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"abstract": "BACKGROUND\nThe overall prognosis of multiple myeloma has improved significantly over the last 15 years. We wondered whether the overall improvement would also be seen in unselected patients in an academic center in Northwest Louisiana with a high proportion of minority patients, and if second malignant neoplasms are relevant for our patients.\n\n\nMETHODS\nBetween 1998 and 2009, 215 patients were treated for multiple myeloma at our center and had complete follow-up until May 2013.\n\n\nRESULTS\nThe mean survival of patients with multiple myeloma increased from 3.25 to 5.34 years, which is comparable to patients treated at larger centers. No prognostic difference was observed in the subgroups of myeloma patients. Among 215 patients followed for the development of secondary cancers, 16 already had a preexisting or concomitant malignancy (7.4%) and 10 developed secondary cancers. Our data indicate a significant background of histologically unrelated cancers and a cumulative incidence of new cancers of about 20% after 10 years of follow-up. Based on SEER data, preexisting or secondary cancers were not statistically increased in our population.\n\n\nCONCLUSIONS\nThe use of autologous transplantation and the introduction of new agents resulted in a significant improvement in the prognosis of multiple myeloma. Other cancers are not statistically increased before or after multiple myeloma is diagnosed and are not prognostically relevant.",
"affiliations": "Feist Weiller Cancer Center, Shreveport, La., USA.",
"authors": "Munker|Reinhold|R|;Shi|Runhua|R|;Nair|Binu|B|;Devarakonda|Srinivas|S|;Cotelingam|James D|JD|;McLarty|Jerry|J|;Mills|Glenn M|GM|;Glass|Jonathan|J|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000440970",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0001-5792",
"issue": "135(3)",
"journal": "Acta haematologica",
"keywords": null,
"medline_ta": "Acta Haematol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D015994:Incidence; D008145:Louisiana; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma; D009367:Neoplasm Staging; D016609:Neoplasms, Second Primary; D011379:Prognosis; D012307:Risk Factors; D033581:Stem Cell Transplantation; D016019:Survival Analysis; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "0141053",
"other_id": null,
"pages": "146-55",
"pmc": null,
"pmid": "26588024",
"pubdate": "2016",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "The Shreveport Myeloma Experience: Survival, Risk Factors and Other Malignancies in the Age of Stem Cell Transplantation.",
"title_normalized": "the shreveport myeloma experience survival risk factors and other malignancies in the age of stem cell transplantation"
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"abstract": "Three cases of Epstein-Barr virus (EBV)-negative post-transplant lymphoproliferative disease that occurred 6 to 8 years after renal transplantation are reported. The patients respectively had gastric mucosa-associated lymphoid tissue lymphoma, gastric diffuse large B-cell lymphoma, and atypical Burkitt lymphoma. Absence of EBV in the tissue samples was demonstrated by both in situ hybridization for EBV early RNA and polymerase chain reaction for EBV DNA. Patients were treated with reduction in immunosuppression and combined chemotherapy plus an anti-CD20 monoclonal antibody, rituximab. Despite the reduction in immunosuppression, patients had stable renal functions without loss of graft functions. The patient with atypical Burkitt lymphoma had an abnormal karyotype, did not respond to treatment completely, and died due to disease progression. The other patients are still alive and in remission 5 and 3 years after diagnosis, respectively. EBV-negative post-transplant lymphoproliferative diseases are usually late-onset and are reported to have poor prognosis. Thus, reduction in immunosuppression is usually not sufficient for treatment and more aggressive approaches like rituximab with combined chemotherapy are required.",
"affiliations": "Ankara University School of Medical, Department of Hematology, Ankara, Turkey.;Ankara University School of Medical, Department of Pathology, Ankara, Turkey.;Ankara University School of Medical, Department of Hematology, Ankara, Turkey.;Ankara University School of Medical, Department of Nephrology, Ankara, Turkey.;Ankara University School of Medical, Department of Medical Genetics, Ankara, Turkey.;Ankara University School of Medical, Department of Nephrology, Ankara, Turkey.;Ankara University School of Medical, Department of Pathology, Ankara, Turkey.;Ankara University School of Medical, Department of Hematology, Ankara, Turkey.;Ankara University School of Medical, Department of Hematology, Ankara, Turkey.",
"authors": "Bakanay|Sule Mine|SM|;Kaygusuz|Gülşah|G|;Topçuoğlu|Pervin|P|;Sengül|Sule|S|;Tunçalı|Timur|T|;Keven|Kenan|K|;Kuzu|Işınsu|I|;Uysal|Akın|A|;Arat|Mutlu|M|",
"chemical_list": null,
"country": "Turkey",
"delete": false,
"doi": "10.4274/Tjh.2012.0010",
"fulltext": "\n==== Front\nTurk J HaematolTurk J HaematolTJHTurkish Journal of Hematology1300-77771308-5263Galenos Publishing 10.4274/Tjh.2012.00101195Case ReportEpstein-Barr Virus-Negative Post-Transplant Lymphoproliferative Diseases: Three Distinct Cases from a Single Center Epstein-Barr Virüs-Negatif Post-Transplant Lenfoproliferatif Hastalık: Tek Merkezden Üç Farklı Olgu Bakanay Şule Mine 1*Kaygusuz Gülşah 2Topçuoğlu Pervin 1Şengül Şule 3Tunçalı Timur 4Keven Kenan 3Kuzu Işınsu 2Uysal Akın 1Arat Mutlu 11 \nAnkara University School of Medical, Department of Hematology, Ankara, Turkey\n2 \nAnkara University School of Medical, Department of Pathology, Ankara, Turkey\n3 \nAnkara University School of Medical, Department of Nephrology, Ankara, Turkey\n4 \nAnkara University School of Medical, Department of Medical Genetics, Ankara, Turkey\n* Address for Correspondence: Ankara University School of Medical, Department of Hematology, Ankara, Turkey Phone: +90 312 291 25 25/4812 E-mail: sulemine.ozturk@yahoo.com3 2014 5 3 2014 31 1 79 83 14 1 2012 22 11 2012 © Turkish Journal of Hematology, Published by Galenos Publishing.\n\n2014This 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.Three cases of Epstein-Barr virus (EBV)-negative post-transplant lymphoproliferative disease that occurred 6 to 8 years after renal transplantation are reported. The patients respectively had gastric mucosa-associated lymphoid tissue lymphoma, gastric diffuse large B-cell lymphoma, and atypical Burkitt lymphoma. Absence of EBV in the tissue samples was demonstrated by both in situ hybridization for EBV early RNA and polymerase chain reaction for EBV DNA. Patients were treated with reduction in immunosuppression and combined chemotherapy plus an anti-CD20 monoclonal antibody, rituximab. Despite the reduction in immunosuppression, patients had stable renal functions without loss of graft functions. The patient with atypical Burkitt lymphoma had an abnormal karyotype, did not respond to treatment completely, and died due to disease progression. The other patients are still alive and in remission 5 and 3 years after diagnosis, respectively. EBV-negative post-transplant lymphoproliferative diseases are usually late-onset and are reported to have poor prognosis. Thus, reduction in immunosuppression is usually not sufficient for treatment and more aggressive approaches like rituximab with combined chemotherapy are required. \n\nBöbrek naklinden 6-8 yıl sonra Epstein-Barr virus (EBV) negatif posttransplant lenfoproliferatif hastalık geliştiren 3 olgu rapor edilmektedir. Hastaların tanıları gastrik MALT lenfoma, gastrik diffüz büyük B hücreli lenfoma ve atipik-burkitt lenfoma idi. Hem EBV early RNA için yapılan in-situ hibridizasyon yöntemi hem de EBV DNA için yapılan polimeraz zincir reaksiyonu ile doku örneklerinde EBV saptanamamıştır. Hastalara immünsupresyonun azaltılması ile birlikte rituksimab içeren kombine kemoterapi protokolleri verilmiştir. İmmünsupresyonun azaltılmasına rağmen böbrek fonksiyonlarında önemli bir kayıp gözlenmemiştir. Anormal karyotipe sahip atipik Burkitt lenfomalı hasta tedaviye rağmen hastalık ilerlemesi ile erken dönemde kaybedilmiştir. Diğer hastalar hala remisyonda takip edilmektedir. EBV negatif posttransplant lenfoproliferatif hastalıkların genellikle geç başlangıçlı ve kötü prognozlu olduğu bilinmektedir. Bu hastalarda immünsupresyonun azaltılması tek başına yeterli bir tedavi olmadığı gibi rituksimab içeren kombine kemoterapilerle daha agresif tedaviler gerekli olmaktadır. \n\nRenal transplantationPost-transplant lymphoproliferative diseaseLymphomaImmunosuppressionRituximabAbnormal karyotype\n==== Body\nINTRODUCTION\nPost-transplant lymphoproliferative diseases (PTLDs) are a heterogeneous group of diseases that develop as early or late-onset disease in solid organ or bone marrow transplant recipients with an incidence ranging between 1% and 20% [1,2]. It is reported that in renal transplant recipients PTLD is the second most common malignancy after skin cancer [3,4,5]. Pathogenesis of PTLD is not well understood. Epstein-Barr virus (EBV) infection and prolonged immunosuppression (IS) are the 2 major factors in pathogenesis. Inhibition of cytotoxic T-cell functions due to IS removes the control over EBV-infected B cells, which results in expansion of B cells, acquisition of genetic mutations, and clonal proliferation [6,7]. The highest risk of developing PTLD is within the first year after transplantation. EBV is found to be positive in 60%-80% of PTLDs and is usually associated with early-onset PTLD. However, EBV-negative PTLD is mainly late-onset [8,9,10,11,12]. \n\nThree patients who had received renal transplantation at other centers were admitted to our department, where they received the diagnosis of PTLD and were further followed. The presence of EBV could not be demonstrated in any of the samples by in situ hybridization for EBV early RNA or polymerase chain reaction (PCR) analysis of EBV DNA. Informed consent was obtained.\n\nCASE REPORT\nCase 1\n\nA 28-year-old female patient was diagnosed with Helicobacter pylori (HP)-positive gastric mucosa-associated lymphoid tissue (MALT) lymphoma (stage IE) 6 years after receiving renal transplantation from her mother. She had been on mycophenolate mofetil, tacrolimus, and prednisolone for the last 3 years. After the diagnosis of lymphoma, the immunosuppressive therapy was modified with cessation of mycophenolate mofetil and dose reduction of tacrolimus. The patient received HP eradication therapy and was followed with endoscopic biopsies every 3 months. The HP infection was persistent and all biopsies supported the presence of a MALT lymphoma histologically. One year after the diagnosis, IgH chain clonality analysis by nested PCR revealed 2 separate clones on the polyclonal background, which was consistent with oligoclonal proliferation. The follow-up endoscopy revealed a larger ulcer and the pathology revealed MALT lymphoma invading the muscularis mucosa (Figure 1). The patient responded to combined chemotherapy with rituximab, cyclophosphamide, vincristine, and methyl prednisolone (R-CVP). Five years after diagnosis, she is being followed in complete remission. She is on prednisolone at 5 mg/day per os and tacrolimus at 2 mg/day per os, and her renal functions are stable with serum creatinine levels in the range of 1.3-1.6 mg/dL. \n\nCase 2\n\nA 31-year-old male patient presented with anemia due to chronic blood loss from the gastrointestinal tract. Endoscopic examination revealed a large ulcerated mass of the stomach. A computerized tomography (CT) scan demonstrated an 8.5x4 cm mass extending outside the stomach wall, suggesting an aggressive lymphoma, but endoscopic biopsy revealed MALT lymphoma with lambda monoclonal atypical B cell infiltration. The patient had received renal transplantation 7 years before diagnosis and had been on immunosuppressive therapy with cyclosporine A, azathioprine, and prednisolone since then. After the diagnosis of stage IE PTLD, IS drugs were tapered and stopped. Anti-HP treatment and 6 cycles of combined chemotherapy with R-CVP were administered. Prednisolone at 5 mg/day was resumed due to the deterioration of his renal functions. A CT scan of the abdomen revealed thickening of the stomach wall and perigastric lymphadenopathy. The endoscopy demonstrated the persistence of the giant ulcer in the stomach, with the biopsy revealing diffuse large B-cell lymphoma (DLBCL) (Figure 2). He was treated with total gastrectomy followed by combined chemotherapy with rituximab, cyclophosphamide, vincristine, doxorubicin, and methyl prednisolone, and he is in complete remission 3 years after diagnosis. His serum creatinine levels are in the range of 1.5-2.0 mg/dL with prednisolone at 5 mg/day every other day. \n\nCase 3\n\nA 28-year-old male patient was admitted to the hospital with ptosis of the left eyelid, diplopia, and extreme sweating for the last few weeks. He had received a renal allograft from a living donor 8 years before. The immunosuppressive regimen consisted of azathiopurine, cyclosporine A, and prednisolone. His complete blood count revealed a white blood cell count of 11.3x109/L, hemoglobin of 15.3 g/dL, and platelet count of 49x109/L. On the peripheral blood smear, 60% of the leukocytes were atypical lymphoid cells with cytoplasmic vacuoles. Bone marrow examination revealed the diagnosis of atypical Burkitt lymphoma (aBL) (Figure 3). Flow cytometric analysis revealed that the immature cells were positive for HLA-DR and the B cell antigens CD19, CD10, cytoplasmic CD22 (+/-), surface CD22, FMC7, CD52, cytoplasmic CD79a, and surface IgM (+/-), and were negative for T-cell antigen CD5. The patient had a complex karyotype consisting of clonal trisomy X, add1 (q25), t(3;6) (q23;q23), trisomy 7, t(8;14) (q22;q32), der (10), der (11), der (16), trisomy 18, trisomy 20, and monosomy 22. Fluorescence in situ hybridization analysis revealed positive results for t(8;14), trisomy 7, and MLL gene amplification. Cerebrospinal fluid examination was negative for malignanT-cells but the magnetic resonance imaging of the brain showed disease infiltration at multiple sites. The patient was treated with discontinuation of the immunosuppressive drugs and with combined chemotherapy that contained rituximab, cyclophosphamide, vincristine, dexamethasone, and L-asparaginase. Central nervous system disease was treated with 6 courses of intrathecal chemotherapy followed by cranial irradiation. His renal functions remained within normal ranges. There was a dramatic clinical response after cessation of IS and initiation of the chemotherapy, and the follow-up bone marrow biopsy after chemotherapy did not reveal any atypical cells. However, several weeks after discharge, he died of disease progression in the central nervous system and medullary relapse.\n\nDISCUSSION\nThree patients with PTLD demonstrating distinct pathologies as well as distinct clinical properties are reported. In all patients, the PTLD occurred long after renal transplantation, and all were EBV-negative. Post-transplant lymphoproliferative diseases may occur as early-onset (≤1 year) or late-onset (>1 year) disease after transplantation [9]. Studies comparing EBV-positive and EBV-negative PTLD patients have demonstrated that EBV-negative PTLD occurred later than EBV-positive PTLD [9,10,14,15,16]. The rarity and the heterogeneity of the disease have prevented large randomized studies to compare the overall survival and treatment outcomes. While some of the studies have shown significantly decreased survival of EBV-negative patients, others could not demonstrate a survival difference [3,9,10,15]. Leblond et al. reported that median survival of EBV-negative patients was significantly shorter than that of EBV-positive patients (1 month vs. 37 months) and identified EBV negativity as an adverse prognostic indicator [9]. On the other hand, Tsai et al. could not demonstrate any significant difference between EBV-positive and EBV-negative PTLD patients both in terms of response to reduction in IS and estimated 1-year overall survival (68% vs. 60% for EBV-positive and EBV-negative groups, respectively) [3]. In accordance with these reports, our cases also had different outcomes: patients 1 and 2 are still alive without disease, while patient 3 had incomplete response to therapy and poor survival. \n\nPost-transplant lymphoproliferative diseases are very heterogeneous, ranging from early lesions like infectious mononucleosis-like disease to monoclonal monomorphic diseases like malignant lymphomas. The most common type of monomorphic PTLD is DLBCL [14,15]. On the other hand, MALT lymphoma and atypical or Burkitt-like lymphoma are very rarely observed as PTLD [12,13,14]. Immunohistochemical studies demonstrate that PTLD lesions presenting as DLBCL usually express a late germinal center (CD10+/-/bcl-6+/MUM-1-/CD138-) or early post-germinal center (CD10-/bcl-6+\\-/MUM-1+/CD138+) profile, but the germinal center profile is more commonly expressed in EBV-negative cases. This may suggest that EBV-negative PTLDs actually resemble the lymphomas that develop in immunocompetent hosts [7,17]. \n\n Burkitt lymphoma (BL) or aBL patients typically present with advanced-stage disease and high tumor burden with generalized lymphadenopathy and frequent bone marrow involvement. Typical BL usually has c-myc rearrangement as a sole abnormality. Complex chromosomal abnormalities in addition to c-myc are reported in patients with aggressive B-cell lymphoma with features intermediate between DLBCL and BL, which is also referred to as aBL. In accordance with the literature, patient 3 had very aggressive disease and did not respond to the therapy well [18,19,20,21].