耐药菌株逐渐增多，白色念珠菌感染比例逐渐下降，目前以卡泊芬净为代表的棘白菌素类抗真菌药物的应用日益受到关注。棘白菌素类药物特异性地结合真菌细胞壁结构β-（1-3）-葡聚糖合成酶，引起细胞壁结构破坏从而导致菌体死亡[7],[19]。李岷等[19]研究提示该类药物对氟康唑耐药的念珠菌有较好的抗菌作用。制霉菌素为多烯类抗真菌药，其水溶性差，口服不易吸收，治疗真菌性食管炎安全有效[2]。在本资料中，6例患者予氟康唑注射液治疗均有效，7例予制霉菌素片治疗6例有效。二者治疗相关不良反应均为一过性的转氨酶升高及轻中度胃肠反应，未出现严重心、肾、肝等重要脏器功能损伤。\n\n真菌性食管炎并非血液系统恶性疾病患者继续治疗血液系统原发病的禁忌症。本研究中13例患者均继续接受化疗，3例后续行放射治疗，后续治疗中真菌性食管炎均未复发。\n\n综上所述，恶性血液病并发真菌性食管炎并非少见，且以淋巴系统疾病患者居多。病原菌主要为白色念珠菌。临床症状不典型，约半数以上患者无明显临床表现；临床工作者应对此予以足够的重视，一旦发现疑似症状体征，应行内镜检查；诊断明确后，应积极给予针对性抗真菌治疗。本研究资料提示，氟康唑及制霉菌素单药治疗真菌性食管炎疗效确切，不良反应轻微，可供临床工作者参考。但由于本研究例数较少，所得结论尚需多中心大样本研究进一步验证。\n==== Refs\nReferences\n1 Pochedly C Reichmann I Irwin GA Constrictive esophagitis due to Candida albicans in acute childhood leukemia[J] J Pediatr 1972 80 5 892 893 4502300 \n2 秦 咏梅 张 超贤 刘 竹娥 念珠菌性食管炎76例临床分析[J] 中华消化内镜杂志 2008 25 8 437 439 10.3760/cma.j.issn.1007-5232.2008.08.017 \n3 张 之南 沈 悌 血液病诊断及疗效标准[M] 3版 北京 科学出版社 2007 131 133 \n4 中华医学会血液学分会, 中国抗癌协会淋巴瘤专业委员会 中国弥漫大B细胞淋巴瘤诊断与治疗指南(2013年版)[J] 中华血液学杂志 2013 34 9 816 819 10.3760/cma.j.issn.0253-2727.2013.09.019 \n5 Asayama N Nagata N Shimbo T Relationship between clinical factors and severity of esophageal candidiasis according to Kodsi's classification[J] Dis Esophagus 2014 27 3 214 219 10.1111/dote.12102 23826847 \n6 Song YB Suh MK Ha GY Antifungal Susceptibility Testing with Etest for Candida Species Isolated from Patients with Oral Candidiasis[J] Ann Dermatol 2015 27 6 715 720 10.5021/ad.2015.27.6.715 26719641 \n7 McCoy D Depestel DD Carver PL Primary antifungal prophylaxis in adult hematopoietic stem cell transplant recipients: current therapeutic concepts[J] Pharmacotherapy 2009 29 11 1306 1325 10.1592/phco.29.11.1306 19857148 \n8 Choi JH Lee CG Lim YJ Prevalence and risk factors of esophageal candidiasis in healthy individuals: a single center experience in Korea[J] Yonsei Med J 2013 54 1 160 165 10.3349/ymj.2013.54.1.160 23225813 \n9 Takahashi Y Nagata N Shimbo T Long-Term Trends in Esophageal Candidiasis Prevalence and Associated Risk Factors with or without HIV Infection: Lessons from an Endoscopic Study of 80,219 Patients[J] PLoS One 2015 10 7 e0133589 10.1371/journal.pone.0133589 26208220 \n10 中国侵袭性真菌感染工作组 血液病／恶性肿瘤患者侵袭性真菌病的诊断标准与治疗原则(第四次修订版)[J] 中华内科杂志 2013 52 8 704 709 10.3760/cma.j.issn.0578-1426.2013.08.030 \n11 Pappas PG Kauffman CA Andes D Clinical practice guidelines for the management of candidiasis: 2009 update by the Infectious Diseases Society of America[J] Clin Infect Dis 2009 48 5 503 535 10.1086/596757 19191635 \n12 宋 阿霞 黄 勇 杨 栋林 血液疾病患者并发侵袭性真菌感染的危险因素及预后分析[J] 中华血液学杂志 2011 32 8 507 511 10.3760/cma.j.issn.0253-2727.2011.08.002 \n13 Olmos MA Araya V Concetti H [Oesophageal candidiasis: clinical and mycological analysis][J] Acta Gastroenterol Latinoam 2005 35 4 211 218 16496852 \n14 Wilcox CM Straub RF Clark WS Prospective evaluation of oropharyngeal findings in human immunodeficiency virus-infected patients with esophageal ulceration[J] Am J Gastroenterol 1995 90 11 1938 1941 7484995 \n15 王 晓虎 王 慧芳 陈 滋华 霉菌性食管炎与人体免疫功能的关系[J] 临床内科杂志 2008 25 3 206 206 10.3969/j.issn.1001-9057.2008.03.025 \n16 Tran HA Vincent JM Slavin MA Esophageal perforation secondary to angio-invasive Candida glabrata following hemopoietic stem cell transplantation[J] Clin Microbiol Infect 2003 9 12 1215 1218 14686986 \n17 刘 莎 魏 旭东 尹 青松 急性白血病并发慢性播散性念珠菌病的临床分析[J] 中华血液学杂志 2014 35 8 760 762 10.3760/cma.j.issn.0253-2727.2014.08.023 \n18 中华医学会重症医学分会 重症患者侵袭性真菌感染诊断与治疗指南(2007)[J] 中华内科杂志 2007 46 11 960 966 10.3760/j.issn:0578-1426.2007.11.031 \n19 李 岷 沈 永年 吕 桂霞 棘白菌素对氟康唑耐药的念珠菌体外药物敏感性的研究[J] 中国真菌学杂志 2009 4 2 78 81 10.3969/j.issn.1673-3827.2009.02.004\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0253-2727",
"issue": "37(6)",
"journal": "Zhonghua xue ye xue za zhi = Zhonghua xueyexue zazhi",
"keywords": null,
"medline_ta": "Zhonghua Xue Ye Xue Za Zhi",
"mesh_terms": "D004941:Esophagitis; D015725:Fluconazole; D019337:Hematologic Neoplasms; D006801:Humans; D009181:Mycoses; D011379:Prognosis; D012189:Retrospective Studies; D016896:Treatment Outcome",
"nlm_unique_id": "8212398",
"other_id": null,
"pages": "507-11",
"pmc": null,
"pmid": "27431077",
"pubdate": "2016-06-14",
"publication_types": "D016428:Journal Article",
"references": "25152132;4502300;19191635;19857148;26719641;23826847;24103886;7484995;26208220;14686986;23225813;16496852",
"title": "A clinical study of fungal esophagitis in 13 patients with hematologic malignancies.",
"title_normalized": "a clinical study of fungal esophagitis in 13 patients with hematologic malignancies"
} | [
{
"companynumb": "CN-JNJFOC-20170621388",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DOXORUBICIN HYDROCHLORIDE"
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"drugadditional": "... |
{
"abstract": "Tenofovir (TDF) is an antiviral drug with potential risk of kidney injury. The study is aimed at comparing the incidence of acute kidney injury (AKI) between TDF and entecavir (ETV) treatment in hepatitis B virus- (HBV-) related acute on chronic liver failure (ACLF).\nTreatment-naive patients with HBV-related ACLF were included. Propensity score matching was used to balance the baseline characteristics between ETV and TDF groups. The risk of AKI and the efficacy of TDF and ETV were compared.\nA total of 95 cases with HBV-related ACLF were included in this study, with 74.74% of male and a mean age of 47.01 ± 14.71 years. The antiviral therapy was initiated within 2 days after admission, with 39 cases on the TDF group and 56 on the ETV group. Patients in the TDF group had higher AST, hemoglobin, and serum sodium levels and lower MELD-Na score. After propensity matching, 39 cases of TDF and 39 of ETV were included in the final analysis. No difference was found in the changes of creatinine and cystatin C from baseline to 4 weeks after treatment between ETV and TDF groups. AKI was developed in 1 (2.56%) patient in the ETV group and 2 (5.13%) in the TDF group within one month (P = 0.556). Survival analysis revealed no significant difference in the 6-month mortality between the two groups (P = 0.813). Cox analysis showed that the type of antiviral drug or the development of AKI was not an independent risk factor for the outcomes.\nCompared to ETV, TDF did not increase the risk of AKI nor the mortality in patients with HBV-related ACLF in the short time.",
"affiliations": "Liver Research Center, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China.;Liver Research Center, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China.;Liver Research Center, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China.;Liver Research Center, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China.;Liver Research Center, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China.",
"authors": "Zhang|Kai|K|https://orcid.org/0000-0003-1037-7015;Lin|Su|S|https://orcid.org/0000-0001-7517-9859;Wang|Mingfang|M|https://orcid.org/0000-0001-7306-955X;Huang|Jiaofeng|J|https://orcid.org/0000-0003-1383-6897;Zhu|Yueyong|Y|https://orcid.org/0000-0002-0746-4911",
"chemical_list": "D000998:Antiviral Agents; C413685:entecavir; D006147:Guanine; D000068698:Tenofovir",
"country": "United States",
"delete": false,
"doi": "10.1155/2020/5728359",
"fulltext": "\n==== Front\nBiomed Res Int\nBiomed Res Int\nBMRI\nBioMed Research International\n2314-6133 2314-6141 Hindawi \n\n10.1155/2020/5728359\nResearch Article\nThe Risk of Acute Kidney Injury in Hepatitis B Virus-Related Acute on Chronic Liver Failure with Tenofovir Treatment\nhttps://orcid.org/0000-0003-1037-7015Zhang Kai https://orcid.org/0000-0001-7517-9859Lin Su sumer5129@fjmu.edu.cn https://orcid.org/0000-0001-7306-955XWang Mingfang https://orcid.org/0000-0003-1383-6897Huang Jiaofeng https://orcid.org/0000-0002-0746-4911Zhu Yueyong Liver Research Center, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China\nGuest Editor: Ran Wang\n\n\n2020 \n18 5 2020 \n2020 572835925 3 2020 5 5 2020 Copyright © 2020 Kai Zhang et al.2020This 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.Aims\n Tenofovir (TDF) is an antiviral drug with potential risk of kidney injury. The study is aimed at comparing the incidence of acute kidney injury (AKI) between TDF and entecavir (ETV) treatment in hepatitis B virus- (HBV-) related acute on chronic liver failure (ACLF). \n\nMethods\n Treatment-naive patients with HBV-related ACLF were included. Propensity score matching was used to balance the baseline characteristics between ETV and TDF groups. The risk of AKI and the efficacy of TDF and ETV were compared. \n\nResults\n A total of 95 cases with HBV-related ACLF were included in this study, with 74.74% of male and a mean age of 47.01 ± 14.71 years. The antiviral therapy was initiated within 2 days after admission, with 39 cases on the TDF group and 56 on the ETV group. Patients in the TDF group had higher AST, hemoglobin, and serum sodium levels and lower MELD-Na score. After propensity matching, 39 cases of TDF and 39 of ETV were included in the final analysis. No difference was found in the changes of creatinine and cystatin C from baseline to 4 weeks after treatment between ETV and TDF groups. AKI was developed in 1 (2.56%) patient in the ETV group and 2 (5.13%) in the TDF group within one month (P = 0.556). Survival analysis revealed no significant difference in the 6-month mortality between the two groups (P = 0.813). Cox analysis showed that the type of antiviral drug or the development of AKI was not an independent risk factor for the outcomes. \n\nConclusions\n Compared to ETV, TDF did not increase the risk of AKI nor the mortality in patients with HBV-related ACLF in the short time.\n\nFujian Province Health Youth Research Project2019-1-37Fujian Medical University Sailing Fund Project2018QH1047Fujian provincial health technology project2018-ZQN-54Chinese National Science and Technology Projects2017ZX10202201\n==== Body\n1. Introduction\nHepatitis B virus (HBV) is a major health problem with 3.5% of the population being chronically infected globally [1]. Patients with chronic HBV infection may suffer from various hepatic complications, such as cirrhosis, liver failure, and hepatocellular carcinoma [2]. Acute on chronic liver failure (ACLF) is defined as a precipitating event in a patient with chronic liver disease, leading to jaundice and coagulopathy complicated by clinical ascites and/or encephalopathy [3]. Patients with ACLF due to HBV reactivation (HBV-ACLF) have extremely poor prognosis, with a reported short-term mortality ranging from 29.7% to 40% within 28 days [4–6]. Acute kidney injury (AKI) is common in ACLF and may develop within a very short period and lead to a poor outcome in ACLF [7].\n\nThe management of HBV-ACLF includes antiviral therapy, artificial liver support system, alternative therapies, and liver transplantation [8]. The antiviral therapy is the most evident treatment among them. Currently, tenofovir (TDF) and entecavir (ETV) are both recommended as the first-line antiviral agents for their potent antiviral activity and high genetic barrier for drug resistance [9, 10]. However, TDF has also been demonstrated to have potential kidney toxicity by several observational studies and case reports [11–14]. It is unclear whether or not the use of TDF may increase the risk of AKI in ACLF. The aim of this study was to compare the risk of AKI and the mortality between ETV and TDF groups in HBV-ACLF.\n\n2. Patients and Methods\n2.1. Patients\nWe retrospectively reviewed cases of HBV-related ACLF hospitalized in the First Affiliated Hospital of Fujian Medical University between January 2016 and November 2018. Treatment-naive patients who were diagnosed with ACLF and received TDF or ETV therapy after hospitalization were included in this study. The exclusion criteria were as follows: (1) patients with kidney injury on baseline; (2) patients with nucleotide treatment other than ETV or TDF; (3) patients with malignant tumor; (4) patients concomitant with other liver diseases such as alcoholic liver disease, autoimmune hepatitis, drug-induced liver injury, or other viral infections (hepatitis A, C, and E virus or HIV infection); (5) patients with missing data; and (6) patients who died or were lost to follow-up within one week after admission.\n\nThe diagnosis of ACLF was based on the definition by the Asian Pacific Association for the Study of the Liver (APASL) [3]: jaundice (a serum bilirubin level of ≥5 mg/dL) and coagulopathy (an international normalized ratio (INR) of ≥1.5 or prothrombin activity of <40%). The definition of AKI was based on the criteria by the International Club of Ascites (ICA), which is an increase in serum creatinine (sCr) ≥ 0.3 mg/dL (≥26.5 μmol/L) within 48 hours or a percentage increase in sCr ≥ 50% from baseline which is known, or presumed, to have occurred within the prior 7 days. A value of sCr obtained in the previous 3 months, when available, can be used as baseline sCr. In patients with more than one value within the previous 3 months, the value closest to the admission time to the hospitalization was used [15].\n\n2.2. Treatments\nDuring hospitalization, all patients received supportive treatments including nutrition support, albumin, and other medications that aimed to protect the liver. In patients with liver failure, plasma exchange was given if necessary. Antiviral therapy with TDF or ETV was started immediately when HBV-DNA was detected.\n\n2.3. Data Collection and Follow-Up\nThe clinical and laboratory data were collected on admission, including the presence of ascites or hepatic encephalopathy (HE), the presence of underlying cirrhosis, total bilirubin (TBIL), albumin, alanine aminotransferase (ALT), aspartate transaminase (AST), international normalized ratio (INR), serum creatinine (sCr), cystatin C, glomerular filtration rate (GFR), serum sodium (Na), hemoglobin, platelets, white blood cell (WBC), Child-Turcotte-Pugh (CTP) score, model for end-stage liver disease (MELD) score, chronic liver failure-sequential organ failure assessment (CLIF-SOFA), hepatitis B surface antigen (HBsAg) levels, hepatitis B e antigen (HBeAg), and HBV DNA levels. Patients were divided into ETV and TDF groups according to the antiviral treatment.\n\nThe renal function was reexamined in all survival patients on 4 weeks after antiviral treatment. The survival status was followed up until 2019. For patients being transferred to local hospital, the survival status was collected upon phone contact. The primary outcome was the incidence of AKI within 1 month; the secondary outcome was death or liver transplantation.\n\n2.4. Statistical Analyses\nThe continuous variables were reported as mean ± standard deviation or medium (interquartile rage), while categorical variables were reported as percentage. The Student t-test was used for the comparisons of continuous variables, and the chi-squared test was used for the comparison of categorical variables [16]. Propensity score matching (PSM) analysis was performed to minimize the probability of selection bias [17]. The Cox proportional hazard model was used to analyze the risk factors of mortality. The log-rank test was used to compare the risks between groups. All statistical analyses were performed using SPSS software version 24.0 (SPSS Inc., Chicago, USA).\n\n3. Results\n3.1. Patient Characteristics\nA total of 143 patients were diagnosed with ACLF during the study period, among whom 48 patients were excluded due to various reasons (Figure 1). Ninety-five cases were eligible for the final analysis, including 56 cases with ETV therapy and 39 cases with TDF therapy (Figure 1). The average age was 47.01 ± 14.71 years old, and 71 (74.74%) of them were male. The median follow-up time of the overall population was 531 days (range 14-1207 days). There were 20 patients who died during this time period, with a median survival time of 26 days. The baseline characteristics are shown in Table 1. Patients in the TDF group had higher AST, hemoglobin, and serum sodium levels and lower MELD-Na score. There was no difference in other baseline characteristics, including age, sex, HBV DNA levels, MELD score, and the presence of underlying cirrhosis.\n\nWe performed PSM to balance the baseline factors. After PSM, there were 39 cases with ETV treatment and 39 cases with TDF treatment that were finally included. The baseline characteristics were comparable between the two groups after PSM. There were 15 patients in this PSM cohort who died during this follow-up, with a median survival time of 35 days.\n\n3.2. Virological and Serological Responses in TDF and ETV Groups\nSignificant reductions in HBV-DNA, bilirubin, and ALT were observed in both TDF and ETV groups after two weeks of treatment, with no difference in the reduction level between the two groups (Table 2). The HBV-DNA undetectable rate after 2 weeks of antiviral therapy was 28.21% (11/39) in the ETV group and 35.90% (14/39) in the TDF group (P = 0.467).\n\n3.3. The Dynamic Changes of Renal Function in TDF and ETV Groups\nSlight increases in sCr were found in both TDF and ETV groups after treatment. However, no significant difference in the change of sCr within 2 weeks or 4 weeks was found within each group or between two groups. Significant difference in the change of cystatin C within 2 weeks or 4 weeks was found within each group, but no significant difference in the dynamic changes of cystatin C between ETV and TDF groups (Table 3). Patients were followed up for 1 month, and AKI was developed in 1 (2.56%) patient in the ETV group and 2 (5.13%) patients in the TDF group. This difference was not statistically significant (P = 0.556). All of these 3 patients with AKI had cirrhotic background and pneumonia on admission. Two of them had diabetes. The patients with AKI in the ETV group died at 8 weeks after admission. The other two patients in the TDF group survived (Table 4).\n\n3.4. The Mortality in Overall Study Population and Predictors for Mortality\nA total of 15/78 (19.23%) patients died within 6 months. Survival analysis revealed no significant difference in the 6-month mortality between two groups (P = 0.813). The results of univariate analysis showed that age, HE, HBeAg positive, MELD score-Na, CTP score, and SOFA score were related to the overall mortality.\n\nBefore multivariate analysis, collinearity diagnostics was conducted to assess the sources of collinearity among MELD-Na, CTP, and SOFA scores. The result showed that the tolerance of all variables > 0.1 and the variance inflation factor < 5, indicating limited collinearity among the above variables. As the presence of cirrhosis, HBV DNA, and AKI and gender had been reported to be important predictive factors for the prognosis of ACLF [18–21], those were included in multivariate analysis as well.\n\nThe results of multivariate Cox regression analysis showed that the age (HR = 1.103, 95% CI: 1.038-1.172, P = 0.002), CTP score (HR = 1.990, 95% CI: 1.210-3.271, P = 0.007), SOFA score (HR = 3.000, 95% CI: 1.366-3.171, P < 0.001), and cirrhosis (HR = 47.232, 95% CI: 5.538-402.802, P < 0.001) were independent risk factors for mortality (Table 5). The types of antiviral drug and the development of AKI were not independently associated with the outcome (Figure 2 and Table 5).\n\n4. Discussion\nThis study compared the impact of TDF and ETV in renal function in patients with HBV-ACLF. The results showed that TDF did not increase the risk of AKI nor the mortality in patients with HBV-related ACLF within 6 months.\n\nBoth TDF and ETV are currently recommended as the first-line treatment for chronic hepatitis B (CHB) for their high efficacy and low resistance rate [9, 22–24]. Previous studies have demonstrated that TDF and ETV have similar effectiveness in treatment-naive CHB patient [25–27]. However, some reports indicate that TDF might lead to a higher incidence of AKI compared to ETV in CHB patients [28, 29]. As AKI is common in ACLF [30], renal injury associated with TDF use has raised some concerns [31]. However, in this single-center study, we found that the use of TDF did not increase the risk of AKI within one month of treatment. This might be due to the short follow-up period of this study. As reported previously, renal injury associated with TDF use usually develops after at least one year of treatment. A recent real-world study from Korea showed that TDF therapy did decrease overall renal function in CHB patients during the first two years of TDF use [13]. Therefore, long-term follow-up might be helpful to access the renal impairment in ACLF patients with different antiviral therapies.\n\nIt is worth noticing that all three patients suffering from AKI had bacterial infection and two of them had comorbidities like diabetes and hypertension. Hypertension and diabetes are both well-known risk factors for chronic kidney injury. The bacterial infection is also a main trigger for AKI in liver failure [32]; thus for patients who had AKI in this cohort, the impact of the other complication/comorbidities might overwhelm the influence of antiviral drugs. Prospective studies with longer follow-up period are greatly needed to reveal the real relationship between AKI and TDF in ACLF patients.\n\nCystatin C is a sensitive marker for renal impairment [33]. In this study, no significant difference in the change of sCr within 1 month was found in both TDF and ETV groups, while there was significant difference in the change of cystatin C in both groups. Cystatin C levels may be more sensitive for evaluating the renal impairment in ACLF [34]. However, in terms of the impact of different antiviral drugs on renal function, the changes of cystatin C were similar as those of sCr, which further consolidated that TDF had limited influence on renal function in an ACLF population in a short-term period.\n\nThe efficacy of different antiviral drugs in ACLF remains controversial. Wan et al. [35] showed that TDF was superior to ETV in the treatment of HBV-ACLF; however, more studies showed no difference between these two groups [27, 36, 37]. The results of our study were in consistence with most studies showing that TDF was not superior to ETV regarding the HBV DNA suppression or mortality.\n\nThere are several limitations of this study. Firstly, the data of HBV-DNA levels, liver function, and kidney function is largely missing after 3 months because most survival patients were transferred to a local hospital after recovery; thus, the long-term changes of renal function were unclear. Secondly, the incidence rate of AKI was low and the sample size relatively small, which may easily lead to false-negative results. Further study with larger sample size is needed to guarantee the results.\n\nIn summary, our study showed that compared with ETV, TDF did not increase the risk of AKI nor the mortality in patients with HBV-related ACLF within a short-term period.\n\nAcknowledgments\nThis study was supported by the Chinese National Science and Technology Projects (2017ZX10202201); Fujian provincial health technology project (2018-ZQN-54); Fujian Medical University Sailing Fund Project (2018QH1047); and Fujian Province Health Youth Research Project (2019-1-37).\n\nData Availability\nThe data in this study are available from the corresponding author on reasonable request.\n\nEthical Approval\nThe study protocol has been approved by the Institutional Ethics Committee of the First Affiliated Hospital of Fujian Medical University. The clinical activities being reported are consistent with the principles of the Declaration of Helsinki.\n\nConflicts of Interest\nThe authors declare that they have no conflicts of interest.\n\nAuthors' Contributions\nKai Zhang, Jiaofeng Huang, and Mingfang Wang collected and analyzed the data. Kai Zhang and Su Lin wrote the primary draft. Yueyong Zhu and Su Lin did the study design and revised the final article for important intellectual content. All authors read and approved the final version of the manuscript.\n\nFigure 1 Flow chart of patient selection.\n\nFigure 2 Cumulative survival of ETV and ETV within 6 months.\n\nTable 1 Baseline characteristics of study population.\n\nVariable\tUnmatched\tMatched\t\nETV group (n = 56)\tTDF group (n = 39)\t\nP value\tETV group (n = 39)\tTDF group (n = 39)\t\nP value\t\nAge (years)\t47.80 ± 14.16\t44.33 ± 15.87\t0.266\t45.97 ± 14.10\t44.33 ± 15.87\t0.631\t\nMale, n (%)\t42 (75.00%)\t29 (74.36%)\t0.944\t30 (76.92%)\t29 (74.36%)\t0.792\t\nAscites, n (%)\t44 (78.57%)\t31 (79.49%)\t0.914\t29 (74.36%)\t31 (79.49%)\t0.591\t\nHE, n (%)\t9 (16.07%)\t5 (12.82%)\t0.884\t7 (17.95%)\t5 (12.82%)\t0.530\t\nCirrhosis, n (%)\t39 (69.62%)\t29 (74.36%)\t0.787\t26 (66.67%)\t29 (74.36%)\t0.456\t\nTBIL (mmol/L)\t282.15 ± 131.00\t259.64 ± 120.26\t0.396\t274.60 ± 138.61\t259.64 ± 120.26\t0.612\t\nALT (U/L)\t624.61 ± 571.32\t861.64 ± 691.44\t0.071\t724.79 ± 601.63\t861.64 ± 691.44\t0.354\t\nAST (U/L)\t419.04 ± 372.70\t645.00 ± 629.04\t0.031\t490.10 ± 405.92\t645.00 ± 629.04\t0.200\t\nAlbumin (g/L)\t30.05 (27.85-32.80)\t30.00 (27.90-34.00)\t0.934\t29.80 (27.40-33.30)\t30.00 (27.90-34.00)\t0.768\t\nINR\t2.14 ± 0.89\t1.96 ± 0.55\t0.249\t1.94 ± 0.59\t1.96 ± 0.55\t0.864\t\nBUN (mmol/L)\t4.33 ± 2.00\t3.58 ± 1.52\t0.052\t4.07 ± 1.84\t3.58 ± 1.52\t0.203\t\nsCr (μmol/L)\t59.81 ± 12.35\t57.86 ± 13.87\t0.474\t59.23 ± 11.24\t57.86 ± 13.87\t0.633\t\nCystatin C (mg/L)\t1.11 ± 0.41\t1.00 ± 0.21\t0.128\t1.06 ± 0.26\t1.00 ± 0.21\t0.301\t\nGFR (mL/min)\t93.00 ± 18.71\t96.72 ± 23.24\t0.392\t94.49 ± 19.79\t96.72 ± 23.24\t0.650\t\nHBsAglog10 (ng/mL)\t3.10 ± 1.08\t2.98 ± 1.07\t0.595\t3.28 ± 1.12\t2.98 ± 1.07\t0.243\t\nHBeAg-positive, n (%)\t26 (46.43%)\t22 (52.79%)\t0.454\t19 (48.72%)\t22 (52.79%)\t0.496\t\nHBVDNAlog10 (IU/mL)\t5.11 ± 2.00\t5.34 ± 1.68\t0.560\t5.39 ± 1.95\t5.34 ± 1.68\t0.903\t\nNa (mmol/L)\t136.16 ± 3.70\t138.12 ± 2.93\t0.007\t136.62 ± 3.91\t138.12 ± 2.93\t0.058\t\nWBC (×109/L)\t6.38 ± 3.24\t7.21 ± 3.57\t0.247\t6.68 ± 3.45\t7.21 ± 3.57\t0.510\t\nHGB (g/L)\t119.07 (102.25-136.50)\t132.67 (119.00-147.00)\t0.011\t124.00 (111.00-143.00)\t132.67 (119.00-147.00)\t0.147\t\nPlatelets (×109/L)\t106.95 ± 52.22\t118.97 ± 60.22\t0.303\t116.03 ± 53.48\t118.97 ± 60.22\t0.820\t\nCTP score\t10.48 ± 1.87\t10.36 ± 2.12\t0.766\t10.18 ± 1.90\t10.36 ± 2.12\t0.694\t\nMELD score\t20.25 ± 6.80\t18.33 ± 5.20\t0.139\t18.22 ± 4.94\t18.33 ± 5.20\t0.928\t\nMELD-Na score\t21.68 ± 7.81\t18.74 ± 5.70\t0.047\t19.46 ± 6.15\t18.74 ± 5.70\t0.593\t\nCLIF-SOFA score\t7.25 ± 1.73\t7.05 ± 1.96\t0.603\t6.97 ± 1.67\t7.05 ± 1.96\t0.852\t\nDiabetes, n (%)\t8 (14.29%)\t3 (7.70%)\t0.508\t5 (12.82%)\t3 (7.70%)\t0.709\t\nHypertension, n (%)\t7 (12.50%)\t2 (5.13%)\t0.395\t4 (10.26%)\t2 (5.13%)\t0.671\t\nHE: hepatic encephalopathy; TBIL: total bilirubin; ALT: alanine aminotransferase; AST: aspartate transaminase; INR: international normalized ratio; BUN: blood urea nitrogen; sCr: serum creatinine; GFR: glomerular filtration rate; HBV: hepatitis B virus; HBsAg: hepatitis B surface antigen; HBeAg: hepatitis B e antigen; WBC: white blood cell; HGB: hemoglobin; CTP: Child-Turcotte-Pugh; MELD: model for end-stage liver disease; CLIF-SOFA: chronic liver failure-sequential organ failure assessment.\n\nTable 2 Index changes between ETV and TDF groups after 2-week treatment.\n\n\tETV (n = 39)\tTDF (n = 39)\t\nP (ETV vs. TDF)\t\nHBVDNA\t\t\t\t\n Before treatment\t5.39 ± 1.95\t5.34 ± 1.68\t\t\n After 2 weeks\t3.36 ± 1.13\t3.22 ± 1.10\t\t\n Reduction\t2.03 ± 1.52\t2.12 ± 1.01\t\nP = 0.776\t\n P (baseline vs. 2 weeks)\t<0.001\t<0.001\t\t\nALT\t\t\t\t\n Before treatment\t724.79 ± 601.63\t861.64 ± 691.44\t\t\n After 2 weeks\t130.90 ± 278.18\t119.51 ± 112.05\t\t\n Reduction\t593.90 ± 540.26\t742.13 ± 689.12\t\nP = 0.294\t\n P (baseline vs. 2 weeks)\t<0.001\t<0.001\t\t\nTBIL\t\t\t\t\n Before treatment\t274.60 ± 138.61\t259.64 ± 120.26\t\t\n After 2 weeks\t239.89 ± 250.38\t223.54 ± 124.94\t\t\n Reduction\t34.71 ± 234.75\t36.09 ± 105.37\t\nP = 0.973\t\n P (baseline vs. 2 weeks)\t0.362\t0.039\t\t\nTable 3 Comparison changes in serum creatinine and cystatin C between the ETV and TDF group.\n\n\tETV (n = 39)\tTDF (n = 39)\t\nP (ETV vs. TDF)\t\nsCr\t\t\t\t\n Before treatment\t59.23 ± 11.24\t57.86 ± 13.87\t\t\n After 2 weeks\t61.06 ± 12.69\t58.82 ± 11.56\t\t\n Changes from baseline to 2 weeks\t−1.57 ± 5.95\t−0.96 ± 10.32\t0.748\t\n P (baseline vs. 2 weeks)\t0.080\t0.565\t\t\n After 4 weeks\t61.71 ± 12.14\t60.92 ± 16.52\t\t\n Changes from baseline to 4 weeks\t−2.68 ± 8.96\t−2.17 ± 11.81\t0.837\t\n P (baseline vs. 4 weeks)\t0.072\t0.285\t\t\nCystatin C\t\t\t\t\n Before treatment\t1.06 ± 0.26\t1.00 ± 0.21\t\t\n After 2 weeks\t1.18 ± 0.32\t1.11 ± 0.24\t\t\n Changes from baseline to 2 weeks\t−0.12 ± 0.31\t−0.11 ± 0.16\t0.810\t\n P (baseline vs. 2 weeks)\t0.02\t<0.001\t\t\n After 4 weeks\t1.15 ± 0.16\t1.28 ± 0.30\t\t\n Changes from baseline to 4 weeks\t−0.08 ± 0.39\t−0.25 ± 0.25\t0.237\t\n P (baseline vs. 4 weeks)\t0.044\t0.011\t\t\nTable 4 The clinical features of the AKI patients.\n\n\tA\tB\tC\t\nAge\t61\t51\t46\t\nSex\tMale\tFemale\tMale\t\nsCr (baseline) (μmol/L)\t64\t64\t67\t\nsCr (after treatment) (μmol/L)\t113\t104\t105\t\nAntivirus therapy\tETV\tTDF\tTDF\t\nCirrhosis\tYes\tYes\tYes\t\nHypertension\tYes\tYes\tNo\t\nDiabetes\tYes\tNo\tNo\t\nPneumonia\tYes\tYes\tYes\t\nOutcome\tDeath\tSurvival\tSurvival\t\nTable 5 Cox analysis of risk factors for mortality.\n\nVariable\tUnivariate analysis (95% CI)\t\nP value\tMultivariate analysis (95% CI)\t\nP value\t\nAge\t1.044 (1.010-1.079)\t0.011\t1.103 (1.038-1.172)\t0.002\t\nMale\t1.276 (0.360-4.522)\t0.706\t1.200 (0.277-6.340)\t0.830\t\nHE\t3.291 (1.123-9.644)\t0.030\t7.156 (0.740-69.170)\t0.089\t\nHBeAg-positive\t8.356 (1.884-37.062)\t0.005\t10.611 (1.314-85.709)\t0.027\t\nCirrhosis\t1.253 (0.428-3.667)\t0.681\t47.232 (5.538-402.802)\t<0.001\t\nAntivirus therapy\t0.885 (0.321-2.442)\t0.814\t\t\t\nAKI\t1.617 (0.213-12.302)\t0.642\t5.394 (0.535-54.420)\t0.153\t\nlgHBsAg (ng/mL)\t0.874 (0.551-1.388)\t0.570\t\t\t\nlgHBV-DNA (IU/mL)\t0.920 (0.687-1.233)\t0.577\t0.925 (0.563-1.522)\t0.760\t\nALT (U/L)\t1.000 (1.000-1.001)\t0.407\t\t\t\nsCr (μmol/L)\t0.985 (0.879-1.104)\t0.795\t\t\t\nWBC (1012/L)\t0.993 (0.857-1.151)\t0.929\t\t\t\nPLT (109/L)\t0.997 (0.988-1.007)\t0.598\t\t\t\nMeld-Na score\t1.107 (1.020-1.201)\t0.015\t0.972 (0.837-1.128)\t0.704\t\nCTP score\t1.743 (1.266-2.400)\t0.001\t1.990 (1.210-3.271)\t0.007\t\nSOFA score\t2.146 (1.528-3.013)\t<0.001\t3.000 (1.621-5.553)\t<0.001\n==== Refs\n1 Yuen M. F. Chen D. S. Dusheiko G. M. Hepatitis B virus infection Nature Reviews Disease Primers 2018 4 1, article 18035 10.1038/nrdp.2018.35 2-s2.0-85048246011 \n2 Tada T. Kumada T. Toyoda H. Long-term prognosis of patients with hepatitis B infection: causes of death and utility of nucleos(t)ide analogue therapy Journal of Gastroenterology 2015 50 7 795 804 10.1007/s00535-014-1011-6 2-s2.0-84937253053 25376770 \n3 Sarin S. K. Kedarisetty C. K. Abbas Z. Acute-on-chronic liver failure: consensus recommendations of the Asian Pacific Association for the Study of the Liver (APASL) 2014 Hepatology International 2014 8 4 453 471 10.1007/s12072-014-9580-2 2-s2.0-84919835606 26202751 \n4 Wan Y. M. Li Y. H. Xu Z. Y. Therapeutic plasma exchange versus double plasma molecular absorption system in hepatitis B virus-infected acute-on-chronic liver failure treated by entercavir: a prospective study Journal of Clinical Apheresis 2017 32 6 453 461 10.1002/jca.21535 2-s2.0-85034211105 28304106 \n5 Lin S. Zhang K. Zhang J. Wang M. Velani B. Zhu Y. Long-term outcomes of patients with hepatitis B virus-related acute on chronic liver failure: an observational cohort study Liver International 2019 39 5 854 860 10.1111/liv.14072 2-s2.0-85062715311 30753752 \n6 Zeng Y. Li Y. Xu Z. Myeloid-derived suppressor cells expansion is closely associated with disease severity and progression in HBV-related acute-on-chronic liver failure Journal of Medical Virology 2019 91 8 1510 1518 10.1002/jmv.25466 2-s2.0-85068095891 30905084 \n7 Yuan W. Zhang Y. Y. Zhang Z. G. Zou Y. Lu H. Z. Qian Z. P. Risk factors and outcomes of acute kidney injury in patients with hepatitis B virus-related acute-on-chronic liver failure The American Journal of the Medical Sciences 2017 353 5 452 458 10.1016/j.amjms.2017.03.005 2-s2.0-85017401224 28502331 \n8 Zhao R.-H. Shi Y. Zhao H. Wu W. Sheng J.-F. Acute-on-chronic liver failure in chronic hepatitis B: an update Expert Review of Gastroenterology & Hepatology 2018 12 4 341 350 10.1080/17474124.2018.1426459 2-s2.0-85043986745 29334786 \n9 Terrault N. A. Bzowej N. H. Chang K. M. AASLD guidelines for treatment of chronic hepatitis B Hepatology 2016 63 1 261 283 10.1002/hep.28156 2-s2.0-84951825509 26566064 \n10 Wang J. Ma K. Han M. Nucleoside analogs prevent disease progression in HBV-related acute-on-chronic liver failure: validation of the TPPM model Hepatology International 2014 8 1 64 71 10.1007/s12072-013-9485-5 2-s2.0-84895903455 26202407 \n11 Chan L. Asriel B. Eaton E. F. Wyatt C. M. Potential kidney toxicity from the antiviral drug tenofovir: new indications, new formulations, and a new prodrug Current Opinion in Nephrology and Hypertension 2018 27 2 102 112 10.1097/MNH.0000000000000392 2-s2.0-85042401887 29278542 \n12 Kara A. V. Yıldırım Y. Ozcicek F. Effects of entecavir, tenofovir and telbivudine treatment on renal functions in chronic hepatitis B patients Acta Gastroenterologica Belgica 2019 82 2 273 277 \n13 Lim T. S. Lee J. S. Kim B. K. An observational study on long-term renal outcome in patients with chronic hepatitis B treated with tenofovir disoproxil fumarate Journal of Viral Hepatitis 2019 27 3 316 322 10.1111/jvh.13222 \n14 Viganò M. Loglio A. Labanca S. Effectiveness and safety of switching to entecavir hepatitis B patients developing kidney dysfunction during tenofovir Liver International 2019 39 3 484 493 10.1111/liv.14017 2-s2.0-85059612185 30525275 \n15 Angeli P. Ginès P. Wong F. Diagnosis and management of acute kidney injury in patients with cirrhosis: revised consensus recommendations of the International Club of Ascites Journal of Hepatology 2015 62 4 968 974 10.1016/j.jhep.2014.12.029 2-s2.0-84926420446 25638527 \n16 Zhang Z. Univariate description and bivariate statistical inference: the first step delving into data Annals of Translational Medicine 2016 4 5 91 91 10.21037/atm.2016.02.11 2-s2.0-85006201765 27047950 \n17 Austin P. C. Balance diagnostics for comparing the distribution of baseline covariates between treatment groups in propensity-score matched samples Statistics in Medicine 2009 28 25 3083 3107 10.1002/sim.3697 2-s2.0-70449365700 19757444 \n18 Maiwall R. Sarin S. K. Kumar S. Development of predisposition, injury, response, organ failure model for predicting acute kidney injury in acute on chronic liver failure Liver International 2017 37 10 1497 1507 10.1111/liv.13443 2-s2.0-85026764982 28393476 \n19 Jeng W.