\n\nHelicobacter pylori can be demonstrated in the gastric mucosa in a majority of MALT lymphomas, and HP eradication with antibiotics usually results in complete regression. It is not clear whether the risk of MALT lymphoma is increased due to immunosuppression after solid organ transplantation or if it is completely due to HP infection, or both. Similar to case 1, the reported cases in the literature were all negative for EBV and positive for HP, and most developed as late-onset PTLD. They were clinically and histologically identical to conventional MALT lymphomas, which occur in immunocompetent patients [22,23]. Although most post-transplant MALT lymphomas are clinically indolent and do not require aggressive treatment, it is not known whether anti-HP therapy alone is sufficient to treat the post-transplant gastric lymphomas. Nelson et al., in their series of PTLD, reported that a single gastric PTLD that could represent a high-grade MALT lymphoma responded to only reduction in IS [11]. However, our patient did not sufficiently respond to reduction in IS and anti-HP therapy and eventually required combined chemotherapy.\n\nReduction in IS should be the first line of approach in treatment of PTLD [3]. In the case of kidney transplantation, it is recommended that immunosuppressive therapy should be reduced to a minimum dosage and even ceased as long as the graft rejection is compatible with life. Early lesions and polymorphic PTLD have favorable response to reduction in IS alone, but the monoclonal/monomorphic forms require more aggressive treatment. During the last decade, anti-CD20 monoclonal antibody, rituximab, has become increasingly used in the treatment of CD20+ PTLD with better response rates of up to 60%-70%. Patients who do not respond to reduction in IS and rituximab can be given combined chemotherapy. However, combined chemotherapy with rituximab should be considered as first-line therapy for patients who are not suitable for reduction in IS or who have EBV-negative, late-onset aggressive disease, or for patients who have high tumor burden requiring an upfront rapid intervention [24,25,26,27,28]. In conclusion, EBV-negative PTLDs can be considered as a distinct group of PTLD resembling lymphomas of immunocompetent subjects due to late occurrence, higher proportion of monomorphic cases, and clinically more aggressive behavior.\n\nCONFLICT OF INTEREST STATEMENT\nThe authors of this paper have no conflicts of interest, including specific financial interests, relationships, and/ or affiliations relevant to the subject matter or materials included. \n\nFigure 1 MALT lymphoma. Small monocytoid lymphocytes and some plasma cells in the lamina propria of the gastric mucosa (1a, 1b, 1c). These cells were diffusely positive for CD20 and CD79a, forming a lymphoepithelial lesion. Kappa light chain restriction was demonstrated on neoplastic cells. Bcl10 was negative by immunohistochemistry.\nFigure 2 Diffuse large B cell lymphoma diffusely infiltrating the stomach wall. There were also cells that had anaplastic features (2a, 2b). The tumor cells were positive for CD20, were partially positive for MUM-1 and Bcl-6, and had a high proliferation index of around 60% with Ki-67.\nFigure 3 Atypical Burkitt lymphoma. Atypical cells infiltrating the bone marrow had large cytoplasmic vacuoles consistent with L3 morphology (3a, 3b, 3c). The cells were positively stained with CD20, CD79a, and Bcl-6, and were negative for MUM-1 and Bcl-2. The proliferation index examined by Ki-67 was around 100%.\n==== Refs\nReferences\n1 Penn I Cancers complicating organ transplantation N Engl J Med 1990 323 1767 1769 2247108 \n2 Opelz G Henderson R Incidence of non-Hodgkin lymphoma in kidney and heart transplant recipients Lancet 1993 342 1514 1516 7902900 \n3 Tsai DE Hardy CL Tomaszewski JE Kotloff RM Oltoff KM Somer BG Schuster SJ Porter DL Montone KT Stadtmauer EA Reduction in immunosuppression as initial therapy for posttransplant lymphoproliferative disorder: analysis of prognostic variables and long-term follow-up of 42 adult patients Transplantation 2001 71 1076 1088 11374406 \n4 Penn I Cancers in renal transplant recipients Adv Ren Replace Ther 2000 7 147 156 10782732 \n5 Winkelhorst JT Brokelman WJ Tiggeler RG Wobbes T Incidence and clinical course of de-novo malignancies in renal allograft recipients Eur J Surg Oncol 2001 27 409 413 11417989 \n6 Lim WH Russ GR Coates PT Review of Epstein-Barr virus and post-transplant lymphoproliferative disorder post-solid organ transplantation Nephrology (Carlton) 2006 11 355 366 16889577 \n7 Capello D Rossi D Gaidano G Post-transplant lymphoproliferative disorders: molecular basis of disease histogenesis and pathogenesis Hematol Oncol 2005 23 61 67 16216037 \n8 Thompson MP Kurzrock R Epstein-Barr virus and cancer Clin Cancer Res 2004 10 803 821 14871955 \n9 Leblond V Davi F Charlotte F Dorent R Bitker MO Sutton L Gandjbakhch I Binet JL Raphael M Posttransplant lymphoproliferative disorders not associated with Epstein-Barr virus: a distinct entity? J Clin Oncol 1998;16:2052-2059 1998;16:2052-2059. 1998 16 2052 2059 1998 \n10 Nelson BP Nalesnik MA Bahler DW Locker J Fung JJ Swerdlow SH Epstein-Barr virus-negative post-transplant lymphoproliferative disorders: a distinct entity? Am J Surg Pathol 2000 24 375 385 10716151 \n11 Dotti G Fiocchi R Motta T Gamba A Gotti E Gridelli B Borleri G Manzoni C Viero P Remuzzi G Barbui T Rambaldi A Epstein-Barr virus-negative lymphoproliferate disorders in long-term survivors after heart, kidney, and liver transplant Transplantation 2000 69 827 833 10755535 \n12 Jaffe ES Harris N Stein H Vardiman JW WHO Classification of Neoplastic Diseases of the Hematopoietic and Lymphoid Tissues Lyon IARC Press 2001 \n13 Weissmann DJ Ferry JA Harris NL Louis DN Delmonico F Spiro I Posttransplantation lymphoproliferative disorders in solid organ recipients are predominantly aggressive tumors of host origin Am J Clin Pathol 1995 103 748 755 7785662 \n14 Knight JS Tsodikov A Cibrik DM Ross CW Kaminski MS Blayney DW Lymphoma after solid organ transplantation: risk, response to therapy, and survival at a transplantation center J Clin Oncol 2009 27 3354 3362 19451438 \n15 Ghobrial IM Habermann TM Maurer MJ Geyer SM Ristow KM Larson TS Walker RC Ansell SM Macon WR Gores GG Stegall MD McGregor CG Prognostic analysis for survival in adult solid organ transplant recipients with post-transplantation lymphoproliferative disorders J Clin Oncol 2005 23 7574 7582 16186599 \n16 Nalesnik MA Clinicopathologic features of posttransplant lymphoproliferative disorders Ann Transplant 1997 2 33 40 9869877 \n17 Johnson LR Nalesnik MA Swerdlow SH Impact of Epstein-Barr virus in monomorphic B-cell posttransplant lymphoproliferative disorders: a histogenetic study Am J Surg Pathol 2006 30 1604 1612 17122518 \n18 Ferrari A Perotti D Giardini R Ghio L Riva S Massimino M Disseminated Burkitt’s lymphoma after kidney transplantation: a case report in a boy with Drash syndrome J Pediatr Hematol Oncol 1997 19 151 155 9149747 \n19 Nathanson S Lucidarme N Landman-Parker J Deschenes G Long-term survival of renal graft complicated with Burkitt lymphoma Pediatr Nephrol 2002 17 1066 1068 12478360 \n20 Xicoy B Ribera JM Esteve J Brunet S Sanz MA Fernández-Abellán P Feliu E Post-transplant Burkitt’s leukemia or lymphoma. Study of five cases treated with specific intensive therapy (PETHEMA ALL-3/97 trial). Leuk Lymphoma 2003 44 1541 1543 14565657 \n21 Gong JZ Stenzel TT Bennett ER Lagoo AS Dunphy CH Moore JO Rizzieri DA Tepperberg JH Papenhausen P Buckley PJ Burkitt lymphoma arising in organ transplant recipients: a clinicopathologic study of five cases Am J Surg Pathol 2003 27 818 827 12766587 \n22 Hsi ED Singleton TP Swinnen L Dunphy CH Alkan S Mucosa-associated lymphoid tissue-type lymphomas occurring in post-transplantation patients Am J Surg Pathol 2000 24 100 106 10632493 \n23 Wotherspoon AC Diss TC Pan L Singh N Whelan J Isaacson PG Low grade gastric B-cell lymphoma of mucosa associated lymphoid tissue in immunocompromised patients Histopathology 1996 28 129 134 8834520 \n24 Blaes AH Peterson BA Bartlett N Dunn DL Morrison VA Rituximab therapy is effective for posttransplant lymphoproliferative disorders after solid organ transplantation: results of a phase II trial Cancer 2005 104 1661 1667 16149091 \n25 Choquet S Leblond V Herbrecht R Socié G Stoppa AM Vandenberghe P Fischer A Morschhauser F Salles G Feremans W Vilmer E Peraldi MN Lang P Lebranchu Y Oksenhendler E Garnier JL Lamy T Jaccard A Ferrant A Offner F Hermine O Moreau A Fafi-Kremer S Morand P Chatenoud L Berriot-Varoqueaux N Bergougnoux L Milpied N Efficacy and safety of rituximab in B-cell post-transplantation lymphoproliferative disorders: results of a prospective multicenter phase 2 study Blood 2006 107 3053 3057 16254143 \n26 Elstrom RL Andreadis C Aqui NA Ahya VN Bloom RD Brozena SC Olthoff KM Schuster SJ Nasta SD Stadtmauer EA Tsai DE Treatment of PTLD with rituximab or chemotherapy Am J Transplant 2006 6 569 576 16468968 \n27 Svoboda J Kotloff R Tsai DE Management of patients with post-transplant lymphoproliferative disorder: the role of rituximab Transpl Int 2006 19 259 269 16573540 \n28 Taylor AL Bowles KM Callaghan CJ Wimperis JZ Grant JW Marcus RE Bradley JA Anthracycline-based chemotherapy as first-line treatment in adults with malignant posttransplant lymphoproliferative disorder after solid organ transplantation Transplantation 2006 82 375 381 16906036\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1300-7777",
"issue": "31(1)",
"journal": "Turkish journal of haematology : official journal of Turkish Society of Haematology",
"keywords": "Abnormal karyotype; Immunosuppression; Lymphoma; Post-transplant lymphoproliferative disease; Renal transplantation; Rituximab",
"medline_ta": "Turk J Haematol",
"mesh_terms": null,
"nlm_unique_id": "9606065",
"other_id": null,
"pages": "79-83",
"pmc": null,
"pmid": "24764734",
"pubdate": "2014-03",
"publication_types": "D016428:Journal Article",
"references": "19451438;9626203;10716151;16149091;9869877;11374406;16906036;17122518;16468968;2247108;16216037;10755535;10025990;7785662;12766587;16889577;12478360;16186599;14565657;14871955;10632493;9149747;7902900;10782732;11417989;16254143;8834520;16573540",
"title": "Epstein-barr virus-negative post-transplant lymphoproliferative diseases: three distinct cases from a single center.",
"title_normalized": "epstein barr virus negative post transplant lymphoproliferative diseases three distinct cases from a single center"
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"abstract": "Therapeutic hypothermia or targeted temperature management has been used after cardiac arrest to improve neurological outcomes and mortality. However, a side effect of temperature modulation is a centrally mediated shivering response. The Columbia Anti-Shivering Protocol sets up a systematic method of intravenous (IV) and oral medication escalation to suppress this response and preserve the benefits of this therapy. We present the case of a 59-year-old male who began shivering after therapeutic hypothermia for cardiac arrest, leading to a persistent rise in core temperature despite adequate sedation. He was also found to have gastric contents similar to coffee grounds through nasogastric tube suction. The shivering was effectively suppressed and the rising core temperature plateaued using rectal acetaminophen and buspirone administered by means of a novel device, the Macy Catheter. Also, when used in conjunction with other protocol-driven medications, the patient was able to achieve a core temperature of 33°C. The Macy Catheter appears to be a useful approach to rectally administer buspirone and acetaminophen, using an easy-to-place, nonsterile atraumatic device that requires no radiographic confirmation of placement.",
"affiliations": "1 College of Medicine, University of Illinois at Chicago , Chicago, Illinois.;2 Department of Emergency Medicine, Advocate Christ Medical Center , Oak Lawn, Illinois.;2 Department of Emergency Medicine, Advocate Christ Medical Center , Oak Lawn, Illinois.;3 Department of Pharmacy Services, Advocate Christ Medical Center , Oak Lawn, Illinois.;2 Department of Emergency Medicine, Advocate Christ Medical Center , Oak Lawn, Illinois.",
"authors": "Honasoge|Akilesh|A|;Parker|Braden|B|;Wesselhoff|Kelly|K|;Lyons|Neal|N|;Kulstad|Erik|E|",
"chemical_list": "D014151:Anti-Anxiety Agents; D058633:Antipyretics; D000082:Acetaminophen; D002065:Buspirone",
"country": "United States",
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"doi": "10.1089/ther.2015.0022",
"fulltext": "\n==== Front\nTher Hypothermia Temp ManagTher Hypothermia Temp ManagtherTherapeutic Hypothermia and Temperature Management2153-76582153-7933Mary Ann Liebert, Inc. 140 Huguenot Street, 3rd FloorNew Rochelle, NY 10801USA 2680777510.1089/ther.2015.002210.1089/ther.2015.0022Case StudyFirst Use of a New Device for Administration of Buspirone and Acetaminophen to Suppress Shivering During Therapeutic Hypothermia Honasoge Akilesh MA1Parker Braden MD2Wesselhoff Kelly CCRN2Lyons Neal PharmD3Kulstad Erik MD, MS21 College of Medicine, University of Illinois at Chicago, Chicago, Illinois.2 Department of Emergency Medicine, Advocate Christ Medical Center, Oak Lawn, Illinois.3 Department of Pharmacy Services, Advocate Christ Medical Center, Oak Lawn, Illinois.Address correspondence to:Akilesh Honasoge, MACollege of MedicineUniversity of Illinois at ChicagoChicago, IL 60612E-mail:ahonaso2@uic.edu01 3 2016 01 3 2016 6 1 48 51 © Akilesh Honasoge et al. 2016; Published by Mary Ann Liebert, Inc.2016This Open Access article is distributed under the terms of the Creative Commons Attribution Noncommercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.Therapeutic hypothermia or targeted temperature management has been used after cardiac arrest to improve neurological outcomes and mortality. However, a side effect of temperature modulation is a centrally mediated shivering response. The Columbia Anti-Shivering Protocol sets up a systematic method of intravenous (IV) and oral medication escalation to suppress this response and preserve the benefits of this therapy. We present the case of a 59-year-old male who began shivering after therapeutic hypothermia for cardiac arrest, leading to a persistent rise in core temperature despite adequate sedation. He was also found to have gastric contents similar to coffee grounds through nasogastric tube suction. The shivering was effectively suppressed and the rising core temperature plateaued using rectal acetaminophen and buspirone administered by means of a novel device, the Macy Catheter. Also, when used in conjunction with other protocol-driven medications, the patient was able to achieve a core temperature of 33°C. The Macy Catheter appears to be a useful approach to rectally administer buspirone and acetaminophen, using an easy-to-place, nonsterile atraumatic device that requires no radiographic confirmation of placement.\n==== Body\nHospitals are treating an increasing number of cardiac arrest patients after return of spontaneous circulation (ROSC) with therapeutic hypothermia or targeted temperature management (TTM). Multiple studies have shown benefits of this approach such as improved neurological outcomes and decreased mortality (Bernard et al., 2002; HACA, 2002; Arrich et al., 2009; Nielsen et al., 2014). One of the common complications of temperature reduction during TTM is the shivering response. Shivering is a centrally mediated response, which has the potential to reverse many of the theoretical benefits of the cooling. The detriments of shivering include increased extracranial oxygen consumption and blood flow, ultimately depriving the brain of the benefits the cooling was meant to provide. In 2011, the Columbia Anti-Shivering Protocol (Table 1) was published to provide guidance on the stepwise pharmacological suppression of this shivering response, with the aim to decrease the need for prolonged sedation and unnecessarily lengthy ICU stays (Choi et al., 2011).\n\nTable 1. Comparison of the Advocate Christ Medical Center Therapeutic Hypothermia Protocol Followed in the Treatment of This Patient to the Columbia Anti-Shivering Protocol\n\nShivering assessment\tAdvocate Christ Medical Center Therapeutic Hypothermia Protocol\tColumbia Anti-Shivering Protocol\t\nBSAS (Bedside Shivering Assessment Scale) = 0\nNo shiver\t□ Ensure sedation is optimized (two agents if needed)\t□ Acetaminophen 650–1000 mg Q4–6h\t\n \t (1) Fentanyl\t□ Buspirone 30 mg Q8h\t\n \t (2) Propofol, midazolam, or lorazepam\t□ Magnesium sulfate 0.5–1 mg/h IV\t\n \t□ Acetaminophen 650 mg PO Q6h\t Goal serum magnesium level of 3–4 mg/dL\t\n \t□ Buspirone 30 mg PO once then 15 mg PO Q8h\t□ Skin counterwarming of 43°C/MAX Temp\t\nBSAS = 1 Mild\nShivering localized to the neck and/or thorax; or fine artifact on cardiac rhythm; or fine artifact on BIS tracing; or unexplained, significant increase in BIS value\t□ All interventions above, then add:\t□ Choose one:\t\n \t□ Meperidine 25 mg IV push once, then 12.5 mg IV bolus Q30min PRN\t□ Dexmedetomidine 0.2–1.5 μg/(kg·h)\t\n \t (For GFR <50 mL/min/1.73 m2) Meperidine 6.25 mg IV push Q30min PRN\t□ Opioid: Meperidine 50–100 mg IM or IV\t\nBSAS = 2 Moderate\nShivering involves gross movement of the upper extremities (in addition to neck and thorax)\t□ All interventions above, then add:\t□ Use both:\t\n \t□ Meperidine 25 mg IV push Q30min PRN\t Dexmedetomidine 0.2–1.5 μg/(kg·h)\t\n \t (For GFR <50 mL/min/1.73 m2) Meperidine 12.5 mg IV push Q30min PRN\t Opioid: Meperidine 50–100 mg IM or IV\t\n \t□ Magnesium 0.5 g/h continuous IV infusion\t \t\n \t Titrate by 0.5 g/h to maintain serum magnesium level of 3–4 mg/dL\t \t\nBSAS = 3\nSevere\nShivering involves gross movements of the trunk and upper and lower extremities\t□ All interventions above, then add:\t□ Propofol 50–75 μg/(kg·min)\t\n \t□ Neuromuscular blockade\t□ Neuromuscular blockade: Vecuronium 0.1 mg/kg IV\t\nChoi et al., 2011.\n\nBSAS, Bedside Shivering Assessment Scale; PO, per os; PRN, pro re nata; IV, intravenous; IM, intramuscular; GFR, glomerular filtration rate; BIS, bispectral index.\n\nAlthough effective, the first-stage medications utilized in this protocol are not generally available in intravenous formulation. A new rectal administration device, the Macy Catheter (Hospi Corp.), has recently become available, offering an easy route to quickly provide first-stage antishivering medications such as acetaminophen and buspirone even before placement of nasogastric (NG) or orogastric (OG) tubes (Lyons et al., 2015). In cases in which an NG or OG tube cannot be placed, or contraindications to NG/OG tube medication administration (such as upper gastrointestinal [GI] bleeding or a need for continuous suction) exist, the Macy Catheter may offer the only practical method of administration.