-J. Sheen I.-S. Liaw Y.-F. Hepatitis B virus DNA level predicts hepatic decompensation in patients with acute exacerbation of chronic hepatitis B Clinical Gastroenterology and Hepatology 2010 8 6 541 545 10.1016/j.cgh.2010.02.023 2-s2.0-77952742728 20298811 \n20 Chen T. Yang Z. Choudhury A. K. Complications constitute a major risk factor for mortality in hepatitis B virus-related acute-on-chronic liver failure patients: a multi-national study from the Asia-Pacific region Hepatology International 2019 13 6 695 705 10.1007/s12072-019-09992-x 31650510 \n21 Wang S.-H. Chen P.-J. Yeh S.-H. Gender disparity in chronic hepatitis B: mechanisms of sex hormones Journal of Gastroenterology and Hepatology 2015 30 8 1237 1245 10.1111/jgh.12934 2-s2.0-84937406883 25708186 \n22 Liaw Y. F. Kao J. H. Piratvisuth T. Asian-Pacific consensus statement on the management of chronic hepatitis B: a 2012 update Hepatology International 2012 6 3 531 561 10.1007/s12072-012-9365-4 2-s2.0-84865376141 26201469 \n23 Lampertico P. Agarwal K. Berg T. EASL 2017 clinical practice guidelines on the management of hepatitis B virus infection Journal of Hepatology 2017 67 2 370 398 10.1016/j.jhep.2017.03.021 2-s2.0-85017533115 28427875 \n24 Hsu C. W. Yeh C. Yeh C. T. Maintaining complete virological suppression by reduced doses of nucleos(t)ide analogue in patients with chronic hepatitis B Journal of Medical Virology 2019 91 7 1360 1363 10.1002/jmv.25443 2-s2.0-85062792296 30817845 \n25 Wu I.-T. Hu T. H. Hung C. H. Comparison of the efficacy and safety of entecavir and tenofovir in nucleos(t)ide analogue-naive chronic hepatitis B patients with high viraemia: a retrospective cohort study Clinical Microbiology and Infection 2017 23 7 464 469 10.1016/j.cmi.2017.02.001 2-s2.0-85014798296 28189857 \n26 Kim S. U. Seo Y. S. Lee H. A. A multicenter study of entecavir vs. tenofovir on prognosis of treatment-naïve chronic hepatitis B in South Korea Journal of Hepatology 2019 71 3 456 464 10.1016/j.jhep.2019.03.028 2-s2.0-85067170621 30959156 \n27 Park J. W. Kwak K. M. Kim S. E. Comparison of the long-term efficacy between entecavir and tenofovir in treatment-naïve chronic hepatitis B patients BMC Gastroenterology 2017 17 1 p. 39 10.1186/s12876-017-0596-7 2-s2.0-85014756320 28279168 \n28 Chen T. M. Lin C. C. Letter: tenofovir is associated with higher probability of acute kidney injury compared with entecavir Alimentary Pharmacology & Therapeutics 2014 40 4 406 407 10.1111/apt.12854 2-s2.0-84904433973 25040928 \n29 Tsai M.-C. Chen C. H. Tseng P. L. Comparison of renal safety and efficacy of telbivudine, entecavir and tenofovir treatment in chronic hepatitis B patients: real world experience Clinical Microbiology and Infection 2016 22 1 95.e1 95.e7 10.1016/j.cmi.2015.05.035 2-s2.0-84959269249 \n30 Zang H. Liu F. Liu H. Incidence, risk factors and outcomes of acute kidney injury (AKI) in patients with acute-on-chronic liver failure (ACLF) of underlying cirrhosis Hepatology International 2016 10 5 807 818 10.1007/s12072-016-9756-z 2-s2.0-84982786638 27485174 \n31 Buti M. Roade L. Riveiro-Barciela M. Esteban R. Optimal management of chronic hepatitis B patients receiving nucleos(t)ide analogues Liver International 2020 40 Supplement 1 15 21 10.1111/liv.14367 32077604 \n32 Ginès P. Solà E. Angeli P. Wong F. Nadim M. K. Kamath P. S. Hepatorenal syndrome Nature Reviews Disease Primers 2018 4 1 p. 23 10.1038/s41572-018-0022-7 2-s2.0-85053378341 \n33 Kar S. Paglialunga S. Islam R. Cystatin C is a more reliable biomarker for determining eGFR to support drug development studies Journal of Clinical Pharmacology 2018 58 10 1239 1247 10.1002/jcph.1132 2-s2.0-85047446869 29775220 \n34 Wan Z. H. Wang J. J. You S. L. Cystatin C is a biomarker for predicting acute kidney injury in patients with acute-on-chronic liver failure World Journal of Gastroenterology 2013 19 48 9432 9438 10.3748/wjg.v19.i48.9432 2-s2.0-84891377924 24409073 \n35 Wan Y. M. Li Y. H. Xu Z. Y. Tenofovir versus entecavir for the treatment of acute-on-chronic liver failure due to reactivation of chronic hepatitis B with genotypes B and C Journal of Clinical Gastroenterology 2019 53 4 e171 e177 10.1097/MCG.0000000000001038 2-s2.0-85062605392 29659382 \n36 Han Y. Zeng A. Liao H. Liu Y. Chen Y. Ding H. The efficacy and safety comparison between tenofovir and entecavir in treatment of chronic hepatitis B and HBV related cirrhosis: a systematic review and meta-analysis International Immunopharmacology 2017 42 168 175 10.1016/j.intimp.2016.11.022 2-s2.0-84998996695 27915131 \n37 Sriprayoon T. Mahidol C. Ungtrakul T. Efficacy and safety of entecavir versus tenofovir treatment in chronic hepatitis B patients: a randomized controlled trial Hepatology Research 2017 47 3 E161 e168 10.1111/hepr.12743 2-s2.0-84973582585 27176630\n\n",
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"mesh_terms": "D058186:Acute Kidney Injury; D065290:Acute-On-Chronic Liver Failure; D000328:Adult; D000998:Antiviral Agents; D005260:Female; D006147:Guanine; D006509:Hepatitis B; D006801:Humans; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D012307:Risk Factors; D000068698:Tenofovir; D016896:Treatment Outcome",
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"references": "30959156;29278542;26201469;30753752;30905084;30213943;32077604;25376770;24409073;26202751;31314188;25638527;28393476;28189857;27485174;30525275;20298811;28279168;26566064;19757444;31639240;27176630;29775220;26202407;28304106;29877316;28502331;30817845;31650510;25708186;29334786;26055419;27915131;29659382;27047950;25040928;28427875",
"title": "The Risk of Acute Kidney Injury in Hepatitis B Virus-Related Acute on Chronic Liver Failure with Tenofovir Treatment.",
"title_normalized": "the risk of acute kidney injury in hepatitis b virus related acute on chronic liver failure with tenofovir treatment"
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"abstract": "BACKGROUND\nTiclopidine is a platelet inhibitor used to prevent thrombosis in patients with cerebrovascular or coronary artery disease. The most common side effects are mild and transitory: diarrhea, dyspepsia, nausea and rashes. More serious, but less frequent, adverse effects are hematological dyscrasia and cholestatic hepatitis. We report a rare case of agranulocytosis associated with hepatic toxicity, probably related to the use of ticlopidine.\n\n\nMETHODS\nA 70-year-old Caucasian woman, with no previous history of hematological or liver diseases, was treated with ticlopidine 250 mg twice daily immediately after a vertebrobasilar stroke. Upon admission, her blood tests were normal. About four weeks later she developed agranulocytosis and hepatic toxicity. Ticlopidine was discontinued immediately, and aspirin 25 mg and dipyridamole 200 mg were given twice daily. She was treated with hematopoietic growth factors (granulocyte colony stimulating factor), with a rapidly increased white blood count and progressive normalization of liver tests as a result.\n\n\nCONCLUSIONS\nIn the first three months following initiation of ticlopidine therapy, regular monitoring of complete blood cell count and of liver function tests is essential for the early detection of serious and unpredictable side effects.",
"affiliations": "University of Milan, Department of Medicine, Surgery and Dentistry, Rehabilitation Unit, San Paolo Hospital, Milan, Italy. antonino.previtera@unimi.it.",
"authors": "Previtera|Antonino M|AM|;Pagani|Rossella|R|",
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"fulltext": "\n==== Front\nJ Med Case ReportsJournal of Medical Case Reports1752-1947BioMed Central 1752-1947-4-2692070470010.1186/1752-1947-4-269Case ReportAgranulocytosis and hepatic toxicity with ticlopidine therapy: a case report Previtera Antonino M 1antonino.previtera@unimi.itPagani Rossella 2rossella.pagani@ao-sanpaolo.it1 University of Milan, Department of Medicine, Surgery and Dentistry, Rehabilitation Unit, San Paolo Hospital, Milan, Italy2 Rehabilitation Unit, San Paolo Hospital, Milan, Italy2010 12 8 2010 4 269 269 26 1 2010 12 8 2010 Copyright ©2010 Previtera and Pagani; licensee BioMed Central Ltd.2010Previtera and Pagani; licensee BioMed Central Ltd.This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Introduction\nTiclopidine is a platelet inhibitor used to prevent thrombosis in patients with cerebrovascular or coronary artery disease. The most common side effects are mild and transitory: diarrhea, dyspepsia, nausea and rashes. More serious, but less frequent, adverse effects are hematological dyscrasia and cholestatic hepatitis. We report a rare case of agranulocytosis associated with hepatic toxicity, probably related to the use of ticlopidine.\n\nCase presentation\nA 70-year-old Caucasian woman, with no previous history of hematological or liver diseases, was treated with ticlopidine 250 mg twice daily immediately after a vertebrobasilar stroke. Upon admission, her blood tests were normal. About four weeks later she developed agranulocytosis and hepatic toxicity. Ticlopidine was discontinued immediately, and aspirin 25 mg and dipyridamole 200 mg were given twice daily. She was treated with hematopoietic growth factors (granulocyte colony stimulating factor), with a rapidly increased white blood count and progressive normalization of liver tests as a result.\n\nConclusion\nIn the first three months following initiation of ticlopidine therapy, regular monitoring of complete blood cell count and of liver function tests is essential for the early detection of serious and unpredictable side effects.\n==== Body\nIntroduction\nTiclopidine is a thienopyridine derivative with platelet inhibitor capability. It acts by inhibiting the platelet aggregation induced by adenosine diphosphate and by blocking the membrane receptors of fibrinogen. It is used to prevent thrombosis in patients with cerebrovascular or coronary artery disease. Two randomized clinical studies [1,2] proved the drug's efficacy versus placebo [1] and aspirin [2] in reducing the risk of transient ischemic attack and stroke in patients with a history of cerebrovascular events. Because of its adverse effects, the use of this drug is reserved for patients in whom aspirin is contraindicated, not tolerated, or when treatment with aspirin fails.\n\nThe most common side effects are mild and transitory: diarrhea, dyspepsia, nausea and rashes. More serious, but less frequent, adverse effects are hematological dyscrasia (particularly agranulocytosis, aplastic anemia, neutropenia, pancytopenia, thrombocytopenia and thrombotic thrombocytopenia purpura) and cholestatic hepatitis. However, to our knowledge, there are only a few published reports of the simultaneous occurrence of hematological and hepatic toxicity induced by ticlopidine. We report a case of agranulocytosis associated with cholestatic hepatitis related to the use of ticlopidine.\n\nCase presentation\nA 70-year-old Caucasian woman was admitted to our Rehabilitation Ward (San Paolo Hospital, Milan) because of gait ataxia after right bulbar stroke, which occurred 10 days previously. Her medical history pointed out hypertension and hypercholesterolemia. She had no prior history with regard to hematological or liver diseases, alcohol abuse or blood transfusion. Her habitual medications were aspirin 100 mg/day, atorvastatin 20 mg/day and amlodipine 5 mg/day. Immediately after her stroke, she discontinued aspirin and started therapy with ticlopidine 250 mg twice daily.\n\nUpon admission, her blood tests were normal. About four weeks later, she developed agranulocytosis. Her white blood count was 2600 cells/μL (reference range: 4000 to 10,000 cells/μL), neutrophil count was 100 cells/μL (reference range: 2000 to 7000 cells/μL), and liver function tests revealed a mixed cholestasis and hepatocellular injury. She had no fever and she was asymptomatic. She had elevated levels of alanine aminotransferase (560 U/L, reference range 5 to 41 U/L), of aspartate aminotransferase (551 U/L, reference range 5 to 41 U/L), of γ-glutamyl transpeptidase (449 U/L, reference range 11 to 50 U/L), of alkaline phosphatase (821 U/L, reference range 98 to 279 U/L). Total and direct bilirubin and the coagulation tests were normal.\n\nSerology tests for hepatitis A, B and C, and for Epstein-Barr virus (EBV) and cytomegalovirus (CMV) were negative. The anti-nuclear antibodies (ANA), the anti-mitochondrial antibodies (AMA) and anti-smooth muscle antibodies (LKM) were all negative. Cobalamin and folate dosages were normal.\n\nAn abdominal ultrasound scan showed liver steatosis but did not highlight any alterations in the intra-hepatic and extra-hepatic biliary pathways and, in particular, no sign of dilatation emerged. A bone marrow aspirate showed myeloid maturation arrest, with decreased myeloid precursors and immature forms, like by iatrogenic attack. A cytogenetic analysis on bone marrow blood was 46, XX.\n\nTiclopidine was immediately discontinued. Aspirin 25 mg and dipyridamole 200 mg twice daily were started [3]. She was treated with granulocyte colony stimulating factor (Filgastrim, 0.3 mg/day) with an excellent evolution. On the second day, her white blood count was normal (white blood cells: 5300 cells/μL; neutrophil count 1500 cells/μL); her liver function tests progressively got better with normalization after four weeks. A liver biopsy was not performed because of her serious hemathological dyscrasia and the self-limiting nature of liver disorder.\n\nThe pathogenesis of the various types of toxic effects associated with ticlopidine therapy is unclear. There is no test available that can confirm the diagnostic hypothesis of the drug toxicity apart from the exclusion of other possible causes and the normalization of the blood tests after the drug discontinuation.\n\nIn our patient, ticlopidine may have been responsible of concomitant hematological and hepatic toxicity. In fact, other diagnostic hypothesises were excluded and when the drug was discontinued, the blood cell count and the liver function tests rapidly normalized.\n\nThe onset of hematological dyscrasia is temporally related to the initiation of ticlopidine therapy, generally occurring within the first three months, and the dyscrasia resolves within three weeks after discontinuation of therapy [4].\n\nThe latent period between the introduction of ticlopidine and the appearance of hepatotoxicity is variable, ranging from one week to six months, but it is in the range of two to 12 weeks in most patients [5]. Hepatic toxicity is not dose dependent [6] and is not related to the treatment duration [7]. When ticlopidine is discontinued, symptoms and liver abnormalities usually resolve within one to three months. In the cases of drug-induced hepatotoxicity, the liver biopsy can suggest but not establish the diagnosis, and is mainly directed to exclude other diagnosis.\n\nWhile severe neutropenia is a life-threatening adverse effect due to the occurrence of fatal infections, there are no fatal cases and no irreversible hepatic damages. The only reported fatal case was due to the co-occurrence of neutropenia, which led to septic shock [8].\n\nWe emphasize that, in the first three months following initiation of ticlopidine therapy, besides a complete blood cell count, periodic checks of liver function are recommended. Hepatic toxicity induced by ticlopidine is underestimated. Regular monitoring of complete blood cell count and of liver function tests is important for prompt detection and treatment of adverse reactions but is unlikely to prevent their occurrence altogether.\n\nConclusions\nIn the first three months after starting ticlopidine therapy, regular monitoring of complete blood cell counts and of liver function tests should be recommended for the early detection of serious side effects, even if infrequent.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nAuthors' contributions\nAMP designed the study, treated our patient, drafted the manuscript, and contributed to the data collection. RP helped to design the study, treated our patient, contributed to manuscript drafts, and contributed to the data collection. All authors have read and approved the final version of the manuscript.\n\nConsent\nWritten informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nAcknowledgements\nWe wish to thank Dr Giuseppina Frigo who helped with data collection.\n==== Refs\nGent M Blakely JA Easton JD Ellis DJ Hachinski VC Harbison JW Panak E Roberts RS Sicurella J Turpie AG The Canadian American Ticlopidine Study (CATS) in the thromboembolic stroke Lancet 1989 1 1215 1220 10.1016/S0140-6736(89)92327-1 2566778 \nHass WK Easton JD Adams HP JrPryse-Phillips W Molony BA Anderson S Kamm B A randomized trial comparing ticlopidine hydrochloride with aspirin for the prevention of stroke in high-risk patients. Ticlopidine Aspirin Stroke Study Group N Engl J Med 1989 321 501 507 10.1056/NEJM198908243210804 2761587 \nSPREAD Stroke Prevention And Educational Awerness Diffusion - V Edizione 2007 - Ictus cerebrale: linee guida italiane di prevenzione e trattamento, 319 \nParadiso-Hardy F Angelo MC Lanctot KL Cohen EA Hematologic dyscrasia associated with ticlopidine therapy: evidence for casuality CMAJ 2000 163 1441 1448 11192649 \nGrieco A Vecchio FM Greco AV Gasbarrini G Cholestatic hepatitis due to ticlopidine: clinical and histological recovery after drug withdrawal. Case report and review of the literature Eur J Gastroenterol Hepatol 1998 10 713 715 9744703 \nAlberti L Alberti-Flor JJ Ticlopidine-induced cholestatic hepatitis successfully treated with corticosteroids (letter) Am J Gastroenterol 2002 97 107 10.1111/j.1572-0241.2002.05642.x \nKubin Cj Shermann O Hussain KB Feinman L Delayed onset ticlopidine induced cholestatic jaundice Pharmacotherapy 1999 18 1006 1010 10.1592/phco.19.11.1006.31567 \nCelyan C Kirimli O Akarsu M Under B Guneri S Early ticlopidine-induced hepatic dysfunction, dermatitis and irreversible aplastic anemia after coronary artery stenting Am J Hematol 1998 59 260 264\n\n",
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"title": "Agranulocytosis and hepatic toxicity with ticlopidine therapy: a case report.",
"title_normalized": "agranulocytosis and hepatic toxicity with ticlopidine therapy a case report"
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"abstract": "Iron may accumulate in excess due to a mutation in the HFE gene that upregulates absorption or when it is ingested or infused at levels that exceed the body's ability to clear it. Excess iron deposition in parenchymal tissue causes injury and ultimately organ dysfunction. Diabetes mellitus and hepatic cirrhosis due to pancreas and liver damage are just two examples of diseases that result from iron overload. Despite the rapid growth of information regarding iron metabolism and iron overload states, the most effective treatment is still serial phlebotomies. We present a patient who developed iron overload due to chronic ingestion of oral ferrous sulfate. This case illustrates the importance of querying geriatric patients regarding their use of nonprescription iron products without a medical indication.",
"affiliations": "The University of Tennessee, Graduate School of Medicine, Knoxville, TN, USA.;The University of Tennessee, Graduate School of Medicine, Knoxville, TN, USA.",
"authors": "Lands|Ronald|R|0000-0002-6956-8812;Isang|Emmanuel|E|",
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"doi": "10.1155/2017/2494167",
"fulltext": "\n==== Front\nCase Rep HematolCase Rep HematolCRIHEMCase Reports in Hematology2090-65602090-6579Hindawi Publishing Corporation 10.1155/2017/2494167Case ReportSecondary Hemochromatosis due to Chronic Oral Iron Supplementation http://orcid.org/0000-0002-6956-8812Lands Ronald \n*\nIsang Emmanuel The University of Tennessee, Graduate School of Medicine, Knoxville, TN, USA*Ronald Lands: rlands@utmck.eduAcademic Editor: Marie-Christine Kyrtsonis\n\n2017 4 1 2017 2017 249416724 6 2016 19 12 2016 Copyright © 2017 R. Lands and E. Isang.2017This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Iron may accumulate in excess due to a mutation in the HFE gene that upregulates absorption or when it is ingested or infused at levels that exceed the body's ability to clear it. Excess iron deposition in parenchymal tissue causes injury and ultimately organ dysfunction. Diabetes mellitus and hepatic cirrhosis due to pancreas and liver damage are just two examples of diseases that result from iron overload. Despite the rapid growth of information regarding iron metabolism and iron overload states, the most effective treatment is still serial phlebotomies. We present a patient who developed iron overload due to chronic ingestion of oral ferrous sulfate. This case illustrates the importance of querying geriatric patients regarding their use of nonprescription iron products without a medical indication.\n==== Body\n1. Introduction\nIron overload syndromes may be genetic or acquired. Hemochromatosis, a common genetic disorder in Caucasians, is the result of a mutation in the HFE gene that causes iron to be absorbed in excess. Iron overload may also accompany anemias characterized by significant ineffective erythropoiesis, chronic transfusions, or both as is the case in thalassemia. There is no excretory organ for iron, so the only mechanism for its clearance is through epithelial sloughing or bleeding. A sustained imbalance of iron intake and absorption that is greater than the ability to remove it results in iron overload. We describe a patient who was supplemented with oral ferrous sulfate, 1–3 325 mg tablets per day, for 30 years after menopause because of a mistaken belief that it would provide some benefit in her general health. She developed iron overload despite the absence of any of the common detectable HFE mutations.\n\n2. Case Report\nA 78-year-old Caucasian female was referred to hematology after her primary physician noted a persistent elevation in her serum ferritin level. Her primary concern was a profound sense of fatigue and recent erratic control of her thyroid medication despite years of stability. She had developed atrial fibrillation within the year prior to detection of the elevated ferritin. In the remote past, she had breast cancer treated with lumpectomy, radiation therapy, and adjuvant chemotherapy. She was actively being treated for hyperlipidemia, gastroesophageal reflux with Barrett's esophagus, and vitamin B12 deficiency. There was no family history of unexplained liver disease.\n\nShe was a healthy appearing woman who looked younger than her stated age. Her sclera were not icteric. The liver and spleen were not palpable. She had no stigmata of chronic liver disease. Her cardiac rhythm was regular with a normal rate.\n\nLaboratory data revealed hemoglobin of 12.5 g/dL (12.0–16.0) with normal WBC and platelets. Liver transaminases and alkaline phosphatase levels were normal. PT was 10.7 sec (9.1–12.0), and INR was 0.97 (0.90–1.10). Serum ferritin was 1,379 ng/mL (10–162 ng/mL). Serum iron was 77 μg/dL (25–156), TIBC was 226 μg/dL (250–450), and transferrin saturation was 34% (20–50). She did not carry any of the mutations C282Y, H63D, or S65C.\n\nMRI of the abdomen demonstrated iron deposition in the liver and spleen compatible with secondary hemochromatosis. Liver biopsy documented increased iron uptake in the hepatocytes and Kupffer cells (Figure 1). There was focal periportal fibrosis but no cirrhosis. The dry weight iron content in a biopsy of liver tissue was 6,153 μg/g (270–1,600 μg/g).\n\nThe iron supplements were discontinued. She was prescribed one 300–350 mL phlebotomy of whole blood per week. After approximately 4 phlebotomies, her hemoglobin fell to 9.7 while her ferritin remained elevated. Erythropoietin injections were added in an attempt to minimize delays and interruptions in the phlebotomy schedule, and with some difficulty, she tolerated 17 phlebotomies over a span of 5 months. Her hemoglobin the week following her 17th phlebotomy was 8 g/dL despite the erythropoietin stimulants. Her ferritin at that point was 65 ng/mL. She had one more phlebotomy about six months later when her ferritin rose again to more than 100 ng/mL. After that, because of the symptoms induced by the procedure and based on the rationale that she had no apparent mutation causing excessive absorption, we have accepted the normal range for our lab as our goal. To date, the iron saturation has remained less than 30% and her ferritin has remained stable between 70 and 100 ng/mL.\n\n3. Discussion\nIron is a micronutrient which if deficient or excessive may cause morbidity and mortality. In 1889, Von Reclinghasen observed the association of iron accumulation in the pancreas and the development of diabetes due to its associated tissue injury. Knowledge about hemochromatosis has grown dramatically from the era when Von Reclinghasen made his observations to the current understanding of iron homeostasis [1, 2].\n\nThe availability of molecular genotyping of the HFE gene highlights the paradox of a common mutation but a rare disease. The prevalence of detectable mutations in North America is between 1 in 200 and 1 in 500 and is even more common in some northern European countries. They are transmitted, with rare exceptions, in an autosomal recessive pattern. Most people with mutations never develop the disease. Likewise, a significant number of patients with the clinical phenotype of primary hemochromatosis have no detectable HFE mutation [3].\n\nThe liver is the conductor of systemic iron balance, sensing a variety of iron related signals and modulating iron absorption and storage by hepcidin expression [4]. The relationship of serum ferritin and total body iron stores has been clearly established. As the ferritin increases, the risk of significant liver disease rises [5]. It may be elevated in the absence of iron overload, however, and competing comorbidities such as alcoholic liver disease, hepatic steatosis, or viral infections may confuse the diagnosis because of the clinical similarities.\n\nThe diagnosis of iron overload is often overlooked because the signs and symptoms are commonly associated with other diseases, such as chronic fatigue, cirrhosis, diabetes, congestive heart failure, hypogonadism, osteoporosis, and arthritis. In the absence of acute or chronic inflammation, screening for iron overload is warranted upon discovery of ferritin levels above 200 ng/mL and transferrin saturation above 45% in women or ferritin more than 300 ng/mL and transferrin saturation greater than 50% in men. Specialized MRI scanning of the liver provides indirect evidence of iron overload. Liver biopsy provides a direct measurement of liver iron concentration along with the pathologist's assessment of liver histology [6].\n\nA wide array of treatment strategies exploiting the role of hepcidin in the regulation of iron homeostasis are under development [7]. Currently, however, the treatment of hemochromatosis whether genetic or acquired is serial phlebotomies continuing until the ferritin is less than 50 ng/mL and iron saturation is less than 50%. Those patients with genetic hyperabsorption of iron will require periodic phlebotomies indefinitely to maintain their iron stores at a safe level. As in our patient, iron overload due to chronic ingestion of iron in the absence of mutations that upregulate iron absorption should not require phlebotomies after reaching acceptable levels of ferritin and iron saturation.\n\n4. Conclusion\nNutritional iron overload requires years of supplementation to develop. Patients may take over the counterpreparations of iron supplements for a perceived health benefit and be unaware that it carries potential risks when taken for a long period of time. Medical professionals of all specialties should query their patients as to whether they take supplements with iron and discontinue it if there is no medical indication.\n\nCompeting Interests\nThe authors declare that there is no conflict of interests regarding the publication of this paper.\n\nFigure 1 Liver biopsy demonstrating increased iron content in hepatocytes and Kupffer cells.\n==== Refs\n1 Von Reclinghasen F. D. Hämochromatose 1889 324 Heidelberg, Germany Tageblatt der Naturforschenden Versammlung \n2 Andrews N. C. Forging a field: the golden age of iron biology Blood 2008 112 2 219 230 10.1182/blood-2007-12-077388 2-s2.0-47649126246 18606887 \n3 Thachil J. Solberg L. A. Kahn M. J. Mccrae K. R. Mccrae K. Steensma D. Iron metabolism, iron overload, and the porphyrias American Society of Hematology—Self Assessment Program 2013 5th American Society of Hematology 89 97 http://www.ash-sap.org/ \n4 Meynard D. Babitt J. L. Lin H. Y. The liver: conductor of systemic iron balance Blood 2014 123 2 168 176 10.1182/blood-2013-06-427757 2-s2.0-84892657750 24200681 \n5 Adams P. C. Epidemiology and diagnostic testing for hemochromatosis and iron overload International Journal of Laboratory Hematology 2015 37 supplement 1 25 30 10.1111/ijlh.12347 25976957 \n6 Fleming R. E. Ponka P. Iron overload in human disease New England Journal of Medicine 2012 366 4 348 359 10.1056/nejmra1004967 22276824 \n7 Arezes J. Nemeth E. Hepcidin and iron disorders: new biology and clinical approaches International Journal of Laboratory Hematology 2015 37 1 92 98 10.1111/ijlh.12358 2-s2.0-84929353756 25976966\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2090-6579",
"issue": "2017()",
"journal": "Case reports in hematology",
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"medline_ta": "Case Rep Hematol",
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"references": "25976957;22276824;18606887;24200681;25976966",
"title": "Secondary Hemochromatosis due to Chronic Oral Iron Supplementation.",
"title_normalized": "secondary hemochromatosis due to chronic oral iron supplementation"
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"abstract": "Protein-losing enteropathy (PLE) is a condition characterized by gut mucosal injury that typically manifests with edema and hypoalbuminemia due to protein loss in the GI tract. We present a rare case of lupus-associated PLE (LUPLE) manifested by profound edema, diarrhea, and thrombotic complications. Through our case report, we discuss the typical clinical presentation, diagnostic studies available, and treatment options for these patients. Our patient's clinical picture and laboratory markers improved with the initiation of corticosteroids and belimumab, which is a novel treatment regimen for LUPLE. Moreover, our patient was found to have a clinically significant hypercoagulable state that was ultimately attributed to PLE in the setting of systemic lupus erythematosus (SLE). We highlight the increased thrombotic risk in these patients and the subsequent management implications with regard to anticoagulation. Gastroenterologists are likely to be involved in the care of these patients, and may be the first to recognize the constellation of findings in PLE, leading to potentially very effective treatment.",
"affiliations": "Department of Medicine, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Mail Code L461, Portland, OR, 97239, USA. lewisjus@ohsu.edu.;Division of Gastroenterology and Hepatology, Oregon Health and Science University, Portland, OR, USA.;Division of Arthritis and Rheumatic Diseases, Oregon Health and Science University, Portland, OR, USA.;Division of Arthritis and Rheumatic Diseases, Oregon Health and Science University, Portland, OR, USA.;Division of Gastroenterology and Hepatology, Oregon Health and Science University, Portland, OR, USA.",
"authors": "Lewis|Justin S|JS|http://orcid.org/0000-0002-1391-8852;Sharma|Anil|A|;Horton|Joel B|JB|;Deodhar|Atul|A|;Modiano|Nir|N|",
"chemical_list": "D000305:Adrenal Cortex Hormones; D061067:Antibodies, Monoclonal, Humanized; C511911:belimumab",
"country": "Japan",
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"issue": "13(5)",
"journal": "Clinical journal of gastroenterology",
"keywords": "Belimumab; Hypercoagulable state; Hypoalbuminemia; Protein-losing enteropathy; Systemic lupus erythematosus",
"medline_ta": "Clin J Gastroenterol",
"mesh_terms": "D000305:Adrenal Cortex Hormones; D061067:Antibodies, Monoclonal, Humanized; D006801:Humans; D008180:Lupus Erythematosus, Systemic; D011504:Protein-Losing Enteropathies",
"nlm_unique_id": "101477246",
"other_id": null,
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"pubdate": "2020-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
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"title": "Lupus-associated protein losing enteropathy (LUPLE) complicated by a hypercoagulable state and successfully treated with belimumab.",
"title_normalized": "lupus associated protein losing enteropathy luple complicated by a hypercoagulable state and successfully treated with belimumab"
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"abstract": "Treatment guidelines for symptomatic polypoidal choroidal vasculopathy (PCV) have been described, but the management of recurrent or recalcitrant PCV is a challenge. The newer anti-vascular endothelial growth factor: aflibercept has shown promise in the treatment of both treatment naive and recalcitrant PCV in studies outside India. We present the minimum 6 months results of intravitreal aflibercept in recurrent and recalcitrant PCV in Indian eyes after multiple injections of bevacizumab/ranibizumab with or without photodynamic therapy. Of 10 eyes, 7 resolved of which 4 recurred needing continued aflibercept. Three of the ten eyes did not show a response. To the best of our knowledge, this is the first report from India in this challenging situation.",