\n\nWe present the case of a 59-year-old male brought into the emergency department (ED) as a full cardiac arrest outside of the hospital. The patient had ROSC in the ED after multiple rounds of epinephrine and defibrillation. After this, the patient was intubated and placed in an Arctic Sun Cooling System to institute therapeutic hypothermia at 33°C. Temperature feedback was monitored with a continuous bladder thermometer, and his treatment followed the Advocate Christ Medical Center Therapeutic Hypothermia Protocol (Table 1), which closely resembles the Columbia Anti-Shivering Protocol. An NG tube was also placed to suction, which revealed the gastric contents to be similar in appearance to coffee grounds without a clear etiology. In addition, a fecal occult blood test was performed and found to be positive. The source of the bleeding was felt to be GI in nature rather than secondary to a traumatic airway placement. In accordance with the hypothermia protocol, the patient was initially sedated on fentanyl with a core temperature of 36.5°C (Fig. 1). Despite the addition of midazolam and a later increased dose of the midazolam drip, the patient's core temperature continued to rise. After about 4 hours with the Arctic Sun Cooling System set to 33°C and despite adequate doses of sedation, the patient's core temperature curve demonstrated a steady upslope, and the patient began to shiver. In accordance with the hypothermia protocol (Table 1), a step 0 baseline medication administration was initiated to control the shivering. The initial medications selected included liquid acetaminophen 650 mg and buspirone 30 mg. Due to the evidence of upper GI bleeding, these medications were administered rectally using a Macy Catheter. In addition, aspirin 325 mg was administered rectally for its antiplatelet effect, the benefits of which were felt to outweigh risks (e.g., antiprostaglandin effects on the stomach) based on the patient's elevated troponin.\n\nFIG. 1. Patient's core body temperature after return of spontaneous circulation and placement of Arctic Sun Cooling System set to 33°C with subsequent anti-shivering interventions noted directly on the graph. IV, intravenous.\n\nThe Macy Catheter used is a thin silicone tube, 14F in diameter, with a 15 mL balloon at the tip that is sized to allow secure retention in the rectum, yet allow for easy passage in the event of defecation. Placement does not require any sterile technique. Multiple exit ports exist at the distal catheter tip for fluid and medication passage, and an internal one-way check valve is present in the proximal administration port to prevent backflow of fluids. The buspirone was crushed using the pill crusher supplied with the Macy Catheter kit, mixed with normal tap water, and administered alongside the acetaminophen and aspirin. Subsequently, the Macy Catheter was flushed with normal tap water. Shortly after the administration of these medications, the patient's previously rising core temperature effectively plateaued at 36.9°C and he clinically stopped shivering. Further acceleration in temperature reduction was then achieved in accordance with the hypothermia protocol (Table 1) by switching sedation agents to a low-dose propofol drip, then administering meperidine 25 mg IV push, and later use of magnesium 2 g IV (Fig. 1).\n\nAbsorption of fluids and medications by the rectal mucosa is well described, and has a long history of use, dating back to at least the early 1900s (Murphy, 1909; Trout, 1912; Nabil et al., 1982; Bruera et al., 1994; Needham, 1995; Zweig et al., 2006; Fouad et al., 2010; Pasero, 2010; Chiang et al., 2011). Because no sterility, complex training, or follow-up X-ray confirmation is required, this approach has also been utilized in both emergent and remote settings (Tremayne, 2010). Practical use of this route has likely been limited by the lack of a simple, effective means of administration and catheter retention, which has been addressed now by the Macy Catheter.\n\nThere are no previous studies or guidelines on the rectal administration of buspirone for shivering suppression after therapeutic hypothermia. Buspirone is a 5-HT agonist that has been used effectively to suppress shivering secondary to therapeutic hypothermia, by lowering the shivering threshold without providing overt sedation and paralysis. Acetaminophen acts through a centrally mediated prostaglandin inhibition to decrease the hypothalamic temperature set point (Choi et al., 2011). Buspirone is typically administered orally or using the NG/OG tube, however, given the presence of GI bleeding in this case, this method of administration was felt to be unadvisable. Buspirone has an extensive first-pass metabolism through hepatic oxidation when taken orally, with a mean systemic availability of about 4% and the main metabolite, 1-pyrimidinylpiperazine, at most 25% as potent as buspirone (Gammans et al., 1986). Research on the pharmacokinetics of rectal buspirone is limited; however, the avoidance of the first-pass metabolism may increase the serum concentration over the expected range when compared with oral administration. Clinically, the rectal administration through the Macy Catheter of the combined acetaminophen and buspirone effectively stopped the patient's shivering and plateaued his previously rising core temperature. This combined with other hypothermia protocol-driven medications led to a sustained and continuous decline in the patient's core temperature.\n\nThis novel method of medication administration using the Macy Catheter has the potential to change current practices. The large first-pass hepatic metabolism of buspirone may initially be avoided as a result of rectal administration. This may allow for less escalation of protocol-driven shivering suppression leading to quicker hypothermia induction and fewer sedating agents used. Further research into this matter is needed. This method also has the ability to ease medication administration issues (e.g., nausea and emesis) in patients with difficulty taking oral medications, a common problem in patients suffering from acute coronary syndrome.\n\nLimitations in this case report include the concurrent administration of acetaminophen and aspirin alongside the buspirone, which may alone have been enough to cause the cessation of shivering. Shivering was assessed clinically and thought to be the only reason delaying the patient's achievement of goal temperature. We did not perform pharmacokinetic measurements of the medications administered and relied solely on clinical response to guide our treatment plans.\n\nIn summary, rectal administration of buspirone and acetaminophen through a new medical device, the Macy Catheter, was effective and offered an easy to use first-line method of shivering suppression in the setting of therapeutic hypothermia.\n\nAuthor Disclosure Statement\nNo competing financial interests exist.\n==== Refs\nReferences\nArrich J , Holzer M , Herkner H , Mullner M \nHypothermia for neuroprotection in adults after cardiopulmonary resuscitation . Cochrane Database Syst Rev \n2009 ;CD004128 19821320 \nBernard SA , Gray TW , Buist MD , Jones BM , Silvester W , Gutteridge G , Smith K \nTreatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia . N Engl J Med \n2002 ;346 :557 –563 11856794 \nBruera E , Schoeller T , Pruvost M \nProctoclysis for hydration of terminal cancer patients . Lancet \n1994 ;344 :1699 7996971 \nChiang LM , Wang HS , Shen HH , Deng ST , Tseng CH , Chen YI , Chou ML , Hung PC , Lin KL \nRectal diazepam solution is as good as rectal administration of intravenous diazepam in the first-aid cessation of seizures in children with intractable epilepsy . Pediatr Neonatol \n2011 ;52 :30 –33 21385654 \nChoi HA , Ko SB , Presciutti M , Fernandez L , Carpenter AM , Lesch C , Gilmore E , Malhotra R , Mayer SA , Lee K , Claassen J , Schmidt JM , Badjatia N \nPrevention of shivering during therapeutic temperature modulation: the Columbia anti-shivering protocol . Neurocrit Care \n2011 ;14 :389 –394 21210305 \nFouad EA , El-Badry M , Alanazi FK , Arafah MM , Al-Ashban R , Alsarra IA \nPreparation and investigation of acetyl salicylic acid-caffeine complex for rectal administration . Pharm Dev Technol \n2010 ;15 :249 –257 22716465 \nGammans RE , Mayol RF , LaBudde JA \nMetabolism and disposition of buspirone . Am J Med \n1986 ;80 :41 –51 3515929 \nHACA . Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest . N Engl J Med \n2002 ;346 :549 –556 11856793 \nLyons N , Nejak D , Lomotan N , Mokszycki R , Jamieson S , McDowell M , Kulstad E \nAn alternative for rapid administration of medication and fluids in the emergency setting using a novel device . Am J Emerg Med \n2015 ;33 :1113.e1115 –e1116 25662805 \nMurphy JB \nProctoclysis in the treatment of peritonitis . JAMA \n1909 ;LII :1248 –1250 \nNabil N , Miner DJ , Amatruda JM \nMethimazole: an alternative route of administration . J Clin Endocrinol Metab \n1982 ;54 :180 –181 7054215 \nNeedham D \nProctoclysis for hydration . Lancet \n1995 ;345 :596 7776814 \nNielsen N , Wetterslev J , Friberg H \nTargeted temperature management after cardiac arrest . N Engl J Med \n2014 ;370 :1360 24693900 \nPasero C \nPerioperative rectal administration of nonopioid analgesics . J Perianesth Nurs \n2010 ;25 :5 –6 20159528 \nTremayne V \nEmergency rectal infusion of fluid in rural or remote settings . Emerg Nurse \n2010 ;17 :26 –28 20209752 \nTrout HH \nProctoclysis: some clinical and experimental observations . JAMA \n1912 ;LVIII :1352 –1354 \nZweig SB , Schlosser JR , Thomas SA , Levy CJ , Fleckman AM \nRectal administration of propylthiouracil in suppository form in patients with thyrotoxicosis and critical illness: case report and review of literature . Endocr Pract \n2006 ;12 :43 –47 16524862\n\n",
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"title": "First Use of a New Device for Administration of Buspirone and Acetaminophen to Suppress Shivering During Therapeutic Hypothermia.",
"title_normalized": "first use of a new device for administration of buspirone and acetaminophen to suppress shivering during therapeutic hypothermia"
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"abstract": "In the present study, two female patients with unilateral scleritis without systemic complications were examined. Both patients were suffering from ocular pain and received corticosteroid therapy. The first patient, a 45-year-old woman, was diagnosed with scleritis and iritis in her right eye. Topical corticosteroid treatment could eradicate the iritis but not the scleritis. Oral corticosteroid administration and corticosteroid pulse therapy were applied with little effect. The application of systemic cyclosporine had a satisfactory effect in controlling the scleritis. The other patient, a 60-year-old woman, was suffering from scleritis and lid swelling in her right eye. Not only did topical and systemic corticosteroid therapy prove insufficient, they also resulted in the elevation of her intraocular pressure. After termination of corticosteroid therapy, the systemic cyclosporine was applied orally. Subsequently, the patient's scleritis improved without any severe side effects. Scleritis is a painful and destructive inflammatory disease of the sclera that causes congestion of the scleral venous plexus. In this study, we have established a new grading system for assessing activity in scleritis that can score the extent of ocular pain and the area of congestion. This system provides a practical method for following the clinical course and monitoring the outcome of therapy. We report two cases of unilateral scleritis that were resistant to corticosteroid therapy but responsive to systemic administration of cyclosporine. Findings from these cases indicate that cyclosporine is an effective drug for controlling severe scleritis.",
"affiliations": "Department of Ophthalmology, School of Medicine, Sapporo Medical University, Sapporo, Japan.;Department of Ophthalmology, School of Medicine, Sapporo Medical University, Sapporo, Japan.;Department of Ophthalmology, School of Medicine, Sapporo Medical University, Sapporo, Japan.;Department of Ophthalmology, School of Medicine, Sapporo Medical University, Sapporo, Japan.",
"authors": "Aoki|Haruka|H|;Hiraoka|Miki|M|;Hashimoto|Masato|M|;Ohguro|Hiroshi|H|",
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"fulltext": "\n==== Front\nCase Rep OphthalmolCase Rep OphthalmolCOPCase Reports in Ophthalmology1663-2699S. 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 10.1159/000430490cop-0006-0149Published online: May, 2015Systemic Cyclosporine Therapy for Scleritis: A Proposal of a Novel System to Assess the Activity of Scleritis Aoki Haruka Hiraoka Miki *Hashimoto Masato Ohguro Hiroshi Department of Ophthalmology, School of Medicine, Sapporo Medical University, Sapporo, Japan*Miki Hiraoka, MD, PhD, Department of Ophthalmology, School of Medicine, Sapporo Medical University, S1 W16 Chuo-ku, Sapporo, Hokkaido 060-8543 (Japan), E-Mail mikihira@sapmed.ac.jpMay-Aug 2015 5 5 2015 5 5 2015 6 2 149 157 Copyright © 2015 by S. Karger AG, Basel2015This is an Open Access article licensed under the terms of the Creative Commons Attribution-NonCommercial 3.0 Unported license (CC BY-NC) (www.karger.com/OA-license), applicable to the online version of the article only. Users may download, print and share this work on the Internet for noncommercial purposes only, provided the original work is properly cited, and a link to the original work on http://www.karger.com and the terms of this license are included in any shared versions.In the present study, two female patients with unilateral scleritis without systemic complications were examined. Both patients were suffering from ocular pain and received corticosteroid therapy. The first patient, a 45-year-old woman, was diagnosed with scleritis and iritis in her right eye. Topical corticosteroid treatment could eradicate the iritis but not the scleritis. Oral corticosteroid administration and corticosteroid pulse therapy were applied with little effect. The application of systemic cyclosporine had a satisfactory effect in controlling the scleritis. The other patient, a 60-year-old woman, was suffering from scleritis and lid swelling in her right eye. Not only did topical and systemic corticosteroid therapy prove insufficient, they also resulted in the elevation of her intraocular pressure. After termination of corticosteroid therapy, the systemic cyclosporine was applied orally. Subsequently, the patient's scleritis improved without any severe side effects. Scleritis is a painful and destructive inflammatory disease of the sclera that causes congestion of the scleral venous plexus. In this study, we have established a new grading system for assessing activity in scleritis that can score the extent of ocular pain and the area of congestion. This system provides a practical method for following the clinical course and monitoring the outcome of therapy. We report two cases of unilateral scleritis that were resistant to corticosteroid therapy but responsive to systemic administration of cyclosporine. Findings from these cases indicate that cyclosporine is an effective drug for controlling severe scleritis.\n\nKey Words\nUnilateral scleritisSystemic cyclosporine administrationScoring system\n==== Body\nIntroduction\nScleritis is a serious inflammatory disease that can cause severe ocular pain and occasionally impaired vision. The etiology of scleritis can be idiopathic, autoimmune (it is often associated with systemic diseases such as rheumatoid arthritis, granulomatosis with polyangiitis, and systemic lupus erythematosus), or infectious [1]. The disease can be classified into anterior and posterior types according to the anatomical location of the lesions [2]. Anterior scleritis commonly presents with severe pain not restricted to the eye but also associated with headaches and periorbital pain. Furthermore, anterior scleritis causes congestion of the blood vessels and redness and edema of the sclera. The affected lesion can be sectoral or consist of the entire external anterior sclera. In some cases, scleral thinning and necrosis emerge. The condition of anterior scleritis can be evaluated through the redness of the lesion and ocular pain.\n\nCorticosteroids in topical and/or systemic administration are widely accepted as an effective treatment for noninfectious scleritis [3, 4]. However, there are several cases in which corticosteroid treatment has a minimal effect or its administration must even be terminated due to accompanying side effects. Recently, other immunosuppressive agents have been shown to be effective in improving the outcome of severe scleritis. There are several reports about the successful use of cyclosporine in treating various ocular inflammatory diseases [5].\n\nAssessment of the degree of activity in scleritis is important for patient care. A quantitative grading system of the severity of scleritis is beneficial not only to describe the extent of inflammation in individual cases, but also to trace the therapeutic value.\n\nIn the present report, we describe two cases of idiopathic unilateral anterior scleritis that were unresponsive to topical or systemic corticosteroid therapy but responsive to systemic cyclosporine therapy. Their clinical course was monitored using a unique grading system we designed to assess the manifestation of scleritis.\n\nMaterials and Methods\nThe medical records of two patients with unilateral anterior scleritis were retrospectively reviewed. Scleritis symptoms were graded with scores as described in table 1.\n\nResults\nCase 1\nA 45-year-old woman developed ocular pain and blurred vision in her right eye a month prior to presentation. She initially visited a separate clinic and received intravenous injections of antibiotics. These proved ineffectual, and she was referred to another hospital, where she was diagnosed with iritis with ciliary injection, keratic precipitate, hypopyon, and posterior synechia in her right eye. Topical betamethasone and oral prednisolone (30 mg/day) were applied. Although this treatment proved effective in healing the iritis, the redness and pain in her right eye deteriorated and she was referred to our hospital. Her left eye had mild visual impairment due to a childhood trauma. She did not have any medical history of systemic disease.\n\nThe initial ophthalmic examination disclosed a best-corrected visual acuity (BCVA) of 20/20 in the right eye and 20/32 in the left eye. The intraocular pressure was 15 mm Hg in the right eye and 18 mm Hg in the left eye. A slit-lamp examination demonstrated no sign of uveitis or retinal disease besides conjunctival injection and scleral venous plexus congestion in the right eye. Both eyes showed substantial anterior chamber depth without peripheral anterior synechia. The clinical course is described in figure 1. Results of the laboratory investigations of serum including antinuclear antibodies, anti-double-stranded DNA antibodies, rheumatoid factors, and antineutrophil cytoplasmic antibodies were unremarkable. Serological analysis indicated that there was no active infection.\n\nThe patient continued to receive topical betamethasone and oral prednisolone (10 mg/day), and subconjunctival triamcinolone injections were additionally administered, resulting in modest improvement. Neither topical cyclosporine nor topical antibiotics showed any effect on her ocular symptoms. One month later, brain magnetic resonance imaging indicated that there was no thickening of the posterior sclera or other abnormalities. When oral prednisolone was tapered, the patient's scleral congestion and ocular pain were aggravated. After admission, two sets of pulse therapy with intravenous methylprednisolone (1 g/day for 3 days) following oral prednisolone (40 mg/day) were applied, yielding a moderately positive response. She then received systemic cyclosporine (3 mg/kg/day), administered orally to treat aggravated scleritis, and her ocular symptoms subsequently declined. When the oral prednisolone treatment was terminated and the cyclosporine dosage was reduced to 2 mg/kg/day, the scleritis relapsed. When cyclosporine was increased to 3 mg/kg/day, the trough value was 37 ng/ml, and her right eye developed peripheral cornea edema (fig. 2a). Upon increasing the amount of cyclosporine to 4 mg/kg/day, her ocular symptoms improved (fig. 2b). Although there was another relapse 3 months later, the cyclosporine dosage was retained. Since then, no relapse has occurred even after tapering the cyclosporine. During the clinical course, there was a temporal intraocular pressure elevation which could be maintained by topical antiglaucoma medication. Blood tests were examined monthly to check the trough value of cyclosporine and to monitor the cell counts and biochemical markers, particularly the renal function marker. No side effects resulting from systemic cyclosporine administration were observed.\n\nCase 2\nA 60-year-old woman presented with redness in her right eye. Before admission to our hospital, topical betamethasone was initially administered at another clinic, but there was no response. Moreover, 3 weeks later, a swelling appeared in the right upper eyelid and right lacrimal gland. After oral prednisolone (15 mg/day) was applied, the eyelid swelling diminished, but the redness and pain in the patient's right eye increased and she was referred to our hospital. She did not have any medical history of systemic disease or ocular disease.\n\nThe initial ophthalmic examination disclosed a BCVA of 20/20 in the right eye and 20/16 in the left eye. The intraocular pressure was 21 mm Hg in the right eye and 18 mm Hg in the left eye. A slit-lamp examination indicated conjunctival injection and scleral venous plexus congestion in the right eye, but no sign of uveitis or retinal disease. The clinical course is described in figure 3. Results of the laboratory investigations of serum including antinuclear antibodies, rheumatoid factors, antineutrophil cytoplasmic antibodies, the level of IgG4, and SSA/Ro and SSB/La antibodies were unremarkable. Serological analysis showed no active infection. However, although a computed tomographic scan detected right lacrimal gland enlargement, symptoms such as dry eye or corneal erosion were not seen (fig. 2c). Additionally, the patient showed no symptoms of diplopia or impaired ocular movement.\n\nTopical betamethasone drops and oral prednisolone (30 mg/day) were applied frequently and proved effective. Neither topical cyclosporine nor topical antibiotics showed any effect on her ocular symptoms. During oral prednisolone tapering, the intraocular pressure was elevated to 35 mm Hg in the right eye and 25 mm Hg in the left eye. The intraocular pressure elevation was controlled with topical antiglaucoma medication and the termination of oral and topical corticosteroids. Due to a scleritis relapse, topical betamethasone administration was resumed, but had little effect. Subsequently, systemic cyclosporine (3 mg/kg/day) was administered orally to treat the aggravated scleritis, and this proved effective. A blood test was administered monthly to check the trough value of the cyclosporine and to monitor the influence of the medication. The dosage of cyclosporine administration was reduced gradually without recurrence of scleritis or development of side effects.\n\nDiscussion\nIn the present study, we described two cases that shared similar phenotype traits. First, in both cases, the patients had unilateral anterior scleritis. Their intraocular inflammation was not controlled by the administration of either topical or systemic corticosteroids but showed a greater response to systemic cyclosporine administration. Neither was identified with any systemic disease that could be associated with scleritis.\n\nThe causes of scleritis vary and include infection, autoimmune diseases, and idiopathic diseases. The redness is mostly observed in anterior scleritis with severe pain. When inflammation is reduced, these symptoms will decline. To evaluate the severity and the effect of treatment, it has been necessary to establish an accurate and reproducible system for quantifying the severity of scleritis. At present, there are a few grading systems that make these evaluations [6, 7]. The scoring system proposed by Wakefield and McCluskey [6] is useful in order to assess the presence of complications with other ocular conditions such as uveitis, intraocular pressure elevation, and retinal detachment. However, when using that system, it is difficult to describe differences when the lesion is limited to the sclera. Another grading system described by Sen et al. [7] uses photograph-based methods. Grades are determined by the extent of redness and dilation of scleral vessels. This is a practical system for evaluating the severity of anterior scleritis. However, when calculating mild and modest grades (0.5, 1, and 2), the scores may vary subjectively according to individual graders. To clarify these problems, we have established a new grading system that can assess the severity of scleritis based on common clinical signs, such as the area of inflammation in sclera and ocular pain. This system is simple, rapid, and convenient. In the present study, this grading system was employed to examine its advantages in comparing clinical outcomes.\n\nScleritis often presents with uveitis and retinitis, and it can affect the extraocular muscles. In this study, the first case involved complications with iritis and the second showed complications of lacrimal gland swelling without any symptoms. In both cases, inflammation was controlled successfully through treatment.\n\nAlthough scleritis is not a rare ocular disease, its response to therapy can vary among individual cases, making it difficult to establish a standard protocol of treatment. Topical corticosteroids are usually the first choice of treatment for noninfectious scleritis, but the success rate is reported to be under 50% [8]. Recently, subconjunctival triamcinolone injection treatment has been lauded as an effective means to combat scleritis that does not respond to topical corticosteroids [9]. This treatment was applied to our first case, but remission was minimal.\n\nFor cases that are resistant to topical corticosteroids, systemic corticosteroids are widely considered to be the treatment of choice. Oral prednisolone is commonly administered, and intravenous pulse methylprednisolone is occasionally applied to persistent cases [10, 11]. In our study, both cases were treated with oral prednisolone with unsatisfactory results. In addition, pulse therapy was performed twice in the first patient, but results were insufficient. The long-term application of corticosteroids increases the risk of side effects, including elevated blood glucose. Neither of our cases showed any systemic side effects, but they had an elevation in intraocular pressure. This made it necessary to apply an alternative therapy.\n\nCorticosteroid treatment is the first line of scleritis therapy; however, other immunosuppressive agents are applied additionally when conditions are poorly controlled with corticosteroids alone or when side effects from the corticosteroids make an alternative treatment necessary. Recently, cyclosporine has been recognized as an effective therapeutic agent for several ocular pathologies such as uveitis and scleritis; additionally, it helps prevent rejection after corneal transplantation. It is reported that 2–3.5 mg/kg/day of cyclosporine is effective and has a low risk of side effects. The ideal trough value ranges from 50 to 150 ng/ml [5]. Although the two patients in our study had similar body weights (approximately 50 kg) and initially were administered similar amounts of cyclosporine, there was a great difference between the two cases in the drug concentration of the serum. The trough value in the first case did not exceed 50 ng/ml until cyclosporine administration was increased to 200 mg/day. Conversely, the trough value in the second case was greater than 100 ng/ml even when cyclosporine administration was reduced to 100 mg/day. This discrepancy may depend on the metabolic differences in each patient. The outcomes of our cases suggest that a trough value of approximately 100 ng/ml is efficient to control scleritis. The dosage should be monitored to reduce the overall exposure to the drug and still achieve disease remission.\n\nThe present findings suggest the importance of exploring the trough value of cyclosporine in order to control scleritis without side effects. Further investigations with increased numbers of case studies and statistical analysis may result in the establishment of a standard protocol to treat scleritis.\n\nStatement of Ethics\nThe present study protocol was approved by the Ethics Committee of the Sapporo Medical University School of Medicine and conducted in accordance with the Declaration of Helsinki. After a full explanation of the purpose and protocol for this study was provided to the patients, informed consent was obtained.\n\nDisclosure Statement\nThe authors declare that they have no conflicts of interest.\n\nFig. 1 The clinical course of patient 1. a The extent of anterior scleritis in the right eye. The vertical axis shows the scleritis score. The congestion scores are displayed as triangles, and the ocular pain scores are displayed as circles. b Cyclosporine application and serum concentration. The columns indicate the dose of oral cyclosporine. Dose volume is indicated by the left vertical axis. Circles indicate the dosage of serum cyclosporine concentration as trough value. The dosage is indicated by the right vertical axis. c Administration of corticosteroids. The columns indicate the dose of oral prednisolone. Dose volume is indicated by the left vertical axis. The triangles indicate the application of corticosteroid pulse therapy, and asterisks indicate the subconjunctival triamcinolone injection. The horizontal axis displays the duration of observation.\n\nFig. 2 a Slit-lamp photographs of case 1 at month 8 with congestion in three quadrants of the anterior sclera, which is defined as a score of 3. b Slit-lamp photograph of case 1 in month 10 without congestion in the anterior sclera, which is defined as a score of 0. c Computed tomographic scanning image of the head of case 2; the horizontal section (left panel) and coronal section (right panel) showed right lacrimal gland enlargement.\n\nFig. 3 The clinical course of patient 2. a The extent of anterior scleritis in the right eye. b Cyclosporine application and serum concentration. c The administration of corticosteroids is indicated in columns, and the intraocular pressure is indicated in circles (right eye) or in triangles (left eye). The notations are the same as those in figure 1.\n\nTable 1 Scoring system for scleritis\n\nArea of congestion\tOcular pain\t\t\n0\tNone\t0 (none)\t\t\n1\tOne quadrant\t1 (mild)\tAnalgesic unnecessary\t\n2\tTwo quadrants\t2 (moderate)\tAnalgesic necessary\t\n3\tThree quadrants\t3 (severe)\tAnalgesic insufficient\t\n4\tWhole\n==== Refs\nReferences\n1 Lin P Bhullar SS Tessler HH Goldstein DA Immunologic markers as potential predictors of systemic autoimmune disease in patients with idiopathic scleritis Am J Ophthalmol 2008 145 463 471 18061135 \n2 Watson PG Hayreh SS Scleritis and episcleritis Br J Ophthalmol 1976 60 163 191 1268179 \n3 Watson PG Doyne Memorial Lecture, 1982. The nature and the treatment of scleral inflammation Trans Ophthalmol Soc UK 1982 102 257 281 6963521 \n4 Meyer PA Watson PG Franks W Dubord P ‘Pulsed’ immunosuppressive therapy in the treatment of immunologically induced corneal and scleral disease Eye (Lond) 1987 1 487 495 3443202 \n5 Kacmaz RO Kempen JH Newcomb C Cyclosporine for ocular inflammatory diseases Ophthalmology 2010 117 576 584 20031223 \n6 Wakefield D McCluskey P Cyclosporin therapy for severe scleritis Br J Ophthalmol 1989 73 743 746 2804030 \n7 Sen HN Sangave AA Goldstein DA A standardized grading system for scleritis Ophthalmology 2011 118 768 771 21093921 \n8 McMullen M Kovarik G Hodge WG Use of topical steroid therapy in the management of nonnecrotizing anterior scleritis Can J Ophthalmol 1999 34 217 221 10396658 \n9 Sohn EH Wang R Read R Long-term, multicenter evaluation of subconjunctival injection of triamcinolone for non-necrotizing, noninfectious anterior scleritis Ophthalmology 2011 118 1932 1937 21708408 \n10 Sainz de la Maza M Jabbur NS Foster CS An analysis of therapeutic decision for scleritis Ophthalmology 1993 100 1372 1376 8371926 \n11 McCluskey P Wakefield D Intravenous pulse methylprednisolone in scleritis Arch Ophthalmol 1987 105 793 797 3579710\n\n",
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"issue": "6(2)",
"journal": "Case reports in ophthalmology",
"keywords": "Scoring system; Systemic cyclosporine administration; Unilateral scleritis",
"medline_ta": "Case Rep Ophthalmol",
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"pubdate": "2015",
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"references": "3579710;21708408;1268179;3443202;21093921;18061135;2804030;20031223;8371926;10396658;6963521",
"title": "Systemic Cyclosporine Therapy for Scleritis: A Proposal of a Novel System to Assess the Activity of Scleritis.",
"title_normalized": "systemic cyclosporine therapy for scleritis a proposal of a novel system to assess the activity of scleritis"
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"abstract": "We assessed safety and tolerability of treatment with pirfenidone (1602-2403 mg·day-1) and nintedanib (200-300 mg·day-1) in patients with idiopathic pulmonary fibrosis (IPF).This 24-week, single-arm, open-label, phase IV study (ClinicalTrials.gov identifier NCT02598193) enrolled patients with IPF with forced vital capacity % pred ≥50% and diffusing capacity of the lung for carbon monoxide % pred ≥30%. Before initiating nintedanib, patients had received pirfenidone for ≥16 weeks and tolerated a stable dose of ≥1602 mg·day-1 for ≥28 days. The primary end-point was the proportion of patients who completed 24 weeks of combination treatment on pirfenidone (1602-2403 mg·day-1) and nintedanib (200-300 mg·day-1). Investigators recorded treatment-emergent adverse events (TEAEs), attributing them to pirfenidone, nintedanib, both or neither.89 patients were enrolled; 73 completed 24 weeks of treatment (69 meeting the primary end-point) and 16 discontinued treatment prematurely (13 due to TEAEs). 74 patients had 418 treatment-related TEAEs, of which diarrhoea, nausea and vomiting were the most common. Two patients had serious treatment-related TEAEs.Combined pirfenidone and nintedanib use for 24 weeks was tolerated by the majority of patients with IPF and associated with a similar pattern of TEAEs expected for either treatment alone. These results encourage further study of combination treatment with pirfenidone and nintedanib in patients with IPF.",
"affiliations": "Division of Pulmonary and Critical Care Medicine, University of Michigan, Ann Arbor, MI, USA.;Division of Respirology, University of Calgary, Calgary, AB, Canada.;Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, Medical University of South Carolina, Charleston, SC, USA.;Dept of Respiratory Medicine, EA2363, Avicenne University Hospital, Paris, France.;Atlantic Health System, Overlook Medical Center, Summit, NJ, USA.;Servicio de Neumología, Hospital Universitario de La Princesa, Instituto de Investigación Princesa, Madrid, Spain.;Clinipace-Accovion GmbH, Eschborn, Germany.;Genentech, Inc., South San Francisco, CA, USA.;F. Hoffmann-La Roche, Ltd, Basel, Switzerland.;F. Hoffmann-La Roche, Ltd, Basel, Switzerland.;Dept of Respiratory Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands.",
"authors": "Flaherty|Kevin R|KR|;Fell|Charlene D|CD|;Huggins|J Terrill|JT|;Nunes|Hilario|H|;Sussman|Robert|R|;Valenzuela|Claudia|C|;Petzinger|Ute|U|;Stauffer|John L|JL|;Gilberg|Frank|F|;Bengus|Monica|M|;Wijsenbeek|Marlies|M|",
"chemical_list": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D007211:Indoles; D011728:Pyridones; C093844:pirfenidone; C530716:nintedanib",
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"doi": "10.1183/13993003.00230-2018",