"affiliations": "Shri Bhagwan Mahavir Vitreoretinal Services, Sankara Nethralaya, Chennai, Tamil Nadu, India.;Shri Bhagwan Mahavir Vitreoretinal Services, Sankara Nethralaya, Chennai, Tamil Nadu, India.;Shri Bhagwan Mahavir Vitreoretinal Services, Sankara Nethralaya, Chennai, Tamil Nadu, India.;Shri Bhagwan Mahavir Vitreoretinal Services, Sankara Nethralaya, Chennai, Tamil Nadu, India.;Vitreoretinal Services, Aditya Birla Sankara Nethralaya, Kolkata, West Bengal, India.",
"authors": "Bansal|Aditya|A|;Bhende|Muna|M|;Sharma|Tarun|T|;Bhende|Pramod|P|;Mukherjee|Suchetana|S|",
"chemical_list": "D011993:Recombinant Fusion Proteins; C533178:aflibercept; D040262:Receptors, Vascular Endothelial Growth Factor",
"country": "India",
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"doi": "10.4103/ijo.IJO_1003_16",
"fulltext": "\n==== Front\nIndian J OphthalmolIndian J OphthalmolIJOIndian Journal of Ophthalmology0301-47381998-3689Medknow Publications & Media Pvt Ltd India 28820169IJO-65-75810.4103/ijo.IJO_1003_16Brief CommunicationAflibercept for recurrent or recalcitrant polypoidal choroidal vasculopathy in Indian eyes: Early experience Bansal Aditya Bhende Muna Sharma Tarun Bhende Pramod Mukherjee Suchetana 1Shri Bhagwan Mahavir Vitreoretinal Services, Sankara Nethralaya, Chennai, Tamil Nadu, India1 Vitreoretinal Services, Aditya Birla Sankara Nethralaya, Kolkata, West Bengal, IndiaCorrespondence to: Dr. Muna Bhende, Sankara Nethralaya, 18/41, College Road, Nungambakkam, Chennai - 600 006, Tamil Nadu, India. E-mail: drmuna@snmail.org8 2017 65 8 758 760 29 12 2016 12 5 2017 Copyright: © 2017 Indian Journal of Ophthalmology2017This 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.Treatment guidelines for symptomatic polypoidal choroidal vasculopathy (PCV) have been described, but the management of recurrent or recalcitrant PCV is a challenge. The newer anti-vascular endothelial growth factor: aflibercept has shown promise in the treatment of both treatment naive and recalcitrant PCV in studies outside India. We present the minimum 6 months results of intravitreal aflibercept in recurrent and recalcitrant PCV in Indian eyes after multiple injections of bevacizumab/ranibizumab with or without photodynamic therapy. Of 10 eyes, 7 resolved of which 4 recurred needing continued aflibercept. Three of the ten eyes did not show a response. To the best of our knowledge, this is the first report from India in this challenging situation.\n\nKey words\nAfliberceptanti-VEGF therapypolypoidal choroidal vasculopathy\n==== Body\nPolypoidal choroidal vasculopathy (PCV) is a leading cause of visual morbidity in Asians. Current epidemiological data show the prevalence of 22.3%–61.6% among Asians and 8%–13% in Caucasians who present with presumed neovascular age-related macular degeneration (hospital/clinic based).[1] Treatment guidelines for symptomatic PCV do not include the role of aflibercept.[2]\n\nYamamoto et al.[3] and Hara et al.[4] reported effectivity of anti-vascular endothelial growth factor (VEGF) aflibercept (Eylea, Regeneron, Tarrytown, NY, and Bayer HealthCare, Berlin, Germany) for treatment naïve PCV. Saito et al.[5] and Azuma et al.[6] reported that switching to aflibercept is effective for patients with PCV who develop resistance to ranibizumab. We report anatomical and functional outcomes of aflibercept for recurrent or recalcitrant PCV in Indian eyes.\n\nMethods\nWe conducted a retrospective case series of consecutive patients with recalcitrant or recurrent indocyanine green angiography (ICG) confirmed PCV treated with aflibercept and followed for a minimum 6 months at a tertiary care eye between February and November 2016. Institutional review board approved the study. All had received monthly bevacizumab or ranibizumab for 3 months followed by pro re nata (PRN) basis and/or photodynamic therapy (PDT). Recurrence was defined as an anatomical response to anti-VEGF injections with reactivation if the monthly injections were discontinued. Resistance/recalcitrance was defined as persistence or increase in the intra/subretinal fluid, pigment epithelial detachment (PED) or hemorrhage after minimum three injections on a monthly basis. Treatment-naive PCV was excluded. We followed published criteria for diagnosing active PCV.[2] All patients underwent ICG at baseline, and spectral domain optical coherence tomography (OCT) or swept-source OCT at baseline and each follow-up visit.\n\nTreatment guidelines and technique\nAll patients underwent intravitreal aflibercept (2 mg/0.05 ml) on a planned monthly followed by PRN basis. Patients were examined at 1st and 3rd postinjection day then monthly thereafter. Response to treatment was defined in terms of complete resolution of intra- and sub-retinal fluid and/or decrease in the height of PED and maintenance of inactivity for minimum 8 weeks. Partial resolution was defined as a reduction in sub/intraretinal fluid and PED. Resistance/recalcitrance was defined as either persistence or increase in the intra/subretinal fluid, PED or hemorrhage after minimum 3 injections on a monthly basis. Recurrence was defined as the presence of intra/subretinal fluid/enlargement of PED/development of new PED/subretinal or subretinal pigment epithelium hemorrhage after 8 weeks of inactivity. ICG was repeated in resistant cases. In case of complete resolution at 4th week from the last injection, the patient was asked to review at 6th and 8th week, injection was repeated if activity recurred. All patients with residual fluid were retreated.\n\nBest-corrected visual acuity (BCVA) was recorded in logMAR scale. Values of numerical characteristics were tested for normality and presented as mean value (± standard deviation). Student's paired sample t-test for comparing pre- and post-aflibercept BCVA and central foveal thickness (CFT). P < 0.05 was considered statistically significant.\n\nResults\nTen eyes of 10 patients with recurrent or recalcitrant PCV were included. Five males and five females, aged 53–83 years (mean 66 ± 9.2 years). All patients had received multiple intravitreal anti-VEGF injections (bevacizumab/ranibizumab) with median of 15.5 ± 7.3 (range 4–24) with/without PDT. One eye had vitrectomy for PCV-related vitreous hemorrhage.\n\nBaseline mean logMAR BCVA was 0.39 ± 0.37 (range 0–1). All patients had branching vascular network (BVN) on ICG. Baseline characteristic, OCT features and treatment outcomes are tabulated in Tables 1 and 2. Mean baseline CFT was 243.7 ± 106.7 microns. Mean number of aflibercept injections were 3 ± 1.4 (range 2–6). Patients had a mean follow-up of 6.8 ± 1.31 months (range 6–9) after the first aflibercept, whereas median of total follow-up was 53 ± 44.8 (range 16–130 months). Mean final logMAR BCVA was 0.37 ± 0.35 (P = 0.49). Mean CFT reduced to181.7 ± 167.6 microns (P = 0.049). No ocular or systemic complications were noted.\n\nTable 1 Baseline characteristics and treatment outcomes\n\nTable 2 Spectral domain optical coherence tomography characteristics before and after aflibercept\n\nComplete resolution was seen in seven eyes [Figs. 1 and 2 – Case no. 2]. Three eyes had a reduction in PED and partial resolution of sub- and intra-retinal fluid even after minimum three injections. ICG in all these showed the persistence of BVN in one eye and enlargement in two. Two eyes switched back to maintenance with ranibizumab, and one eye underwent PDT with ranibizumab. Four of the seven eyes that showed initial resolution developed recurrence after a period of quiescence of which all were re-treated with aflibercept and responded satisfactorily to the same.\n\nFigure 1 (a-c) Color fundus, indocyanine green angiography and swept source optical coherence tomography images of the right eye of a patient with active macular polypoidal choroidal vasculopathy 8 years after treatment with multiple sessions of anti-vascular endothelial growth factor monotherapy, two sessions of combination photodynamic therapy and anti-vascular endothelial growth factor. The fundus image shows exudation at the macula with a partly fibrotic lesion. Indocyanine green angiography shows a large branching vascular network. Swept source optical coherence tomography image shows the polypoidal network involving the fovea, pigment epithelial detachment and intraretinal cystic spaces\n\nFigure 2 (a-c) Fundus image, indocyanine green angiography and swept source optical coherence tomography images after 2 monthly aflibercept injections shows a decrease in exudation, reduction in the branching vascular network on indocyanine green angiography. The swept source optical coherence tomography image shows resolution of the intraretinal cystic spaces as well as the pigment epithelial detachment\n\nDiscussion\nAflibercept, a fusion protein with binding sequences from VEGF receptors 1 and 2 possesses high binding affinity for isomers of VEGF-A, VEGF-B and placental growth factor (PGF), and prevents VEGF from initiating proliferation and migration of vascular endothelial cells.[7] Other members of the VEGF family, including PGF[8] and VEGF-B[9] have critical roles for angiogenesis and hyperpermeability. Because of wider spectrum pharmacological targets, aflibercept might have greater effectiveness for suppression of PCV vascular lesions.\n\nTill date, there are no treatment guidelines for aflibercept in PCV. Most studies have used 3 monthly followed by PRN injections. We analyzed eyes with recurrent and recalcitrant PCV who had already received multiple (median: 15.5 ± 7.3) intravitreal anti-VEGF injections (bevacizumab/ranibizumab) with/without PDT. We treated these patients with intravitreal aflibercept on planned monthly followed by PRN basis in contrast to Saito et al.[5] and Azuma et al.[6] who gave minimum three injections on a monthly basis.\n\nIn our cohort, BCVA improved in two eyes, maintained in seven and deteriorated in one. Mean BCVA (logMAR) improved to 0.37 from 0.39, but the difference was statistically not significant. Mean CFT improved to 181.7 from 243.7 microns, and difference was statistically significant. Hirakata et al.[10] found no significant gain in vision or CFT at 6 months but gain was significant at 1 year. Saito et al.[5] and Azuma et al.[6] reported significant CFT reduction and visual gain at month 3 and 12, respectively. No ocular or systemic adverse events were seen.\n\nLimitations were small sample size, short follow-up which could explain the limited visual improvement. To the best of our knowledge, this is the first series from India reporting the results of aflibercept in recurrent or recalcitrant PCV.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n==== Refs\nReferences\n1 Wong CW Wong TY Cheung CM Polypoidal choroidal vasculopathy in Asians J Clin Med 2015 4 782 821 26239448 \n2 Expert PCV Panel Koh AH Chen LJ Chen SJ Chen Y Giridhar A Iida T Polypoidal choroidal vasculopathy: Evidence-based guidelines for clinical diagnosis and treatment Retina 2013 33 686 716 23455233 \n3 Yamamoto A Okada AA Kano M Koizumi H Saito M Maruko I One-year results of intravitreal aflibercept for polypoidal choroidal vasculopathy Ophthalmology 2015 122 1866 72 26088619 \n4 Hara C Sawa M Sayanagi K Nishida K One-year results of intravitreal aflibercept for polypoidal choroidal vasculopathy Retina 2016 36 37 45 26383709 \n5 Saito M Kano M Itagaki K Oguchi Y Sekiryu T Switching to intravitreal aflibercept injection for polypoidal choroidal vasculopathy refractory to ranibizumab Retina 2014 34 2192 201 25077530 \n6 Azuma K Obata R Nomura Y Tan X Takahashi H Yanagi Y Angiographic findings of ranibizumab-resistant polypoidal choroidal vasculopathy after switching to a treat-and-extend regimen with intravitreal aflibercept Retina 2016 36 2158 65 27258669 \n7 Stewart MW Aflibercept (VEGF Trap-Eye) for the treatment of exudative age-related macular degeneration Expert Rev Clin Pharmacol 2013 6 103 13 23473589 \n8 Rakic JM Lambert V Devy L Luttun A Carmeliet P Claes C Placental growth factor, a member of the VEGF family, contributes to the development of choroidal neovascularization Invest Ophthalmol Vis Sci 2003 44 3186 93 12824270 \n9 Zhang F Tang Z Hou X Lennartsson J Li Y Koch AW VEGF-B is dispensable for blood vessel growth but critical for their survival, and VEGF-B targeting inhibits pathological angiogenesis Proc Natl Acad Sci U S A 2009 106 6152 7 19369214 \n10 Hirakata T Fujinami K Watanabe K Sasaki M Noda T Akiyama K One-year outcome of intravitreal aflibercept injection for age-related macular degeneration resistant to ranibizumab: Rapid morphologic recovery and subsequent visual improvement Clin Ophthalmol 2016 10 969 77 27307700\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0301-4738",
"issue": "65(8)",
"journal": "Indian journal of ophthalmology",
"keywords": null,
"medline_ta": "Indian J Ophthalmol",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D002829:Choroid; D015862:Choroid Diseases; D004305:Dose-Response Relationship, Drug; D005260:Female; D005451:Fluorescein Angiography; D005500:Follow-Up Studies; D005654:Fundus Oculi; D006801:Humans; D058449:Intravitreal Injections; D008297:Male; D008875:Middle Aged; D011127:Polyps; D040262:Receptors, Vascular Endothelial Growth Factor; D011993:Recombinant Fusion Proteins; D012008:Recurrence; D012189:Retrospective Studies; D013997:Time Factors; D041623:Tomography, Optical Coherence; D016896:Treatment Outcome; D014792:Visual Acuity",
"nlm_unique_id": "0405376",
"other_id": null,
"pages": "758-760",
"pmc": null,
"pmid": "28820169",
"pubdate": "2017-08",
"publication_types": "D016428:Journal Article",
"references": "23473589;26383709;27307700;12824270;23455233;26088619;26239448;25077530;27258669;19369214",
"title": "Aflibercept for recurrent or recalcitrant polypoidal choroidal vasculopathy in Indian eyes: Early experience.",
"title_normalized": "aflibercept for recurrent or recalcitrant polypoidal choroidal vasculopathy in indian eyes early experience"
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"abstract": "Aggressive angiomyxoma (AA) is an uncommon mesenchymal tumor that mainly affects the perineum and pelvis in females of reproductive age. AA is commonly misdiagnosed as a Bartholin's duct cyst, abscess or levator hernia. A 42-year-old female presented with a large, progressive and painless perineal swelling. She was initially diagnosed with an obturator hernia three times over the past 10 years and underwent multiple surgeries for recurrences. For this presentation, she underwent exploratory laparotomy. No hernia was identified. A large mass over the perineal area extending from the vulvar commissure to the anus was visualized. The diagnosis of AA was made on histopathology. Leuprolide (GnRHa) was used as hormonal therapy postoperatively. AA should be considered in any pelvic mass in a young female that recurs after excision. Prompt diagnosis will contribute toward minimizing local destruction of surrounding structures.",
"affiliations": "College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia.;King Abdullah International Medical Research Center, Riyadh, Saudi Arabia.;King Abdullah International Medical Research Center, Riyadh, Saudi Arabia.;King Abdullah International Medical Research Center, Riyadh, Saudi Arabia.;King Abdullah International Medical Research Center, Riyadh, Saudi Arabia.",
"authors": "Alomary|Nawaf Abdulkareem|NA|0000-0002-0748-8286;Albeeshi|Majid Zaab|MZ|;Al Thebaity|Rasha Eidah|RE|;Yousef|Zeyad Mohammed|ZM|;El-Boghdadly|Sami Abdelkereim|SA|",
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"doi": "10.1093/jscr/rjaa330",
"fulltext": "\n==== Front\nJ Surg Case Rep\nJ Surg Case Rep\njscr\nJournal of Surgical Case Reports\n2042-8812 Oxford University Press \n\n32913627\n10.1093/jscr/rjaa330\nrjaa330\nAcademicSubjects/MED00910\njscrep/040\nCase Report\nAggressive angiomyxoma persistently misdiagnosed as an obturator hernia managed with resection and hormonal therapy: case report\nhttp://orcid.org/0000-0002-0748-8286Alomary Nawaf Abdulkareem \nCollege of Medicine, King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia\n\nKing Abdullah International Medical Research Center, Riyadh, Saudi Arabia\n http://orcid.org/0000-0002-9386-3838Albeeshi Majid Zaab \nKing Abdullah International Medical Research Center, Riyadh, Saudi Arabia\n\nDepartment of Surgery, Ministry of the National Guard-Health Affairs, Riyadh, Saudi Arabia\n https://orcid.org/0000-0002-4981-8239Al Thebaity Rasha Eidah \nKing Abdullah International Medical Research Center, Riyadh, Saudi Arabia\n\nDepartment of Surgery, Ministry of the National Guard-Health Affairs, Riyadh, Saudi Arabia\n https://orcid.org/0000-0002-3665-6795Yousef Zeyad Mohammed \nKing Abdullah International Medical Research Center, Riyadh, Saudi Arabia\n\nDepartment of Surgery, Ministry of the National Guard-Health Affairs, Riyadh, Saudi Arabia\n https://orcid.org/0000-0002-8318-6781El-Boghdadly Sami Abdelkereim \nKing Abdullah International Medical Research Center, Riyadh, Saudi Arabia\n\nDepartment of Surgery, Ministry of the National Guard-Health Affairs, Riyadh, Saudi Arabia\n Correspondence address. College of Medicine, King Saud bin Abdulaziz University for Health Science, Riyadh, Saudi Arabia. Tel: +966553279922; E-mail: nawaf.13.alomary@gmail.com\n9 2020 \n05 9 2020 \n05 9 2020 \n2020 9 rjaa3303 7 2020 27 7 2020 Published by Oxford University Press and JSCR Publishing Ltd. All rights reserved. © The Author(s) 2020.2020This 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 non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.comAbstract\nAggressive angiomyxoma (AA) is an uncommon mesenchymal tumor that mainly affects the perineum and pelvis in females of reproductive age. AA is commonly misdiagnosed as a Bartholin’s duct cyst, abscess or levator hernia. A 42-year-old female presented with a large, progressive and painless perineal swelling. She was initially diagnosed with an obturator hernia three times over the past 10 years and underwent multiple surgeries for recurrences. For this presentation, she underwent exploratory laparotomy. No hernia was identified. A large mass over the perineal area extending from the vulvar commissure to the anus was visualized. The diagnosis of AA was made on histopathology. Leuprolide (GnRHa) was used as hormonal therapy postoperatively. AA should be considered in any pelvic mass in a young female that recurs after excision. Prompt diagnosis will contribute toward minimizing local destruction of surrounding structures.\n==== Body\nINTRODUCTION\nAggressive angiomyxoma (AA) was first described by Steeper and Rosai in 1983 as a soft-tissue mass that mostly occurs in the pelvis and perineum, with a female-to-male ratio of ~6:1. [1,2] Prevalence is undetermined due to the rarity of the condition, which makes management and counseling difficult [3]. AAs are characterized by their large size, and their noncapsulated, locally infiltrative nature. [4] Although it is a slow-growing tumor with a low metastatic capacity, it has a great tendency for local recurrence [2]. Wide local excision with tumor-free margins is the mainstay of surgical management [4]. We report the case of a 42-year-old female with a large, AA over the perineal area that was misdiagnosed and operated three times over the past 10 years before being correctly diagnosed and managed.\n\nFigure 1 Gross images of the mass in a standing view showing the relations to the vulva and gluteal regions, (A) posterior view showing the scar from a previous surgery in the right gluteal area and the extension of the mass, (B) anterior view in a standing position and (C) lithotomy, respectively.\n\nFigure 2 Multiple cuts of a CT abdomen and pelvis scan showing a multicompartmental, multilobulated, low pelvic and perineal soft-tissue lesion, with heterogeneous enhancement, measuring almost 21 × 17 × 5 cm.\n\nCASE PRESENTATION\nA 42-year-old anemic female presented to the clinic, complaining of a recurrent obturator hernia for the past 10 years. It was a large, painless, progressive swelling in the perineum, involving the labial fold. There were no bowel obstruction symptoms. She was previously operated for the hernia three times in different centers. On examination, there was a large swelling extending from the right medial gluteal area to the right labial fold measuring 20 × 15 cm. It was nontender and had a firm consistency, with no overlying skin changes (Fig. 1). Laboratory investigations were within normal limits. Computed tomography (CT) scans of the abdomen and pelvis showed a massive, multicompartmental, multilobulated soft-tissue lesion in the lower pelvis and perineum, exerting a mild mass effect (Fig. 2). Perineal mass excision, possible mesh placement and stoma creation was planned. At exploratory laparotomy, the abdominal and pelvic cavities were examined. There was no evidence of a defect or hernia. The extraperitoneal space was explored and the obturator foramen was identified without any hernia. The procedure then shifted to excision of the mass. It was lobulated within a capsule and extending from the vulvar commissure to the anus. It was also involving part of the lateral vaginal wall, the lower part of the rectum and anal canal which needed to be excised (Fig. 3). The mass was directly subdermal at the vulvar commissure site, so part of the labia minora skin was excised with the mass. The vaginal wall was repaired by a urogynecologist. The rectum was repaired by the primary surgeon. A diversion end sigmoid colostomy was created. Wound closure was assisted by plastic surgery. No tissue or skin coverage was required. The histopathological report revealed an AA extending to the margins with ulcerated and reactive skin tissue. Immunostaining for estrogen and progesterone were both positive. The postoperative course was uneventful. At 8 months follow-up, abdomen and pelvis CT concluded that there was a minimal residual perineal mass without extension to the pelvis. Following discussion in the multidisciplinary tumor board, she was started on hormonal therapy after ~1 year of surgery with leuprolide 22.5 mg, intramuscular, every 3 months. Hormonal therapy was continued for a total of 15 months with frequent follow-up images which showed no change in the residual mass. She underwent colostomy reversal 3 years after and was doing well on regular follow-ups. The patient consented to the publication of this case report with images. All measures were taken to ensure her privacy and anonymity.\n\nFigure 3 Excised specimen, soft-tissue mass consisting of an irregular piece of red-tan soft to firm tissue, measuring 31.5 × 20.0 × 0.8 cm along with overlying skin (not shown).\n\nDISCUSSION\nAA is an uncommon mesenchymal tumor that mainly arises from the perineum and pelvis in females of reproductive age [5]. Patients who suffer from AA can have a variable presentation, from a large pelvic mass diagnosed on imaging, to an asymptomatic vulvar or perineal nodule [4]. The most encountered presentation of AA is a vaginal or vulvar soft mass, usually misdiagnosed as a Bartholin’s duct cyst, vulvar mass, lipoma, vulvar abscess, vaginal cyst, Gardner’s duct cyst, vaginal prolapse or levator hernia [6]. Misdiagnosed cases of AA have been reported to be as high as 82% [3]. Definitive diagnosis is made on the basis of histopathological features, typically stellate and spindle cells with poorly demarcated cytoplasm, separated by loose myxoid stroma abundant in collagen fibrils [4]. AA is a benign tumor, but due to the high rate of local recurrence after surgery, it is characterized as aggressive [7]. The tumor is hormone-sensitive, as it expresses estrogen and progesterone receptors [2]. Primary surgery for AA is frequently extensive, due to the local invasion of the tumor into the surrounding tissue. Furthermore, the recurrence rate is not associated with the surgical margin status [8]. Recurrence of the tumor usually happens within the first 5 years after the initial surgery, however recurrences were reported as far as 14 years after initial resection in some studies [9]. In this case, the patient presented with a fourth recurrence, and similar to other cases, it was misdiagnosed. The initial diagnosis was obturator hernia, which resembles AA in that both of them are hard to diagnose, predominant in females, and present with a palpable mass in the groin [5,10]. However, this patient did not have any signs of intestinal obstruction or pain in the middle aspect of the thigh (Howship–Romberg sign). Although there was intraoperative suspicion, final diagnosis was only confirmed postoperatively. Due to the variability in location and size of AA, there is no standardized surgical procedure, and each surgical treatment should be individualized to the case [4]. In this case, part of the skin from the labia minora, and part of the rectal and vaginal walls were excised. If suspicious for recurrence, examination accompanied by imaging should be included in follow-up surveillance [4]. As in this case and other reported cases, hormonal therapy is an alternative method of treatment with a different variation of response [2]. In this case, hormonal therapy with leuprolide was used postoperatively as the preoperative diagnosis was uncertain. In the literature, gonadotrophic-releasing hormone agonists (GnRHa) are said to be the first-line hormonal therapy, and in some cases, it can be definitive treatment [2].\n\nCONCLUSION\nAA is a rare condition with a high rate of recurrence. Due to the rarity of this condition, misdiagnosis is very common. Knowledge of its characteristics and an index of suspicion will allow clinicians to provide these patients with the necessary treatment, through earlier diagnosis.\n\nCONFLICT OF INTEREST STATEMENT\nNone declared.\n\nFUNDING\nNone.\n==== Refs\nReferences\n1. \nSteeper TA , Rosai J \nAggressive angiomyxoma of the female pelvis and perineum. Report of nine cases of a distinctive type of gynecologic soft-tissue neoplasm\n. Am J Surg Pathol 1983 ;7 :463 –75\n.6684403 \n2. \nKiran G , Yancar S , Sayar H , Kiran H , Coskun A , Arikan DC \nLate recurrence of aggressive angiomyxoma of the vulva\n. J Low Genit Tract Dis 2013 ;17 :85 –7\n.22885644 \n3. \nBrzezinska BN , Clements AE , Rath KS , Reid GC \nA persistent mass: a case of aggressive Angiomyxoma of the vulva\n. Gynecol Oncol Rep 2018 ;24 :15 –7\n.29552629 \n4. \nSong M , Glasgow M , Murugan P , Rivard C \nAggressive angiomyxoma of the vulva and bladder\n. Obstet Gynecol 2017 ;130 :885 –8\n.28885430 \n5. \nSmith HO , Worrell RV , Smith AY , Dorin MH , Rosenberg RD , Bartow SA \nAggressive angiomyxoma of the female pelvis and perineum: review of the literature\n. Gynecol Oncol 1991 ;42 :79 –85\n.1916515 \n6. \nElchalal U , Lifschitz-Mercer B , Dgani R , Zalel Y \nAggressive angiomyxoma of the vulva\n. Gynecol Oncol 1992 ;47 :260 –2\n.1468706 \n7. \nAl-Umairi RS , Kamona A , Al-Busaidi FM \nAggressive angiomyxoma of the pelvis and perineum: a case report and literature review\n. Oman Med J 2016 ;31 :456 –8\n.27974964 \n8. \nChan IM , Hon E , Ngai SW , Ng TY , Wong LC \nAggressive angiomyxoma in females: is radical resection the only option?\nActa Obstet Gynecol Scand 2000 ;79 :216 –20\n.10716303 \n9. \nHaldar K , Martinek IE , Kehoe S \nAggressive angiomyxoma: a case series and literature review\n. Eur J Surg Oncol 2010 ;36 :335 –9\n.19954923 \n10. \nKulkarni SR , Punamiya AR , Naniwadekar RG , Janugade HB , Chotai TD , Vimal Singh T , et al. \nObturator hernia: a diagnostic challenge\n. Int J Surg Case Rep 2013 ;4 :606 –8\n.23708307\n\n",
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"abstract": "Amikacin is a major drug used for the treatment of Mycobacterium avium complex (MAC) disease, but standard laboratory guidelines for susceptibility testing are not available. This study presents in vitro amikacin MICs for 462 consecutive clinical isolates of the MAC using a broth microdilution assay. Approximately 50% of isolates had amikacin MICs of 8 μg/ml, and 86% had MICs of ≤16 μg/ml. Of the eight isolates (1.7%) with MICs of 64 μg/ml, five had an MIC of 32 μg/ml on repeat testing. Ten isolates (2.1%) had an initial amikacin MIC of >64 μg/ml, of which seven (1.5%) had MICs of >64 μg/ml on repeat testing. These seven isolates had a 16S rRNA gene A1408G mutation and included M. avium, Mycobacterium intracellulare, and Mycobacterium chimaera. Clinical data were available for five of these seven isolates, all of which had received prolonged (>6 months) prior therapy, with four that were known to be treated with amikacin. The 16S mutation was not detected in isolates with MICs of ≤64 μg/ml. We recommend primary testing of amikacin against isolates of the MAC and propose MIC guidelines for breakpoints that are identical to the CLSI guidelines for Mycobacterium abscessus: ≤16 μg/ml for susceptible, 32 μg/ml for intermediate, and ≥64 μg/ml for resistant. If considered and approved by the CLSI, this will be only the second drug recommended for primary susceptibility testing against the MAC and should facilitate its use for both intravenous and inhaled drug therapies.",
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"abstract": "Previous studies have indicated a convergent and bidirectional relationship between metabolic syndrome (MetS) and bipolar disorder (BD). As most of these studies focused mainly on adults diagnosed with BD, our study aims to investigate and characterize metabolic disturbances in child-adolescents diagnosed with BD.\nWe retrospectively examined the medical records of psychiatric hospitalizations with admitting diagnosis of BD in child-adolescents (age ＜ 18 years). Body mass index (BMI), lipid profile, fasting blood glucose, and blood pressure were primary variables. National Cholesterol Education Program criteria were used to define MetS. Reference group data was obtained from the National Health and Nutrition Examination Survey study. Statistical analyses included t tests, chi-square tests, and Fisher's exact tests.\nWe identified 140 child-adolescent patients with BD (mean age = 15.12 ± 1.70 years, 53% male). MetS was significantly more common in BD compared to the reference group: 14% (95% confidence interval [95% CI] 8-20) vs. 6.7% (95% CI 4.1-9.2), p = 0.001 with no significant difference by sex. MetS components were higher in the BD group, particularly BMI ≥ 95% (25% vs. 11.8%, p ＜ 0.001) and high blood pressure (17% vs. 8%, p = 0.05). Moreover, female patients had lower odds of high blood pressure (odds ratio = 0.24 [95% CI 0.08-0.69], p = 0.005).\nCompared with the general child-adolescent population, the prevalence of MetS was significantly higher in patients with BD of same age. This reiterates the notion of an increased risk of MetS in patients diagnosed with BD; and thus, further exploration is warranted.",
"affiliations": "The University of Texas Harris County Psychiatric Center, Houston, TX, USA.;The University of Texas Harris County Psychiatric Center, Houston, TX, USA.;The University of Texas Harris County Psychiatric Center, Houston, TX, USA.;The University of Texas Harris County Psychiatric Center, Houston, TX, USA.;The University of Texas Harris County Psychiatric Center, Houston, TX, USA.;The University of Texas Harris County Psychiatric Center, Houston, TX, USA.;The University of Texas Harris County Psychiatric Center, Houston, TX, USA.;The University of Texas Harris County Psychiatric Center, Houston, TX, USA.",
"authors": "Mohite|Satyajit|S|https://orcid.org/0000-0002-2873-3025;Wu|Hanjing|H|https://orcid.org/0000-0003-1208-8516;Sharma|Shiva|S|https://orcid.org/0000-0002-3270-9087;Lavagnino|Luca|L|https://orcid.org/0000-0003-1377-6871;Zeni|Cristian P|CP|https://orcid.org/0000-0001-9810-3929;Currie|Terrence T|TT|https://orcid.org/0000-0003-2562-5931;Soares|Jair C|JC|https://orcid.org/0000-0002-5466-5628;Pigott|Teresa A|TA|https://orcid.org/0000-0001-7608-9273",
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"fulltext": "\n==== Front\nClin Psychopharmacol Neurosci\nClin Psychopharmacol Neurosci\nClinical Psychopharmacology and Neuroscience\n1738-1088 2093-4327 Korean College of Neuropsychopharmacology \n\n32329308\n10.9758/cpn.2020.18.2.279\nCPN-18-279\nOriginal Article\nHigher Prevalence of Metabolic Syndrome in Child-adolescent Patients with Bipolar Disorder\nhttps://orcid.org/0000-0002-2873-3025Mohite Satyajit 12 https://orcid.org/0000-0003-1208-8516Wu Hanjing 12 https://orcid.org/0000-0002-3270-9087Sharma Shiva 1 https://orcid.org/0000-0003-1377-6871Lavagnino Luca 12 https://orcid.org/0000-0001-9810-3929Zeni Cristian P. 12 https://orcid.org/0000-0003-2562-5931Currie Terrence T. 1 https://orcid.org/0000-0002-5466-5628Soares Jair C. 12 https://orcid.org/0000-0001-7608-9273Pigott Teresa A. 12 \n1 The University of Texas Harris County Psychiatric Center, Houston, TX, USA\n\n\n2 Department of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center, Houston, TX, USA\n\nAddress for correspondence: Satyajit Mohite Department of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center, 1941 East Rd, Houston, TX 77054, USA E-mail: Satyajit.S.Mohite@uth.tmc.edu ORCID: https://orcid.org/0000-0002-2873-3025\n31 5 2020 \n31 5 2020 \n18 2 279 288\n22 11 2019 8 1 2020 7 2 2020 Copyright © 2020, Korean College of Neuropsychopharmacology2020This 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.Objective\nPrevious studies have indicated a convergent and bidirectional relationship between metabolic syndrome (MetS) and bipolar disorder (BD). As most of these studies focused mainly on adults diagnosed with BD, our study aims to investigate and characterize metabolic disturbances in child-adolescents diagnosed with BD.\n\nMethods\nWe retrospectively examined the medical records of psychiatric hospitalizations with admitting diagnosis of BD in child-adolescents (age < 18 years). Body mass index (BMI), lipid profile, fasting blood glucose, and blood pressure were primary variables. National Cholesterol Education Program criteria were used to define MetS. Reference group data was obtained from the National Health and Nutrition Examination Survey study. Statistical analyses included ttests, chi-square tests, and Fisher’s exact tests.\n\nResults\nWe identified 140 child-adolescent patients with BD (mean age = 15.12 ± 1.70 years, 53% male). MetS was significantly more common in BD compared to the reference group: 14% (95% confidence interval [95% CI] 8−20) vs. 6.7% (95% CI 4.1−9.2), p = 0.001 with no significant difference by sex. MetS components were higher in the BD group, particularly BMI ≥ 95% (25% vs. 11.8%, p < 0.001) and high blood pressure (17% vs. 8%, p = 0.05). Moreover, female patients had lower odds of high blood pressure (odds ratio = 0.24 [95% CI 0.08−0.69], p = 0.005).\n\nConclusion\nCompared with the general child-adolescent population, the prevalence of MetS was significantly higher in patients with BD of same age. This reiterates the notion of an increased risk of MetS in patients diagnosed with BD; and thus, further exploration is warranted.\n\nBipolar disorderMetabolic syndromeChild-adolescentsBody mass indexLipidsBlood glucose\n==== Body\nINTRODUCTION\nBipolar disorder (BD) is a chronic and debilitating disorder associated with recurring episodes of (hypo-) mania and/or depression and is diagnosed based on the severity of symptoms [1]. The international prevalence rate was noted to be 1.8% (95% confidence interval [95% CI], 1.1%−3.0%) [2]. Per the National Comorbidity Survey Adolescent Supplement data, American adolescents (age 13−18 years) have a 2.9% lifetime prevalence of bipolar disorder, with 2.6% experiencing severe impairment [3]. However, under-reporting and misdiagnosis of BD has been noted in adolescents BD [4]. BD can drastically impair functioning in adolescents due to cognitive impairment in their formative years [5-7].\n\nAn estimated 4% of adolescents in the United States (US) meet criteria for metabolic syndrome (MetS); based on an age modified definition of the Adult Treatment Panel (ATP) III criteria established for adults [8]. MetS was reported highly prevalent (16.7%−67%) among patients with BD worldwide [9-11]. Metabolic abnormalities are a major clinical concern due to their relationship with psychiatric outcomes [12]. Specifically, obesity and MetS have routinely been linked to BD [12]. Reviews by Taylor and MacQueen [13], Fagiolini et al. [14] addressed the common pathophysiological link between BD and MetS through several mechanisms, namely-dysregulations in glucose, insulin, hemostasis, sympathetic nervous system, and disturbances in the hypothalamic-pituitary-adrenal and the hypothalamic-pituitary-thyroid axes. Genetic studies have further contributed to the understanding of this association between BD and MetS through interconnected genes [15,16]. In the light of such recent evidences, the link between BD and metabolic abnormalities has been postulated to be bidirectional [17].\n\nMoreover, studies have demonstrated a higher prevalence of manic and depressive symptoms in the setting of metabolic disturbances as well as poor medication compliance and lower functional outcome [18]. A cohort study on a population of adolescents diagnosed with BD reported an increased prevalence of obesity, type 2 diabetes mellitus, endocrine abnormalities and cardiovascular disorders [19]. This study also reported a significant association between adolescent-onset BD and pre-existing obesity, hypertension and endocrine disorders, postulating that MetS precedes early-onset BD [19]. Additionally, studies have found differences in MetS prevalence by sex in the patients with BD; including increased waist circumference in women and increased triglycerides (TG) in men [20-22]. To the best of our knowledge, there is a lack of literature examining any individual and combined metabolic disturbances in youth diagnosed with BD, or any sex differences within this age group.\n\nOur study aims to review the prevalence of metabolic syndrome and its individual components (i.e., body mass index [BMI], lipid profile, fasting blood glucose, and blood pressure) in a sample of children and adolescent patients (< 18 years) with BD; and to compare our findings with reference group data from the National Health and Nutrition Examination Survey (NHANES) study for under age 18 individuals without BD.\n\nMETHODS\nThis study employed a cross-sectional design. After acquiring Institutional Review Board (IRB) approval (IRB No. HSC-MS-16-0746) and de-identified data consent waiver, data was retrospectively obtained from records of patients (age < 18 years) admitted to the University of Texas Health Harris County Psychiatric Center between January 2010 and December 2015. Records were de-identified and then uploaded to a secure, confidential server prior to data analysis. Inclusion criteria included: (i) age < 18 years, (ii) discharge diagnosis of bipolar I disorder, bipolar II disorder and bipolar disorder not otherwise specified (NOS) based on Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) criteria, determined by the assessing psychiatrist, and (iii) inpatient hospitalization between January 2010 and December 2015. Patients who were not fasting at least 10 hours before blood drawn were excluded.\n\nIn addition to demographic information, age of onset, prior hospitalization history, previous psychotropic medication history, and discharge psychotropic medications regimen were identified. Family psychiatric history was gathered from patient interviews and obtained collateral information. Blood samples were drawn within 24 hours of admission in a fasting state, before starting any medications. Systolic and diastolic blood pressures, tobacco smoking status, height, weight, fasting serum glucose and lipid panel including total cholesterol, high-density lipoprotein (HDL), and TG were retrieved for metabolic disturbance assessment.\n\nBlood pressures were manually measured and recorded by trained medical staff using age-appropriate cuff sizes with auscultation at time of admission. BMI was calculated by the electronic medical record after trained staff members entered manually measured heights and weights at the time of admission. National Cholesterol Education Program (NCEP) ATP III-modified criteria was used for MetS diagnosis [23], and at least 3 out of the 5 following components were required for diagnosis of MetS: (i) TG ≥ 150 mg/dl, (ii) HDL ≤ 40 mg/dl in men and ≤ 50 mg/dl in women, (iii) blood pressure ≥ 130/85 mmHg, (iv) fasting blood glucose ≥ 110 mg/dl, and (v) BMI ≥ 28.8 kg/m2 [23]. We used equivalent BMI parameters instead of the waist circumference (> 102 cm in men and > 88 cm in women) [23,24]. Reference group data was obtained from the findings of the NHANES 1999−2000 dataset [25-27]. Data was analyzed using SPSS 20 for Windows (IBM Co., Armonk, NY, USA) [28]. A univariate statistical analysis was performed with calculation of means and standard deviations (SD). Normality assumptions were verified using the Kolmogorov−Smirnov test, with application of 95% CI. Bivariate statistical analyses were conducted on all study variables, with presence or absence of MetS as the dependent variable. Quantitative variable comparisons were performed using the student’s ttest. Qualitative variable comparisons were performed using the chi-square test and Fisher’s exact tests (for n < 5).\n\nRESULTS\nSociodemographic and Clinical Characteristics of the Study Population\nOne hundred forty patients diagnosed with BD were identified ([age 15.12 ± 1.7 years, average ± SD]; 53% males; 52% African-American, 39% Caucasian). The predominant diagnosis was Bipolar NOS (95.71%) In comparison, the reference group was comprised of younger age (9.22 ± 5.93 years) and predominant Hispanic population (46.8%) as seen in Table 1. The groups were not statistically significant from each other for sexes; but were significantly different by age and race/ethnicity.\n\nIndividual Components of MetS in Study Population\nPatients diagnosed with BD had mean BMI: 26.12 ± 6.73 kg/m2, mean systolic blood pressure: 120.12 ± 12.50 mmHg, mean diastolic pressure: 73.99 ± 8.86 mmHg, mean serum glucose: 89.22 ± 14.35 mg/dl, mean serum triglycerides: 104.66 ± 87.15 mg/dl, and mean HDL: 48.82 ± 12.78 mg/dl (Table 2).\n\nPatients with ≥ 1 MetS components had a positive psychiatric family history (67%), were diagnosed with the following: comorbid conduct disorder (42%) and cannabis use disorder (42%), and history of following psychotropic medication use: antipsychotics (83%), valproic acid (67%), and antidepressants (42%).\n\nPrevalence of Individual Risk Factors of MetS in Study Population and Comparison with Normal Healthy Controls\nWhen assessed for MetS individual criteria, 25% of patients with BD had BMI ≥ 95th percentile, 13% had TG ≥ 150 mg/dl, 24% had HDL ≤ 40 mg/dl in males or ≤ 50 mg/dl in females, 17% had systolic blood pressure (SBP) ≥ 130 mmHg and/or diastolic blood pressure (DBP) ≥ 85 mmHg. Nine percent of patients diagnosed with BD had fasting blood glucose ≥ 110 mg/dl (Table 3).\n\nBMI\nWhen comparing BMI of the study and reference groups, the study sample had a significantly higher percentage with BMI ≥ 95th percentile (25% vs. 11.8%, respectively) (odds ratio [OR] = 2.49 [95% CI 1.62−3.82], p < 0.001). This correlation remained consistent between sexes in the study sample: males (25% vs. 12.1%) and females (25% vs. 11.6%).\n\nSystolic and/or diastolic blood pressure\nTwenty six percent of males (vs. 10.8% in the reference group) and 7% of females (vs. 5.1% in the reference group) in the study group met MetS criteria by blood pressure alone. Patients with BD had higher systolic and/or DBP than controls (17% vs. 8%) (OR = 1.82 [95% CI 1.05−3.13], p < 0.05).\n\nSerum glucose\nNo significant statistical difference in percentage fasting serum glucose ≥ 110 mg/dl was found between the study and reference groups (OR = 1.25 [95% CI 0.67−2.32], p = 0.48).\n\nLipids\nSurprisingly, a lower percentage of patients with BD had increased triglycerides compared to controls (13% vs. 23.2%) (OR = 0.49 [95% CI 0.29−0.81], p = 0.005). The difference in percentages between the study and reference groups was even greater when comparing sexes: males (14% vs. 25.5%) and females (12% vs. 20.9%). No significant statistical difference of HDL was observed between the study and reference groups (OR = 1.06 [95% CI 0.7−1.6], p = 0.77).\n\nCombined MetS criteria\nConsidering all individual components, patients diagnosed with BD had a higher prevalence of MetS than healthy controls (14% vs. 6.7%) even when accounting for differences in sex: males (16% vs. 9.6%) and females (12% vs. 3.8%). The study group had significantly higher odds of having MetS compared to the reference group (OR = 2.33 [95% CI 1.37−4.0], p = 0.001).\n\nPrevalence of MetS, Individual MetS Components, and Sex Differences in BD Patients\nIn the study group, 14% of patients with BD met diagnostic criteria for MetS. The mean age of patients with MetS was 14.73 ± 1.55 years and MetS prevalence was highest in Whites (n = 10, 19% of all White patients with BD). In the group with BD also diagnosed with MetS, females were less likely to have high blood pressure (OR = 0.24 [95% CI 0.08−0.69], p = 0.005). The remaining individual MetS components and the combination of MetS components were not significant different between sexes (p > 0.05) (Table 4).\n\nDISCUSSION\nOur study demonstrated that patients with BD met MetS criteria more often than healthy controls through BMI and SBP and/or DBP; as well combined MetS components. A strong correlation exists between MetS with in adults with BD [11,29,30], however there is a paucity of studies on MetS in children and adolescents diagnosed with BD. To the best of our knowledge, our study is a distinctive one to directly examine the prevalence of MetS and its individual subcomponents in this patient population.\n\nA previous study addressed BMI in BD patients of age 7−17 years [31], and reported that 16.5% patients had BMI ≥ 95th percentile, while 25% patients in our study met such BMI criteria. In contrast to their predominantly non- Caucasian BD patients with high BMI [31], our study sample meeting MetS diagnostic criteria were predominantly White. Our findings align with another study that reported 64.7% adolescents with BD had ≥ 1 MetS component, mainly elevated TG and DBP [32]. Naiberg’s study sample had higher TG levels than their controls, but in contrast we found significantly lower TG levels in our patients with BD in comparison to our controls. This variability could be attributed to patients’ diets, as TG levels are known to be affected by fasting status [33]. It also raises the possibility of the involvement of another unknown mechanism, as both the study and NHANES reference groups were assessed with an overnight fasting [26]. Previously MetS components were thought to precede BD [19]. If true, MetS demands more attention in the context BD management for better prognosis.\n\nGenetics may play a crucial role as a positive family history of MetS, especially high blood pressure and serum glucose, is associated with a 1.5 relative risk of developing MetS in patients with BD [34,35]. Our study found 67% of patients with BD and MetS had a positive family psychiatric history, but family history for MetS or its components was unavailable. The risk for developing MetS or its components in young patients with BD may differ by sex as a study reported females (mean age 12.6 ± 3.6 years) had larger waist circumference and higher BMI, TG, LDL and total cholesterol, but had lower systolic blood pressure and fasting blood glucose than males (mean age 12.5 ± 3.5 years). After 6.6 years of follow-up in this study, females (mean age 16.6 ± 5.4 years) continued to have larger waist circumference, higher BMI and higher TG. Additionally, females had higher SBP and DBP and fasting blood glucose than males (mean age 16.0 ± 5.6 years) [36]. Our study did not find a significant difference in all MetS components between sexes in patients with BD, except female patients with BD showed a significantly lower frequency of high blood pressure.\n\nDifferent theories seek to explain the relationship between metabolic abnormalities and BD. Patients diagnosed with BD show increased levels of inflammatory markers and altered steroid hormone concentrations and inflammation is associated with BMI and mood symptom severity [37,38]. Obesity is further exacerbated by poor dietary habits and an altered lifestyle [39,40]. Binge eating and emotionally driven eating behavior are highly prevalent in adolescent populations with BD [12,41].\n\nMany psychotropic medications used in the treatment of BD have been linked with metabolic abnormalities [42]. Certain atypical antipsychotics (e.g., Olanzapine, Risperidone) prescribed as monotherapy or in combination with other psychotropics such as mood stabilizers, have been found to cause weight gain, metabolic abnormalities, and increased cardiovascular risk in adolescents [43-48]. In contrast, another study reported a high prevalence of obesity and metabolic syndrome in medication-naïve patients [49]. The patients in our study were on psychotropic medications: antipsychotics (83%), valproic acid (67%), and antidepressants (42%) treatment. These medications exhibit a propensity to increase specifically BMI in adolescents with BD [50]. Although these psychotropics significantly impact MetS profile, this can be ameliorated through cautious medication selection based on careful therapeutic risk-benefit analysis. Several studies have scrutinized the safety data for antipsychotics in younger aged populations and have postulated a few recommendations [51-54]. Quetiapine, Ziprasidone, Aripiprazole, and Paliperidone were comparatively found to have a less-severe impact on the MetS profile [43,55,56]. Our study also found the presence of MetS in patients with BD who were not on medications (13%). These divergent findings suggest metabolic abnormalities could be an inherent part of the BD disease process [57].\n\nOur study is noteworthy because the adolescent population diagnosed with BD has not been well explored. Additional study strengths include comparison with a national reference group, MetS assessment via based on the NCEP individual and combined component criteria. Although this study was effective in assessing the differences between adolescent BD with patients and controls in setting of MetS and its associated components, it had certain limitations. Chart review yielded some significant variables especially comorbid conduct disorder and cannabis use disorder, family psychiatric history, and psychotropic medication history, but the overall analysis lacked some vital clinic information including history of self-harm and suicidality, duration and severity of the illness, and average length of hospitalization. The cross-sectional study design is limiting because the predictability and the temporal relationship between BD and MetS in younger aged patients cannot be assessed. Although demographic variables like mean age in the groups was significantly different, use of an inpatient sample for study purposes may not accurately reflect the prevalence of BD and MetS in adolescent patients in the community. Most patients were prescribed and taking psychotropic medication prior to admission which may confound the association between BD and MetS. Considering the role of psychotropics in treatment of BD and effect upon MetS, detailed retrospective data was warranted, but was not available for this study. Another overlapping and limiting aspects were the high percentage of comorbid conduct disorder and cannabis use disorder in patient population. As literature suggests the strong interlink of BD with conduct disorder [58-60] and cannabis use disorder [61,62], thorough studies are needed in such BD population by excluding the comorbidities. A recent study reported the fluctuations in the discharge medications dosing and length of stay in adult BD population using cannabis and synthetic cannabis [63]. With a dearth of such studies in young BD population and increased prevalence of synthetic cannabis use in the community [64-66], it is crucial to integrate this factor in adolescent BD patients for further insight.\n\nThe reference group data used for this study is from the NHANES 1999−2000 report and a 2004 descriptive study [67]. To address the timeline difference between the data collected from the study and reference groups, we compared the prevalence of MetS in same age group from 2003 to 2011, which was reported to be 2.9% and 5.6% for younger and older age children and adolescent groups, respectively [68]. In contrast, mean weight, waist circumference, and BMI in adults has noticed to be increased over time [69]. It is safe to assume that prevalence of MetS in the young population did not drastically increase over time, otherwise it would have convoluted the impact of BD on MetS. All significant covariates from the NHANES were unable to be obtained which significantly restricts our ability to understand the clinical depth in BD and MetS. Our study sample was distorted by a higher frequency of BD-NOS, compared to BD-I or BD-II. The younger age population has high incidence of BD-NOS [70], with a conversion rate of 30−50% from BD-NOS to BD-I or BD-II later on in life [71,72]. The inpatient setting from which the study sample was derived is focused on acute stabilization and length of stays are relatively short. This may lead to difficulties in clinically differentiating BD-I and BD-II. In such a limited setting, with lack of in-depth historical information and a short window of clinical monitoring, the assessing psychiatrist might have preferred a discharge diagnosis of BD-NOS in light of insufficient data for BD-I or BD-II diagnoses. Adequate follow-up of this cohort and subsequent comparison to baseline data could better elucidate this slant in discharge diagnosis.\n\nThe selection of the appropriate MetS-defining criteria for this study was another substantial challenge as various criteria are recognized. The World Health Organization (WHO) criteria (1998) has insulin resistance as an absolute requirement [73], the European Group for the Study of Insulin Resistance (EGIR) deems hyperinsulinemia compulsory [74], and the International Diabetes Foundation (IDF) mandates obesity as a requirement for MetS diagnosis [75]. In contrast to these differing defining criteria, NCEP ATP-III does not necessitate any specific criteria as an absolute requirement for MetS diagnosis. For simplicity, NCEP criteria were selected and BMI was used as a proxy to waist circumference which limits our scope of obesity as a MetS component.\n\nCompared to the general adolescent population, the prevalence of metabolic abnormalities in child and adolescents with BD found to be significantly higher. These findings support the notion of amplified risk of metabolic disturbances at an early age in patients diagnosed with BD. Keeping in mind the pubertal hormonal changes and its influence on several physiological changes [76]; such as body fat changes [77], increased leptin resistance [78], adiponectin and resistin fluctuations etc. [79], it is pertinent to incorporate the notion of age while assessing BD and MetS spectrum in young population. Majority of studies in the past were focused primarily on adults; as opposed to adolescent populations with BD. It is noteworthy that metabolic disturbances within the child and adolescent population presents with an array of additional issues; that are distinct from the adult population, raises unique concerns especially future quality of life. Furthermore, heterogeneity in MetS is observed in sex-based comparison in adult population [80,81]. Such data is conflicting in children and adolescent population, with some reporting higher prevalence in males and in Hispanic ethnicity [76,82,83], thus demanding a better grasp of the pathophysiology of MetS and its influence on BD.\n\nThis study recognizes metabolic disturbances in young patients diagnosed with BD to be a significant problem. It is essential to understand the effects of abnormal metabolic factors in early-onset BD; to allow the development of an improved patient-centered approach; to embrace preventive treatment, and thus to diminish morbidity and mortality associated with BD and metabolic abnormalities.\n\nAcknowledgments\nWe would like to thank all the research personnel at HCPC and department of Psychiatry for helping in this and every endeavor.\n\n\nCDC Disclaimer\n\n\nThe findings and conclusions in this paper are those of the author(s) and do not necessarily represent the views of the Research Data Center, the National Center for Health Statistics, or the Centers for Disease Control and Prevention.\n\n\nConflicts of Interest\n\n\nNo potential conflict of interest relevant to this article was reported.\n\n\nAuthor Contributions\n\n\nHanjing Wu, Teresa A. Pigott, and Jair C. Soares helped in conceptualization, Hanjing Wu and Teresa A. Pigott helped in data acquisition, formal analysis was performed by Hanjing Wu, original draft’s writing was done by Satyajit Mohite, review and edits were provided by Shiva Sharma, Hanjing Wu, Luca Lavagnino, Christian P. Zeni, Terrence T. Currie, Jair C. Soares, Teresa A. Pigott.\n\nTable 1 Sociodemographic and clinical characteristics of study and reference groups\n\nParameter\tPatients with BD (n = 140)\tControls (n = 4,804)\t\np value\t\nAge (yr)\t15.12 ± 1.7\t9.22 ± 5.93\t0.000\t\nSex, male (%)\t53\t51.5\t0.909\t\nRace/Ethnicity\t\t\t0.000\t\nWhite\t54 (39)\t1,092 (22.7)\t\t\nAfrican-American\t73 (52)\t1,260 (26.2)\t\t\nHispanic\t11 (8)\t2,246 (46.8)\t\t\nOther/unknown\t2 (1)\t206 (4.3)\t\t\nDiagnosis (DSM-IV)\t\t\t\t\nBipolar I\t2 (1.43)\t-\t\t\nBipolar II\t4 (2.86)\t-\t\t\nBipolar NOS\t134 (95.71)\t-\t\t\nValues are presented as or mean ± standard deviation or number (%).\n\nBD, bipolar disorder; DSM-IV, the Diagnostic and Statistical Manual of Mental Disorders 4th edition; NOS, not otherwise specified.\n\nTable 2 Individual components of MetS in study population\n\nParameter\tBD cases (n = 140)\t\nBody mass index 95th percentile\t26.12 ± 6.73\t\nSystolic blood pressure (mmHg)\t120.12 ± 12.50\t\nDiastolic blood pressure (mmHg)\t73.99 ± 8.86\t\nSerum glucose (mg/dl)\t89.22 ± 14.35\t\nTriglycerides (mg/dl)\t104.66 ± 87.15\t\nHDL-C (mg/dl)\t48.82 ± 12.78\t\nValues are presented as mean ± standard deviation.\n\nMetS, metabolic syndrome; BD, bipolar disorder; HDL-C, high-density lipoprotein-C.\n\nTable 3 Prevalence of individual risk factors of metabolic syndrome among patients with BD vs. reference group\n\nVariables of MetS\tBipolar disorder (n = 140)\tReference group (n = 991)\tOR (95% CI)\t\np value\t\n\n\n\t\n\n\t\nFemale\tMale\tTotal\tFemale\tMale\tTotal\t\nBMI 95th percentile\t25 \t25\t35 (25)\t11.6 \t12.1 \t117 (11.8)\t2.49 (1.62−3.82)\t< 0.001*\t\nSBP and/or DBP (mmHg) \t7 \t26 \t18 (17) \t5.1 \t10.8 \t79 (8)\t1.82 (1.05−3.13)\t0.05*\t\nSerum glucose (mg/dl) \t12 \t7 \t13 (9)\t5.3 \t10\t75 (7.6) \t1.25 (0.67−2.32) \t0.48\t\nTriglycerides (mg/dl) \t12 \t14 \t18 (13)\t20.9 \t25.5 \t230 (23.2) \t0.49 (0.29−0. 81) \t0.005*\t\nHDL-C (mg/dl) \t25 \t23 \t34 (24)\t19.3 \t27.3 \t230 (23.4) \t1.06 (0.7−1.6)\t0.77\t\nMetabolic syndrome \t12 \t16 \t20 (14) \t3.8 \t9.6 \t66 (6.7) \t2.33 (1.37−4.0)\t0.001*\t\nValues are presented as percent only or number (%).\n\nBD, bipolar disorder; OR, odds ratio; CI, confidence interval; BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure; HDL-C, high-density lipoprotein-C.\n\nAn asterisk indicates the significant difference (p ≤ 0.05).\n\nTable 4 Prevalence of metabolic syndrome and its individual components by sex within patients with BD\n\nVariables of MetS\tFemale\tMale\tOR (95% CI)\t\np value\t\nBMI 95th percentile\t17 (25)\t18 (25)\t1.09 (0.51−2.35)\t0.82\t\nHypertriglyceridemia\t8 (12)\t10 (14)\t0.89 (0.33−2.41)\t0.82\t\nLow HDL\t17 (25)\t17 (23)\t1.18 (0.54−2.55)\t0.67\t\nHigh blood pressure\t5 (7)\t19 (26)\t0.24 (0.08−0.69)\t0.005*\t\nHigh fasting glucose\t8 (12)\t5 (7)\t1.92 (0.6−6.2)\t0.27\t\nMetS (three or more criteria)\t8 (12)\t12 (16)\t1.38 (0.53−3.6)\t0.63\t\nValues are presented as number (%).\n\nBD, bipolar disorder; BMI, body mass index; HDL, high-density lipoprotein; MetS, metabolic syndrome; OR, odds ratio. \n\nAn asterisk indicates the significant difference (p ≤ 0.05).\n==== Refs\nREFERENCES\nWalther A Penz M Ijacic D Rice TR 2017 Bipolar spectrum disorders in male youth: the interplay between symptom severity, inflammation, steroid secretion, and body composition Front Psychiatry 8 207 10.3389/fpsyt.2017.00207 29093685 \nVan Meter AR Moreira AL Youngstrom EA 2011 Meta-analysis of epidemiologic studies of pediatric bipolar disorder J Clin Psychiatry 72 1250 1256 10.4088/JCP.10m06290 21672501 \nMerikangas KR He JP Burstein M Swanson SA Avenevoli S Cui L 2010 Lifetime prevalence of mental disorders in U.S. adolescents: results from the National Comorbidity Survey Replication--Adolescent Supplement (NCS-A) J Am Acad Child Adolesc Psychiatry 49 980 989 10.1016/j.jaac.2010.05.017 20855043 \nFaedda GL Baldessarini RJ Glovinsky IP Austin NB 2004 Pediatric bipolar disorder: phenomenology and course of illness Bipolar Disord 6 305 313 10.1111/j.1399-5618.2004.00128.x 15225148 \nEl-Badri SM Ashton CH Moore PB Marsh VR Ferrier IN 2001 Electrophysiological and cognitive function in young euthymic patients with bipolar affective disorder Bipolar Disord 3 79 87 10.1034/j.1399-5618.2001.030206.x 11333067 \nPavuluri MN Schenkel LS Aryal S Harral EM Hill SK Herbener ES 2006 Neurocognitive function in unmedicated manic and medicated euthymic pediatric bipolar patients Am J Psychiatry 163 286 293 10.1176/appi.ajp.163.2.286 16449483 \nPerlis RH Miyahara S Marangell LB Wisniewski SR Ostacher M DelBello MP STEP-BD Investigators 2004 Long-term implications of early onset in bipolar disorder: data from the first 1000 participants in the systematic treatment enhancement program for bipolar disorder (STEP-BD) Biol Psychiatry 55 875 881 10.1016/j.biopsych.2004.01.022 15110730 \nCook S Weitzman M Auinger P Nguyen M Dietz WH 2003 Prevalence of a metabolic syndrome phenotype in adolescents: findings from the third National Health and Nutrition Examination Survey, 1988-1994 Arch Pediatr Adolesc Med 157 821 827 10.1001/archpedi.157.8.821 12912790 \nGrover S Malhotra N Chakrabarti S Kulhara P 2012 Metabolic syndrome in bipolar disorders Indian J Psychol Med 34 110 118 10.4103/0253-7176.101767 23162184 \nMcIntyre RS Danilewitz M Liauw SS Kemp DE Nguyen HT Kahn LS 2010 Bipolar disorder and metabolic syndrome: an international perspective J Affect Disord 126 366 387 10.1016/j.jad.2010.04.012 20541810 \nVancampfort D Vansteelandt K Correll CU Mitchell AJ De Herdt A Sienaert P 2013 Metabolic syndrome and metabolic abnormalities in bipolar disorder: a meta-analysis of prevalence rates and moderators Am J Psychiatry 170 265 274 10.1176/appi.ajp.2012.12050620 23361837 \nGoldstein BI Blanco C He JP Merikangas K 2016 Correlates of overweight and obesity among adolescents with bipolar disorder in the National Comorbidity Survey-Adolescent Supplement (NCS-A) J Am Acad Child Adolesc Psychiatry 55 1020 1026 10.1016/j.jaac.2016.08.010 27871636 \nTaylor V MacQueen G 2006 Associations between bipolar disorder and metabolic syndrome: a review J Clin Psychiatry 67 1034 1041 10.4088/JCP.v67n0704 16889445 \nFagiolini A Chengappa KN Soreca I Chang J 2008 Bipolar disorder and the metabolic syndrome: causal factors, psychiatric outcomes and economic burden CNS Drugs 22 655 669 10.2165/00023210-200822080-00004 18601304 \nMaciukiewicz M Dmitrzak-Weglarz M Pawlak J Leszczynska-Rodziewicz A Zaremba D Skibinska M 2014 Analysis of genetic association and epistasis interactions between circadian clock genes and symptom dimensions of bipolar affective disorder Chronobiol Int 31 770 778 10.3109/07420528.2014.899244 24673294 \nEllingrod VL Taylor SF Dalack G Grove TB Bly MJ Brook RD 2012 Risk factors associated with metabolic syndrome in bipolar and schizophrenia subjects treated with antipsychotics: the role of folate pharmacogenetics J Clin Psychopharmacol 32 261 265 10.1097/JCP.0b013e3182485888 22370993 \nMansur RB Brietzke E McIntyre RS 2015 Is there a \"metabolic- mood syndrome\"? 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A Fulkerson PC Abonia JP 2006 Eotaxin-3 and a uniquely conserved gene-expression profile in eosinophilic esophagitis J Clin Invest 116 536 547 10.1172/JCI26679 16453027 \nMcElroy SL Keck PE Jr Jr 2012 Obesity in bipolar disorder: an overview Curr Psychiatry Rep 14 650 658 10.1007/s11920-012-0313-8 22903246 \nCorrell CU 2007 Weight gain and metabolic effects of mood stabilizers and antipsychotics in pediatric bipolar disorder: a systematic review and pooled analysis of short-term trials J Am Acad Child Adolesc Psychiatry 46 687 700 10.1097/chi.0b013e318040b25f 17513981 \nAlmandil NB Liu Y Murray ML Besag FM Aitchison KJ Wong IC 2013 Weight gain and other metabolic adverse effects associated with atypical antipsychotic treatment of children and adolescents: a systematic review and meta-analysis Paediatr Drugs 15 139 150 10.1007/s40272-013-0016-6 23519708 \nFraguas D Correll CU Merchán-Naranjo J Rapado-Castro M Parellada M Moreno C 2011 Efficacy and safety of second-generation antipsychotics in children and adolescents with psychotic and bipolar spectrum disorders: comprehensive review of prospective head-to-head and placebo-controlled comparisons Eur Neuropsychopharmacol 21 621 645 10.1016/j.euroneuro.2010.07.002 20702068 \nDe Hert M Dobbelaere M Sheridan EM Cohen D Correll CU 2011 Metabolic and endocrine adverse effects of second-generation antipsychotics in children and adolescents: a systematic review of randomized, placebo controlled trials and guidelines for clinical practice Eur Psychiatry 26 144 158 10.1016/j.eurpsy.2010.09.011 21295450 \nVitiello B Correll C van Zwieten-Boot B Zuddas A Parellada M Arango C 2009 Antipsychotics in children and adolescents: increasing use, evidence for efficacy and safety concerns Eur Neuropsychopharmacol 19 629 635 10.1016/j.euroneuro.2009.04.008 19467582 \nLeonardi A Jose PJ Zhan H Calder VL 2003 Tear and mucus eotaxin-1 and eotaxin-2 in allergic keratoconjunctivitis Ophthalmology 110 487 492 10.1016/S0161-6420(02)01767-0 12623809 \nBen Amor L 2012 Antipsychotics in pediatric and adolescent patients: a review of comparative safety data J Affect Disord 138 Suppl S22 S30 10.1016/j.jad.2012.02.030 22405602 \nGálvez JF Sanches M Bauer IE Sharma AN Hamilton J Mwangi B 2015 Premorbid obesity and metabolic disturbances as promising clinical targets for the prevention and early screening of bipolar disorder Med Hypotheses 84 285 293 10.1016/j.mehy.2015.01.016 25678233 \nKovacs M Pollock M 1995 Bipolar disorder and comorbid conduct disorder in childhood and adolescence J Am Acad Child Adolesc Psychiatry 34 715 723 10.1097/00004583-199506000-00011 7608044 \nGeller B Luby J 1997 Child and adolescent bipolar disorder: a review of the past 10 years J Am Acad Child Adolesc Psychiatry 36 1168 1176 10.1097/00004583-199709000-00008 9291717 \nChen MH Su TP Chen YS Hsu JW Huang KL Chang WH 2013 Higher risk of developing mood disorders among adolescents with comorbidity of attention deficit 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prevalence, motives, and correlates Drug Alcohol Depend 143 268 271 10.1016/j.drugalcdep.2014.07.009 25096272 \nMehta JJ Mahendran AK Bajaj RK Doshi AR 2017 Myocardial ischemia with cannabinoid use in an adolescent Cureus 9 e1899 10.7759/cureus.1899 29399427 \nCastellanos D Gralnik LM 2016 Synthetic cannabinoids 2015: an update for pediatricians in clinical practice World J Clin Pediatr 5 16 24 10.5409/wjcp.v5.i1.16 26862498 \nRansohoff RM 2002 The chemokine system in neuroinflammation: an update J Infect Dis 186 Suppl 2 S152 S156 10.1086/344266 12424691 \nTeixeira AL Jr Jr Cardoso F Souza AL Teixeira MM 2004 Increased serum concentrations of monokine induced by interferon- gamma/CXCL9 and interferon-gamma-inducible protein 10/ CXCL-10 in Sydenham's chorea patients J Neuroimmunol 150 157 162 10.1016/j.jneuroim.2004.01.013 15081261 \nTeixeira AL Reis HJ Nicolato R Brito-Melo G Correa H Teixeira MM 2008 Increased serum levels of CCL11/eotaxin in schizophrenia Prog Neuropsychopharmacol 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Part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation Diabet Med 15 539 553 10.1002/(SICI)1096-9136(199807)15:7<539::AID-DIA668>3.0.CO;2-S 9686693 \nBalkau B Charles MA 1999 Comment on the provisional report from the WHO consultation. European Group for the Study of Insulin Resistance (EGIR) Diabet Med 16 442 443 10.1046/j.1464-5491.1999.00059.x 10342346 \nZimmet P Magliano D Matsuzawa Y Alberti G Shaw J 2005 The metabolic syndrome: a global public health problem and a new definition J Atheroscler Thromb 12 295 300 10.5551/jat.12.295 16394610 \nJessup A Harrell JS 2005 The metabolic syndrome: look for it in children and adolescents, too! 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"fulltext_license": "CC BY-NC",