"fulltext": "\n==== Front\nEur Respir JEur. Respir. JERJerjThe European Respiratory Journal0903-19361399-3003European Respiratory Society 10.1183/13993003.00230-2018ERJ-00230-2018Original ArticlesInterstitial Lung Diseases13Safety of nintedanib added to pirfenidone treatment for idiopathic pulmonary fibrosis Safety of nintedanib and pirfenidone treatment for IPFFlaherty Kevin R. 1Fell Charlene D. 2Huggins J. Terrill 3Nunes Hilario 4Sussman Robert 5Valenzuela Claudia 6Petzinger Ute 7Stauffer John L. 8Gilberg Frank 9Bengus Monica 9Wijsenbeek Marlies 101 Division of Pulmonary and Critical Care Medicine, University of Michigan, Ann Arbor, MI, USA2 Division of Respirology, University of Calgary, Calgary, AB, Canada3 Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, Medical University of South Carolina, Charleston, SC, USA4 Dept of Respiratory Medicine, EA2363, Avicenne University Hospital, Paris, France5 Atlantic Health System, Overlook Medical Center, Summit, NJ, USA6 Servicio de Neumología, Hospital Universitario de La Princesa, Instituto de Investigación Princesa, Madrid, Spain7 Clinipace-Accovion GmbH, Eschborn, Germany8 Genentech, Inc., South San Francisco, CA, USA9 F. Hoffmann-La Roche, Ltd, Basel, Switzerland10 Dept of Respiratory Medicine, Erasmus University Medical Center, Rotterdam, The NetherlandsKevin R. Flaherty, Division of Pulmonary and Critical Care Medicine, University of Michigan, 3916 Taubman Center, 1500 East Medical Center Drive, Ann Arbor, MI 48109, USA. E-mail: flaherty@med.umich.edu8 2018 02 8 2018 52 2 180023001 2 2018 16 5 2018 Copyright ©ERS 20182018This ERJ Open article is open access and distributed under the terms of the Creative Commons Attribution Non-commercial Licence 4.0.We assessed safety and tolerability of treatment with pirfenidone (1602–2403 mg·day−1) and nintedanib (200–300 mg·day−1) in patients with idiopathic pulmonary fibrosis (IPF).\n\nThis 24-week, single-arm, open-label, phase IV study (ClinicalTrials.gov identifier NCT02598193) enrolled patients with IPF with forced vital capacity % pred ≥50% and diffusing capacity of the lung for carbon monoxide % pred ≥30%. Before initiating nintedanib, patients had received pirfenidone for ≥16 weeks and tolerated a stable dose of ≥1602 mg·day−1 for ≥28 days. The primary end-point was the proportion of patients who completed 24 weeks of combination treatment on pirfenidone (1602–2403 mg·day−1) and nintedanib (200–300 mg·day−1). Investigators recorded treatment-emergent adverse events (TEAEs), attributing them to pirfenidone, nintedanib, both or neither.\n\n89 patients were enrolled; 73 completed 24 weeks of treatment (69 meeting the primary end-point) and 16 discontinued treatment prematurely (13 due to TEAEs). 74 patients had 418 treatment-related TEAEs, of which diarrhoea, nausea and vomiting were the most common. Two patients had serious treatment-related TEAEs.\n\nCombined pirfenidone and nintedanib use for 24 weeks was tolerated by the majority of patients with IPF and associated with a similar pattern of TEAEs expected for either treatment alone. These results encourage further study of combination treatment with pirfenidone and nintedanib in patients with IPF.\n\nCombined pirfenidone and nintedanib was tolerated by the majority of patients with IPF, encouraging further study\nhttp://ow.ly/1Iq030kaZuD\n\nF. Hoffmann-La Rochehttp://doi.org/10.13039/100007013\n==== Body\nIntroduction\nIdiopathic pulmonary fibrosis (IPF) is a progressive, irreversible, fatal, fibrosing lung disease of unknown cause [1, 2], with a survival rate lower than that reported for many common cancer types [1, 3–5]. Pirfenidone and nintedanib are approved as monotherapies for treatment of IPF [6, 7], and both received a conditional recommendation for use in the 2015 update to the American Thoracic Society (ATS)/European Respiratory Society (ERS)/Japanese Respiratory Society (JRS)/Latin American Thoracic Association (ALAT) clinical practice guideline [8]. Although pirfenidone and nintedanib have both demonstrated efficacy in reducing rates of disease progression compared with placebo, the disease is neither stopped nor reversed and patients continue to experience lung function decline while on treatment [9–11].\n\nThe differing putative mechanisms of action of pirfenidone and nintedanib [12–14] provide a physiological rationale for combining these two agents in an attempt to further reduce lung function decline in patients with IPF [15]. Even though both agents target the fibrotic cascade, decreasing fibroblast and myofibroblast production, and accumulation of extracellular matrix [12–14, 16, 17], evidence suggests that they may target distinct aspects of the fibrotic cascade. Although its mechanism of action has not been fully established, pirfenidone has been shown to act on multiple targets in vitro, including transforming growth factor-β-triggered events, mediated through glioma-associated oncogene homolog 2 [12, 13]. Nintedanib is a tyrosine kinase inhibitor that blocks intracellular signalling of platelet-derived growth factor receptors, fibroblast growth factor receptors and vascular endothelial growth factor receptor [14].\n\nPirfenidone and nintedanib are both associated with gastrointestinal adverse events (AEs), with pirfenidone mainly associated with nausea and nintedanib mainly associated with diarrhoea [9, 10, 18]. A small Japanese randomised, double-blind, phase II dose-escalation trial of nintedanib (100–300 mg·day−1) added to ongoing pirfenidone treatment (≤1800 mg·day−1) for ≤28 days, and its 1-year, open-label extension, indicated that safety and tolerability of combination treatment in patients with IPF was in line with AE profiles for each drug alone [19, 20]. Similarly, the recent INJOURNEY trial, an open-label, randomised trial of pirfenidone (≤2403 mg·day−1) added to nintedanib treatment (≤300 mg·day−1) for 12 weeks, also found that the safety and tolerability profile of combination treatment was comparable with that of the individual drugs [21]. However, there are limited data on long-term safety of combination treatment. Here, we report results from a 24-week study investigating safety and tolerability of adding nintedanib to stable pirfenidone treatment in patients with IPF.\n\nMethods\nPatients\nEligible patients were aged 40–80 years at start of screening, with IPF based on the ATS/ERS/JRS/ALAT 2011 guideline [2]. Patients had received pirfenidone for ≥16 weeks and tolerated a stable dose of 1602–2403 mg·day−1 for ≥28 days without experiencing any moderate or severe adverse reactions considered by the investigator to be related to pirfenidone, or a pirfenidone treatment interruption for >7 days for any reason. Patients also had forced vital capacity (FVC) % pred ≥50% and diffusing capacity of the lung for carbon monoxide (DLCO) % pred ≥30% at screening. Informed consent was obtained from each patient before any study activity or treatment was undertaken. Other inclusion and exclusion criteria are listed in supplementary table S1.\n\nStudy design\nThis was an international, single-arm, open-label, phase IV study (ClinicalTrials.gov identifier NCT02598193) that assessed safety and tolerability of 24 weeks of treatment with pirfenidone (1602–2403 mg·day−1) and nintedanib (200–300 mg·day−1) in patients with IPF (figure 1). Patients started nintedanib treatment that was added to stable pirfenidone treatment on day 1 of the study. Combination treatment administration is further described in the supplementary methods.\n\nFIGURE 1 Study design. ICF: informed consent form. #: patients receiving prohibited medication discontinued that medication during washout (other patients entered directly into screening); ¶: taking place 28–35 days after the end of combination treatment for patients who completed the 24-week combination treatment period, or 28–35 days after the decision to discontinue nintedanib for patients who discontinued prematurely or had treatment interrupted for ≥28 consecutive days.\n\nMedications prohibited during the study are described in supplementary table S2.\n\nAssessments\nThe primary objective was to investigate safety and tolerability of adding nintedanib to stable pirfenidone treatment in patients with IPF. This was assessed with the following end-points. 1) Primary end-point: proportion of patients who completed 24 weeks of combination treatment on pirfenidone (1602–2403 mg·day−1) and nintedanib (200–300 mg·day−1). 2) Secondary end-points: a) proportion of patients who discontinued pirfenidone, nintedanib or both treatments before week 24 due to treatment-emergent AEs (TEAEs; AEs occurring after initiation of combination treatment until 28 days after the last dose of pirfenidone and nintedanib), b) total patient days of combination treatment, c) total duration in days from initiation of combination treatment to discontinuation of pirfenidone, nintedanib or both treatments, and d) frequency and timing of TEAEs and serious TEAEs. Changes from baseline in FVC, DLCO and King's Brief Interstitial Lung Disease (K-BILD) questionnaire [22] score were assessed as exploratory end-points. Further details on study assessments are described in the supplementary methods.\n\nStatistical analysis\nThis study planned to enrol 80 patients based on the sample size prediction described in the supplementary methods.\n\nThe safety population was defined as the population of all patients enrolled who received at least one dose of pirfenidone or nintedanib at baseline. Percentages were calculated based on number of patients with nonmissing data. Confidence intervals were based on a binomial distribution. This was a safety and tolerability study, with only one treatment group, which was not designed to assess efficacy of combination treatment. Thus, no formal statistical hypotheses were assessed and analyses were limited to descriptive statistics with no adjustments for multiplicity of end-points or within-subgroup comparisons.\n\nResults\nIn total, 89 patients were enrolled from 36 centres in Canada, Denmark, France, Germany, Italy, the Netherlands, Spain and the USA between January and November 2016. Baseline patient demographics and characteristics are shown in table 1. Patients had a mean±se FVC % pred 71.8±1.7% and DLCO % pred 48.4±1.3% at baseline (table 1). Measurements of FVC and DLCO closest to 6 months before start of screening were mean±se 72.6±1.7% and 50.0±1.4% (table 1).\n\nTABLE 1 Demographic and baseline characteristics (safety population)\n\nPatients\t89\t\nAge years\t68.2±6.8\t\nMale\t71 (80)\t\nRace\t\t\n White\t84 (94)\t\n Black or African-American\t3 (3)\t\n Other#\t2 (2)\t\nWeight kg\t84.9±15.5\t\nBody mass index kg·m−2\t28.6±4.6\t\nPrevious tobacco use\t61 (69)\t\nDuration of previous pirfenidone treatment months\t20.4±12.3\t\nFVC % pred mean±se\t\t\n Historical value closest to 6 months prior to screening¶\t72.6±1.7\t\n At baseline\t71.8±1.7\t\nPatients categorised by baseline FVC % pred\t\t\n <65%\t32 (36)\t\n 65– <80%\t31 (35)\t\n ≥80%\t26 (29)\t\nDLCO\n% pred mean±se\t\t\n Historical value closest to 6 months prior to screening+\t50.0±1.4\t\n At baseline\t48.4±1.3\t\nData are presented as n, mean±sd or n (%), unless otherwise stated. FVC: forced vital capacity; DLCO: diffusing capacity of the lung for carbon monoxide. #: includes Asian and mixed Asian/White; ¶: mean±sd time from assessment of historical value to screening was 3.0±1.9 months (n=87); +: mean±sd time from assessment of historical value to screening was 3.3±2.6 months (n=87).\n\nThe most commonly reported medical history preferred terms (>10% of patients) were: gastro-oesophageal reflux disease (49 patients (55%)), hypertension (44 patients (49%)), hyperlipidaemia (20 patients (23%)), cough (18 patients (20%)), seasonal allergy (17 patients (19%)), IPF (16 patients (18%); entering IPF as medical history was optional), sleep apnoea syndrome (16 patients (18%)), hypercholesterolaemia (14 patients (16%)), diabetes mellitus (13 patients (15%)), osteoarthritis (12 patients (14%)), allergic rhinitis (11 patients (12%)), hypothyroidism (11 patients (12%)), depression (10 patients (11%)), anxiety (nine patients (10%)), insomnia (nine patients (10%)), benign prostatic hyperplasia (nine patients (10%)) and obesity (nine patients (10%)).\n\nThe most commonly reported concomitant medications (>25% of patients) were: proton pump inhibitors (66 patients (74%)), bronchodilators and antiasthmatics (e.g. salbutamol, ipratropium and budesonide; 52 patients (58%)), statins (41 patients (46%)), vitamins and minerals (41 patients (46%)), steroids (38 patients (43%)), salicylates (35 patients (39%)), antidiarrhoeals (28 patients (32%)), antihistamines (26 patients (29%)), herbal, homeopathic and dietary supplements (24 patients (27%)), and nonsteroidal anti-inflammatory drugs (23 patients (26%)).\n\n73 out of 89 (82%, 95% CI 72.5–89.4%) patients completed 24 weeks of treatment plus follow-up and 69 out of 89 patients (78%, 95% CI 67.4–85.7%) met the primary end-point (completion of 24 weeks of combination treatment at doses of pirfenidone 1602–2403 mg·day−1 and nintedanib 200–300 mg·day−1) (figure 2). For the 16 patients who discontinued treatment prematurely, 13 patients discontinued due to TEAEs, one patient withdrew herself from the study and two patients discontinued for other reasons (one patient did not want to continue nintedanib and the other was listed for a lung transplant) (figure 2).\n\nFIGURE 2 Patient disposition. TEAE: treatment-emergent adverse event. #: combined pirfenidone and nintedanib taken at any dose; ¶: one patient was listed in the active lung transplant list and one patient did not wish to take nintedanib.\n\nThe mean±sd daily doses taken during combination treatment were pirfenidone 2339.3±183.7 mg·day−1 and nintedanib 255.4±43.7 mg·day−1 (including nintedanib titration period doses). Although 78 patients (88%) received the target dose of >1602 mg·day−1 pirfenidone and >200 mg·day−1 nintedanib, 61 patients (69%) received less than the full dose of pirfenidone (2403 mg·day−1) and/or nintedanib (287 mg·day−1 when including nintedanib titration period doses) overall during the study; the majority of patients did so because of temporary dose reductions and/or interruptions following TEAEs. The total number of patient days of combination treatment with pirfenidone and nintedanib was 13 304 days, excluding dose interruptions (the expected patient days on treatment being 14 952 days). Mean±sd duration of treatment during the study period was 21.3±6.3, 20.8±6.2 and 21.4±6.3 weeks for pirfenidone, nintedanib and combination treatment, respectively, excluding dose interruptions. As the exposure analysis considered treatments administered from the start of combination treatment until study drug completion/early discontinuation from combination treatment period (as per the electronic case report form), interruptions of either drug before completion of the combination treatment period caused the mean duration of individual treatments to be shorter than that recorded for combination treatment.\n\n23 patients (26%) had treatment interruptions: one patient (1%) had one interruption of pirfenidone alone, 16 patients (18%) had 28 interruptions of nintedanib alone and six patients (7%) had one interruption each of combination treatment (pirfenidone and nintedanib simultaneously interrupted); interruptions of combination treatment lasted a mean duration of 4.3 days. Mean length of all pirfenidone and nintedanib interruptions was 7.6 and 10.3 days, respectively.\n\n88 patients (99%) experienced 670 TEAEs; these were considered to be related to treatment in 74 patients (83%; 418 treatment-related TEAEs) (table 2). Median (interquartile range) duration of TEAEs was 1.9 (0.3–11.3), 0.4 (0.1–7.1) and 0.5 (0.1–6.4) weeks for TEAEs considered related to pirfenidone, nintedanib, and both pirfenidone and nintedanib, respectively. 67 patients (75%) experienced gastrointestinal treatment-related TEAEs; the majority of gastrointestinal events were attributed by investigators to nintedanib alone (61 patients). Seven patients (8%) experienced treatment-related photosensitivity or rash TEAEs (table 2).\n\nTABLE 2 Summary of common treatment-emergent adverse events (TEAEs) and TEAEs leading to discontinuation (safety population#)\n\n\tPatients with at least one TEAE¶\tPatients with at least one TEAE related to pirfenidone only+\tPatients with at least one TEAE related to nintedanib only+\tPatients with at least one TEAE related to both pirfenidone and nintedanib+\t\nTEAEs occurring in ≥5% of patients\t\n ≥1 TEAE\t88 (99)\t\t\t\t\n ≥1 treatment-related TEAE\t74 (83)\t15 (17)\t67 (75)\t26 (29)\t\n Diarrhoea\t44 (49)\t2 (2)\t38 (43)\t5 (6)\t\n Nausea\t41 (46)\t3 (3)\t31 (35)\t12 (14)\t\n Vomiting\t21 (24)\t1 (1)\t16 (18)\t7 (8)\t\n Decreased appetite\t14 (16)\t2 (2)\t7 (8)\t5 (6)\t\n Fatigue\t11 (12)\t0\t8 (9)\t3 (3)\t\n Dyspepsia\t8 (9)\t1 (1)\t6 (7)\t1 (1)\t\n Headache\t8 (9)\t0\t7 (8)\t1 (1)\t\n Weight decreased\t6 (7)\t1 (1)\t3 (3)\t2 (2)\t\n Photosensitivity or rash TEAEs\t7 (8)\t4 (5)\t2 (2)\t1 (1)\t\n Abdominal pain upper\t5 (6)\t1 (1)\t2 (2)\t2 (2)\t\n Dizziness\t5 (6)\t0\t4 (5)\t1 (1)\t\nTEAEs leading to discontinuation\t\n ≥1 TEAE\t13 (15)\t\t\t\t\n ≥1 treatment-related TEAE\t11 (12)\t0\t10 (11)\t1 (1)\t\n Nausea\t4 (5)\t0\t3 (3)\t1 (1)\t\n Diarrhoea\t4 (5)\t0\t3 (3)\t1 (1)\t\n Fatigue\t2 (2)\t0\t2 (2)\t0\t\n Weight decreased\t2 (2)\t0\t2 (2)\t0\t\n Deep vein thrombosis\t1 (1)\t0\t1 (1)\t0\t\n Epigastric discomfort\t1 (1)\t0\t1 (1)\t0\t\n Malaise\t1 (1)\t0\t1 (1)\t0\t\n Migraine\t1 (1)\t0\t1 (1)\t0\t\n Vomiting\t1 (1)\t0\t1 (1)\t0\t\nData are presented as n (%). #: n=89; ¶: each of the patients could have experienced one or more treatment-related TEAE, with the potential for different events to be related to different treatments; +: assessed by investigators for each therapy using their previous experience with pirfenidone and/or nintedanib, knowledge of the patient, the circumstances surrounding the event, and an evaluation of any potential alternative causes.