"issn_linking": "1738-1088",
"issue": "18(2)",
"journal": "Clinical psychopharmacology and neuroscience : the official scientific journal of the Korean College of Neuropsychopharmacology",
"keywords": "Bipolar disorder; Blood glucose; Body mass index; Child-adolescents; Lipids; Metabolic syndrome",
"medline_ta": "Clin Psychopharmacol Neurosci",
"mesh_terms": null,
"nlm_unique_id": "101207332",
"other_id": null,
"pages": "279-288",
"pmc": null,
"pmid": "32329308",
"pubdate": "2020-05-31",
"publication_types": "D016428:Journal Article",
"references": "20702068;26539073;22959686;29399427;23519708;16263831;18782643;27871636;16394610;9686693;15225148;26627487;12485966;16889445;23361837;21672501;23734806;19026266;23162184;18687321;22370993;18096286;20541810;8941651;10194423;25579847;24962329;26890288;10342346;22405602;9240429;15081261;31014468;20584522;18458192;22903246;22577529;17513981;27329743;9267993;7627249;18601304;24673294;8631813;15477412;12424691;10637571;9291717;20021321;19467582;15620436;20674033;7608044;11786310;11333067;20855043;24255079;15110730;21295450;29093685;15111486;16867033;16453027;16176435;12532148;22040193;16598526;26646032;26862498;25678233;23062212;23643104;12912790;16540813;14728103;25096272;26407790;24072812;16449483;12623809",
"title": "Higher Prevalence of Metabolic Syndrome in Child-adolescent Patients with Bipolar Disorder.",
"title_normalized": "higher prevalence of metabolic syndrome in child adolescent patients with bipolar disorder"
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"abstract": "Epidermal growth factor receptor (EGFR) inhibitors are biological factors used in the treatment of non-small-cell lung cancers (NSCLC) that are positive for EGFR mutations. Afatinib is one such drug that has been approved for use in this capacity. Cutaneous toxicity is the second most commonly reported adverse event with the use of afatinib. A 39-year-old woman with inoperative right lung adenocarcinoma was initially treated with afatinib. She not only developed a severe papulopustular eruption but also had a dramatic reduction of her tumor. Her cutaneous symptoms and lesions were effectively treated with oral and topical corticosteroids, oral antibiotics, and oral antihistamines. After one month of afatinib treatment, her tumor was resected, and there was no evidence of metastases. Afatinib-induced cutaneous toxicity has a positive correlation with tumor response to anti-neoplastic therapy. Supplemental systemic and topical treatments can be initiated to palliate adverse skin events in order to enable adequate duration of treatment with afatinib.",
"affiliations": "Medical College of Georgia.;Department of Dermatology, University of California, San Diego.",
"authors": "Osborn|Lindsay P|LP|;Cohen|Philip R|PR|",
"chemical_list": null,
"country": "United States",
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"doi": "10.7759/cureus.763",
"fulltext": "\n==== Front\nCureusCureus2168-8184Cureus2168-8184Cureus Palo Alto (CA) 10.7759/cureus.763OncologyDermatologyAfatinib-Associated Cutaneous Toxicity: A Correlation of Severe Skin Reaction with Dramatic Tumor Response in a Woman with Exon 19 Deletion Positive Non-Small-Cell Lung Cancer Muacevic Alexander Adler John R Osborn Lindsay P 1Cohen Philip R 21 \nMedical College of Georgia 2 \nDepartment of Dermatology, University of California, San Diego \nLindsay P. Osborn osbornlindsay@gmail.com1 9 2016 9 2016 8 9 e7635 8 2016 1 9 2016 Copyright © 2016, Osborn et al.2016Osborn 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 http://www.cureus.com/articles/5056-afatinib-associated-cutaneous-toxicity-a-correlation-of-severe-skin-reaction-with-dramatic-tumor-response-in-a-woman-with-exon-19-deletion-positive-non-small-cell-lung-cancerEpidermal growth factor receptor (EGFR) inhibitors are biological factors used in the treatment of non-small-cell lung cancers (NSCLC) that are positive for EGFR mutations. Afatinib is one such drug that has been approved for use in this capacity. Cutaneous toxicity is the second most commonly reported adverse event with the use of afatinib. A 39-year-old woman with inoperative right lung adenocarcinoma was initially treated with afatinib. She not only developed a severe papulopustular eruption but also had a dramatic reduction of her tumor. Her cutaneous symptoms and lesions were effectively treated with oral and topical corticosteroids, oral antibiotics, and oral antihistamines. After one month of afatinib treatment, her tumor was resected, and there was no evidence of metastases. Afatinib-induced cutaneous toxicity has a positive correlation with tumor response to anti-neoplastic therapy. Supplemental systemic and topical treatments can be initiated to palliate adverse skin events in order to enable adequate duration of treatment with afatinib.\n\nafatinibexon 19egfr mutations in lung adenocarcinomacutaneous toxicityskinnon-small-cell lung canceradverse eventsThe 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\nEpidermal growth factor receptor (EGFR) inhibitors are a class of biological agents which act on the ErbB family of tyrosine kinases. Afatinib is an irreversible, multi-receptor inhibitor used for patients with non-small cell lung cancer (NSCLC) who demonstrate EGFR mutations consisting of exon 19 deletion or exon 21 substitution mutation. Due to its irreversible inhibition of multiple ErbB receptors, afatinib offers an option for patients with acquired resistance to the first-generation EGFR reversible inhibitors, namely gefitinib and erlotinib [1-2]. Cutaneous adverse events are more common and severe with afatinib, but afatinib also demonstrates greater progression-free survival when compared with gefitinib [1]. We describe a woman with an inoperable lung cancer demonstrating an exon 19 deletion. She subsequently developed severe cutaneous toxicity associated with dramatic tumor response afatinib, enabling surgical resection of her entire tumor.\n\nCase presentation\nA 39-year-old Caucasian woman presented with a new and persistent cough. Radiographic imaging of her chest demonstrated a mass in the upper lobe of the right lung. Fine-needle aspirate biopsy demonstrated adenocarcinoma. Genomic testing showed the patient’s tumor to be EGFR-mutation positive with exon 19 deletion. She was referred to a comprehensive cancer center for treatment. Her initial computed tomography (CT) scan suggested possible mediastinal invasion at the level of the right brachiocephalic vein. Therefore, she was treated with neoadjuvant afatinib therapy prior to possible surgical intervention. The patient agreed to participate and was explained the nature and objectives of this study, and informed consent was formally obtained. No reference to the patient's identity was made at any stage during data analysis or in the report.\n\nThe patient began developing small papules within 24 hours of starting afatinib and by the fourth day of therapy was experiencing severe dermatologic toxicity. Lesions initially appeared on the face, neck, and chest. Individual lesions became confluent and involved 80% of the affected areas. The patient noted her lesions to be extremely pruritic. Her oncologist prescribed oral doxycycline 100 mg twice daily, topical treatment to her skin lesions with clindamycin 1% gel twice daily, and hydrocortisone 2.5% cream.\n\nThe patient’s cutaneous symptoms and lesions continued to progress rapidly during the next several days. She was severely debilitated to the point of considering discontinuation of afatinib therapy. Therefore, her oncologist referred her to the dermatology clinic for evaluation and treatment of the drug-associated skin toxicity. After obtaining written consent from the patient, photos of all of the affected areas were taken.\n\nCutaneous examination after starting afatinib revealed diffuse erythema with individual and confluent papules and pustules on the forehead, face, neck, chest, upper abdomen, and upper back (Figures 1-4).\n\n\nFigure 1 Face and Chest\nFront view of a 39-year-old woman with NSCLC who developed papulopustular lesions on the face, neck, chest, abdomen, and back after starting treatment with afatinib. Her arms and below her waist were spared.\n\n\n\n\n\nFigure 2 Back\n\n\n\n\nFigure 3 Close-Up of Chest\nCloser inspection of the chest and back demonstrates numerous pustules on a background of erythema.\n\n\n\n\n\nFigure 4 Close-Up of Back\n\n\n\nHer forehead lesions also had superficial scaling, and the lesions on the nose were crusted (Fig 5). There was also diffuse involvement of the scalp. No other hair, nail, or other mucocutaneous lesions were observed.\n\n\nFigure 5 Face\nSevere acneiform eruption is seen on the face. Crusted papules and pustules involve not only the forehead and nose but also the perioral areas and chin. Papulopustules and scaling on the forehead and scalp are seen.\n\n\n\n\nTherapeutic intervention included oral dexamethasone 4 mg daily for seven days and doxycycline 100 mg twice daily. The clindamycin gel was discontinued since it had elicited severe irritation and pain; topical triamcinolone 0.1% ointment was applied to the face and neck twice daily, and clobetasol propionate 0.05% cream was applied to the chest and back twice daily. To alleviate her pruritis, she received oral fexofenadine 180 mg each morning as well as hydroxyzine 50 mg each evening. During the seven-day course of dexamethasone, she stopped afatinib for three days and then resumed therapy at a 30 mg dose--a 25% reduction from the initial dose of 40 mg.\n\nFollow-up examination one week later showed significant improvement in both skin symptoms and lesions. Her skin pain and pruritis had resolved. There were both a resolution of the pustules and a flattening of the papules (Figures 6-7).\n\n\nFigure 6 Face and Chest\nFront view seven days after initiating treatment to ameliorate the cutaneous symptoms and lesions; the papulopustules have flattened, and the associated pain has completely resolved.\n\n\n\n\n\nFigure 7 Back\nBack view seven days after initiation of treatment.\n\n\n\n\nErythema persisted on the affected skin areas. Forehead scaling had also resolved, and the crusted lesions on her nose had cleared (Figure 8).\n\n\nFigure 8 Face \nA closer view of her face after one week of adjuvant skin treatment shows dramatic improvement of the afatinib-induced cutaneous lesions, particularly on the nose and chin. In addition, the forehead and scalp scaling have resolved.\n\n\n\n\nImprovement of the cutaneous toxicity allowed the patient to complete the four-week course of afatinib therapy. A repeat CT scan following the EGFR inhibitor therapy showed a dramatic decrease in the size of the tumor. Additionally, there was no longer any vascular involvement of the right brachiocephalic vein.\n\nSurgical excision of the upper lobe of the right lung and multiple lymph nodes was performed. Pathology demonstrated complete removal of the tumor and showed absence of tumor in any lymph nodes. Within one month of discontinuing afatinib, the patient’s skin lesions completely resolved, and she was able to discontinue all oral and topical therapy.\n\nThe patient’s case was reviewed by the cancer center tumor board; the benefit of adjuvant chemotherapy following the successful resection of her tumor was found to be less than 2%. Therefore, the tumor board recommended observation. She will be closely monitored with re-staging every three months.\n\nDiscussion\nEGFR inhibitors act by causing dysfunction of the ErbB family of tyrosine kinase receptors. Afatinib specifically acts to inhibit multiple receptors, including ErbB1 (EGFR), ErbB2 (HER2), and ErbB4 (HER4) [3-4]. It does so through covalent binding, thus irreversibly inhibiting these receptors.\n\nEGFR inhibitors have been incorporated into the management of solid tumors. Recently, afatinib was approved for the management of NSCLC. Specifically, afatinib is indicated for use in EGFR-mutation positive patients, including either exon 19 deletion or exon 21 substitution mutation.\n\nEGFR inhibitors are associated with numerous cutaneous adverse events including a papulopustular (acneiform) eruption, paronychia, pruritis, and xerosis [1, 3, 5]. Ranges of cutaneous toxicity from clinical studies of afatinib are shown in Table 1 [9]. Hypertrichosis has also been described in some individuals who have been treated with EGFR inhibitors [6-7].\n\n\nTable 1 Cutaneous Adverse Events Associated with Afatinib [a]\n[a] Reported ranges from various studies [1, 3, 5, 8].\n\n[b] This classification of drug-associated adverse events includes:\n\nGrade 1 (mild symptoms with no intervention indicated),\n\nGrade 2 (moderate symptoms with local or noninvasive intervention indicated), and\n\nGrade 3 (severe but not life-threatening symptoms; disabling; hospitalization may be necessary) [9].\n\n[c] “Acne” (as cited in the oncology literature) refers to the papulopustular eruption characteristically associated with EGFR inhibitors.\n\n\nAdverse Event [a]\n\t\nAll grades [b]\n\t\nGrade 3 [b]\n\t\n\nRash/acne [c]\n\t\n79-89%\n\t\n6 - 9%\n\t\n\nParonychia\n\t\n40-56%\n\t\n2 - 11%\n\t\n\nPruritis\n\t\n18-56%\n\t\n0 - 0.4%\n\t\n\nXerosis\n\t\n29-33%\n\t\n0 - 0.4%\n\t\n\n\n\nThere is a direct relationship between the development of skin manifestations of EGFR inhibitors and tumor response to these drugs. The patients who experience more severe cutaneous adverse events have a greater response to the anti-tumor agents. This is also the situation for patients treated with afatinib [8]. At our patient’s initial presentation, she demonstrated an inoperable pulmonary neoplasm due to the suggestion of vascular invasion on her imaging studies. The presence of an exon 19 mutation made her a candidate for neoadjuvant treatment with afatinib. She developed severe cutaneous toxicity that nearly required discontinuation of the therapy. However, successful symptomatic management with oral and topical treatment allowed her to complete the course of afatinib. Indeed, she experienced a marked reduction in the size of her tumor which was subsequently able to be completely excised.\n\nConclusions\nAfatinib is an EGFR tyrosine kinase inhibitor that acts by irreversible covalent binding to ErbB receptors. It is approved for the treatment of non-small-cell lung cancer in patients who have the exon 19 deletion or exon 21 substitution mutation. Our patient had the exon 19 deletion variety of NSCLC and was treated with afatinib. She developed severe cutaneous toxicity characterized by a diffuse papulopustular eruption on her face, neck, chest, abdomen, and back. She also had a dramatic tumor response to the therapy, thus enabling resection of a previously inoperable neoplasm. In conclusion, similar to other EGFR inhibitors, the severity of a cutaneous reaction to afatinib correlates with the effective response of the tumor to the agent.\n\nThe authors have declared that no competing interests exist.\n\nHuman Ethics\nN/A issued approval Written photo consent was obtained from patient.. N/A\n==== Refs\nReferences\n1 Afatinib versus gefitinib as first-line treatment of patients with EGFR mutation-positive non-small-cell lung cancer (LUX-Lung 7): a phase 2B, open-label, randomised controlled trial Lancet Oncol Park K Tan EH O’Byrne K 577 589 17 2016 27083334 \n2 Afatinib versus placebo for patients with advanced, metastatic non-small-cell lung cancer after failure of erlotinib, gefitinib, or both, and one or two lines of chemotherapy (LUX-Lung 1): a phase 2b/3 randomised trial Lancet Oncol Miller VA Hirsh V Cadranel J 528 538 13 2012 22452896 \n3 Afatinib: first global approval Drugs Dungo RT Keating GM 1503 1515 73 2013 23982599 \n4 Comparison of skin toxic effects associated with gefitinib, erlotinib, or afatinib treatment for non-small cell lung cancer JAMA Dermatol Chen KL Lin CC Cho YT 340 342 152 2016 26649681 \n5 Afatinib: a review of its use in the treatment of advanced non-small cell lung cancer Drugs Keating Keating GM GM 207 221 74 2014 24435321 \n6 Cetuximab-associated elongation of the eyelashes: case report and review of eyelash trichomegaly secondary to epidermal growth factor receptor inhibitors Am J Clin Dermatol Cohen PR Escudier SM Kurzrock R 63 67 12 2011 20726623 \n7 Afatinib-induced hypertrichosis of the eyelashes and eyebrows Indian J Dermatol Venereol Leprol Miguel-Gomez L Vano-Galvan S Garrido-Lopez P Jaen-Olasolo P 192 193 82 2016 26585846 \n8 Development of a skin rash within the first week and the therapeutic effect in afatinib monotherapy for EGFR-mutant non-small cell lung cancer (NSCLC): okayama lung cancer study group experience Cancer Chemother Pharmacol Kudo K Hotta K Bessho A 1005 1009 77 2016 27029623 \n9 Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 9 2016 US Department of Health and Human Services Bethesda, Maryland National Institutes of Health, National Cancer Institute 2010 http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2168-8184",
"issue": "8(9)",
"journal": "Cureus",
"keywords": "adverse events; afatinib; cutaneous toxicity; egfr mutations in lung adenocarcinoma; exon 19; non-small-cell lung cancer; skin",
"medline_ta": "Cureus",
"mesh_terms": null,
"nlm_unique_id": "101596737",
"other_id": null,
"pages": "e763",
"pmc": null,
"pmid": "27725919",
"pubdate": "2016-09-01",
"publication_types": "D002363:Case Reports",
"references": "24435321;20726623;26585846;22452896;27029623;26649681;27083334;23982599",
"title": "Afatinib-Associated Cutaneous Toxicity: A Correlation of Severe Skin Reaction with Dramatic Tumor Response in a Woman with Exon 19 Deletion Positive Non-Small-Cell Lung Cancer.",
"title_normalized": "afatinib associated cutaneous toxicity a correlation of severe skin reaction with dramatic tumor response in a woman with exon 19 deletion positive non small cell lung cancer"
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"abstract": "Meningitis is a common and life-threatening infection of the central nervous system (CNS) in infants with long-term and disabling sequelae like hydrocephalus. Hydrocephalus is treated by diverting cerebrospinal fluid (CSF) either to another body cavity (via CSF shunt) or externally (via CSF drain) which are prone to infection. Though rare, Candida parapsilosis (C. parapsilosis) is a known pathogen in device-associated CNS infections and has been reported in both, infants and adults. A six-month-old male infant was brought to the hospital with disproportionate head enlargement of three months duration. Magnetic resonance imaging (MRI) was suggestive of gross asymmetrical hydrocephalus. An external ventricular drain (EVD) was placed, and vancomycin and meropenem were started. Four weeks later, he developed a fever with a blocked EVD. Repeat MRI revealed gross asymmetric dilatation of left lateral ventricle along with pneumocephalus in the right periventricular region. A right temporoparietal craniotomy with drainage of a multiloculated abscess was done along with the removal of right EVD and placement of left EVD. CSF showed pan-susceptible C. parapsilosis and fluconazole was started. Despite treatment, CSF continued to grow C. parapsilosis through day 10. The EVD was removed, and an Ommaya reservoir along with the ventricular catheter was placed for better interventricular antibiotic administration. After day 13 CSF became sterile. Ommaya reservoir was removed, fluconazole was continued for three weeks, and a ventriculoperitoneal shunt was placed five weeks later. The device-associated CNS infections are insidious with nonspecific manifestations making diagnosis difficult. C. parapsilosis has been increasing in prevalence, especially in immunocompromised hosts, infants, and in patients with indwelling catheters. Amphotericin B or fluconazole is the usual treatment with excellent outcomes and no mortality. This case underscores the need for suspicion of C. parapsilosis as a cause of device-associated CNS infections.",
"affiliations": "Microbiology, Army Hospital/Research and Referral, New Delhi, IND.;Microbiology, Army Hospital/Research and Referral, Delhi, IND.;Internal Medicine, UPMC Pinnacle, Harrisburg, USA.;Station Health Organization, Military Hospital, Amritsar, Amritsar, IND.;Internal Medicine, UPMC Pinnacle, Harrisburg, USA.;Internal Medicine, Hackensack Meridian - Ocean Medical Center, Edison, USA.;Microbiology, Army Hospital/Research and Referral, New Delhi, IND.",
"authors": "Bhalla|Gurpreet S|GS|;Malik|Muqtadir|M|;Sarao|Manbeer S|MS|;Bandyopadhyay|Kuntal|K|;Singh|Pratiksha|P|;Tadepalli|Satish|S|;Singh|Lavan|L|",
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"doi": "10.7759/cureus.3140",
"fulltext": "\n==== Front\nCureusCureus2168-8184Cureus2168-8184Cureus Palo Alto (CA) 10.7759/cureus.3140Internal MedicinePediatricsInfectious DiseaseDevice-associated Central Nervous System Infection Caused by Candida parapsilosis Muacevic Alexander Adler John R Bhalla Gurpreet S 1Malik Muqtadir 2Sarao Manbeer S 3Bandyopadhyay Kuntal 4Singh Pratiksha 3Tadepalli Satish 5Singh Lavan 1\n1 \nMicrobiology, Army Hospital/Research and Referral, New Delhi, IND \n2 \nMicrobiology, Army Hospital/Research and Referral, Delhi, IND \n3 \nInternal Medicine, UPMC Pinnacle, Harrisburg, USA \n4 \nStation Health Organization, Military Hospital, Amritsar, Amritsar, IND \n5 \nInternal Medicine, Hackensack Meridian - Ocean Medical Center, Edison, USA \nManbeer S. Sarao manbir.sarao@gmail.com14 8 2018 8 2018 10 8 e314016 7 2018 14 8 2018 Copyright © 2018, Bhalla et al.2018Bhalla 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/13770-device-associated-central-nervous-system-infection-caused-by-candida-parapsilosisMeningitis is a common and life-threatening infection of the central nervous system (CNS) in infants with long-term and disabling sequelae like hydrocephalus. Hydrocephalus is treated by diverting cerebrospinal fluid (CSF) either to another body cavity (via CSF shunt) or externally (via CSF drain) which are prone to infection. Though rare, Candida parapsilosis (C. parapsilosis) is a known pathogen in device-associated CNS infections and has been reported in both, infants and adults.\n\nA six-month-old male infant was brought to the hospital with disproportionate head enlargement of three months duration. Magnetic resonance imaging (MRI) was suggestive of gross asymmetrical hydrocephalus. An external ventricular drain (EVD) was placed, and vancomycin and meropenem were started. Four weeks later, he developed a fever with a blocked EVD. Repeat MRI revealed gross asymmetric dilatation of left lateral ventricle along with pneumocephalus in the right periventricular region. A right temporoparietal craniotomy with drainage of a multiloculated abscess was done along with the removal of right EVD and placement of left EVD. CSF showed pan-susceptible C. parapsilosis and fluconazole was started. Despite treatment, CSF continued to grow C. parapsilosis through day 10. The EVD was removed, and an Ommaya reservoir along with the ventricular catheter was placed for better interventricular antibiotic administration. After day 13 CSF became sterile. Ommaya reservoir was removed, fluconazole was continued for three weeks, and a ventriculoperitoneal shunt was placed five weeks later.\n\nThe device-associated CNS infections are insidious with nonspecific manifestations making diagnosis difficult. C. parapsilosis has been increasing in prevalence, especially in immunocompromised hosts, infants, and in patients with indwelling catheters. Amphotericin B or fluconazole is the usual treatment with excellent outcomes and no mortality. This case underscores the need for suspicion of C. parapsilosis as a cause of device-associated CNS infections.\n\ndevice-associatedcns infectioncandidahydrocephalusevdommayaThe 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\nMeningitis of bacterial or nonbacterial origin is a common and life-threatening infection of the central nervous system (CNS) in infants. With the advent of modern medicine, the mortality rate has decreased with a proportionate increase in the risk for long-term and disabling sequelae. Meningitis in infants can lead to various postinfectious sequelae among which hydrocephalus is common. It can result from blockage of the cerebrospinal fluid (CSF) flow at the aqueduct of Sylvius or the outlets of the fourth ventricle, obstruction of flow within the subarachnoid spaces, or an impediment to CSF absorption.\n\nHydrocephalus requires hospital admission and is treated by diverting CSF either to another body cavity (via CSF shunt) or externally (via CSF drain). Both CSF shunts and CSF drains are prone to infection with higher infection rates noted in those undergoing successive shunt revisions. Gram-positive cocci account for a majority of these cases, but Gram-negative and positive bacilli, fungi, and antimicrobial resistant bacteria have also been reported [1-2]. Fungi, especially Candida species (Candida spp.), have emerged as an important pathogen in such infections as evidenced by increasing literature. Though rare, Candida parapsilosis (C. parapsilosis) is a known pathogen in device-associated CNS infections and has been reported not only in infants but also in adults [3].\n\n A case of device-associated CSF infection by C. parapsilosis in an infant with hydrocephalus is being reported.\n\nCase presentation\nA six-month-old male infant, with a significant past medical history of neonatal meningitis on the second day of life, was brought with complaints of disproportionate head enlargement for three months duration. Initial magnetic resonance imaging (MRI) was suggestive of gross asymmetrical hydrocephalus with obstruction at the level of the aqueduct, and no signs of ependymal thickening (Figure 1).\n\nFigure 1 Magnetic resonance imaging scan showing gross asymmetrical hydrocephalus.\nVentricular tap was done, and CSF was received for cytology, biochemical analysis, and culture. Cultures were sterile, and there were no features of infection.\n\nFor intra-cranial pressure reduction, an external ventricular drain (EVD) was placed, and intraventricular vancomycin (10 mg 12 hourly) was started along with parenteral vancomycin (120 mg 8 hourly) and meropenem (240 mg 8 hourly). Serial CSF monitoring was continued.\n\nFour weeks later, the child developed a fever. It was noted that the EVD had blocked and a repeat MRI scan revealed gross asymmetric dilatation of left lateral ventricle along with air-fluid level in right periventricular region suggestive of pneumocephalus. The child was managed by right temporoparietal craniotomy and excision of multiloculated abscess done along with the removal of right EVD and placement of left EVD.\n\nThe CSF samples received showed features of infection and Gram-positive budding yeast was seen on a direct stain (Figure 2).\n\nFigure 2 Gram stain of cerebrospinal fluid showing gram-positive budding yeast.\nCandida parapsilosis was isolated from culture and was susceptible to all antifungals. Fluconazole (50 mg 24 hourly) was started, and serial monitoring of CSF continued. Despite treatment, daily CSF samples continued to grow C. parapsilosis through day 10. The EVD was removed, and an Ommaya reservoir along with a ventricular catheter was placed for better intraventricular antibiotic administration (vancomycin 10 mg 12 hourly). CSF samples taken 13 days and onwards were sterile. Clinically, the infant became afebrile and stable.\n\nAntifungal therapy was continued for three weeks. The Ommaya reservoir was removed, and a ventriculoperitoneal shunt was placed five weeks later. Three months later, the infant remains asymptomatic.\n\nDiscussion\nThe device-associated CNS infections have nonspecific manifestations and have an insidious nature, which makes diagnosis difficult. Retrograde infection is the most likely mechanism of infection of CSF drains. Microorganisms may enter the device by tracking from the exit site alongside the device, gaining access to the fluid column that drains CSF. CSF shunts and CSF drains are prone to infection with a reported incidence rate varying from 4% to 17% [4].\n\nBacteria remain the most prevalent cause of device-associated CNS infections. Though fungi are rare causes, the growing evidence suggests that fungal infections should be a differential in device-associated infections. Past studies have shown a varying incidence of shunt infections caused by fungi. Chiou et al. [5] in a retrospective study performed in 1994 reported that fungi were responsible for 17% (8/48) of shunt infections. Baradkar et al. [6] reported that 25% of shunt infections were due to fungi. Much higher infection rates with Candida spp. of 74% were reported by Fernandez et al. [7].\n\nAs in the present case, literature [8-9] mentions that 77% of Candida infections developed within three months of shunt manipulation, suggesting inoculation of the organism during the procedure. Risk factors reported for candidal device infections include the administration of broad-spectrum antibiotics, prior meningitis, CSF leakage, abdominal surgery, immune suppression and after medical device insertion. Clinical presentation of device-associated infection depends upon its location. Transient candidemia with the secondary colonization of shunts and drains have been suggested by other reports as a possible source of infecting Candida organisms [10].\n\nAs fungal infections are rare causes of device-associated CNS infections, fungi are initially not considered as the implicating pathogen. The only definitive diagnostic test is the direct observation and culture of the CSF. C. parapsilosis has been increasing in prevalence, especially in immunocompromised hosts, neonates, and in patients with indwelling catheters [11].\n\nAs reported by earlier studies, C. albicans remains the most important pathogen, followed by C. parapsilosis and C. glabrata with symptoms appearing as early as one week to as delayed as one year [5-6]. Amphotericin B or fluconazole is the usual treatment with excellent outcomes and no mortality [3, 5-7, 9].\n\nCandida parapsilosis is the most common fungus isolated from human hands, and given its ability to transfer horizontally, it can contaminate medical devices with ease. A study reported hand colonization of more than 25% of healthcare workers in a community hospital with C. parapsilosis [12]. Thus, in patients with CNS devices, adherence to a checklist consisting of hand hygiene and appropriate skin preparation before insertion, use of sterile barriers (sterile gloves, sterile gown, cap, mask, and large sterile drape), and adherence to the policy for EVD maintenance can significantly reduce the infection rates. The use of “practice bundles” may also be valuable in the development of standardized protocols which are effective at lowering CSF shunt infection rates.\n\nThis case underscores the need for suspicion of C. parapsilosis as a cause of device-associated CNS infections.\n\nConclusions\nDevice-associated CNS infections are insidious with nonspecific manifestations making diagnosis difficult. C. parapsilosis has been increasing in prevalence, especially in immunocompromised hosts, neonates, and in patients with indwelling catheters. It has a high affinity for parenteral nutrition, frequently colonizes the hands of healthcare workers, and forms a biofilm on prosthetic surfaces and central venous catheters. Extraventricular drainage, therapy with amphotericin B or fluconazole (intravenous or intraventricular), and insertion of a new shunt remain the principal components of the treatment regimen for pediatric fungal shunt infections. There is no established recommendation for the duration of treatment of pediatric fungal shunt infection or the role of other newer antifungal drugs. This case underscores the need for suspicion of C. parapsilosis as a cause of device-associated CNS infection.\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 Ventriculostomy-related infections: a critical review of the literature Neurosurgery Lozier AP Sciacca RR Romagnoli MF Connolly Jr ES 170 182 51 2002 12182415 \n2 Infection rate and risk factors associated with infections related to external ventricular drain \n\nInfection Camacho E Boszczowski I Basso M 47 51 39 2011 21264679 \n3 Candida parapsilosis meningitis associated with shunt infection in an adult male Clin Neurol Neurosurg Bagheri F Cervellione KL Maruf M Marino W Santucci T Jr Jr 248 251 112 2010 20022423 \n4 A search for determinants of cerebrospinal fluid shunt survival: retrospective analysis of a 14-year institutional experience Pediatr Neurosurg Piatt Jr JH Carlson CV 233 242 19 1993 8398847 \n5 Fungal infection of ventriculoperitoneal shunts in children Clin Infect Dis Chiou CC Wong TT Lin HH Hwang B Tang RB Wu KG Lee BH 1049 1053 19 1994 7888533 \n6 Candidal infections of ventriculoperitoneal shunts J Pediatr Neurosci Baradkar VP Mathur M Sonavane A Kumar S 73 75 4 2009 21887187 \n7 Candidal meningitis in neonates: a 10-year review Clin Infect Dis Fernandez M Moylett EH Noyola DE Baker CJ 458 463 31 2000 10987705 \n8 Candida cerebrospinal fluid shunt infection. Report of two new cases and review of the literature \n\nDiagn Microbiol Infect Dis Sánchez-Portocarrero J Martín-Rabadán P J. Saldaña C Pérez-Cecilia E 33 40 20 1994 7867296 \n9 Meningitis caused by Candida species: an emerging problem in neurosurgical patients Clin Infect Dis Nguyen MH Yu VL 323 327 21 1995 8562739 \n10 Candida albicans shunt infection Pediatr Neurosurg Shapiro S Javed T Mealey Jr J 125 130 15 1989 \n11 Neonatal Candida parapsilosis meningitis and empyema related to epidural migration of a central venous catheter Clin Neurol Neurosurg Carter JE Laurini JA Evans TN Estrada B 614 618 110 2008 18471959 \n12 Epidemiologic and molecular characterization of an outbreak of Candida parapsilosis bloodstream infections in a community hospital J Clin Microbiol Clark TA Slavinski SA Morgan J 4468 4472 42 2004 15472295\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2168-8184",