\n\n13 patients (15%) discontinued treatment due to TEAEs; these TEAEs were attributed to nintedanib alone in 10 patients (11%), both pirfenidone and nintedanib in one patient (1%), and were considered unrelated to either treatment in two patients (2%), as assessed by the investigator (table 2). Discontinuation of combination treatment occurred throughout the trial and there was no clear pattern in the timing of early discontinuation over the treatment period (figure 3).\n\nFIGURE 3 Time to discontinuation (safety population): includes time to early discontinuation or study completion. #: 40 patients completed the planned 24 weeks of combination treatment before study day 168 and were therefore censored on the Kaplan–Meier curve (represented by vertical lines).\n\n18 patients (20%) experienced severe (Common Terminology Criteria for Adverse Events grade ≥3) TEAEs; these were considered treatment-related in six patients (7%) (table 3). 16 patients (18%) experienced 18 serious TEAEs (table 3 and supplementary table S3); two patients (2%) experienced one serious treatment-related TEAE each, both of which were attributed to nintedanib alone: one patient experienced a transient ischaemic attack but continued combination treatment without dose modification, and one patient experienced deep vein thrombosis and discontinued nintedanib but continued pirfenidone treatment. No fatal TEAEs were reported during the study.\n\nTABLE 3 Summary of severe, serious and hepatic treatment-emergent adverse events (TEAEs) (safety population#)\n\n\tPatients with at least one TEAE¶\tPatients with at least one TEAE related to pirfenidone only+\tPatients with at least one TEAE related to nintedanib only+\tPatients with at least one TEAE related to both pirfenidone and nintedanib+\t\nSevere TEAEs§\t\t\t\t\t\n ≥1 TEAE\t18 (20)\t\t\t\t\n ≥1 treatment-related TEAE\t6 (7)\t0\t5 (6)\t1 (1)\t\n Diarrhoea\t2 (2)\t0\t1 (1)\t1 (1)\t\n Nausea\t2 (2)\t0\t2 (2)\t0\t\n Fatigue\t1 (1)\t0\t1 (1)\t0\t\n Muscle spasms\t1 (1)\t0\t1 (1)\t0\t\n Weight decreased\t1 (1)\t0\t1 (1)\t0\t\n Deep vein thrombosis\t1 (1)\t0\t1 (1)\t0\t\nSerious TEAEsƒ\t\t\t\t\t\n ≥1 TEAE\t16 (18)\t\t\t\t\n ≥1 treatment-related TEAE\t2 (2)\t0\t2 (2)\t0\t\n Transient ischaemic attack\t1 (1)\t0\t1 (1)\t0\t\n Deep vein thrombosis\t1 (1)\t0\t1 (1)\t0\t\nHepatic TEAEs\t\t\t\t\t\n ≥1 TEAE\t7 (8)\t\t\t\t\n ≥1 treatment-related TEAE\t6 (7)\t0\t5 (6)\t1 (1)\t\n GGT increased\t2 (2)\t0\t2 (2)\t0\t\n ALT increased\t2 (2)\t0\t2 (2)\t0\t\n AST increased\t1 (1)\t0\t1 (1)\t0\t\n Aminotransferase increased\t1 (1)\t0\t1 (1)\t0\t\n Blood ALP increased\t1 (1)\t0\t1 (1)\t0\t\n Hepatic function abnormal\t1 (1)\t0\t1 (1)\t0\t\n Elevated liver function test\t1 (1)\t0\t1 (1)\t0\t\n Elevated liver enzymes\t1 (1)\t0\t0\t1 (1)\t\nData are presented as n (%). GGT: γ-glutamyltransferase; ALT: alanine aminotransferase; AST: aspartate aminotransferase; ALP: alkaline phosphatase. #: n=89; ¶: each of the patients could have experienced one or more treatment-related TEAE, with the potential for different events to be related to different treatments; +: assessed by investigators for each therapy using their previous experience with pirfenidone and/or nintedanib, knowledge of the patient, the circumstances surrounding the event, and an evaluation of any potential alternative causes; §: grade ≥3 using the AE severity grading scale for the Common Terminology Criteria for Adverse Events (version 4.03) [23]; ƒ: meet any of the following criteria: are fatal or life-threatening, require or prolong inpatient hospitalisation, result in persistent or significant disability or incapacity, are congenital anomalies or birth defects in a neonate or infant born to a mother exposed to study drug, or are significant medical events in the investigator's judgement.\n\nTreatment-related hepatic TEAEs were reported in six patients (7%); these were attributed to nintedanib alone in five patients (table 3). All events were grade 1 (n=4) or grade 2 (n=1) elevations in liver enzymes, or grade 1 abnormal hepatic function (n=1).\n\nIn an exploratory analysis of efficacy, mean±se FVC % pred and DLCO % pred declined by 0.8±0.6% and 1.4±0.8%, respectively, from historical values to baseline and by 0.4±0.5% and 1.9±0.8%, respectively, from baseline to week 24 in patients with available data (supplementary figure S1). An exploratory analysis of K-BILD from baseline to week 24 found that mean±sd total score decreased by 1.3±8.7, and mean±sd individual subscores decreased by 2.4±14.3 for the “psychological” domain, 0.7±15.9 for the “breathlessness and activities” domain, and 3.1±17.0 for the “chest symptoms” domain in patients completing 24 weeks of combination treatment; these changes might be due to chance, as the standard deviations are larger than the decreases (supplementary figure S2).\n\nDiscussion\nThis study found that combined treatment with pirfenidone (1602–2403 mg·day−1) and nintedanib (200–300 mg·day−1) for 24 weeks in 89 patients with IPF was completed by 78% of patients. The safety profile of combination treatment did not reveal a different pattern of TEAEs to that expected with either treatment alone. Most TEAEs affected the gastrointestinal system and were mild to moderate in severity. Furthermore, combination treatment taken for 24 weeks was not associated with increased risk of liver toxicity or photosensitivity. However, frequency of TEAEs (99%) was high for a 6-month study, comparable with frequencies observed in the 12-month pirfenidone and nintedanib monotherapy trials [18, 24]; although common gastrointestinal TEAEs occurred less frequently after 6 months of pirfenidone or nintedanib monotherapy in these studies [25, 26].\n\nResults of this 24-week study are in line with those of the recent 12-week INJOURNEY trial in terms of overall TEAE frequency [21]. Both studies found that combination treatment with nintedanib and pirfenidone had a similar safety profile to that of pirfenidone or nintedanib monotherapy in terms of proportion of patients experiencing TEAEs and types of TEAEs reported. In the current study, patients were already tolerating a stable dose of pirfenidone prior to initiation of nintedanib, which may explain the higher incidence of TEAEs attributed to nintedanib versus pirfenidone by investigators. Similarly, the INJOURNEY trial (in which patients had already shown tolerability to nintedanib prior to initiating pirfenidone) found that more patients in the combination therapy group discontinued pirfenidone than nintedanib, although it should be noted that the study protocol recommended reducing pirfenidone dose before nintedanib dose for management of AEs other than diarrhoea [21].\n\nIn this study, treatment-related diarrhoea (49% of patients) was reported more frequently than any diarrhoea TEAEs in previous studies of pirfenidone monotherapy (25%) [24] and for combination treatment in the INJOURNEY trial (38%) [21], but less frequently than any diarrhoea TEAEs in previous studies of nintedanib monotherapy (62%) [18]. Moreover, treatment-related nausea (46% of patients) was reported by more patients than any nausea TEAEs in previous studies of pirfenidone or nintedanib monotherapy (36% and 24%, respectively) [18, 24] and was comparable with nausea TEAEs reported in the INJOURNEY trial (42%) [21]; however, the durations of the two studies were different, making such comparisons difficult.\n\nAlthough the frequency of some TEAEs was higher in this 24-week study than in studies of each therapy alone, discontinuation rates (18% overall and 15% due to TEAEs) were numerically lower than those over 12 weeks in the INJOURNEY trial and over 52 weeks in the INPULSIS trials, and numerically similar to those over 52 weeks or more in the ASCEND and CAPACITY trials [9–11, 21]. Real-world data from the USA suggest that discontinuation rates for pirfenidone and nintedanib are higher in clinical practice (24% for pirfenidone and 34% for nintedanib; mean follow-up of 8–9 months) than in clinical trials [6, 7, 27]. Therefore, it will be important to further investigate tolerability of combination treatment and develop strategies to help reduce the burden of gastrointestinal TEAEs. Current strategies to reduce nausea associated with pirfenidone include taking each dose with food; for reducing diarrhoea or nausea associated with nintedanib, ensuring adequate hydration and use of antidiarrhoea or antiemetic medications are recommended [6, 7, 28, 29]. Dose adjustments are also recommended for management of AEs with both pirfenidone and nintedanib [6, 7], and available data suggest that dose adjustments have a positive impact on treatment persistence [30] while maintaining the benefit of treatment on FVC decline [31]. In this study, 26% of patients had an interruption of combination treatment, but only 7% had both treatments simultaneously interrupted (for an average interruption length of ∼4 days). This overall rate is similar to other clinical trial data for pirfenidone monotherapy (25%) [31].\n\nThe exploratory efficacy analyses found that there was little decline in lung function during treatment with combined pirfenidone and nintedanib, which is similar to results in the INJOURNEY trial [21]. However, with the absence of a control group and larger sample size, no firm conclusions can be drawn regarding efficacy of combination treatment in patients with IPF. Quality of life, measured using the K-BILD questionnaire, did not worsen in patients who completed 24 weeks of treatment, which is in line with quality of life findings from the EuroQoL-5D questionnaire used in the INJOURNEY trial [21].\n\nThe benefits of combining therapies with different mechanisms of action have been demonstrated in a variety of chronic diseases, including chronic obstructive pulmonary disease, asthma and pulmonary arterial hypertension (PAH) [32, 33]. Evidence from long-term studies in PAH has demonstrated that combination treatments targeting endothelin, nitric oxide and/or prostacyclin pathways have the potential to significantly delay disease progression [33]. Indeed, the treatment strategy for PAH is shifting towards use of first-line combination therapy [32]. Results of the current study suggest that combination treatment with pirfenidone and nintedanib could provide a viable future option for patients with IPF. However, combination therapy might not be suitable for all patients, and further research will be necessary to study long-term benefits and risks of combination treatment in a controlled study with treatment duration of >6 months.\n\nLimitations of this study include the lack of a control or comparator group and small sample size, which are due to the exploratory nature of the study. Furthermore, only patients who tolerated pirfenidone were included, which may introduce a bias towards patients less likely to experience TEAEs, and patients could have treatment interrupted for <28 consecutive days and still be considered to have completed 24 weeks of combination treatment. Thus, tolerance to treatment in the real-world might be less than that reflected in the completion rate. Given that pirfenidone and nintedanib treatment can result in similar AEs [9, 10, 18], there may have been uncertainty regarding whether some TEAEs were related specifically to pirfenidone or nintedanib. As nintedanib was added to stable pirfenidone treatment in this study, conclusions cannot be drawn for pirfenidone added to stable nintedanib treatment or when both treatments are started simultaneously. Although patients with more advanced IPF (FVC % pred <50% and DLCO % pred <30%) might also be expected to benefit from combination treatment, these patients were excluded from the trial. However, eligibility criteria were similar to the pivotal trials [9–11], allowing comparison of safety data between this study and clinical trials of pirfenidone monotherapy. Finally, changes in FVC, DLCO and K-BILD were tested as exploratory end-points, and the study was not designed to formally assess efficacy of combination treatment; historical values were used to compare pre-treatment changes in FVC and DLCO.\n\nConclusions\nCombined use of pirfenidone and nintedanib for 24 weeks was tolerated by the majority of patients with IPF, and associated with similar types of TEAEs and discontinuation rates expected with either treatment alone. Results of this trial add to the limited safety data of combination treatment taken for >3 months, and encourage further study to determine the efficacy and safety of pirfenidone and nintedanib taken as combination treatment versus monotherapy in patients with IPF.\n\nSupplementary material\n10.1183/13993003.00230-2018.Supp1Please note: supplementary material is not edited by the Editorial Office, and is uploaded as it has been supplied by the author.\n\nSupplementary methods. ERJ-00230-2018_Supplement\n\nSupplementary table S1. Additional entry criteria not described within the text. ERJ-00230-2018_Supplementary_Table_S1\n\nSupplementary table S2. Medications prohibited in the 28 days before start of screening and during the study. ERJ-00230-2018_Supplementary_Table_S2\n\nSupplementary table S3. Serious treatment-emergent adverse events (safety population). ERJ-00230-2018_Supplementary_Table_S3\n\nSupplementary figure S1. Exploratory analysis of change in percent predicted a) FVC and b) DLCO (safety population). *: pulmonary function values closest to 6 months before start of screening. DLCO: carbon monoxide diffusing capacity; FVC: forced vital capacity; SE: standard error. ERJ-00230-2018_Supplementary_Figure_S1\n\nSupplementary figure S2. Exploratory analysis of K-BILD (safety population). *: all patients with non-missing data. BA: breathlessness and activities; Chest: symptoms; K-BILD: King’s Brief Interstitial Lung Disease questionnaire; Psych: psychological domains; SD: standard deviation. ERJ-00230-2018_Supplementary_Figure_S2\n\n Acknowledgements\nMedical writing support was provided by Rebekah Waters on behalf of CMC AFFINITY, a division of Complete Medical Communications Ltd, Manchester, UK, funded by F. Hoffmann-La Roche, Ltd. The authors would like to thank the patients that participated in this trial and the research teams that facilitated the trial. The independent data monitoring committee members for this study were Marilyn K. Glassberg (Chair; University of Miami, Miami, FL, USA), Ulrich Costabel (Ruhrlandklinik, Essen, Germany) and Diethelm Messinger (PROMETRIS GmbH, Mannheim, Germany).\n\nThis study is registered at ClinicalTrials.gov with identifier number NCT02598193.\n\nThis article has supplementary material available from erj.ersjournals.com\n\nAuthor contributions: All authors were involved in the design of this study and the interpretation of study results, contributed to the manuscript from the outset, and read and approved the final draft. All authors vouch for the accuracy of the content included in the final manuscript.\n\nConflict of interest: K.R. Flaherty has received consultant and research support fees from F. Hoffmann-La Roche/Genentech and Boehringer Ingelheim, consultant fees from FibroGen, Veracyte, Aeolus, PharmaKea, Sanofi-Genzyme and Celgene, and research support fees from Afferent Pharmaceuticals. C.D. Fell has received consultant and research support fees from F. Hoffmann-La Roche Canada and consultant fees from Boehringer Ingelheim. J.T. Huggins has received consultant and research support fees from F. Hoffmann-La Roche/Genentech and Boehringer Ingelheim, and consultant fees from Gilead and iBIOS. H. Nunes has received consultant and research support fees from F. Hoffmann-La Roche/Genentech and Boehringer Ingelheim, and has been an investigator of clinical trials for Sanofi and Gilead. R. Sussman has received research support and speaker and consultation fees from F. Hoffmann-La Roche/Genentech and Boehringer Ingelheim, and research support from Gilead. C. Valenzuela has received speaker and consultation fees from F. Hoffmann-La Roche and Boehringer Ingelheim. J.L. Stauffer is an employee of Genentech and a former employee of FibroGen, and holds shares from both. F. Gilberg is an employee of F. Hoffmann-La Roche. M. Bengus is an employee of F. Hoffmann-La Roche. M. Wijsenbeek has received speaker and consultation fees and unrestricted research grants from F. Hoffmann-La Roche and Boehringer Ingelheim, and consultancy fees from Galapagos; all fees and grants were paid to her institution.\n\nSupport statement: This trial was funded by F. Hoffmann-La Roche, Ltd. Funding information for this article has been deposited with the Crossref Funder Registry.\n==== Refs\nReferences\n1 Ley B , Collard HR , King TE Jr \nClinical course and prediction of survival in idiopathic pulmonary fibrosis . Am J Respir Crit Care Med \n2011 ; 183 : 431 –440 .20935110 \n2 Raghu G , Collard HR , Egan 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 \n2011 ; 183 : 788 –824 .21471066 \n3 American Cancer Society . Cancer Facts & Figures 2017 \n2017 \nwww.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2017/cancer-facts-and-figures-2017.pdf\nDate last accessed: January 15, 2018 .\n4 Nathan SD , Shlobin OA , Weir N , et al. \nLong-term course and prognosis of idiopathic pulmonary fibrosis in the new millennium . Chest \n2011 ; 140 : 221 –229 .21729893 \n5 Siegel RL , Miller KD , Jemal A \nCancer statistics, 2018 . CA Cancer J Clin \n2018 ; 68 : 7 –30 .29313949 \n6 Food and Drug Administration . Highlights of Prescribing Information Ofev \n2017 \nwww.accessdata.fda.gov/drugsatfda_docs/label/2017/205832s004lbl.pdf\nDate last accessed: March 29, 2018 .\n7 Genentech . Product label: Full prescribing information – Esbriet \n2017 \nwww.gene.com/download/pdf/esbriet_prescribing.pdf\nDate last accessed: January 26, 2018 .\n8 Raghu G , Rochwerg B , Zhang Y , et al. \nAn official ATS/ERS/JRS/ALAT clinical practice guideline: treatment of idiopathic pulmonary fibrosis. An update of the 2011 clinical practice guideline . Am J Respir Crit Care Med \n2015 ; 192 : e3 –e19 .26177183 \n9 Noble PW , Albera C , Bradford WZ , et al. \nPirfenidone in patients with idiopathic pulmonary fibrosis (CAPACITY): two randomised trials . Lancet \n2011 ; 377 : 1760 –1769 .21571362 \n10 King TE Jr, Bradford WZ , Castro-Bernardini S , et al. \nA phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis . N Engl J Med \n2014 ; 370 : 2083 –2092 .24836312 \n11 Richeldi L , du Bois RM , Raghu G , et al. \nEfficacy and safety of nintedanib in idiopathic pulmonary fibrosis . 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"fulltext_license": "CC BY-NC",
"issn_linking": "0903-1936",
"issue": "52(2)",
"journal": "The European respiratory journal",
"keywords": null,
"medline_ta": "Eur Respir J",
"mesh_terms": "D000368:Aged; D000894:Anti-Inflammatory Agents, Non-Steroidal; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis; D007211:Indoles; D038622:Internationality; D008168:Lung; D008297:Male; D008875:Middle Aged; D011728:Pyridones; D016896:Treatment Outcome; D014797:Vital Capacity",
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"pages": null,
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"pmid": "29946005",
"pubdate": "2018-08",
"publication_types": "D017429:Clinical Trial, Phase IV; D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": "21729893;28257580;20935110;29313949;24836312;26647432;25439569;28889759;27903663;25504994;21571362;24836310;21719092;21471066;29212837;26846335;26915984;24639005;26400368;26177183;28148565;28571476;22555278",
"title": "Safety of nintedanib added to pirfenidone treatment for idiopathic pulmonary fibrosis.",
"title_normalized": "safety of nintedanib added to pirfenidone treatment for idiopathic pulmonary fibrosis"
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"companynumb": "US-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2018-BI-034378",
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... |
{
"abstract": "Összefoglaló. A veseátültetés a legnagyobb reményt nyújtja a végstádiumú vesebetegségben szenvedő nők számára, akik teherbe kívánnak esni. A veseátültetett beteg terhessége továbbra is kihívást jelent az immunszuppresszív gyógyszerek mellékhatásai, az allograftfunkció romlásának kockázata, a praeeclampsia és a magas vérnyomás káros anyai szövődményeinek rizikója, valamint a koraszülés, az alacsony születési súly kockázata miatt. A terhesség alatt nagy a magas vérnyomás kialakulásának kockázata, a szérum-kretaininszint emelkedik, és a terhesség végére proteinuria is kialakulhat. Az ajánlott fenntartó immunszuppresszió terhes nőknél a kalcineurininhibitorok (takrolimusz/ciklosporin) és alacsony dózisú szteroid adása, melyek biztonságosnak tekinthetők. Fontos, hogy a gyermekvállalási tanácsadás már a vesetranszplantáció előtt megkezdődjön, és a transzplantációt követően minden klinikai kontroll megtörténjen. Orv Hetil. 2021; 162(23): 924-926. Summary. Kidney transplantation offers the best hope to women with end-stage renal disease who wish to become pregnant. Pregnancy in a kidney transplant recipient continues to remain challenging due to side effects of immunosuppressive medication, risk of deterioration of allograft function, risk of adverse maternal complications of preeclampsia and hypertension, and risk of adverse fetal outcomes of premature birth, low birth weight, and small for gestational age infants. The factors associated with poor pregnancy outcomes include the presence of hypertension, serum creatinine greater than normal range and proteinuria. The recommended maintenance immunosuppression in pregnant women is calcineurin inhibitors (tacrolimus/cyclosporine) and low-dose steroid which are considered safe. It is important that counseling for childbearing should start as early as prior to getting a kidney transplant and should be done at every clinic visit after transplant. Orv Hetil. 2021; 162(23): 924-926.",
"affiliations": "1 Szegedi Tudományegyetem, Általános Orvostudományi Kar, Sebészeti Klinika, Szeged, Semmelweis u 8., 6720.;2 Szegedi Tudományegyetem, Szaknyelvi Kommunikációs és Fordítóképző Csoport, Szeged.;3 Szegedi Tudományegyetem, Általános Orvostudományi Kar, Szülészeti és Nőgyógyászati Klinika, Szeged.",
"authors": "Borda|Bernadett|B|;Keresztes|Csilla|C|;Keresztúri|Attila|A|",
"chemical_list": "D016572:Cyclosporine",
"country": "Hungary",
"delete": false,
"doi": "10.1556/650.2021.32127",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0030-6002",
"issue": "162(23)",
"journal": "Orvosi hetilap",
"keywords": "hypertension; hypertonia; kidney transplantation; pregnancy; terhesség; vesetranszplantáció",
"medline_ta": "Orv Hetil",
"mesh_terms": "D016572:Cyclosporine; D005260:Female; D006801:Humans; D006973:Hypertension; D016030:Kidney Transplantation; D019520:Living Donors; D011247:Pregnancy; D011256:Pregnancy Outcome",
"nlm_unique_id": "0376412",
"other_id": null,
"pages": "924-926",
"pmc": null,
"pmid": "34091439",
"pubdate": "2021-06-06",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Therapy-resistant hypertension in pregnancy after live donor kidney transplantation",
"title_normalized": "therapy resistant hypertension in pregnancy after live donor kidney transplantation"
} | [
{
"companynumb": "HU-SUN PHARMACEUTICAL INDUSTRIES LTD-2022R1-332754",
"fulfillexpeditecriteria": "1",
"occurcountry": "HU",
"patient": {
"drug": [
{
"actiondrug": "3",
"activesubstance": {
"activesubstancename": "METHYLDOPA"
},
"drug... |
{
"abstract": "Trastuzumab emtansine is an antibody-drug conjugate that is effective in human epidermal growth factor receptor-2 expressing advanced breast cancer. Trastuzumab emtansine is generally well tolerated and grade 3-4 toxicities are rare. Pulmonary complications were rarely reported. Here we present a patient presenting with dyspnea after trastuzumab emtansine therapy and treated with a diagnosis of interstitial pneumonitis.",
"affiliations": "Medical Oncology, Osmaniye Public Hospital, Osmaniye.",
"authors": "Alkan|Ali|A|https://orcid.org/0000-0002-8253-5046",
"chemical_list": "D000074322:Antineoplastic Agents, Immunological; D008453:Maytansine; C508053:ERBB2 protein, human; D018719:Receptor, ErbB-2; D000068878:Trastuzumab; D000080044:Ado-Trastuzumab Emtansine",
"country": "England",
"delete": false,
"doi": "10.1177/1078155218813716",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1078-1552",
"issue": "25(7)",
"journal": "Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners",
"keywords": "Trastuzumab emtansine; breast cancer; interstitial pneumonitis",
"medline_ta": "J Oncol Pharm Pract",
"mesh_terms": "D000080044:Ado-Trastuzumab Emtansine; D000368:Aged; D000074322:Antineoplastic Agents, Immunological; D001943:Breast Neoplasms; D005260:Female; D006801:Humans; D017563:Lung Diseases, Interstitial; D008453:Maytansine; D018719:Receptor, ErbB-2; D000068878:Trastuzumab",
"nlm_unique_id": "9511372",
"other_id": null,
"pages": "1798-1800",
"pmc": null,
"pmid": "30426834",
"pubdate": "2019-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Interstitial pneumonitis associated with trastuzumab emtansine.",
"title_normalized": "interstitial pneumonitis associated with trastuzumab emtansine"
} | [
{
"companynumb": "TR-ROCHE-2248652",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "LETROZOLE"
},
"drugadditional": null,
"drug... |
{
"abstract": "Rhabdomyolysis is a known complication of hepatic 3-methylglutaryl coenzyme A reductase (HMG-CoA) inhibitor (statin) therapy for posttransplant hyperlipidemia, and thus monitoring for this effect is indicated. We report a case of an herbal preparation-induced rhabdomyolysis in a stable renal-transplant recipient, attributed to the presence of red yeast rice (Monascus purpureus) within the mixture. The condition resolved when consumption of the product ceased. Rice fermented with red yeast contains several types of mevinic acids, including monacolin K, which is identical to lovastatin. We postulate that the interaction of cyclosporine and these compounds through the cytochrome P450 system resulted in the adverse effect seen in this patient. Transplant recipients must be cautioned against using herbal preparations to lower their lipid levels to prevent such complications from occurring.",
"affiliations": "Division of Nephrology, Department of Medicine, St. Michael's Hospital, University of Toronto, 61 Queen Street East, 9th Floor, Toronto, Ontario M5C 2T2 Canada. prasadr@smh.toronto.on.ca",
"authors": "Prasad|G V Ramesh|GV|;Wong|Timothy|T|;Meliton|Galo|G|;Bhaloo|Salma|S|",
"chemical_list": "D001688:Biological Products; D007166:Immunosuppressive Agents; C117343:red yeast rice; D016572:Cyclosporine; D003577:Cytochrome P-450 Enzyme System",
"country": "United States",
"delete": false,
"doi": "10.1097/00007890-200210270-00028",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1337",
"issue": "74(8)",
"journal": "Transplantation",
"keywords": null,
"medline_ta": "Transplantation",
"mesh_terms": "D000328:Adult; D001688:Biological Products; D016572:Cyclosporine; D003577:Cytochrome P-450 Enzyme System; D019587:Dietary Supplements; D004347:Drug Interactions; D005260:Female; D006801:Humans; D006949:Hyperlipidemias; D007166:Immunosuppressive Agents; D016030:Kidney Transplantation; D008517:Phytotherapy; D012206:Rhabdomyolysis",
"nlm_unique_id": "0132144",
"other_id": null,
"pages": "1200-1",
"pmc": null,
"pmid": "12438974",
"pubdate": "2002-10-27",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Rhabdomyolysis due to red yeast rice (Monascus purpureus) in a renal transplant recipient.",
"title_normalized": "rhabdomyolysis due to red yeast rice monascus purpureus in a renal transplant recipient"
} | [
{
"companynumb": "PHBS2002CA15171",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ENALAPRIL"
},
"drugadditional": "3",
"drugadm... |
{
"abstract": "Patients with acute leukemias of undifferentiated lineage (AUL) generally have guarded prognosis. Here, we describe the first reported pediatric patient with AUL refractory to high-dose chemotherapy who achieved clinical remission with ALL maintenance therapy and 5-azacitidine. His induction remission was followed by consolidation with reduced toxicity haploidentical hematopoietic stem cell transplant (HSCT). At 9 months post-HSCT, the patient is alive and in remission. This combination therapy of remission induction with ALL maintenance therapy and 5-azacitidine and consolidation with reduced toxicity haploidentical HSCT is novel and promising for patients who lack conventional donors and are not candidates for myeloablative therapy.",
"affiliations": "Division of Hematology, Oncology and Marrow and Blood Cell Transplantation, Children's Hospital at Montefiore Medical Center, Bronx, New York.;Division of Hematology, Oncology and Marrow and Blood Cell Transplantation, Children's Hospital at Montefiore Medical Center, Bronx, New York.;Department of Pathology, Montefiore Medical Center, Bronx, New York.;Division of Hematology, Oncology and Marrow and Blood Cell Transplantation, Children's Hospital at Montefiore Medical Center, Bronx, New York.;Division of Hematology, Oncology and Marrow and Blood Cell Transplantation, Children's Hospital at Montefiore Medical Center, Bronx, New York.",
"authors": "Polishchuk|Veronika|V|;Khazal|Sajad|S|;Berulava|Giorgi|G|;Roth|Michael|M|;Mahadeo|Kris M|KM|",
"chemical_list": "D000964:Antimetabolites, Antineoplastic; D001374:Azacitidine",
"country": "United States",
"delete": false,
"doi": "10.1002/pbc.25948",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1545-5009",
"issue": "63(6)",
"journal": "Pediatric blood & cancer",
"keywords": "BMT; chemotherapy; leukemia",
"medline_ta": "Pediatr Blood Cancer",
"mesh_terms": "D000293:Adolescent; D000964:Antimetabolites, Antineoplastic; D001374:Azacitidine; D003131:Combined Modality Therapy; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D060828:Induction Chemotherapy; D007938:Leukemia; D060046:Maintenance Chemotherapy; D008297:Male; D012074:Remission Induction; D014184:Transplantation, Homologous",
"nlm_unique_id": "101186624",
"other_id": null,
"pages": "1111-2",
"pmc": null,
"pmid": "26914221",
"pubdate": "2016-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "5-Azacitidine Monotherapy Followed by Related Haploidentical Hematopoietic Stem Cell Transplantation Achieves Durable Remission in a Pediatric Patient With Acute Undifferentiated Leukemia Refractory to High-Dose Chemotherapy.",
"title_normalized": "5 azacitidine monotherapy followed by related haploidentical hematopoietic stem cell transplantation achieves durable remission in a pediatric patient with acute undifferentiated leukemia refractory to high dose chemotherapy"
} | [
{
"companynumb": "US-DRREDDYS-USA/USA/16/0080255",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
"drugadditiona... |
{
"abstract": "BACKGROUND\nThe veracity of the proportional hazards (PH) requirement is rarely scrutinized in most areas of cancer research, although fulfilment of this assumption underpins widely-used Cox survival models. We sought to critically appraise the existence of prognostic factors with time-dependent effects and to characterize their impact on survival among CLM patients.\n\n\nMETHODS\nConsecutive patients who underwent liver resection with curative intent for CLM at the Singapore General Hospital were identified from a prospectively-maintained database. We evaluated PH of 55 candidate variables, and parameters which departed significantly from proportionality were included in Cox models that incorporated an interaction term to account for time-dependent effects. As sensitivity analyses, we fitted Weibull mixture 'cure' models to handle long plateaus in the tails of survival curves, and also analyzed the restricted mean survival time.\n\n\nRESULTS\n318 consecutive patients who underwent curative liver resection for CLM between Jan 2000 and Nov 2016 were included in this analysis. Hazard ratios for tumor grade (poorly-versus well- and moderately-differentiated) were found to decrease from 3.135 (95% CI: 1.637-6.003) at 12 months to 2.048 (95% CI: 1.038-4.042) after 24 months, and ceased to be significant at 26 months. Compared to left-sided tumors, a right-sided tumor location was found to portend worse prognosis for the first 10 months after resection but subsequently confer a survival benefit due to a crossing of survival curves. Corroborating this observation, long-term cure fractions were estimated to be 25.5% (95% CI: 17.4%-33.6%) and 34.2% (95% CI: 17.4%-50.9%) among patients with left-sided and right-sided primary disease respectively.\n\n\nCONCLUSIONS\nPrimary tumor sidedness and grade appear to exert time-varying prognostic effects in CLM patients undergoing curative liver resection.",
"affiliations": "Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital, Singapore; Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Biostatistics & Modelling Domain, Saw Swee Hock School of Public Health, National University of Singapore, Singapore.;Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital, Singapore.;Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital, Singapore.;Yong Loo Lin School of Medicine, National University of Singapore, Singapore.;Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital, Singapore; Duke-NUS Graduate Medical School, Singapore.;Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital, Singapore; Duke-NUS Graduate Medical School, Singapore.;Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital, Singapore; Duke-NUS Graduate Medical School, Singapore.;Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital, Singapore; Duke-NUS Graduate Medical School, Singapore.;Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital, Singapore; Duke-NUS Graduate Medical School, Singapore.;Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital, Singapore; Duke-NUS Graduate Medical School, Singapore.;Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital, Singapore; Duke-NUS Graduate Medical School, Singapore.;Biostatistics & Modelling Domain, Saw Swee Hock School of Public Health, National University of Singapore, Singapore; Saw Swee Hock School of Public Health, National University of Singapore, Singapore; Biostatistics Core, Investigational Medicine Unit, National University Health System, Singapore.;Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital, Singapore; Biostatistics & Modelling Domain, Saw Swee Hock School of Public Health, National University of Singapore, Singapore.;Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital, Singapore; Duke-NUS Graduate Medical School, Singapore. Electronic address: teo.jin.yao@singhealth.com.sg.",
"authors": "Syn|Nicholas L|NL|;Chua|Darren W|DW|;Raphael Chen|Lionel|L|;Tan|Yu Chuan|YC|;Goh|Brian K P|BKP|;Chung Cheow|Peng|P|;Jeyaraj|Prema Raj|PR|;Koh|Yexin|Y|;Chung|Alexander|A|;Yee Lee|Ser|S|;Lucien Ooi|London|L|;Tai|Bee Choo|BC|;Yip Chan|Chung|C|;Teo|Jin Yao|JY|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.suronc.2021.101586",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0960-7404",
"issue": "38()",
"journal": "Surgical oncology",
"keywords": "Colorectal cancer; Colorectal liver metastases; Hepatectomy; Non-proportional hazards; Survival analysis; Time-varying coefficients",
"medline_ta": "Surg Oncol",
"mesh_terms": null,
"nlm_unique_id": "9208188",
"other_id": null,
"pages": "101586",
"pmc": null,
"pmid": "33933898",
"pubdate": "2021-09",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Time-varying prognostic effects of primary tumor sidedness and grade after curative liver resection for colorectal liver metastases.",
"title_normalized": "time varying prognostic effects of primary tumor sidedness and grade after curative liver resection for colorectal liver metastases"
} | [
{
"companynumb": "SG-AMGEN-SGPSP2021154591",
"fulfillexpeditecriteria": "2",
"occurcountry": "SG",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "PANITUMUMAB"
},
"drugadditional": "4",
... |
{
"abstract": "There is growing recognition that the gut microbiome is an important regulator for neurological functions. This review provides a summary on the role of gut microbiota in various neurological disorders including neurotoxicity induced by environmental stressors such as drugs, environmental contaminants, and dietary factors. We propose that the gut microbiome remotely senses and regulates CNS signaling through the following mechanisms: 1) intestinal bacteria-mediated biotransformation of neurotoxicants that alters the neuro-reactivity of the parent compounds; 2) altered production of neuro-reactive microbial metabolites following exposure to certain environmental stressors; 3) bi-directional communication within the gut-brain axis to alter the intestinal barrier integrity; and 4) regulation of mucosal immune function. Distinct microbial metabolites may enter systemic circulation and epigenetically reprogram the expression of host genes in the CNS, regulating neuroinflammation, cell survival, or cell death. We will also review the current tools for the study of the gut-brain axis and provide some suggestions to move this field forward in the future.",