"issue": "10(8)",
"journal": "Cureus",
"keywords": "candida; cns infection; device-associated; evd; hydrocephalus; ommaya",
"medline_ta": "Cureus",
"mesh_terms": null,
"nlm_unique_id": "101596737",
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"pages": "e3140",
"pmc": null,
"pmid": "30345197",
"pubdate": "2018-08-14",
"publication_types": "D002363:Case Reports",
"references": "7888533;15472295;8562739;10987705;7867296;21264679;8398847;12182415;21887187;18471959;2702348;20022423",
"title": "Device-associated Central Nervous System Infection Caused by Candida parapsilosis.",
"title_normalized": "device associated central nervous system infection caused by candida parapsilosis"
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{
"abstract": "BACKGROUND\nWorld Health Organization recommends countries introducing new drug and short treatment regimen for drug resistant tuberculosis (DR-TB) should develop and implement a system for active pharmacovigilance that allows for detection, reporting and management of adverse events. The aim of the study is to evaluate the frequency and severity of adverse events (AEs) of bedaquiline-containing regimen in a cohort of Chinese patients with multidrug-resistant (MDR)/extensively drug-resistant (XDR)-TB based on active drug safety monitoring (aDSM) system of New Drug Introduction and Protection Program (NDIP).\n\n\nMETHODS\nAEs were prospectively collected with demographic, bacteriological, radiological and clinical data from 54 sites throughout China at patient enrollment and during treatment between February, 2018 and December, 2019. This is an interim analysis including patients who are still on treatment and those that have completed treatment. A descriptive analysis was performed on the patients evaluated in the cohort.\n\n\nRESULTS\nBy December 31, 2019, a total of 1162 patients received bedaquiline-containing anti-TB treatment. Overall, 1563 AEs were reported, 66.9% were classified as minor (Grade 1-2) and 33.1% as serious (Grade 3-5). The median duration of bedaquiline treatment was 167.0 [interquartile range (IQR): 75-169] days. 86 (7.4%) patients received 36-week prolonged treatment with bedaquiline. The incidence of AEs and serious AEs was 47.1% and 7.8%, respectively. The most frequently reported AEs were QT prolongation (24.7%) and hepatotoxicity (16.4%). There were 14 (1.2%) AEs leading to death. Out of patients with available corrected QT interval by Fridericia's formula (QTcF) data, 3.1% (32/1044) experienced a post-baseline QTcF ≥ 500 ms, and 15.7% (132/839) had at least one change of QTcF ≥ 60 ms from baseline. 49 (4.2%) patients had QT prolonged AEs leading to bedaquiline withdrawal. One hundred and ninety patients reported 361 AEs with hepatotoxicity ranking the second with high occurrence. Thirty-four patients reported 43 AEs of hepatic injury referred to bedaquiline, much lower than that referred to protionamide, pyrazinamide and para-aminosalicylic acid individually.\n\n\nCONCLUSIONS\nBedaquiline was generally well-tolerated with few safety concerns in this clinical patient population without any new safety signal identified. The mortality rate was generally low. These data inform significant positive effect to support the WHO recent recommendations for the wide use of bedaquiline.",
"affiliations": "Clinical Center on TB, Beijing Chest Hospital, Capital Medical University/Beijing Tuberculosis and Thoracic Tumor Research Institute, No 9, Beiguan Street, Tongzhou District, Beijing, 101149, People's Republic of China.;Department of Tuberculosis, Wuhan Pulmonary Hospital, Wuhan, People's Republic of China.;Department of Tuberculosis, Chengdu Public Health Clinical Center, Chengdu, People's Republic of China.;Department of Tuberculosis, Changsha Central Hospital, Changsha, People's Republic of China.;Department of Tuberculosis, Beijing Chest Hospital, Capital Medical University/Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, People's Republic of China.;Division of Infectious Diseases and Geographic Medicine, School of Medicine, Stanford University, Palo Alto, CA, USA.;Department of Tuberculosis, Shanghai Pulmonary Hospital, Shanghai, People's Republic of China.;Department of Tuberculosis, Shenyang Chest Hospital, Shenyang, People's Republic of China.;Department of Tuberculosis, Beijing Chest Hospital, Capital Medical University/Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, People's Republic of China.;Department of Tuberculosis, The Sixth People's Hospital of Zhengzhou, Zhengzhou, People's Republic of China.;Department of Tuberculosis, Anhui Chest Hospital, Hefei, People's Republic of China.;Department of Tuberculosis, Infectious Diseases Hospital Heilongjiang Province, Harbin, People's Republic of China.;Department of Tuberculosis, The Third People's Hospital of Shenzhen, Shenzhen, People's Republic of China.;Department of Tuberculosis, Jiangxi Chest (Third People) Hospital, Nanchang, People's Republic of China.;Department of Tuberculosis, Shandong Provincial Chest Hospital, Jinan, People's Republic of China.;Department of Tuberculosis, Shanxi Provincial Tuberculosis Institute, Xi'an, People's Republic of China.;Department of Tuberculosis, Kunming Third People's Hospital, Kunming, People's Republic of China.;Department of Tuberculosis, Chongqing Public Health Medical Center, Chongqing, People's Republic of China.;Department of Tuberculosis, The Fourth People's Hospital of Taiyuan, Taiyuan, People's Republic of China.;Department of Tuberculosis, Hangzhou Red Cross Hospital, Hangzhou, People's Republic of China.;Department of Tuberculosis, Guangzhou Chest Hospital, Guangzhou, People's Republic of China.;Department of Tuberculosis, Tianjin Haihe Hospital, Tianjin, People's Republic of China.;Department of Tuberculosis, Hebei Chest Hospital, Shijiazhuang, People's Republic of China.;Department of Tuberculosis, Tuberculosis Hospital of Jilin Province, Changchun, People's Republic of China.;Department of Tuberculosis, The Fifth People's Hospital of Suzhou, Infectious Disease Hospital, Affiliated to Soochow University, Suzhou, People's Republic of China.;Department of Tuberculosis, The Second Hospital of Nanjing, Nanjing, People's Republic of China.;Department of Tuberculosis, Fuzhou Pulmonary Hospital of Fujian, Fuzhou, People's Republic of China.;Department of Tuberculosis, Qingdao Chest Hospital, Qingdao, People's Republic of China.;Department of Tuberculosis, Guiyang Public Health Clinical Center, Guiyang, People's Republic of China.;Department of Tuberculosis, The Second Affiliated Hospital of Hainan Medical University, Haikou, People's Republic of China.;Department of Tuberculosis, The Fourth People's Hospital of QingHai Province, Xining, People's Republic of China.;Department of Tuberculosis, Lanzhou Pulmonary Hospital, Lanzhou, People's Republic of China.;Department of Tuberculosis, Chest Hospital of Xinjiang Uyghur Autonomous Region of the PRC, Urumchi, People's Republic of China.;Department of Tuberculosis, The Fourth People's Hospital of Ningxia Hui Autonomous Region, Yinchuan, People's Republic of China.;Department of Tuberculosis, Wenzhou Central Hospital, Wenzhou, People's Republic of China.;Clinical Center on TB, Beijing Chest Hospital, Capital Medical University/Beijing Tuberculosis and Thoracic Tumor Research Institute, No 9, Beiguan Street, Tongzhou District, Beijing, 101149, People's Republic of China.;Beijing Innovation Alliance of TB Diagnosis and Treatment, Beijing, People's Republic of China.;Beijing Innovation Alliance of TB Diagnosis and Treatment, Beijing, People's Republic of China.;Clinical Center on TB, Beijing Chest Hospital, Capital Medical University/Beijing Tuberculosis and Thoracic Tumor Research Institute, No 9, Beiguan Street, Tongzhou District, Beijing, 101149, People's Republic of China.;Clinical Center on TB, Beijing Chest Hospital, Capital Medical University/Beijing Tuberculosis and Thoracic Tumor Research Institute, No 9, Beiguan Street, Tongzhou District, Beijing, 101149, People's Republic of China.;Clinical Center on TB, Beijing Chest Hospital, Capital Medical University/Beijing Tuberculosis and Thoracic Tumor Research Institute, No 9, Beiguan Street, Tongzhou District, Beijing, 101149, People's Republic of China.;Clinical Center on TB, Beijing Chest Hospital, Capital Medical University/Beijing Tuberculosis and Thoracic Tumor Research Institute, No 9, Beiguan Street, Tongzhou District, Beijing, 101149, People's Republic of China.;Clinical Center on TB, Beijing Chest Hospital, Capital Medical University/Beijing Tuberculosis and Thoracic Tumor Research Institute, No 9, Beiguan Street, Tongzhou District, Beijing, 101149, People's Republic of China. liuyuhong0516@126.com.",
"authors": "Gao|Jing-Tao|JT|;Du|Juan|J|;Wu|Gui-Hui|GH|;Pei|Yi|Y|;Gao|Meng-Qiu|MQ|;Martinez|Leonardo|L|;Fan|Lin|L|;Chen|Wei|W|;Xie|Li|L|;Chen|Yu|Y|;Wang|Hua|H|;Jin|Long|L|;Li|Guo-Bao|GB|;Zong|Pei-Lan|PL|;Xiong|Yu|Y|;Wu|Qian-Hong|QH|;Li|Ming-Wu|MW|;Yan|Xiao-Feng|XF|;Miao|Yan-Fang|YF|;Cai|Qing-Shan|QS|;Li|Xin-Jie|XJ|;Bai|Da-Peng|DP|;Geng|Shu-Jun|SJ|;Yang|Guo-Li|GL|;Tang|Pei-Jun|PJ|;Zeng|Yi|Y|;Chen|Xiao-Hong|XH|;Li|Tong-Xia|TX|;Cai|Cui|C|;Zhou|Yun|Y|;Zhuo|Ma|M|;Wang|Jian-Yun|JY|;Guan|Wen-Long|WL|;Xu|Lin|L|;Shi|Ji-Chan|JC|;Shu|Wei|W|;Cheng|Li-Li|LL|;Teng|Fei|F|;Ning|Yu-Jia|YJ|;Xie|Shi-Heng|SH|;Sun|Yu-Xian|YX|;Zhang|Li-Jie|LJ|;Liu|Yu-Hong|YH|",
"chemical_list": "D000995:Antitubercular Agents; D064687:Diarylquinolines; C493870:bedaquiline",
"country": "England",
"delete": false,
"doi": "10.1186/s40249-021-00819-2",
"fulltext": "\n==== Front\nInfect Dis Poverty\nInfect Dis Poverty\nInfectious Diseases of Poverty\n2095-5162\n2049-9957\nBioMed Central London\n\n819\n10.1186/s40249-021-00819-2\nResearch Article\nBedaquiline-containing regimens in patients with pulmonary multidrug-resistant tuberculosis in China: focus on the safety\nGao Jing-Tao 1\nDu Juan 2\nWu Gui-Hui 3\nPei Yi 4\nGao Meng-Qiu 5\nMartinez Leonardo 6\nFan Lin 7\nChen Wei 8\nXie Li 5\nChen Yu 9\nWang Hua 10\nJin Long 11\nLi Guo-Bao 12\nZong Pei-Lan 13\nXiong Yu 14\nWu Qian-Hong 15\nLi Ming-Wu 16\nYan Xiao-Feng 17\nMiao Yan-Fang 18\nCai Qing-Shan 19\nLi Xin-Jie 20\nBai Da-Peng 21\nGeng Shu-Jun 22\nYang Guo-Li 23\nTang Pei-Jun 24\nZeng Yi 25\nChen Xiao-Hong 26\nLi Tong-Xia 27\nCai Cui 28\nZhou Yun 29\nZhuo Ma 30\nWang Jian-Yun 31\nGuan Wen-Long 32\nXu Lin 33\nShi Ji-Chan 34\nShu Wei 1\nCheng Li-Li 35\nTeng Fei 35\nNing Yu-Jia 1\nXie Shi-Heng 1\nSun Yu-Xian 1\nZhang Li-Jie 1\nLiu Yu-Hong liuyuhong0516@126.com\n\n1\n1 grid.24696.3f 0000 0004 0369 153X Clinical Center on TB, Beijing Chest Hospital, Capital Medical University/Beijing Tuberculosis and Thoracic Tumor Research Institute, No 9, Beiguan Street, Tongzhou District, Beijing, 101149 People’s Republic of China\n2 grid.508271.9 Department of Tuberculosis, Wuhan Pulmonary Hospital, Wuhan, People’s Republic of China\n3 Department of Tuberculosis, Chengdu Public Health Clinical Center, Chengdu, People’s Republic of China\n4 grid.452210.0 Department of Tuberculosis, Changsha Central Hospital, Changsha, People’s Republic of China\n5 grid.24696.3f 0000 0004 0369 153X Department of Tuberculosis, Beijing Chest Hospital, Capital Medical University/Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, People’s Republic of China\n6 grid.168010.e 0000000419368956 Division of Infectious Diseases and Geographic Medicine, School of Medicine, Stanford University, Palo Alto, CA USA\n7 grid.412532.3 Department of Tuberculosis, Shanghai Pulmonary Hospital, Shanghai, People’s Republic of China\n8 Department of Tuberculosis, Shenyang Chest Hospital, Shenyang, People’s Republic of China\n9 grid.508014.8 Department of Tuberculosis, The Sixth People’s Hospital of Zhengzhou, Zhengzhou, People’s Republic of China\n10 Department of Tuberculosis, Anhui Chest Hospital, Hefei, People’s Republic of China\n11 Department of Tuberculosis, Infectious Diseases Hospital Heilongjiang Province, Harbin, People’s Republic of China\n12 grid.410741.7 Department of Tuberculosis, The Third People’s Hospital of Shenzhen, Shenzhen, People’s Republic of China\n13 Department of Tuberculosis, Jiangxi Chest (Third People) Hospital, Nanchang, People’s Republic of China\n14 grid.492464.9 Department of Tuberculosis, Shandong Provincial Chest Hospital, Jinan, People’s Republic of China\n15 Department of Tuberculosis, Shanxi Provincial Tuberculosis Institute, Xi’an, People’s Republic of China\n16 grid.508183.7 Department of Tuberculosis, Kunming Third People’s Hospital, Kunming, People’s Republic of China\n17 grid.507893.0 Department of Tuberculosis, Chongqing Public Health Medical Center, Chongqing, People’s Republic of China\n18 grid.477987.2 Department of Tuberculosis, The Fourth People’s Hospital of Taiyuan, Taiyuan, People’s Republic of China\n19 grid.413644.0 0000 0004 1757 9776 Department of Tuberculosis, Hangzhou Red Cross Hospital, Hangzhou, People’s Republic of China\n20 grid.413422.2 0000 0004 1773 0966 Department of Tuberculosis, Guangzhou Chest Hospital, Guangzhou, People’s Republic of China\n21 grid.417026.6 Department of Tuberculosis, Tianjin Haihe Hospital, Tianjin, People’s Republic of China\n22 Department of Tuberculosis, Hebei Chest Hospital, Shijiazhuang, People’s Republic of China\n23 Department of Tuberculosis, Tuberculosis Hospital of Jilin Province, Changchun, People’s Republic of China\n24 grid.263761.7 0000 0001 0198 0694 Department of Tuberculosis, The Fifth People’s Hospital of Suzhou, Infectious Disease Hospital, Affiliated to Soochow University, Suzhou, People’s Republic of China\n25 grid.452675.7 Department of Tuberculosis, The Second Hospital of Nanjing, Nanjing, People’s Republic of China\n26 grid.490081.4 Department of Tuberculosis, Fuzhou Pulmonary Hospital of Fujian, Fuzhou, People’s Republic of China\n27 Department of Tuberculosis, Qingdao Chest Hospital, Qingdao, People’s Republic of China\n28 Department of Tuberculosis, Guiyang Public Health Clinical Center, Guiyang, People’s Republic of China\n29 grid.443397.e 0000 0004 0368 7493 Department of Tuberculosis, The Second Affiliated Hospital of Hainan Medical University, Haikou, People’s Republic of China\n30 Department of Tuberculosis, The Fourth People’s Hospital of QingHai Province, Xining, People’s Republic of China\n31 Department of Tuberculosis, Lanzhou Pulmonary Hospital, Lanzhou, People’s Republic of China\n32 Department of Tuberculosis, Chest Hospital of Xinjiang Uyghur Autonomous Region of the PRC, Urumchi, People’s Republic of China\n33 grid.507992.0 Department of Tuberculosis, The Fourth People’s Hospital of Ningxia Hui Autonomous Region, Yinchuan, People’s Republic of China\n34 grid.507993.1 0000 0004 1776 6707 Department of Tuberculosis, Wenzhou Central Hospital, Wenzhou, People’s Republic of China\n35 Beijing Innovation Alliance of TB Diagnosis and Treatment, Beijing, People’s Republic of China\n19 3 2021\n19 3 2021\n2021\n10 328 12 2020\n5 3 2021\n© The Author(s) 2021\nOpen AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.\nBackground\n\nWorld Health Organization recommends countries introducing new drug and short treatment regimen for drug resistant tuberculosis (DR-TB) should develop and implement a system for active pharmacovigilance that allows for detection, reporting and management of adverse events. The aim of the study is to evaluate the frequency and severity of adverse events (AEs) of bedaquiline-containing regimen in a cohort of Chinese patients with multidrug-resistant (MDR)/extensively drug-resistant (XDR)-TB based on active drug safety monitoring (aDSM) system of New Drug Introduction and Protection Program (NDIP).\n\nMethods\n\nAEs were prospectively collected with demographic, bacteriological, radiological and clinical data from 54 sites throughout China at patient enrollment and during treatment between February, 2018 and December, 2019. This is an interim analysis including patients who are still on treatment and those that have completed treatment. A descriptive analysis was performed on the patients evaluated in the cohort.\n\nResults\n\nBy December 31, 2019, a total of 1162 patients received bedaquiline-containing anti-TB treatment. Overall, 1563 AEs were reported, 66.9% were classified as minor (Grade 1–2) and 33.1% as serious (Grade 3–5). The median duration of bedaquiline treatment was 167.0 [interquartile range (IQR): 75–169] days. 86 (7.4%) patients received 36-week prolonged treatment with bedaquiline. The incidence of AEs and serious AEs was 47.1% and 7.8%, respectively. The most frequently reported AEs were QT prolongation (24.7%) and hepatotoxicity (16.4%). There were 14 (1.2%) AEs leading to death. Out of patients with available corrected QT interval by Fridericia's formula (QTcF) data, 3.1% (32/1044) experienced a post-baseline QTcF ≥ 500 ms, and 15.7% (132/839) had at least one change of QTcF ≥ 60 ms from baseline. 49 (4.2%) patients had QT prolonged AEs leading to bedaquiline withdrawal. One hundred and ninety patients reported 361 AEs with hepatotoxicity ranking the second with high occurrence. Thirty-four patients reported 43 AEs of hepatic injury referred to bedaquiline, much lower than that referred to protionamide, pyrazinamide and para-aminosalicylic acid individually.\n\nConclusions\n\nBedaquiline was generally well-tolerated with few safety concerns in this clinical patient population without any new safety signal identified. The mortality rate was generally low. These data inform significant positive effect to support the WHO recent recommendations for the wide use of bedaquiline.\n\nSupplementary Information\n\nThe online version contains supplementary material available at 10.1186/s40249-021-00819-2.\n\nKeywords\n\nTuberculosis\nMultidrug-resistant\nBedaquiline\nSafety\nSurveillance program\nChina\nissue-copyright-statement© The Author(s) 2021\n==== Body\nBackground\n\nMultidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB) are critical threats to global health [1, 2]. It is newly reported approximately 361 000 new cases of MDR-TB emerged globally [1], and China accounted for 14% [1]. In 2019, 7.1% of new cases and 23% of previously treated cases were estimated rifampicin resistant TB (RR-TB)/MDR-TB in China. However, the average treatment success of MDR/RR-TB is 57% while it is only 39% of XDR-TB [1]. Novel effective and safe drugs are urgently needed to improve treatment outcomes of MDR/XDR-TB and prevent further drug resistance.\n\nPreviously considered a group D2 drug, bedaquiline now belongs to group A in the World Health Organization (WHO) guidelines [3]. Bedaquiline is now considered effective against MDR/XDR-TB, with a manageable toxicity profile [4–9]. Among the major safety concerns of bedaquiline is alterations in the QT interval [10], requiring regular electrocardiogram (ECG) monitoring.\n\nInappropriate antibiotic use including anti-TB drugs is a common phenomenon in some hospitals in China [11–13]. Regulation of antibiotic circulation, supply, and application is critical to prevent resistance among novel drugs. However, this is uncommon, potentially greatly compromising decades of drug development by the international community. On November 23, 2016, bedaquiline received conditional approval by the China National Medical Products Administration. At the time of its approval in China, bedaquiline utilization data for Chinese MDR-TB patients were very limited. The first access to bedaquiline was via a national program named New anti-TB Drugs Introduction and Protection Program (NDIP). It was set up under the umbrella of China-BMGF stage III project during 2016–2019 and was implemented by the Clinical Center on Tuberculosis of the Chinese Center for Disease Control and Prevention (China CDC) under the guidance and support of the National Health Commission of China and the Gates Foundation. The aim of NDIP is to establish effective mechanisms for ensuring the correct, appropriate and safe use as well as to prevent resistance to novel anti-TB drugs in China under surveillance. Bedaquiline is the first drug to test the new model and mechanism of NDIP.\n\nThe electronic pharmacovigilance system at NDIP is developed according to WHO recommendation to implement “active and systematic clinical and laboratory assessment of patients on treatment with new TB medicines, or novel MDR-TB regimens in order to detect and report potential or confirmed drug toxicities” [14–16].\n\nWe aimed to prospectively evaluate the frequency and severity of AEs in MDR/XDR-TB patients treated with bedaquiline-containing regimen in China. An interim finding was summarized of patients who completed or were still on treatment through the NDIP at the time of data collection.\n\nMethods\n\nStudy participant enrollment\n\nEligible patients were enrolled to NDIP from 54 hospitals around China from February 2018 to December 2019 with China first approved new anti-TB drug, bedaquiline, donated by Global Drug Facility under active drug safety monitoring (aDSM) framework. Inclusion criteria were: (1) laboratory diagnosis of MDR/XDR-TB; (2) failure to respond to current MDR-TB regimens lacking bedaquiline; (3) ≥ 18 years of age; (4) no respiratory failure, cardiac failure, clinically significant arrhythmia, or corrected QT interval by Fridericia's formula (QTcF) < 450 ms. Exclusion criteria were: (1) allergy to bedaquiline; (2) participation in other clinical trials within the past three months; (3) pregnant or breast-feeding; (4) concomitant serious illness, including alanine aminotransferase/aspartate aminotransferase (ALT/AST) > 3 × upper limits of normal (ULN) or total bilirubin > 2 × ULN, creatinine clearance < 30 ml/min, haemoglobin ≤ 70 g/L and/or platelets < 50 × 109/L at screening. (5) history of high-risk cardiac comorbidities (e.g., ventricular arrhythmia, myocardial infarction) with risk factors of QT prolongation: a. ECG at screening showing evident QT interval or QTcF ≥ 450 ms (an unscheduled visit was allowed for ECG reexamination during the screening period to re-evaluate patient eligibility); b. pathologic Q wave (Q wave > 40 ms or depth of Q wave > 0.4–0.5 mV); c. evidence of ventricular preexcitation (e.g., Wolff-Parkinson-White syndrome); d. ECG showed evidence of complete or clinically significant incomplete left bundle branch block or right bundle branch block; e. evidence of Grade II or III heart block; f. intraventricular conduction delay, QRS duration > 120 ms; g. bradycardia (sinus heart rate < 50 bpm); h. personal or family history of long QT syndrome; i. history of heart disease, symptomatic or asymptomatic arrhythmia (except for sinus arrhythmia); j. cardiogenic syncope; or k. have risk factors for developing torsades de pointes (TdP), such as heart failure, hypokalemia, or hypomagnesemia.\n\nProtocol training and data management\n\nAccording to the NDIP protocol, medical professionals of selected TB specialized hospitals capable of MDR-TB diagnosis and treatment were well trained for patient enrolment, bedaquiline-containing regimen design, drug administration, treatment outcome and safety monitoring and evaluation. Standardized electronic case report form (eCRF) were filled in by trained doctors in each hospital and data was reviewed by an independent data monitoring committee of NDIP routinely. NDIP was approved by the ethics committee of each participating hospital. All patients enrolled provided written informed consent.\n\nTreatment regimen\n\nAccording to WHO guidelines and NDIP protocol, local physicians developed individualized background regimens based on patients’ previous histories of anti-TB treatment and drug susceptibility testing (DST) results as well as drug tolerance. For patients with DST results, bedaquiline was used in combination with at least three background drugs to which their TB isolate was susceptible. For patients without definitive DST results, bedaquiline was used in combination with at least four drugs to which the isolate was likely to be susceptible based on treatment history and local epidemiology of drug resistance. Bedaquiline was administered at the recommended dose of 400 mg once a day for 14 days then at a dose of 200 mg three times per week for the remaining 22 weeks.\n\nBackground regimens consisted of the anti-TB drug formulations guided by DST, including moxifloxacin, levofloxacin, linezolid, clofazimine, amikacin, capreomycin, protionamide, cycloserine, pyrazinamide, ethambutol, para-aminosalicylic acid, high-dose isoniazid, meropenem and amoxicillin/clavulanate. To ensure patient adherence to outpatient treatment, patients were supervised by trained professional clinicians, who monitored patient treatment progress and provided medical and psychosocial support. Prolongations of QTcF more than 500 ms were investigated, and treatment was modified if the prolongation was considered to be drug related by the site investigators.\n\nSafety monitoring and evaluation\n\nPatients were followed every 2 weeks for the first month and every 4 weeks thereafter. Information regarding demographic characteristics including age, sex, height, weight, clinical history, medication history, background regimens, laboratory test results, ECG and AEs, bacteriological, radiological findings were collected from the NDIP information monitoring system.\n\nAEs in the NDIP CRF were coded using the Medical Dictionary for Regulatory Activities (MedDRA). Number and percentage of patients with AEs were summarized by MedDRA system organ class (SOC) and preferred term (PT). Number and proportion of patients with AEs were also summarized by severity (Grade 1, Grade 2, Grade 3, Grade 4 and Grade 5). Number and percentage of patients with AEs were summarized by causality (related, not related) with bedaquiline. Adverse events were judged as related with bedaquiline if the causality was related, probably related, possibly related, unable to determine or missing; judged as not-related with bedaquiline if the causality was unlikely related or as not-related.\n\nAEs were graded according to the guidelines Division of AIDS for Grading the Severity of Adult and Pediatric Adverse Events, version 2.1 [17]. Serious AEs included death or a life-threatening event, hospitalization or prolongation of hospitalization, persistent or significant disability, or congenital anomaly. Serious AEs included Grade 3–5 AEs (Grade 3: serious; Grade 4: life threatening; Grade 5: death) [14, 17]. Minor AEs included those of Grade 1 (mild) and Grade 2 (moderate) [14, 17].\n\nThis paper reported the results of the interim analysis conducted on the data from February 24, 2018 up to December 31, 2019.\n\nData analysis\n\nA descriptive analysis was performed on the patients evaluated in the cohort using SAS 9.4 (SAS Institute Inc., Cary, NC, USA). Continuous variables with normal distribution were reported as mean ± standard deviation (SD) while non-normal distribution variables were reported as median [interquartile range (IQR)]. Categorical variables were summarized using numbers and percentages. The numbers of patients with absolute value ≥ 450 ms and ≥ 500 ms, and changes from baseline ≥ 30 ms and ≥ 60 ms were summarized for the QTcF results. Boxplots of QTcF for 24 weeks and the trend chart of QTcF changes from baseline to 24 weeks were plotted.\n\nResults\n\nCharacteristics of the participants\n\nOverall, 1162 eligible patients were enrolled into NDIP and treated with bedaquiline-containing regimens from 54 hospitals of 32 provinces nationwide between February 2018 and December 2019.\n\nThe characteristics of the patients is presented in Table 1. The median age was 36.0 (IQR: 28–50) years, and 70.0% of patients were male. Among the 1162 patients, 288 (24.8%) were diagnosed with XDR-TB, 492 (42.3%) were diagnosed with pre-XDR-TB, and 382 (32.9%) were diagnosed with MDR-TB. Most (79.9%) patients were previously treated, while 233 (20.1%) patients were treatment-naïve. Pulmonary TB was diagnosed in all the cases (100%), with 103 (8.8%) involvement of both pulmonary and extra pulmonary sites (66 pleural, 10 bone and joint, 15 lymph nodes, 7 central nervous system, 5 gastrointestinal). A total of 360 (31%) patients reported the use of concomitant medications. The most frequently used concomitant medications by anatomical therapeutic chemical (ATC) class II included biliary and liver therapy (n = 120, 10.3%), diabetic drugs (n = 100, 8.6%), all other therapeutic products (n = 89, 7.7%), vitamin supplements (n = 118, 10.2%), and unspecified herbal and traditional Chinese medicine (n = 44, 3.8%).Table 1 Demographic and clinical characteristics of 1162 MDR/XDR tuberculosis patients in China\n\nCharacteristics\tPatients (n = 1162)\t\nMedian age (IQR), years\t36.0 (28, 50)\t\nSex, n (%)\t\n Male\t813 (70.0)\t\n Female\t349 (30.0)\t\nHeight (cm), mean ± SD\t169.3 ± 7.9\t\nWeight (kg), mean ± SD\t59.4 ± 12.2\t\nPattern of drug resistance, n (%)\t\n MDR-TB\t382 (32.9)\t\n Pre-XDR-TB\t492 (42.3)\t\n XDR-TB\t288 (24.8)\t\nPrevious anti-TB therapy, n (%)\t\n New\t233 (20.1)\t\n Previously treated\t929 (79.9)\t\nSite of TB, n (%)\t\t\n Pulmonary TB\t1162 (100)\t\n Concomitant extra-pulmonary TB\t103 (8.9)\t\nIQR, interquartile range; SD, standard deviation; MDR, multidrug-resistant; XDR, extensively drug-resistant; TB, tuberculosis\n\nThe median duration of bedaquiline treatment in the cohort was 167.0 (IQR: 75–169) days. Eighty-six (7.4%) patients received 36-week prolonged treatment of bedaquiline. Among the 1162 patients, 99.3% of the patients had good adherence (≥ 80%) to bedaquiline. As of December 31, 2019, there were 619 (53.3%) patients who completed bedaquiline treatment, 52 (4.5%) patients with bedaquiline discontinued due to AEs and the remaining 491 (42.3%) continue to be on a bedaquiline-containing regimen.\n\nBackground regimens\n\nThe most frequently used background drugs included linezolid (n = 1030, 88.6%), cycloserine (n = 962, 82.8%), clofazimine (n = 694, 59.7%), protionamide (n = 592, 50.9%), amikacin (n = 482, 41.5%), moxifloxacin (n = 467, 40.2%), para-aminosalicylic acid (n = 399, 34.3%), and pyrazinamide (n = 293, 25.2%) (Table 2). Clofazimine and moxifloxacin are the known QT prolonging drugs among them.Table 2 Background regimens used in combination with bedaquiline\n\nDrug\tPatients (n = 1162), n (%)\t\nLinezolid\t1030 (88.6)\t\nCycloserine\t962 (82.8)\t\nClofazimine\t694 (59.7)\t\nProtionamide\t592 (50.9)\t\nAmikacin\t482 (41.5)\t\nMoxifloxacin\t467 (40.2)\t\nAminosalicylic acid\t399 (34.3)\t\nPyrazinamide\t293 (25.2)\t\nCapreomycin\t214 (18.4)\t\nLevofloxacin\t157 (13.5)\t\nEthambutol\t132 (11.4)\t\nAmoxicillin; clavulanate potassium\t61 (5.2)\t\nPasiniazid\t17 (1.5)\t\nIsoniazid\t14 (1.2)\t\nClarithromycin\t8 (0.7)\t\nCilastatin; imipenem\t1 (0.1)\t\nGatifloxacin\t1 (0.1)\t\nMeropenem\t1 (0.1)\t\nRifabutin\t1 (0.1)\t\nStreptomycin\t1 (0.1)\t\nTerizidone\t1 (0.1)\t\n\nAdverse events and adverse drug reactions\n\nFrom February 24, 2018 to December 31, 2019, 547 (47.1%) patients reported 1563 AEs. The frequently reported AEs (≥ 2% of patients) were QT prolongation (n = 287, 24.7%), hepatotoxicity (n = 190, 16.4%), blood disorder (n = 64, 5.5%), nephrotoxicity (n = 53, 4.6%), electrolyte imbalance (n = 49, 4.2%), gastrointestinal disorder (n = 48, 4.1%), peripheral neuropathy (n = 48, 4.1%), ototoxicity (n = 31, 2.7%), vestibular disorder (n = 31, 2.7%), and optic neuritis (n = 28, 2.4%) (Table 3). Summary of AE by SOC and PT is presented in Additional file 1: Table S1. Grades of the 1563 AEs are categorized in Additional files 1 as well.Table 3 Frequency of adverse events reported\n\nEvents\tPatients (n = 1162), n (%)\t\nAny AE\t547 (47.1)\t\nBedaquiline-related AE\t278 (23.9)\t\nSAE\t91 (7.8)\t\nBedaquiline-related SAE\t45 (3.9)\t\nAE leading to death\t14 (1.2)\t\nBedaquiline-related AE leading to death\t0\t\nAE leading to bedaquiline withdrawal\t52 (4.5)\t\nQT prolongation leading to bedaquiline discontinuation\t49 (4.2)\t\nAE reported ≥ 2% of patients\t\n QT prolongation\t287 (24.7)\t\n Hepatotoxicity\t190 (16.4)\t\n Blood disorder\t64 (5.5)\t\n Nephrotoxicity\t53 (4.6)\t\n Electrolyte imbalance\t49 (4.2)\t\n Gastrointestinal disorder\t48 (4.1)\t\n Peripheral neuropathy\t48 (4.1)\t\n Ototoxicity\t31 (2.7)\t\n Vestibular disorder\t31 (2.7)\t\n Optic neuritis\t28 (2.4)\t\nAE, adverse event; SAE, serious adverse event\n\nAdverse drug reactions (ADRs) are AEs with causality and AEs with missing causality were not reported as ADR in this study. As of the study cut-off date, 278 (23.9%) patients reported 516 ADRs (Table 3). Three most frequently reported ADRs (≥ 1.0% of patients) were QT prolongation (n = 243, 20.9%), hepatotoxicity (n = 34, 2.9%), and gastrointestinal disorder (n = 14, 1.2%). Summary of ADR by SOC, PT is presented in Additional file 1: Table S2.\n\nSerious adverse events and serious adverse drug reactions\n\nNinety-one (7.8%) patients experienced 151 serious AEs (SAEs). A summary of SAE by SOC, PT is presented in Additional file 1: Table S3. Forty-five (3.9%) patients experienced 68 serious ADRs (SADRs). Summary of SADR by SOC and PT is presented in Additional file 1: Table S4.\n\nSeverity of adverse events and adverse drug reactions\n\nGrade 1 and Grade 2 AEs were reported by 149 (12.8%) and 122 (10.5%) patients, respectively. Two hundred and nineteen (18.8%) patients experienced Grade 3 AEs among whom QT prolongation (12.4%) was reported in high incidence. Grade 4 and Grade 5 AEs were reported by 38 (3.3%) and 13 (1.1%) patients. As per AE reporting page and NDIP database, one patient with Grade 1 hepatotoxicity died suddenly and the outcome of the hepatotoxicity was written death but no Grade 5 AE was reported. Thus 14 subjects with outcome of death, while 13 subjects with Grade 5 AEs were reported. A summary of AEs by SOC, PT and severity is provided in Additional file 1: Table S5. The number of patients who experienced Grade 3 and Grade 4 ADRs was 148 (12.7%) and 12 (1.0%), respectively. No Grade 5 ADRs were reported. Summary of ADR by SOC, PT and severity is presented in Additional file 1: Table S6.\n\nOutcomes of adverse events and adverse drug reactions\n\nAE outcomes were reported as improvement in 263 (22.6%) patients, no improvement in 95 (8.2%) patients, cured in 78 (6.7%) patients, recovery with sequelae in 5 (0.4%) patients, unknown in 41 (3.5%) patients, death in 14 (1.2%) patients and with sequelae in 5 (0.4%) patients. Summary of AEs by SOC, PT and outcome is presented in Additional file 1: Table S7. ADR outcomes were reported as improvement in 119 (10.2%) patients, cured in 67 (5.8%) patients, no improvement in 34 (2.9%) patients and unknown in 33 (2.8%) patients. There was no reported recovery with sequelae or death due to ADRs. Summary of ADR by SOC, PT and outcome is presented in Additional file 1: Table S8.\n\nAEs leading to death and leading to bedaquiline withdrawal\n\nFourteen (1.2%) patients experienced AEs leading to death. Summary of AEs leading to death by SOC and PT is presented in Additional file 1: Table S9. No patient experienced ADRs leading to death. Fifty-two (4.5%) patients experienced AEs leading to bedaquiline withdrawal. Out of 52 patients, 49 (4.2%) patients with QT prolonged AEs led to bedaquiline withdrawal, and Grade 3 and Grade 4 QT prolongation were reported by 45 and 4 patients, respectively.\n\nHepatobiliary disorders\n\nOne hundred and ninety (16.4%) patients reported 361 AEs of hepatobiliary disorders including hepatotoxicity, hepatic function abnormal and hyperbilirubinemia. Grade 1 and Grade 2 AEs of hepatobiliary disorders were reported by 132 (69.5%) and 43 (22.6%) patients, respectively. The numbers of patients who experienced Grade 3 and Grade 4 AEs were 10 (5.3%) and 5(2.6%) accordingly. No Grade 5 AEs of hepatobiliary disorders were reported. Eighty-six patients reported 156 AEs with the causality of protionamide being related, probably related or possibly related, followed by para-aminosalicylic acid with 52 patients reported 88 AEs, pyrazinamide with 50 patients reported 88 AEs, and left the bedaquiline least with 34 patients reported 43 AEs of hepatobiliary disorders. Among the 34 patients with ADRs caused by bedaquiline, the numbers of patients with Grade 1 and Grade 2 ADRs were 22 (64.7%) and 6 (17.6%). Grade 3 and Grade 4 ADRs were reported by 1 (2.9%) and 5 (14.7%) patients. No Grade 5 ADRs referred to bedaquiline was reported.\n\nQT prolongation profiles\n\nAt baseline, the median QTcF was 413 (IQR: 398–429) ms. No patient had a QTcF ≥ 500 ms at baseline. The median change in QTcF from baseline to week 24 was 16 (IQR: -3–35) ms. Among 1,044 (89.8%) patients with at least one QTcF value over follow-up, 424 (40.6%) demonstrated follow-up QTcF ≥ 450 ms; 32 (3.1%) patients had follow-up QTcF ≥ 500 ms. Among 839 (72.2%) patients with both baseline and at least one post-baseline value, 439 (52.3%) patients reported an increase of more than 30 ms from baseline. In addition, 132 (15.7%) patients reported an increase of more than 60 ms from baseline (Table 4). Fluctuations in QTcF intervals were generally stable from week 2 to 24 (Fig. 1).Table 4 QTcF profiles of patients who received bedaquiline-containing regimen in the cohort\n\nVariable\tPatients (n = 1162), n (%)\t\nMedian QTcF at baseline (IQR), ms\t413 (398, 429)\t\nMedian change in QTcF from baseline to week 24 (IQR), ms\t16 (−3, 35)\t\nWorsening QTcF from baseline to follow-up, n (%)\t\n n\t1044\t\n ≥ 450 ms\t424 (40.6)\t\n ≥ 500 ms\t32 (3.1)\t\nChange in QTcF from baseline, n (%)\t\n n\t839\t\n ≥ 30 ms\t439 (52.3)\t\n ≥ 60 ms\t132 (15.7)\t\nIQR, interquartile range; QTcF, corrected QT interval by Fridericia's formula\n\nFig. 1 QTcF values monitoring at different time points during treatment with bedaquiline-containing regimen. a Overall trend chart of QTcF increment from baseline at different time points. b QTcF values at different time points during treatment. Boxes represented the median and IQR. QTcF, corrected QT interval by Fridericia's formula\n\nDiscussion\n\nThis large-scale, multi-center and prospective study aimed to evaluate the frequency and severity of AEs with novel anti-TB drug bedaquiline-containing regimen in China. Out of 1162 enrolled MDR/XDR-TB patients, 1563 AEs were reported from 547 (47.1%) patients. The first important contribution of the study presented the first step and efforts China has made in implementing aDSM in practice and scientific evidence has been actively collected nationwide. The second important finding of this study is trying to explore attribution of the AEs to a specific drug based on evidence-based profile. The results demonstrated that 278 patients have reported 516 ADRs. The AEs were referred to bedaquiline for 285 (24.5%) patients which is much higher than that at 11.1% from recent first global report [18], close and intensified safety monitoring acted on in NDIP. Thirdly, there is no new safety signals were uncovered of Chinese MDR/XDR-TB patients exposed to bedaquiline-containing regimen. Our results also demonstrated again that QT prolongation and hepatotoxicity are the most frequent adverse effects exposed to bedaquiline.\n\nDrug adherence to bedaquiline was generally good as more than 80% of doses were taken of those prescribed, indicating the acceptability and tolerability of it. The concomitant medications for other comorbidities may also lead to the occurrence of AEs. In this study, approximately 10% of patients were using drugs for biliary and hepatic diseases as well as diabetes. Unfortunately, the NDIP database did not contain data about the exact concomitant drugs used by each patient, limiting our ability to analyze drug interactions among patients with both TB and other comorbidities.\n\nADR with hepatotoxicity was reported with higher frequency in patients with protionomide, followed by para- aminosalicylic acid, pyrazinamide and bedaquiline which could be explained by the number of patients with their concurrent use as background components with bedaquiline (see Table 2).\n\nAll reported AEs were expected and manageable with symptomatic treatments. Considering previous reports on the safety of bedaquiline [4, 5, 7, 18–22], patient QTcF profiles should continue to be monitored. Our results on acceptable safety profile of bedaquiline supports previous data published by a multi-centre study conducted in 15 countries [5], a phase 2b TMC207-C208 study [19], and a phase 2 TMC207-C209 study [20]. QT prolongation is associated with increased risk of TdP which may cause sudden cardiac death if severe. The frequent use of clofazimine (59.7%) and moxifloxacin (40.2%) as part of the background regimen for many patients in the present study may contribute to QT prolongation due to the WHO guideline update and access of these off-label drugs in China recent years, while only 21.6% of patients co-administrating clofazimine and 2.0% moxifloxacin in C209 Chinese subgroup during 24-week bedaquiline-containing regimen treatment. Notably, according to the first global aDSM report [18], overall 2.6% patients experienced a QTcF prolongation ≥ 500 ms and 8 patients reported serious cardiological AEs among whom 4 attributed to bedaquiline, 2 due to clofazimine, 1 due to moxifloxacin and PAS, while 1 due to a non-TB drug. Nevertheless, under the strict monitoring of ECG by NDIP, QT prolongation was infrequent (3.4%). As for the detailed QTcF profile, 15.7% of patients had change in QTcF ≥ 60 ms from baseline, but only 3.1% of patients had post-baseline QTcF ≥ 500 ms. This was within the acceptable range.\n\nRegarding bedaquiline discontinuation due to AEs (4.5%) and QTcF prolongation (4.2%), it was slightly higher than what was reported in other studies. In the largest systematic and critical analysis report with published data including clinical trial and observational studies in 2017, the drug was discontinued in 3.4% and 0.6% of patients due to AEs and QTcF prolongation, respectively. And in another larger study conducted by TBNet [23], out of 1044 bedaquiline-treated patients, this drug had to be stopped in 8 cases following QTcF prolongation (0.77%, 95% CI: 0.04–1.57%). This was similar to what was observed in conditional access program of bedaquiline conducted in India [24], with permanent withdrawal of bedaquiline in 4% (27 of 620 patients) patients for AEs, including prolonged QTcF (2.9%, 18 of 620 patients). Recent published meta analysis [25] showed that bedaquiline, together with fluoroquinolones, clofazimine had the lowest incidence of AEs leading to permanent drug discontinuation, whereas second-line injectable drugs, aminosalicylic acid, and linezolid had the highest incidence.\n\nMortality occurred in approximately 1% of our study cohort, none directly related to bedaquiline use. This rate is substantially lower than those from prior studies. For example, the mortality rate was 13%, 7%, and 12% in the TMC207–C208 study [19], the TMC207–C209 study [20], and a pooled analysis of five observational studies [22]. Bedaquiline received conditional regulatory approval in the initial stages of drug evaluation due to an apparent increased risk of death in a preliminary clinical trial. However, an abundant of subsequent studies have shown substantially reduced mortality among those taking bedaquiline [8, 26]. Nevertheless, pharmacovigilance is essential and we await the coming results of several randomized phase III clinical trials and observational studies to bring more safety evidence. Reasons for the low incidence of death may be attributed to the cautious management and strict patient monitoring in our study. Further research is needed to understand differences in mortality among patients taking bedaquiline in our settings.\n\nThere are limitations to this study. First, there was no control group of comparable patients who did not take bedaquiline. Second, patients had a heterogeneous exposure to bedaquiline. A proportion of patients completed bedaquiline treatment while the remaining were still on treatment as of study cut-off date. Different exposure may have an impact on the occurrence of AEs. Third, causality assessment of bedaquiline associated adverse events is challenging because patients often have co-morbid conditions which may be implicated in the adverse event. Moreover, patients are always taking several background medicines for treatment of MDR/XDR-TB. Many of these have overlap effects on adverse reaction with bedaquiline. Fourth, higher frequency of QTcF prolongation than what was reported in other studies may be explained by data collection including that non-anti-TB drugs data was not available; data on concomitant use of other QT-prolonging drugs (moxifloxacin, clofazimine and clarithromycin) was not analyzed; issues with either manual (differences between people reading) or automated readings (if different machines used) may affect. Fifth, we only analyzed changes in QT interval from baseline to 24 weeks of treatment, however, bedaquiline was extended to 36 weeks in 7.4% of patients. Follow-up time may be inadequate to observe QT interval changes. In addition, since bedaquiline has a long half-life of 5.5 months [27], specific AEs may occur after ceasing bedaquiline use. Future studies are necessary to determine the optimal use of bedaquiline and obtain an overall, accurate safety evaluation.\n\nConclusions\n\nThe study results affirmed the relative safety of bedaquiline-containing regimen in patient cohort with MDR/XDR-TB in China which informs significant positive effect to support the WHO recent recommendations for the wide use of bedaquiline. Furthermore, the aDSM system established and applied in NDIP provided standardized, regular, close and active recording and reporting model with common protocol which is feasible and valuable for safety monitoring and evaluation of coming new drugs and regimens.\n\nSupplementary Information\n\nAdditional file 1: Table S1. Summary of AE by System Organ Class and Preferred Term. Table S2. Summary of ADR by System Organ Class, Preferred Term. Table S3. Summary of SAE by System Organ Class, Preferred Term. Table S4. Summary of SADR by System Organ Class and Preferred Term. Table S5. Summary of AE by System Organ Class, Preferred Term and Severity. Table S6. Summary of ADR by System Organ Class, Preferred Term and Severity. Table S7. Summary of AE by System Organ Class, Preferred Term and Outcomes. Table S8. Summary of ADR by System Organ Class, Preferred Term and Outcomes. Table S9. Summary of AE Leading to Death by System Organ Class and Preferred Term.\n\nAbbreviations\n\naDSM Active drug safety monitoring\n\nAEs Adverse events\n\nALT Alanine aminotransferase\n\nAST Aspartate aminotransferase\n\nChina CDC Chinese Center for Disease Control and Prevention\n\nDR-TB Drug resistant tuberculosis\n\nDST Drug susceptibility testing\n\nECG Electrocardiogram\n\neCRF Electronic case report form\n\nIQR Interquartile range\n\nMDR-TB Multidrug-resistant tuberculosis\n\nMedDRA Medical Dictionary for Regulatory Activities\n\nNDIP New Drug Introduction and Protection Program\n\nPT Preferred term\n\nQTcF Corrected QT interval by Fridericia's formula\n\nSOC System organ class\n\nTB Tuberculosis\n\nTdP Torsades de pointes\n\nULN Upper limits of normal\n\nWHO World Health Organization\n\nXDR-TB Extensively drug-resistant tuberculosis\n\nAcknowledgements\n\nWe expressed our thanks to all authors for their time and efforts in patients’ follow-up and data collection. We also acknowledged the outstanding contributions from the Clinical Center on Tuberculosis, China CDC and all workers of the NDIP programme.\n\nAuthors' contributions\n\nJG, MG, YL contributed to the study conception and design. Statistical analysis was performed by WS and YS. The first draft of the manuscript was written by JG and YL. MG and LM commented on previous versions of the manuscript. The rest are responsible for patients’ management and data collection. All authors read and approved the final manuscript.\n\nFunding\n\nThis work was partially supported by China National Health Commission and Gates Foundation TB Prevention and Control Project Phase III.\n\nAvailability for data and materials\n\nThe datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.\n\nDeclarations\n\nEthical approval and consent to participate\n\nThis study was approved by the Ethics Committee of Beijing Chest Hospital, Capital Medical University as leading center.\n\nConsent for publication\n\nAll authors read and approved the final manuscript.\n\nCompeting interests\n\nAll authors declare that they have no competing interests.\n\nJing-Tao Gao, Juan Du, Gui-Hui Wu, Yi Pei, Meng-Qiu Gao and Leonardo Martinez are the co-first authors and contributed equally to this study\n==== Refs\nReferences\n\n1. World Health Organization. Global Tuberculosis Report. Geneva: World Health Organization 2020. https://www.who.int/teams/global-tuberculosis-programme/tb-reports. Accessed 14 Oct 2020.\n2. World Health Organization. WHO treatment guidelines for drug-resistant tuberculosis. 2016 update. Geneva: World Health Organization 2016. https://www.who.int/tb/areas-of-work/drug-resistant-tb/treatment/en/. Accessed 5 Aug 2016.\n3. World Health Organization. WHO consolidated guidelines on drug-resistant tuberculosis treatment. Geneva: World Health Organization 2019. https://www.who.int/tb/publications/2019/consolidated-guidelines-drug-resistant-TB-treatment/en/. Accessed 1 Apr 2019.\n4. Borisov SE D'Ambrosio L Centis R Tiberi S Dheda K Alffenaar JW Outcomes of patients with drug-resistant-tuberculosis treated with bedaquiline-containing regimens and undergoing adjunctive surgery J Infect 2019 78 35 39 10.1016/j.jinf.2018.08.003 30096332\n5. Borisov SE Dheda K Enwerem M Romero Leyet R D'Ambrosio L Centis R Effectiveness and safety of bedaquiline-containing regimens in the treatment of MDR- and XDR-TB: a multicentre study Eur Respir J 2017 49 1700387 10.1183/13993003.00387-2017 28529205\n6. Ndjeka N Schnippel K Master I Meintjes G Maartens G Romero R High treatment success rate for multidrug-resistant and extensively drug-resistant tuberculosis using a bedaquiline-containing treatment regimen Eur Respir J 2018 52 1801528 10.1183/13993003.01528-2018 30361246\n7. Conradie F Diacon AH Ngubane N Howell P Everitt D Crook AM Treatment of highly drug-resistant pulmonary tuberculosis N Engl J Med 2020 382 893 902 10.1056/NEJMoa1901814 32130813\n8. Schnippel K Ndjeka N Maartens G Meintjes G Master I Ismail N Effect of bedaquiline on mortality in South African patients with drug-resistant tuberculosis: a retrospective cohort study Lancet Respir Med 2018 6 699 706 10.1016/S2213-2600(18)30235-2 30001994\n9. Centers for Disease C, Prevention. Provisional CDC guidelines for the use and safety monitoring of bedaquiline fumarate (Sirturo) for the treatment of multidrug-resistant tuberculosis. MMWR Recomm Rep. 2013; 62: 1–12. https://www.cdc.gov/mmwr/preview/mmwrhtml/rr6209a1.htm. Accessed 25 Oct 2013.\n10. Pontali E Sotgiu G Tiberi S D'Ambrosio L Centis R Migliori GB Cardiac safety of bedaquiline: a systematic and critical analysis of the evidence Eur Respir J 2017 50 1701462 10.1183/13993003.01462-2017 29146605\n11. Lin L Harbarth S Wang X Zhou X Survey of parental use of antimicrobial drugs for common childhood infections, China Emerg Infect Dis 2020 26 1517 1520 10.3201/eid2607.190631 32568044\n12. He P Sun Q Shi L Meng Q Rational use of antibiotics in the context of China's health system reform BMJ. 2019 365 l4016 10.1136/bmj.l4016 31227479\n13. Wang M Antimicrobial resistance in China: Challenges and actions Clin Infect Dis 2018 67 S127 10.1093/cid/ciy702 30423044\n14. World Health Organization. Active TB drug-safety monitoring and management (aDSM). WHO/HTM/TB/2015.28. Geneva, World Health Organization 2015. https://www.who.int/tb/areas-of-work/drug-resistant-tb/treatment/pharmacovigilance/en/. Accessed 19 Mar 2016.\n15. Halleux CM Falzon D Merle C Jaramillo E Mirzayev F Olliaro P The World Health Organization global aDSM database: generating evidence on the safety of new treatment regimens for drug-resistant tuberculosis Eur Respir J. 2018 51 1701643 10.1183/13993003.01643-2017 29567719\n16. Akkerman O Aleksa A Alffenaar JW Al-Marzouqi NH Arias-Guillén M Belilovski E Surveillance of adverse events in the treatment of drug-resistant tuberculosis: a global feasibility study Int J Infect Dis 2019 83 72 76 10.1016/j.ijid.2019.03.036 30953827\n17. Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, version 2.1. 2017. https://rsc.niaid.nih.gov/sites/default/files/daidsgradingcorrectedv21.pdf. Accessed 30 Sep 2020.\n18. Borisov S Danila E Maryandyshev A Dalcolmo M Miliauskas S Kuksa L Surveillance of adverse events in the treatment of drug-resistant tuberculosis: first global report Eur Respir J. 2019 54 1901522 10.1183/13993003.01522-2019 31601711\n19. Diacon AH Pym A Grobusch MP de los Rios JM Gotuzzo E Vasilyeva I Multidrug-resistant tuberculosis and culture conversion with bedaquiline N Engl J Med. 2014 371 723 732 10.1056/NEJMoa1313865 25140958\n20. Pym AS Diacon AH Tang SJ Conradie F Danilovits M Chuchottaworn C Bedaquiline in the treatment of multidrug-and extensively drug-resistant tuberculosis Eur Respir J 2016 47 564 574 10.1183/13993003.00724-2015 26647431\n21. Mase S Chorba T Parks S Belanger A Dworkin F Seaworth B Bedaquiline for the treatment of multidrug-resistant tuberculosis in the United States Clin Infect Dis 2020 71 1010 1016 10.1093/cid/ciz914 31556947\n22. Mbuagbaw L Guglielmetti L Hewison C Bakare N Bastard M Caumes E Outcomes of bedaquiline treatment in patients with multidrug-resistant tuberculosis Emerg Infect Dis 2019 25 936 943 10.3201/eid2505.181823 31002070\n23. Guglielmetti L Tiberi S Burman M Kunst H Wejse C Togonidze T QT prolongation and cardiac toxicity of new tuberculosis drugs in Europe: a Tuberculosis Network European Trialsgroup (TBnet) study Eur Respir J 2018 52 1800537 10.1183/13993003.00537-2018 29880656\n24. Salhotra VS Sachdeva KS Kshirsagar N Parmar M Ramachandran R Padmapriyadarsini C Effectiveness and safety of bedaquiline under conditional access program for treatment of drug-resistant tuberculosis in India: an interim analysis Indian J Tuberc 2020 67 29 37 10.1016/j.ijtb.2019.10.002 32192613\n25. Lan Z Ahmad N Baghaei P Barkane L Benedetti A Brode SK Drug-associated adverse events in the treatment of multidrug-resistant tuberculosis: an individual patient data meta-analysis Lancet Respir Med 2020 8 383 394 10.1016/S2213-2600(20)30047-3 32192585\n26. Cohen K Maartens G A safety evaluation of bedaquiline for the treatment of multi-drug resistant tuberculosis Expert Opin Drug Saf 2019 18 875 882 10.1080/14740338.2019.1648429 31339384\n27. Worley MV Estrada SJ Bedaquiline: a novel antitubercular agent for the treatment of multidrug-resistant tuberculosis Pharmacotherapy 2014 34 1187 1197 10.1002/phar.1482 25203970\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2049-9957",
"issue": "10(1)",
"journal": "Infectious diseases of poverty",
"keywords": "Bedaquiline; China; Multidrug-resistant; Safety; Surveillance program; Tuberculosis",
"medline_ta": "Infect Dis Poverty",
"mesh_terms": "D000328:Adult; D000995:Antitubercular Agents; D002681:China; D064687:Diarylquinolines; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D012449:Safety; D018088:Tuberculosis, Multidrug-Resistant",
"nlm_unique_id": "101606645",
"other_id": null,
"pages": "32",
"pmc": null,
"pmid": "33736710",
"pubdate": "2021-03-19",
"publication_types": "D016428:Journal Article",
"references": "30423044;29880656;31556947;31227479;31002070;31339384;30096332;30361246;25140958;29567719;31601711;32192613;28529205;32192585;32130813;32568044;29146605;30953827;30001994;25203970;26647431;24157696",
"title": "Bedaquiline-containing regimens in patients with pulmonary multidrug-resistant tuberculosis in China: focus on the safety.",
"title_normalized": "bedaquiline containing regimens in patients with pulmonary multidrug resistant tuberculosis in china focus on the safety"
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"abstract": "Recurrent acute pancreatitis associated with metronidazole developed in a 49-year-old woman who was taking the drug as treatment for vaginal trichomoniasis. The lack of alternative effective therapies for trichomoniasis governed the decision to rechallenge the patient with metronidazole despite a vague history of this reaction on a previous occasion. Six reports of this reaction are found in the literature. The patient was admitted to the hospital 12 hours after taking a single dose of metronidazole. Severe epigastric pain and elevated amylase and lipase concentrations led to the diagnosis of acute pancreatitis, although results of an abdominal ultrasound were unremarkable. The patient made a full recovery. Although this reaction occurs infrequently, this case report illustrates the need to develop additional therapies for treatment of trichomoniasis.",
"affiliations": "Department of Pharmaceutical Sciences, University of Kentucky College of Pharmacy, Lexington, USA.",
"authors": "Feola|David J|DJ|;Thornton|Alice C|AC|",
"chemical_list": "D008795:Metronidazole",
"country": "United States",
"delete": false,
"doi": "10.1592/phco.22.16.1508.33691",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0277-0008",
"issue": "22(11)",
"journal": "Pharmacotherapy",
"keywords": null,
"medline_ta": "Pharmacotherapy",
"mesh_terms": "D005260:Female; D006801:Humans; D008795:Metronidazole; D008875:Middle Aged; D010195:Pancreatitis; D014247:Trichomonas Vaginitis",
"nlm_unique_id": "8111305",
"other_id": null,
"pages": "1508-10",
"pmc": null,
"pmid": "12432979",
"pubdate": "2002-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Metronidazole-induced pancreatitis in a patient with recurrent vaginal trichomoniasis.",
"title_normalized": "metronidazole induced pancreatitis in a patient with recurrent vaginal trichomoniasis"
} | [
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"companynumb": "US-STRIDES ARCOLAB LIMITED-2017SP010789",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
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"actiondrug": "5",
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"activesubstancename": "METRONIDAZOLE"
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"abstract": "Fanconi Anemia (FA) is an inherited disorder characterized by the variable presence of multiple congenital somatic abnormalities, bone marrow failure and cancer susceptibility. Medulloblastoma (MB) has been described only in few cases of FA with biallelic inactivation in the tumor suppressor gene BRCA2/FANCD1 or its associated gene PALB2/FANCN. We report the case of a patient affected by Fanconi Anemia with Wilms tumor and unusual presentation of two medulloblastomas (MB1 and MB2). We identified a new pathogenetic germline BRCA2 mutation: c.2944_2944delA. Molecular analysis of MBs allowed us to define new features of MB in FA. MBs were found to belong to the Sonic Hedgehog (SHH) molecular subgroup with some differences between MB1 and MB2. We highlighted that MB in FA could share molecular aspects and hemispheric localization with sporadic adult SHH-MB. Our report provides new findings that shed new light on the genetic and molecular pathogenesis of MB in FA patients with implications in the disease management.",
"affiliations": "Department of Molecular Medicine Sapienza University, Viale Regina Elena 291, 00161 Rome, Italy.;Department of Hematology/Oncology and Stem Cell Transplantation, Bambino Gesù Children's Hospital, IRCCS, Piazza Sant'Onofrio 4, 00165 Rome, Italy.;Department of Molecular Medicine Sapienza University, Viale Regina Elena 291, 00161 Rome, Italy.;Department of Neuroscience and Neurorehabilitation, Bambino Gesù Children's Hospital, IRCCS, Piazza Sant'Onofrio 4, 00165 Rome, Italy.;Department of Molecular Medicine Sapienza University, Viale Regina Elena 291, 00161 Rome, Italy.;Department of Hematology/Oncology and Stem Cell Transplantation, Bambino Gesù Children's Hospital, IRCCS, Piazza Sant'Onofrio 4, 00165 Rome, Italy.;Department of Radiology, Bambino Gesù Children's Hospital, IRCCS, Piazza Sant'Onofrio 4, 00165 Rome, Italy.;Department of Hematology/Oncology and Stem Cell Transplantation, Bambino Gesù Children's Hospital, IRCCS, Piazza Sant'Onofrio 4, 00165 Rome, Italy.;Department of Radiological, Oncological and Pathological Science, Sapienza University, Viale Regina Elena 291, 00161 Rome, Italy.;Department of Radiological, Oncological and Pathological Science, Sapienza University, Viale Regina Elena 291, 00161 Rome, Italy.;Department of Molecular Medicine Sapienza University, Viale Regina Elena 291, 00161 Rome, Italy.;Department of Molecular Medicine Sapienza University, Viale Regina Elena 291, 00161 Rome, Italy.;Department of Molecular Medicine Sapienza University, Viale Regina Elena 291, 00161 Rome, Italy.;Department of Experimental Medicine, Sapienza University, Viale Regina Elena 291, 00161 Rome, Italy.;Department of Molecular Medicine Sapienza University, Viale Regina Elena 291, 00161 Rome, Italy.;Department of Radiological, Oncological and Pathological Science, Sapienza University, Viale Regina Elena 291, 00161 Rome, Italy.;Department of Molecular Medicine Sapienza University, Viale Regina Elena 291, 00161 Rome, Italy.;Department of Hematology/Oncology and Stem Cell Transplantation, Bambino Gesù Children's Hospital, IRCCS, Piazza Sant'Onofrio 4, 00165 Rome, Italy.;Department of Experimental Medicine, Sapienza University, Viale Regina Elena 291, 00161 Rome, Italy.",
"authors": "Miele|Evelina|E|;Mastronuzzi|Angela|A|;Po|Agnese|A|;Carai|Andrea|A|;Alfano|Vincenzo|V|;Serra|Annalisa|A|;Colafati|Giovanna Stefania|GS|;Strocchio|Luisa|L|;Antonelli|Manila|M|;Buttarelli|Francesca Romana|FR|;Zani|Massimo|M|;Ferraro|Sergio|S|;Buffone|Amelia|A|;Vacca|Alessandra|A|;Screpanti|Isabella|I|;Giangaspero|Felice|F|;Giannini|Giuseppe|G|;Locatelli|Franco|F|;Ferretti|Elisabetta|E|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/s40364-015-0038-z",
"fulltext": "\n==== Front\nBiomark ResBiomark ResBiomarker Research2050-7771BioMed Central London 3810.1186/s40364-015-0038-zCase ReportCharacterization of medulloblastoma in Fanconi Anemia: a novel mutation in the BRCA2 gene and SHH molecular subgroup Miele Evelina evelina.miele@uniroma1.it Mastronuzzi Angela angela.mastronuzzi@opbg.net Po Agnese agnese.po@uniroma1.it Carai Andrea andrea.carai@opbg.net Alfano Vincenzo vincenzo.alfano@uniroma1.it Serra Annalisa annalisa.serra@opbg.net Colafati Giovanna Stefania psp.immagini@opbg.net Strocchio Luisa luisa.strocchio@opbg.net Antonelli Manila manila.antonelli@uniroma1.it Buttarelli Francesca Romana francesca.buttarelli@uniroma1.it Zani Massimo massimo.zani@uniroma1.it Ferraro Sergio sergio.ferraro@uniroma1.it Buffone Amelia amelia.buffone@uniroma1.it Vacca Alessandra alessandra.vacca@uniroma1.it Screpanti Isabella isabella.screpanti@uniroma1.it Giangaspero Felice felice.giangaspero@uniroma1.it Giannini Giuseppe giuseppe.giannini@uniroma1.it Locatelli Franco franco.locatelli@opbg.net Ferretti Elisabetta +39 0649255135elisabetta.ferretti@uniroma1.it Department of Molecular Medicine Sapienza University, Viale Regina Elena 291, 00161 Rome, Italy Center for Life NanoScience@Sapienza, Istituto Italiano di Tecnologia, Viale Regina Elena 291, 00161 Rome, Italy Department of Hematology/Oncology and Stem Cell Transplantation, Bambino Gesù Children’s Hospital, IRCCS, Piazza Sant’Onofrio 4, 00165 Rome, Italy Department of Neuroscience and Neurorehabilitation, Bambino Gesù Children’s Hospital, IRCCS, Piazza Sant’Onofrio 4, 00165 Rome, Italy Department of Radiology, Bambino Gesù Children’s Hospital, IRCCS, Piazza Sant’Onofrio 4, 00165 Rome, Italy Department of Radiological, Oncological and Pathological Science, Sapienza University, Viale Regina Elena 291, 00161 Rome, Italy Department of Experimental Medicine, Sapienza University, Viale Regina Elena 291, 00161 Rome, Italy Neuromed Institute, Via Atinense 18, 0865 Pozzilli IS, Italy Pasteur Institute/Cenci Bolognetti Foundation, Viale Regina Elena 291, 00161 Rome, Italy 6 6 2015 6 6 2015 2015 3 1326 3 2015 26 5 2015 © Miele et al. 2015This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. 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.Fanconi Anemia (FA) is an inherited disorder characterized by the variable presence of multiple congenital somatic abnormalities, bone marrow failure and cancer susceptibility. Medulloblastoma (MB) has been described only in few cases of FA with biallelic inactivation in the tumor suppressor gene BRCA2/FANCD1 or its associated gene PALB2/FANCN.\n\nWe report the case of a patient affected by Fanconi Anemia with Wilms tumor and unusual presentation of two medulloblastomas (MB1 and MB2). We identified a new pathogenetic germline BRCA2 mutation: c.2944_2944delA. Molecular analysis of MBs allowed us to define new features of MB in FA. MBs were found to belong to the Sonic Hedgehog (SHH) molecular subgroup with some differences between MB1 and MB2. We highlighted that MB in FA could share molecular aspects and hemispheric localization with sporadic adult SHH-MB. Our report provides new findings that shed new light on the genetic and molecular pathogenesis of MB in FA patients with implications in the disease management.\n\nElectronic supplementary material\nThe online version of this article (doi:10.1186/s40364-015-0038-z) contains supplementary material, which is available to authorized users.\n\nKeywords\nFanconi anemiaMedulloblastomaBRCA2FANCD1SHH molecular subgroupissue-copyright-statement© The Author(s) 2015\n==== Body\nBackground\nFanconi Anemia (FA) is a genetically and phenotypically heterogeneous disorder, inherited with an autosomal (or rarely X-linked) recessive pattern, occurring in approximately 1/100,000 births per year [1]. Main features of FA are the presence of multiple congenital somatic abnormalities, the gradual onset of bone marrow failure, and a strong predisposition to cancer. The most common malignancies include acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), followed by solid tumors, mostly squamous-cell carcinomas at young age [2–4].\n\nSolid tumors may represent the first manifestation of FA in individuals without congenital somatic abnormalities or hematological manifestations [5]. These tumors include squamous cell carcinomas of head and neck, esophagus, vulva and cervix, liver tumors, and rarely embryonic tumors.\n\nThe hallmark of FA is chromosome fragility and hypersensitivity to DNA interstrand cross-linking agents [6, 7, 1, 8–10]. To date, 17 genes (FANCA, FANCB, FANCC, FANCD1/BRCA2, FANCD2, FANCE, FANCF, FANCG/XRCC9, FANCI, FANCJ/BRIP1, FANCL, FANCM, FANCN/PALB2/BRIP1, FANCO/RAD51C, FANCP/SLX4, FANCQ/ERCC4, and FANCS/BRCA1) are known to be involved in the pathogenesis of FA [1, 8, 9, 11]. The 17 gene products appear to interact in a common cellular pathway involved in the regulation of DNA repair. Mutations in eight FA genes (FANCA, FANCB, FANCC, FANCE, FANCF, FANCG, FANCL, and FANCM) result in loss of FANCD2 and FANCI monoubiquitination, the central regulatory event of the FA pathway, while FA proteins downstream to FANCD2 (e.g. FANCJ/BRIP1, FANCN/PALB2, and FANCD1/BRCA2) cooperate in DNA repair [5].\n\nAlthough a clear picture of genotype-phenotype correlation in FA is currently not completely elucidated, many data suggest that specific complementation groups play a significant role in both phenotypic expression and survival [12, 13].\n\nIn particular, biallelic mutations in FANCD1/BRCA2 (about 2 % of all FA patients) [14] and FANCN/PALB2 are associated with an extremely high predisposition to leukemia and solid tumors (e.g. medulloblastoma, Wilms tumor) at a very early age [15, 16], with a cumulative incidence probability of malignancy of 97 % by the age of 5.2 years in FANCD1/BRCA2 patients [17].\n\nThe sequential onset of Wilms Tumor (WT), medulloblastoma (MB) and AML has been reported in association with mutation in BRCA2 [16–32] (Table 1).Table 1 Previously reported cases of brain tumors associated with BRCA2 mutations\n\nTumor\tAge (yrs)\tSex\t\nBRCA2 mutation I\t\nBRCA mutation 2\tLocalization\tNote\tRefs\t\nMB, WT\t1.5\tF\t-\t-\tNR\t-\t[22]\t\nMB\t3.5\tF\tc.2830A > T\tc.7964A > G\tHemispheric\t-\t[19, 30]\t\nBT\t3\tF\t7691/insAT\t9900/insA\tNR\t-\t[32]\t\nPFT\t4.9\tM\tc.5946delT\t9435 T > A\tMidline\tAshkenazi Jewish congenital anomalies Sibling of the following\t[23, 24]\t\nMAs\t2\tM\tc.5946delT\t9435 T > A\tCerebellum\tAshkenazi Jewish Sibling of the previous\t[24]\t\nexon 24\t\nMB\t4.5\tF\tc.5946delT\tc.658_659delGT\tCerebellum\tMixed Ashkenazi Jewish\t[24]\t\nMB\t2.5\tF\t5301insA\tc.7469 T > C\tNR\tLatin American\t[24]\t\nMB\t3.5\tF\tc.3922G > T\tc.9196C > T\tNR\tAfrican American\t[24]\t\nMB\t2.3\tM\tc.658_659delGT\t8447 T > A\tHemispheric\tSibling of the following\t[16]\t\nMB, WT (15 mo)\t4.3\tM\tc.658_659delGT\t8447 T > A\tHemispheric\tSibling of the previous\t[16]\t\nMB\t2.9\tM\t-\t-\tHemispheric\t-\t[20]\t\nGB, WT (3.5 yrs)\t9\tM\tc.658_659delGT\tc.5645C > A\tCerebellum\tSibling of the following\t[27]\t\nMB, WT (7mo) ALL-B (10 yrs)\t5.7\tM\tc.658_659delGT\tc.5645C > A\tCerebellum\tSibling of the previous\t[27]\t\nPFT\t1\tF\t1548del4\t1548del4\tCerebellum\tConsanguinity VACTERL syndrome\t[25]\t\nMB\t3.1\tF\tc.5946delT\tc.9196C > T\tCerebellum\tVACTERL syndrome\t[17]\t\nPNET or HGG\t1.3\tM\tc.5946delT\tc.658_659delGT\tIntramedullary\tSibling of the following\t[21]\t\nMB\t1.7\tM\tc.5946delT\tc.658_659delGT\tHemispheric\tSibling of the previous\t[21]\t\nMB\t2\tNR\tc.3264dup\tc.IVS19 + 3A > G (c. 8487 + 3A > G)\tNR\t-\t[21]\t\nMB, WT (8 mo) AML (24 mo)\t2.9\tF\t-\t-\tHemispheric\tConsanguinity\t[18, 31]\t\nMB\t13\tM\tc.1114A > C\tc.1114A > C\tCerebellum\tDesmoplastic histology\t[26]\t\nMB WT (4 yrs)\t6\tF\t-\t-\tHemispheric\tConsanguinity\t[28]\t\nMB WT(15 mo)\t2.9\tF\tc.658_659delGT\tc.2944delA\tMB1: Hemispheric; MB2: vermian\tMB1, MB2: SHH subtype\tCurrent report\t\n\nMB Medulloblastoma, WT Wilms Tumor, BT Brain Tumor, PFT Posterior Fossa Tumor, MAs Multiple Astrocitomas, GB Glioblastoma, ALL-B Acute Lymphatic Leukemia – B, PNET Primitive Neuroectodermal Tumor, HGG High Grade Glioma, AML Acute Myeloid Leukemia, NR not reported, yrs Years, mo Months\n\n\n\nHere, we report a case of a patient affected by FA, who sequentially developed WT and unexpected two distinct MBs, in which we identified a novel pathogenetic germline BRCA2 mutation and MB molecular subgroup.\n\nCase presentation\nClinical and neurophatologic features\nA 15-month-old female patient born at term, small for gestational age, the second daughter of non-consanguineous parents was referred to the Bambino Gesù Children Hospital for macroscopic hematuria due to a large renal neoplasm in a solitary pelvic cake kidney.\n\nLaboratory tests showed mild renal failure (creatinine 1.37 mg/dl, BUN 46 mg/dl), normocytic anemia (Hb 7.5 g/dl; MCV 77 fl), hyperuricemia (8.4 mg/dl) and increased LDH (1963 UI/dl). Hypertension (both diastolic and systolic blood pressure exceeding the 90th percentile) required pharmacological treatment.\n\nPhysical examination revealed growth retardation (both weight and height lower than 3rd percentile), abnormal skin pigmentation (both café au lait spots and hypopigmentation), elfin facies with epicanthus. Echocardiography showed a mitral valve insufficiency. The patient also had right-convex scoliosis and ribs anomalies. A clinical suspect of FA was formulated and a DEB-test was performed which showed multiple spontaneous and DEB-induced chromosomal breaks per cell. Radiologic tumor assessment confirmed the presence of a renal neoplasm (78.1 × 42.2 × 62.8 mm) (Additional file 1: Figure S1a) with bilateral lung metastases (Additional file 1: Figure S1b).\n\nNeoadjuvant chemotherapy was started, according to SIOP WT 2001 protocol, obtaining a partial response on both primary tumor (44 × 33 × 22 mm) (Additional file 1: Figure S1c) and metastatic lesions. Despite dose-adapted chemotherapy, chosen considering chromosomal fragility and according to renal function, the child experienced a grade-IV hematological toxicity and respiratory failure requiring admission to the intensive care unit. Afterwards, tumorectomy was performed, sparing residual renal functioning tissue. Histologic analysis confirmed a grade-III nephroblastoma, according to SIOP 2001 classification [33]. Post-surgical chemotherapy was resumed until completion of the protocol. At that point, a single residual lung metastasis was present and therefore resected by thoracotomy with no significant complications. Follow up confirmed stable remission with a mild chronic renal failure.\n\nAt the age of 35 months the child was seen with headache and vomiting at the emergency room. A brain computed tomography (CT) scan showed a left cerebellar hemispheric lesion exerting significant mass effect on the fourth ventricle. Cranio-spinal magnetic resonance imaging (MRI) confirmed a localized rounded heterogeneously enhancing mass with intralesional cystic components and perilesional edema (Fig. 1a-f). Cytologic evaluation of the cerebrospinal fluid resulted negative for neoplastic cells. Gross total resection of the lesion was performed.Fig. 1 Imaging and Histopatological features of MB1. Axial CT (a) and axial conventional MR (b T2w, c FLAIR T2w, d T1w) images demonstrate a heterogeneous posterior fossa tumor in the left cerebellar hemisphere with mild surrounding edema (arrowheads) and significant mass effect on the fourth ventricle. The lesion shows a hypointense rim (white arrows) and a cystic component on its medial side (*). Apparent diffusion coefficient map (e) reveals restricted diffusion in solid tissue (black arrows). On the perfusion sequences (f) by arterial spin labeling, the tumor was depicted as a low perfusion area. (g) Neoplasm is composed of densely cells with round to oval shaped hyperchromatic nuclei with scanty cytoplasm. (h) Neoplastic cells are arranged in nodule surrounded by a reticular fiber network (Gomori stain)\n\n\n\nHistology showed a neoplasm with an expanded lobular architecture, due to the reticulin-free zones rich in neuropil-like tissue. Such zones contained a population of small cells with rounded nuclei diagnostic of a desmoplastic/nodular medulloblastoma (Fig. 1g-h) without C/N-myc amplification evaluated by FISH analysis. Due to previous clinical history and to the persistence of a mild chronic renal failure, a tailored chemotherapeutic regimen with Carboplatin and Vincristine was chosen. Despite the low dose of chemotherapy employed, the patient presented a significant toxicity after the first course of treatment including pancytopenia (WHO grade IV), sepsis and deterioration of renal function that slowly recovered in 3 months. Considering this relevant toxicity no further treatment was offered.\n\nAt a follow-up MRI, 17 months after the previous surgery for MB, a midline cerebellar mass was detected (Fig. 2a-d). Complete surgical resection was performed, and histology showed a large cell neoplasm with vesicular nuclei, prominent nucleoli and variably abundant eosinophilic cytoplasm consistent with large cell/anaplastic MB (Fig. 2e-f). FISH analysis showed N-myc amplified medulloblastoma cells (Fig. 2g). One month after surgery, a local recurrence with leptomeningeal dissemination was documented.Fig. 2 Imaging and Histopatological features of MB2. MRI. Axial T2-weighted image (a) and sagittal T1-weighted image (b) show a nodular mass originating from the vermis and bulging into the fourth ventricle. Apparent diffusion coefficient (ADC) map (c) shows lack of diffusion restriction. Perfusion weighted imaging (d) reveals hyperperfusion within the lesion. (e) Tumor is characterized by pleomorphic cells with large nuclei, prominent nucleoli and moderate eosinophilic cytoplasm. (f) Large cells show immunoreactivity for synaptophysin. (g) N-Myc oncogene amplification (green spots) detected in neoplastic nuclei (blue) and centromere 8 signals (red spots) using CEP8/BAC as FISH probes. Red arrow: N-Myc amplified cell. White arrow: N-Myc dyploid cell\n\n\n\nConsidering the toxicity shown during previous treatments, an evaluation of target molecular expression on the tumor was performed. Based on the evidence of expression of P-mTor, a personalized treatment with rapamycin [34] associated with intrathecal liposomal cytarabine [35] was started. Despite therapy, patient died of relapse and disease progression two months after the diagnosis of the second MB at 55 months of age.\n\nGenetics\nBased on published data, the onset of MB after a WT in this FA patient raised the suspicion of a biallelic mutation in FANCD1/BRCA2. To confirm this hypothesis, we performed a genetic analysis of FANC1/BRCA2 on patient’s DNA extracted from both from peripheral blood and MB1 cells, which revealed the presence of compound heterozygosis for BRCA2 frameshift mutations.\n\nGene-specific BRCA2 analysis, including sequencing of all translated exons and adjacent intronic regions of the BRCA2 gene, was performed on the DNA samples. Both the truncating and novel genetic variants were confirmed by sequencing two different blood samples on both DNA strands. Sequencing was performed using an ABI PRISM DyeDeoxy Terminator Cycle Sequencing Kit and an ABI 3100 Genetic Analyzer (Thermo Fisher Scientific, Waltham, MA USA). Reference sequence for BRCA2: Genebank, NM_000059.1. By this mean, we revealed a compound heterozigosity for two distinct framshift mutations: the already described c.658_659delGT (p.Val220Ilefs) mutation on BRCA2 exon 8, and a previously unknown c.2944_2944delA (p.Ile982Tyrfs) mutation on BRCA2 exon 11 (Fig. 3)a and b, both of which are predicted to lead to truncated BRCA2 proteins. Genetic testing of the parents confirmed they both were heterozygous carriers; in particular, the father carried the c.658_659delGT mutation, while the mother carried the c.2944_2944delA mutation (Fig. 3c and d). Further analysis of the pedigree suggested the segregation of the mutations in the paternal grandfather and in the maternal grandmother, not affected by cancer. The original donor of the new mutation could be the mother’s maternal grandfather affected with pancreatic cancer, which belongs to the spectrum of FA/BRCA-associated tumors (Fig. 3e). Overall, the genealogical chart was characterized by a low occurrence of tumors both in paternal and maternal families and in particular by the absence of breast and ovarian cancer cases (Fig. 3e). Analysis of the MB1 tumor tissue from the affected child revealed heterozygosis for both alleles, thus suggesting both of them are selected for in tumor development.Fig. 3 Genetic Analyses. Direct sequencing data relative to the indicated region of BRCA2 gene demonstrating the biallelic mutations c.2944_2944delA exon 11 and c.658_659delGT exon 8 in patient’s blood (a) and tumor (b), present in mother’s blood (c) and father’s blood (d) respectively. MUT: mutated case, WT: wild type case. (e) Family pedigree: closed symbol: affected with cancer, open symbol: unaffected with cancer. The type of cancer and age at presentation are given under the symbol. Arrow: proband, blue plus sign: BRCA2 c.658_659delGT exon 8 mutation, red plus sign: BRCA2 c.2944_2944delA exon11 mutation. Pro: prostate cancer, Pan: pancreatic cancer, Ov: ovarian cancer, CNS: central nervous system tumor, Gas: Gastric cancer, WT: Wilms Tumor, MB: Medulloblastoma\n\n\n\nMBs molecular features\nWe performed gene expression analysis of both hemispheric MB1 and vermian MB2 by real-time quantitative PCR (RT-QPCR). We used TaqMan Low Density Array custom designed with TaqMan assays (Life Technologies - Thermo Fisher Scientific, Waltham, MA USA) for genes of interest for medulloblastoma subgrouping, according to Northcott 2012 [36, 37], while we used single TaqMan assay (Life Technologies - Thermo Fisher Scientific, Waltham, MA USA) for all other shown mRNA analyses [38]. Gene expression analysis on samples was performed using a ViiA7 sequence detection system according to the manufacturer’s instructions. RNA of normal human cerebellum (7 adult samples from 25- to 70-year-old subjects were purchased from Biocat (Heidelberg, Germany), Ambion (Life Technologies - Thermo Fisher Scientific, Waltham, MA USA) and BD Biosciences (San Jose, CA) [38].\n\nUnsupervised clustering and heatmaps were generated using the analyzed transcript levels expressed as Delta Ct values as input. We used Spotfire software (TIBCO Software, Inc. CA, USA) to cluster the samples and to generate the heatmaps, as previously described [39, 40].\n\nThe results showed a clear Sonic-hedgehog (SHH) molecular subgroup for MB1 (Fig. 4a and Additional file 2: Figure S2) while MB2, though characterized as SHH-MB, was found to express genes associated with group 3 and 4 MBs (such as GABRA5, KHDRBS2 - Fig. 4b).Fig. 4 Molecular characterization of MB1 and MB2. Histograms showing mRNA levels of the indicated genes in MB1 (a) and MB2 (b) compared to normal cerebella (average of n = 7) as control (CTR). Genes are grouped and depicted in different colors, depending on the molecular subgroups, which they identify (SHH, WNT, GROUP 3, GROUP 4). The values of Relative Quantification are expressed in log10 scale\n\n\n\nFurther analysis showed gene expression differences between the two MBs. Gli1, the transcription factor of the Hedgehog (Hh) pathway, was highly expressed in MB1, together with all its downstream targets (PTCH1, PTCH2, IGF2, HHIP, SFRP1, CCND1) (Fig. 5a and b); while MB2 showed lower levels of Gli1 and its target genes (Fig. 5b). Conversely, Gli2 was highly expressed in MB2 (Fig. 5a), while CCND2 was expressed at very low levels (Fig. 5c). Of note, N-myc amplification was only found in MB2 (Fig. 2g and Fig. 5d). Moreover, differences were found in the expression of stem cell/differentiation genes: MB2 was characterized by low expression of lineage differentiation genes (ZIC1, BMP2, GFAP, GABRA6) (Fig. 5e) accompanied by expression of stemness genes, such as PROM1 and C-MYC (Fig. 5d), when compared to MB1.Fig. 5 Gene expression analysis of MB1 and MB2. Histograms show mRNA levels of the indicated genes in MB1 and MB2 compared to normal cerebella (average of n = 7) as control (CTR). In detail (a) GLI family members; (b) Sonic Hedgehog pathway (Hh) molecules and direct targets. (c) Cyclins. (d) Myc genes and Stemness molecules; (e) Differentiation molecules; (f) Epigenetic modifiers. The values of Relative Quantification are expressed in linear scale for panels (a), (c), (d), (e) and (f) and log scale for panel (b)\n\n\n\nGenes associated with chromatin modifications, such as histone methylases/demethylases and polycomb (EZH2, KDM6B, KDM6A, BMI1) and the homeobox transcription factor OTX2 [41], were also evaluated. Indeed, large cell/anaplastic MB2 showed higher levels of EZH2, OTX2 and KDM6B and lower levels of KDM6A and BMI1 (Fig. 5f).\n\nFinally, hemispheric localization of MB is rare in infancy, while is common in adulthood. Moreover, despite the common activation of Hh signaling, infant, childhood and adult SHH MBs have been demonstrated to be clinically, transcriptionally, genetically and prognostically distinct [42, 43].\n\nThus, we investigated the gene expression pattern of MB1 and MB2, compared to adult, childhood and infant sporadic SHH-MBs. We analyzed a panel of genes by RT-QPCR among the top 250 reported to be differentially expressed in the three classes of ages [43]. Our data are consistent with those reported by Kool 2014 that identified two major clusters mainly separating infant from childhood and adult SHH MBs. Moreover, our analysis showed that hemispheric MB1 (diagnosed under 3 years of age) clustered with adult/childhood MBs (Fig. 6), while vermian MB2 (diagnosed after 3 years of age) clustered with infant SHH MBs (Fig. 6).Fig. 6 Heatmap and results of an unsupervised hierarchical clustering derived from the -DCt values of the analyzed genes in MB1 and MB2 (Case FA) and in adult (n = 4, A1, A2, A3, A4), childhood (n = 4, Ch1, Ch2, Ch3, Ch4) and infant (n = 4, I1, I2, I3, I4) SHH-MBs. Nodal numbers indicate bootstrap values obtained by resampling the data\n\n\n\nDiscussion\nThis analysis allowed us to better define features of MBs in FA. We identified a new pathogenetic germline BRCA2 mutation in FA; both MBs belonged to SHH molecular subgroup with a more “aggressive” phenotype in MB2, and, finally, we documented that MB1 shared similarities with sporadic adult SHH-MB, such as hemispheric localization and gene expression pattern.\n\nIn our patient, the first manifestation that led to the diagnosis of FA was the onset of WT.\n\nWT and MB in FA have been reported in few cases and are associated with mutations of FANCD1/BRCA2 and more rarely with mutations of FANCN/PALB2 [24, 44]. Based on this evidence, we investigated BRCA2 mutational status and confirmed the presence of biallelic truncating mutations in the FA patient. The c.658_659delGT mutation occurring on BRCA2 exon 8 had been previously reported in hereditary breast/ovarian cancer cohorts (see in example [45]) and is one of the most frequently occurring in FANCD1/BRCA2 mutated FA cases [29]. The second truncating mutation, the previously undescribed c.2944_2944delA (p.Ile982Tyrfs), occurs on BRCA2 exon 11. The segregation analysis among the available relatives allowed us to assign the two mutations as of paternal and maternal origin, respectively. The absence of breast and ovarian cancer cases in the pedigree could appear surprising, at first. However, both paternal and maternal sides of the tree were characterized by a relatively small number of potential female carriers. Indeed, the c.658_659delGT allele was inherited by the patient via two male carriers (father and grandfather) and the only female member on this line (affected by gastric cancer) was not available for segregation analysis. The c.2944_2944delA allele, possibly coming from the mother’s maternal grandfather affected with pancreatic cancer, reached the patients via a 64 years old grandmother and a 36 years old mother, a female carrier of rather young age compared to 43 and 54 years, the mean ages of breast and ovarian cancer diagnosis, respectively, recently reported in a very large cohort analysis [46]. The preponderance of male relatives in this side of the tree further hindered any possible speculation on the role of the c.2944_2944delA on breast and ovarian cancer predisposition.\n\nComplete BRCA1 or BRCA2 loss is lethal in mice [47]. This is likely to be the case also in humans, since no biallelic BRCA2 mutations occurring 5′ to exon 7 have been reported in FA patients so far, while monoallelic truncating mutations from exon 2 to exon 7 have been frequently associated with breast/ovarian cancer susceptibility. In three out of four FA patients, the c.658_659delGT mutation occurred in association with a truncating mutations of exon 11 [29]. This is also the case for the patient described here, in which the c.658_659delGT mutation is associated with a truncating mutation of BRCA2 exon 11, the previously undescribed c.2944_2944delA (p.Ile982Tyrfs) mutation. Overall, these data suggest that BRCA2 truncation downstream of exon 7/8 is probably hypomorphic, but still compatible with life especially in association with exon 11 truncated BRCA2 forms. However, as already noticed by Meyer, homozygous or compound heterozygous exon 11 mutations have not been reported in FA patients despite the relatively high frequency of these alleles. Together with the report of the recurrent miscarriages in Jewish BRCA2 mutation carriers [29], this suggests that biallelic exon 11 BRCA2 mutation may also be incompatible with life. More definitive answers on this topic may come from directly addressing this issue in specifically modeled mice.\n\nMB in FA patients reported in the literature typically show cerebellar hemispheric localization and desmoplastic histology, as we observed in MB1 (Table 1). Cerebellar hemispheric MBs are frequently desmoplastic and belong to the SHH subgroup, especially in adults [48]. Hemispheric location is consistent with the results from MB mouse models that have shown SHH-MB origin from committed granule neuron precursors (GNPs) of the cerebellum. Teo et al., reported hemispheric involvement in 9 of 17 (53 %) SHH-MBs, regardless of age at diagnosis [49]. In Perreault study [48], SHH lesions rarely invaded the brain stem, consistent with a prior study that reported brain stem infiltration by WNT, but not by SHH tumors [50].\n\nGene expression analysis of our MBs allowed us to clearly define that both MB1 and MB2 belonged to SHH subgroup.\n\nBiological explanation of the association between FA and SHH-MB has been analyzed in different papers. Frappart et al. first showed that BRCA2 loss affects neurogenesis and promotes MB growth, using a mouse model harboring neural tissue-restricted BRCA2 inactivation [51]. They also identified PTCH1 (a gatekeeper gene often inactivated in MB) as a critical target in all DNA repair-deficient MB.\n\nIndeed, defective DNA repair mechanisms render FA cells prone to DNA interstrand crosslinks (ICLs) caused by both endogenous (e.g. reactive aldehydes) and exogenous agents (e.g. alkylating chemotherapeutic drugs) [1, 5, 52, 53]. The FA pathway is activated by an ICL during the S phase: the replication fork is stalled and FA core complex is recruited (FANCA, B, C, E, F, G, L, and M). Then, FANCL ubiquitinates the FANCD2-FANCI (ID2) complex, essential for nucleolytic incisions and translesion synthesis repair events. The complex then “unhooks” ICL, allowing homologous recombination repair by FANCD1/BRCA2, FANCJ/BRIP1, FANCN/PALB2, FANCO/RAD51C, and FANCS/BRCA1 (Fig. 7).Fig. 7 Fanconi Anemia Pathway. Endogenous and exogenous agent cause interstrand crosslink lesions (ICL). When an ICL occurs, the replication fork is stalled and the FA pathway is activated with the recruitment of the FA core complex (FANCA, B, C, E, F, G, L, and M). FANCL ubiqiuitinates the FANCD2-FANCI (ID2) complex that guides the nucleolytic incisions and translesion synthesis repair events by “unhooking” the ICL. This allows the homologous recombination repair through FANCD1/BRCA2, FANCJ/BRIP1, FANCN/PALB2, FANCO/RAD51C, and FANCS/BRCA1. Yellow stars highlight FA/HR repair molecules that have been found genetically inactivated in FA patients with medulloblastoma. BCCIP is a BRCA2 interacting protein which is able to induce medulloblastoma growth when genetically loss in concomitance with p53 deletion (See text). Readapted from [52]\n\n\n\nHuang et al. reported that conditional knockdown BCCIP (BRCA2-interacting protein with a role in homologous recombination and chromosome stability) in concomitance with p53 deletion caused rapid development of MB in the external granular layer, triggered by SHH pathway activation [54] via the inactivation of the Ptch1 gatekeeper tumor suppressor [54]. As reported above, biallelic PALB2/FANCN mutation carriers show a cancer spectrum comparable to those with biallelic BRCA2/FANCD1, characterized by early onset AML and embryonic tumors, including MB and WT [44]. This observation strengthens the role of BRCA2 in medulloblastomagenesis, since FANCN (also known as ‘partner and localizer of BRCA2′, PALB2) is well known to co-localize with BRCA2 in the nucleus [55]. Interestingly, BRIP1/FANCJ maps on 17q chromosome, a region frequently deleted in MBs [56]. Thus, deleterious mutations in one of the members of the homologous recombination machinery could lead to MB onset (Fig. 7). This feature may provide the rationale for new therapeutic approaches for MB, as also suggested by Bayrakli et al. [26]. Platinum compounds or similar drugs, inducing growth arrest by ICL-stalled- DNA replication fork, could be combined with agents which take advantage of the incapacity of HR-deficient neoplastic cells to face up this stall (e.g. enzyme poly-ADP-ribose polymerase I) [26]. Indeed, PARP- inhibition has already been shown to sensitize childhood glioma, medulloblastoma and ependymoma to radiation [57].\n\nIt has been reported that MBs do not change subgroup at the time of recurrence and that SHH tumors more frequently have tumor bed recurrence than metastatic dissemination [58–60]. Even though we cannot completely rule out that the second MB was not a distant relapse from the first one, in our patient, the occurrence of MB2 with a different localization, a more aggressive histology, and distinct gene expression patterns could be suggestive for a second tumor. We hypothesize that Hedgehog signaling activation could have been triggered in two distinct cells of origin. Indeed, MBs have long been known to arise in GNPs in the external granule layer (EGL) and, more recently, GNPs derived from cochlear nuclei of the brainstem [61]. SHH-dependent MBs may also arise from neural stem cells (NSCs) of the subventricular zone (SVZ). The different tumor location and expression levels of stemness/differentiation genes sustain this assumption. MB2 was characterized by higher levels of EZH2, which trimethylates histone 3 lysine 27 (H3K27me3), concurrently with down regulation of the lysine demethylase 6A (KDM6A), which removes the same repressive mark on chromatin (Fig. 5e). Both these events converge on shutting off oncosuppressor/differentiation genes and contribute to the maintenance of a more “cancer stem-like” phenotype [37, 62].\n\nIt has been reported that pediatric and adult SHH-MBs are clinically and molecularly distinct [42, 43]. In a data analysis based on Whole Genome Sequencing Kool et al. reported that the molecular differences among infant, childhood and adult SHH-MBs reside not only at the transcriptional level, but also in DNA methylation [43].\n\nIn our report, we found that the hemispheric, desmoplastic, myc-not amplified SHH MB1 was more similar to other adult/childhood SHH-MBs, while the vermian, large cell/anaplastic, N-myc amplified MB2 was more similar to infant SHH-MB. The hypothesis of different cells of origin stands also for such differences between adults and infants SHH-MBs.\n\nLastly, the suspect of SHH-MB in FA could direct the therapy toward a tailored approach, based on the use of PARP inhibitors or/and SHH inhibitors. However, giving the specific genetic background (BRCA2), it is highly unlikely that these tumors have PTCH1 or SMO mutations making them sensitive to the ‘upstream’ Hedgehog inhibitors targeting SMO. It is more likely that they have activated the SHH pathway more downstream at the level of MYCN and probably also GLI2 amplification (as probably in our MB2). Indeed, as Kool et al. have shown in their recent paper, these tumors are resistant to these ‘upstream’ Hedgehog inhibitors [43]. Inhibitors that target downstream components of the Hh pathway are under pre-clinical evaluation [63] (e.g. Gant61 [64], Glabrescione B [65]).\n\nConclusion\nIn conclusion, we report a novel BRCA2 mutation in a FA patient with diagnosis of two distinct MBs. Molecular features of MB in our FANCD1/BRCA2 patient highlight that MB in FA patients belongs to SHH subgroup.\n\nTwo points are worthy of discussion, due to potential clinical implications. First, it is important to suspect a diagnosis of FA in patients whose first manifestations are embryonic tumors with a sequence WT-MB.\n\nSecond, the identification of SHH subtype MB in FA patients with FANCD1/BRCA2 mutations may play a critical role for targeted therapeutic interventions. Indeed, in patients characterized by a peculiar difficulty in cancer therapeutic management, due to the underlying chromosomal instability, a benefit could be provided by target therapy or new combined therapies.\n\nConsent\nWritten informed consent was obtained from the patient’s parents for publication of this Case report and of any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nAdditional files\nAdditional file 1: Figure S1. Imaging of WT. CT scan: two-dimensional coronal post-contrast CT reconstruction. The image (a) shows a large mass (arrows) arising from the fused pelvic kidney (cake kidney). The mass is multi-lobulated and heterogeneous in attenuation; there are many lung metastases (b). CT scan after neoadjuvant chemotherapy (c) showing a decrease in tumor size and central necrotic changes.\n\nAdditional file 2: Figure S2. Molecular characterization of MB1 and MB2. Heatmap showing mRNA levels of the indicated genes in MB1, MB2 and normal cerebella as control (CTR). Genes are grouped depending on the molecular subgroups which they identify (SHH, WNT, GROUP 3, GROUP 4). A green-red color scale depicts normalized Delta Ct values (green, lower expression, red, higher expression).\n\n\n\nAbbreviations\nFAFanconi Anemia\n\nMBMedulloblastoma\n\nSHHSonic Hedgehog\n\nWTWilms Tumor\n\nAMLAcute myeloid leukemia\n\nMDSMyelodysplastic syndrome\n\nSIOPInternational Society of Paediatric Oncology\n\nFISHFluorescent in situ hybridization\n\nCTComputed Tomography\n\nMRIMagnetic Resonance Imaging\n\nDEBDiepoxybutane\n\nWHOWorld Heath Organization\n\nGNPsGranule neuron precursors\n\nEGLExternal granule layer\n\nNSCsNeural stem cells\n\nSVZSubventricular zone\n\nEvelina Miele and Angela Mastronuzzi contributed equally to this work.\n\nCompeting interests\n\nThe authors declare that they have no competing interests.\n\nAuthors’ contributions\n\nEM, AP, VA, AV, IS and EF performed the molecular studies. AM, AC, AS, GSC, LS and FL clinically followed the patient. MA, FRB, FG carried out pathologic assessments. MZ, SF, AB and GG performed the genetic evaluations. All authors read and approved the final manuscript.\n\nAcknowledgements\nWe acknowledge patient’s family for collaboration. This work was supported by Ministry of University and Research (FIRB, PRIN and PON projects), Associazione Italiana Ricerca Cancro (AIRC), Sapienza Ateneo-Awards, Pasteur Institute/Cenci Bolognetti Foundation, Associazione Italiana per la Ricerca sull'Anemia di Fanconi (AIRFA) and Italian Institute of Technology (IIT). EM is supported by a post-doctoral fellowship from IIT.\n==== Refs\nReferences\n1. Kottemann MC Smogorzewska A Fanconi anaemia and the repair of Watson and Crick DNA crosslinks Nature 2013 493 7432 356 63 10.1038/nature11863 23325218 \n2. Rosenberg PS Greene MH Alter BP Cancer incidence in persons with Fanconi anemia Blood 2003 101 3 822 6 10.1182/blood-2002-05-1498 12393424 \n3. Alter BP Greene MH Velazquez I Rosenberg PS Cancer in Fanconi anemia Blood 2003 101 5 2072 10.1182/blood-2002-11-3597 12584146 \n4. 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"fulltext_license": "CC BY",
"issn_linking": "2050-7771",
"issue": "3()",
"journal": "Biomarker research",
"keywords": "BRCA2; FANCD1; Fanconi anemia; Medulloblastoma; SHH molecular subgroup",
"medline_ta": "Biomark Res",
"mesh_terms": null,
"nlm_unique_id": "101607860",
"other_id": null,
"pages": "13",
"pmc": null,
"pmid": "26064523",
"pubdate": "2015",
"publication_types": "D002363:Case Reports",
"references": "24739212;19856400;24145349;20608899;19530235;9126738;23898128;25662941;21681522;22057785;24651015;16015582;25472942;16290230;24305714;22751496;25476449;24259538;23623386;23698033;25689980;8193701;12584146;20307716;23325218;18756266;16825431;14559878;12065746;22184287;23175120;25594185;24737380;22923021;19373780;11389461;23285130;21150899;19464302;23114602;20713514;21701511;19164512;12393516;23623389;23512859;17200671;22044372;14670928;18973228;11813170;2985019;24951114;24831600;11430722;24140199;16793542;14707715;17621875;25849179;24123378;15070707;15689453;23179372;12393424",
"title": "Characterization of medulloblastoma in Fanconi Anemia: a novel mutation in the BRCA2 gene and SHH molecular subgroup.",
"title_normalized": "characterization of medulloblastoma in fanconi anemia a novel mutation in the brca2 gene and shh molecular subgroup"
} | [
{
"companynumb": "IT-TEVA-822253ROM",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CARBOPLATIN"
},
"drugadditional": "1",
"dru... |
{
"abstract": "Bisphosphonates are being used more frequently as part of the multi-disciplinary management of moderate to severe Osteogenesis Imperfecta (OI). This report details the development of respiratory failure during the second infusion of pamidronate in a 3.5 year-old male with osteogenesis imperfecta type 1 and no prior history of respiratory disease.",
"affiliations": "Department of Endocrinology, UCSF Benioff Children's Hospital Oakland, 757 52nd Street, Oakland, CA 94609, USA. Tel.: +1 510 428 3654; Fax: +1 510 450 5614; E-mail: JeOlson@mail.cho.org.",
"authors": "Olson|Jennifer Ann|JA|",
"chemical_list": "D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D000077268:Pamidronate",
"country": "Netherlands",
"delete": false,
"doi": "10.3233/PRM-140284",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1874-5393",
"issue": "7(2)",
"journal": "Journal of pediatric rehabilitation medicine",
"keywords": "Osteogenesis imperfecta; bisphosphonates; pamidronate; respiratory distress; respiratory failure",
"medline_ta": "J Pediatr Rehabil Med",
"mesh_terms": "D050071:Bone Density Conservation Agents; D002675:Child, Preschool; D004164:Diphosphonates; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D010013:Osteogenesis Imperfecta; D000077268:Pamidronate; D012131:Respiratory Insufficiency; D016896:Treatment Outcome",
"nlm_unique_id": "101490944",
"other_id": null,
"pages": "155-8",
"pmc": null,
"pmid": "25096867",
"pubdate": "2014",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Respiratory failure during infusion of pamidronate in a 3 year-old male with osteogenesis imperfecta: a case report.",
"title_normalized": "respiratory failure during infusion of pamidronate in a 3 year old male with osteogenesis imperfecta a case report"
} | [
{
"companynumb": "US-MYLANLABS-2015M1018493",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PAMIDRONATE DISODIUM"
},
"drugadditional": nu... |
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