"affiliations": "Department of Environmental and Occupational Health Sciences, University of Washington, United States.;Department of Environmental and Occupational Health Sciences, University of Washington, United States.;Department of Environmental and Occupational Health Sciences, University of Washington, United States. Electronic address: juliacui@uw.edu.",
"authors": "Dempsey|Joseph L|JL|;Little|Mallory|M|;Cui|Julia Yue|JY|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.neuro.2019.08.005",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0161-813X",
"issue": "75()",
"journal": "Neurotoxicology",
"keywords": "Gut microbiome; Gut-brain axis; Neurotoxicants",
"medline_ta": "Neurotoxicology",
"mesh_terms": "D000818:Animals; D000069196:Gastrointestinal Microbiome; D006801:Humans; D009422:Nervous System Diseases; D020258:Neurotoxicity Syndromes",
"nlm_unique_id": "7905589",
"other_id": null,
"pages": "41-69",
"pmc": null,
"pmid": "31454513",
"pubdate": "2019-12",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't; D016454:Review",
"references": "20579100;29051531;15279046;24111650;23852585;17909124;26679775;10683198;28234468;26468932;29240834;18218342;29211769;15891087;20413691;28111203;23396248;24270005;29095058;29371629;29731182;9741971;29471018;29260466;24333160;23390181;21419222;11121824;18470311;27893703;9534869;28283098;26336637;30254641;27268458;23263478;20051220;15219393;27468758;8725628;29783199;30471306;29262868;30234616;29471030;27520820;22990135;29941795;28358907;27591074;18096363;29787855;26248026;30072879;30089656;28973555;16244432;30001426;26898931;30575732;29854581;30269309;25766736;29035044;28881854;26580313;24413286;24888394;25940477;27988330;29743478;15105259;28965876;25866195;30101312;30423371;1701293;28220542;25288760;25545766;30870710;30268819;30273187;28888971;30051546;30443602;19337518;30160334;23632211;27127406;30373033;25629821;18332718;26797809;16934682;25830558;22902524;27491067;29571571;22997101;25882912;30579705;22866812;26427004;30670726;27760213;26683664;23844187;28691768;30420013;15870311;20338517;23064760;29804833;26868600;24505278;21068828;26682545;30544486;30107083;17718779;31175044;29700420;23224412;29097220;26962054;19716187;29352709;25937051;23135753;17101327;21261675;29614050;26563787;29943971;26261284;20103495;30368255;26549647;18262273;25404571;3876510;21926974;23021477;27814521;30099890;27067014;30406643;30155748;26323631;30423465;29356515;25643018;30688258;28369659;7886816;27018521;27910808;3879207;27376980;28546539;30521978;29545800;30470860;23894355;26261286;30518709;28610994;27203275;29220800;29520144;26626101;30555669;18656495;30154787;28652852;29933742;25658522;17324953;28636959;21727249;29096310;28431184;25402818;30417952;10825391;14594622;26720637;27280682;27716401;29574035;30283047;21593570;29678920;30131809;30136734;19571431;27050322;23608136;28195358;17826170;29171095;17965931;30518676;29601608;27780071;17904639;30384844;29358918;28731859;26777404;29633335;29137973;28035686;25773227;28069751;29160065;28943228;29524051;29950287;28966571;27836847;30374951;30075011;23219589;26989786;29992812;2579853;26947707;30503971;27912057;26918244;19211529;30024041;3117664;29729565;30619212;30428632;24145453;28259042;19014856;25956306;16091364;3091040;28863139;28304169;17587308;21793581;7539162;29881346;30775438;29475860;24636517;30614568;27288567;18438459;26667159;27443609;18351120;24197220;30620405;29100122;25567229;28874832;10761674;23564643;30564103;28176819;26428446;29231279;25353033;3319563;28721242;3726869;29750384;23638009;29582256;29391526;30553491;28528896;28700459;24956966;29475651;28938872;18355640;23326376;27620386;20359995;26972811;28241991;30556271;29674211;28993728;30040410;20446689;26416623;29109040;27827942;29977230;8117145;25105361;27981187;18779308;25690713;10788395;24325943;9226253;20603222;27012897;21679971;30149534;29529432;28887203;30394313;27541692;16002369;29030867;27779624;24636977;27459363;23873346;24062644;25064009;30158912;11449010;30135504;2989436;30321601;28392238;30105432;27567860;29843725;28578396;29537705;30801026;9843779;29751049;30531975;27274912;29564487;29036812;21683297;29808406;19957996;2176588;21458859;15310231;26255803;16260528;27229737;29662737;9745906;26531143;30124852;24130822;28636668;30187502;28674046;30249635;3034844;25038100;27189265;28983453;19664822;30352012;30357543;30171422;21054680;31068712;16119031;15133062;17173049;29635013;27575730;20064778;27767329;29571898;23807240;30111623;9870138;26851597;29580894;28270159;28418756;29410659;24007415;29769268;26529668;30422728;28115022;30496201;28219800;29104061;28115375;29276488;15831718;28349974;21282636;25293764;29432299;22254083;27579024;28215162;27810535;28864748;29131365;30388595;29898983;11100151;25704299",
"title": "Gut microbiome: An intermediary to neurotoxicity.",
"title_normalized": "gut microbiome an intermediary to neurotoxicity"
} | [
{
"companynumb": "US-OTSUKA-2019_033223",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ARIPIPRAZOLE"
},
"drugadditional": "3",
... |
{
"abstract": "To analyze and summarize the clinical characteristics, treatments, and prognosis of Cushing's syndrome (CS) with nocardiosis.\n\n\n\nA patient in our hospital and additional 17 patients of CS with nocardiosis in the English literature were included in this study. Clinical characteristics, laboratory data, imaging studies, treatments, and prognosis were evaluated.\n\n\n\nA 41-year-old man with CS was diagnosed and treated in our hospital. He had co-infections of nocardiosis and aspergillosis. Together with 17 patients of CS with nocardiosis in the English literature, 2 patients (11.1%) were diagnosed as Cushing's disease (CD) while 16 (88.9%) were diagnosed or suspected as ectopic ACTH syndrome (EAS). The average 24hrUFC was 7,587.1 ± 2,772.0 μg/d. The average serum total cortisol and ACTH (8 AM) was 80.2 ± 18.7 μg/dl and 441.8 ± 131.8 pg/ml, respectively. The most common pulmonary radiologic findings in CT scan were cavitary lesions (10/18) and nodules (8/18). Co-infections were found in 33.3% (6/18) patients. The CS patients with co-infections had higher levels of ACTH (671.5 ± 398.2 vs 245.5 ± 217.1 pg/ml, P = 0.047), and 38.9% (7/18) patients survived through the antibiotic therapy and the treatment of CS. Patients with lower level of ACTH (survival vs mortality: 213.1 ± 159.0 vs 554.7 ± 401.0 pg/ml, P = 0.04), no co-infection, underwent CS surgery, and received antibiotic therapy for more than 6 months, had more possibilities to survive.\n\n\n\nNocardia infection should be cautioned when a patient of CS presented with abnormal chest radiographs. The mortality risk factors for CS with nocardiosis are high level of ACTH and co-infections. We should endeavor to make early etiological diagnosis, apply long-term sensitive antibiotics and aggressive treatments of CS.",
"affiliations": "Department of Endocrinology, Key Laboratory of Endocrinology of National Health Commission, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Science, Beijing, China.;Department of Endocrinology, Key Laboratory of Endocrinology of National Health Commission, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Science, Beijing, China.;Department of Endocrinology, Key Laboratory of Endocrinology of National Health Commission, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Science, Beijing, China.;Department of Endocrinology, Key Laboratory of Endocrinology of National Health Commission, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Science, Beijing, China.;Department of Endocrinology, Key Laboratory of Endocrinology of National Health Commission, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Science, Beijing, China.;Department of Endocrinology, Key Laboratory of Endocrinology of National Health Commission, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Science, Beijing, China.;Department of Infectious Diseases, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Science, Beijing, China.",
"authors": "Zhang|Da|D|;Jiang|Yan|Y|;Lu|Lin|L|;Lu|Zhaolin|Z|;Xia|Weibo|W|;Xing|Xiaoping|X|;Fan|Hongwei|H|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fendo.2021.640998",
"fulltext": "\n==== Front\nFront Endocrinol (Lausanne)\nFront Endocrinol (Lausanne)\nFront. Endocrinol.\nFrontiers in Endocrinology\n1664-2392\nFrontiers Media S.A.\n\n10.3389/fendo.2021.640998\nEndocrinology\nCase Report\nCushing’s Syndrome With Nocardiosis: A Case Report and a Systematic Review of the Literature\nZhang Da 1 2\n\nJiang Yan 1 *\n\nLu Lin 1\n\nLu Zhaolin 1\nXia Weibo 1\nXing Xiaoping 1\n\nFan Hongwei 3\n1 Department of Endocrinology, Key Laboratory of Endocrinology of National Health Commission, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Science, Beijing, China\n2 Department of Endocrinology, Air Force Medical Center, Beijing, China\n3 Department of Infectious Diseases, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Science, Beijing, China\nEdited by: Antongiulio Faggiano, Sapienza University of Rome, Italy\n\nReviewed by: Andrea M. Isidori, Sapienza University of Rome, Italy; Hans Ghayee, University of Florida, United States\n\n*Correspondence: Yan Jiang, sinojenny@126.com\nThis article was submitted to Cancer Endocrinology, a section of the journal Frontiers in Endocrinology\n\n29 3 2021\n2021\n12 64099813 12 2020\n08 2 2021\nCopyright © 2021 Zhang, Jiang, Lu, Lu, Xia, Xing and Fan\n2021\nZhang, Jiang, Lu, Lu, Xia, Xing and Fan\nhttps://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.\nObjective\n\nTo analyze and summarize the clinical characteristics, treatments, and prognosis of Cushing’s syndrome (CS) with nocardiosis.\n\nMethods\n\nA patient in our hospital and additional 17 patients of CS with nocardiosis in the English literature were included in this study. Clinical characteristics, laboratory data, imaging studies, treatments, and prognosis were evaluated.\n\nResults\n\nA 41-year-old man with CS was diagnosed and treated in our hospital. He had co-infections of nocardiosis and aspergillosis. Together with 17 patients of CS with nocardiosis in the English literature, 2 patients (11.1%) were diagnosed as Cushing’s disease (CD) while 16 (88.9%) were diagnosed or suspected as ectopic ACTH syndrome (EAS). The average 24hrUFC was 7,587.1 ± 2,772.0 μg/d. The average serum total cortisol and ACTH (8 AM) was 80.2 ± 18.7 μg/dl and 441.8 ± 131.8 pg/ml, respectively. The most common pulmonary radiologic findings in CT scan were cavitary lesions (10/18) and nodules (8/18). Co-infections were found in 33.3% (6/18) patients. The CS patients with co-infections had higher levels of ACTH (671.5 ± 398.2 vs 245.5 ± 217.1 pg/ml, P = 0.047), and 38.9% (7/18) patients survived through the antibiotic therapy and the treatment of CS. Patients with lower level of ACTH (survival vs mortality: 213.1 ± 159.0 vs 554.7 ± 401.0 pg/ml, P = 0.04), no co-infection, underwent CS surgery, and received antibiotic therapy for more than 6 months, had more possibilities to survive.\n\nConclusions\n\nNocardia infection should be cautioned when a patient of CS presented with abnormal chest radiographs. The mortality risk factors for CS with nocardiosis are high level of ACTH and co-infections. We should endeavor to make early etiological diagnosis, apply long-term sensitive antibiotics and aggressive treatments of CS.\n\nCushing’s syndrome\nnocardiosis\ninfection\nectopic ACTH syndrome\nCushing’s disease\nChinese Academy of Medical Sciences10.13039/501100005150\n==== Body\nIntroduction\n\nEndogenous Cushing’s syndrome (CS) is characterized by excessive elevation of glucocorticoid concentrations produced by adrenal cortex. It is generally divided into adrenocorticotropic hormone (ACTH)-dependent and ACTH-independent CS. The most common cause of CS is corticotropin-secreting pituitary adenoma that leads to Cushing’s disease (CD). The ectopic ACTH syndrome (EAS) accounts for 10 to 20% of ACTH-dependent CS (1).\n\nNocardiosis most frequently presents with pulmonary disease, followed by disseminated disease, extra-pulmonary disease [such as in the central nervous system and primary skin and soft tissue disease (2)]. Nocardiosis is regarded as an opportunistic infection, with the majority of infections occurring in immunocompromised patients, including those with long-term corticosteroid exposure, malignancy, human immunodeficiency virus (HIV) infection, and history of transplantation (3–7), associated with high mortality of 34.5–40% (3, 4). Xu L. et al. (8) reviewed 12 patients of nocardiosis in EAS patients. However, reports of nocardiosis in patients with other forms of CS were not included.\n\nIn this study, we presented a patient of nocardiosis with suspected EAS in our hospital and analyzed 17 patients of nocardiosis in CS reported in the literature to summarize the clinical characteristics, treatments, and prognosis of CS with nocardiosis.\n\nMethods\n\nMedical Information of This Case\n\nWe collected the clinical characteristics, laboratory data, imagings, and microbiology results of a patient of CS with nocardiosis in Peking Union Medical College Hospital (PUMCH). This study was approved by the Ethics Committee of PUMCH.\n\nLiterature Review\n\nA systematic literature review was conducted through searched PubMed, Web of Science, and Embase, finding all relevant and available articles published in English. MeSH terms included “Cushing’s syndrome,” “Nocardia Infections,” or “nocardiosis.” Original research, case reports, case series, or review articles published until October, 2020 with detail medical history and laboratory data were included. Studies which analyzed cases of exogenous CS were excluded.\n\nStatistical Analysis\n\nData management and analysis were performed using SPSS 20.0 (SPSS Inc., Chicago, IL, USA). Data were presented as proportions for categorical variables and mean SD or median (interquartile range) for continuous variables. Significant differences between groups for continuous variables were tested using a t-test or the nonparametric Mann–Whitney U test, as appropriate. χ2 tests were used for comparisons of categorical data.\n\nResults\n\nCase Presentation\n\nA 41-year-old man developed fatigue for 2 months with progressive polydipsia and polyuria. A month ago, he went to the local hospital and had the examination revealed that his blood pressure was 150/100 mmHg and his fasting blood-glucose was 17 mmol/L. He was given insulin treatment afterwards. However, he could not uphold the regular treatment and his blood glucose could not be well controlled. He manifested fever of 38.4°C and cough with yellow phlegm following catching a cold 6 days ago. The patient gradually presented with mental disorders of mania and aggressive behavior for 4 days. He was urgently referred to our hospital. On admission, the man appeared weak and confused, thinning of the skin with pigmentation, bruising and edema of face and both lower extremities but no red-purple striae. He presented with mild moon face, no obvious buffalo hump. In laboratory examinations, serum glucose was 24.8 mmol/L, sodium 164 mmol/L, potassium 2.6 mmol/L, albumin 21g/L, creatine 102 μmol/L. Arterial blood gas analysis demonstrated of metabolic alkalosis. The X-ray of chest showed patch shadows of left middle lobe and right upper lobe. Insulin therapy, potassium supplements (oral potassium chloride, 9.0 g/d), spironolactone 60 mg/d, intravenous fluids, and empirical antibiotics moxifloxacin were applied. The patient’s consciousness, serum glucose, and sodium returned to normal 2 days later. He got a normal body temperature and less cough with phlegm 5 days later. On the 6th day, chest CT showed patchy infiltration and small nodules of bilateral lung lobes ( Figures 1A, B ).\n\nFigure 1 Clinical images of our patient. CT scanning of the chest showing continuous development to a large cavitary mass in both lung lobes. (A, B) were taken on the 6th day. (D, E) were taken on the 15th day. (C, F) MRI scanning showing multiple long T1/T2 signal lesions in the brain on the 24th day.\n\nExaminations for CS were performed a week after his admission when the patient’s condition was improved. His serum ACTH was 171 pg/ml (normal range <46 pg/ml), 24-h urinary free cortisol (24hrUFC) was 3,522 μg (normal range 12.3–103.5 μg/24 h), repeated 24hrUFC was 2746 μg. The baseline serum cortisol was 51.21 μg/dl (normal range 4.0–22.3 μg/dl), after overnight 1 mg dexamethasone suppression test (DST) and high-dose DST were 58.76 and 62.74 μg/dl respectively. CS was diagnosed according to the clinical practice guideline of the diagnosis of CS (9). MRI scanning of pituitary gland showed no abnormal signal. In consideration of diabetes and hypertension in young age, mild physical appearance of CS, repeated high levels of 24hrUFC, and no suppression in 1 mg DST, the diagnosis of CS was established. Furthermore, because of rapid onset and severe conditions of the patient with the extreme cortisol excess, markedly elevated ACTH level, no suppression in high-dose overnight DST, no space-occupying lesion in pituitary gland, ectopic ACTH syndrome (EAS) was suspected. But CT scanning of chest and abdomen and 99mTc-octreotide scintigraphy gave no clue for the ectopic location of ACTH-secreting tumor.\n\nChest CT on the 15th day demonstrated multiple enlarged nodules, partial cavitary lesions ( Figures 1D, E ). Lung cancer was suspected but no tumor cell was founded in lung tissues from biopsy. GM test was positive. Modified acid-fast stains of sputum and lung tissues from percutaneous lung needle biopsy showed filamentous branching organisms. Sputum culture after 72 h grew Aspergillus fumigates and Nocardia cyriacigeorgica. Lung tissue culture after 48 h grew Nocardia cyriacigeorgica. Although trimethoprim-sulfamethoxazole (TMP-SMZ), ceftriaxone combined amphotericin B were used, the patient’s situation deteriorated with head MRI scanning displaying multiple long T1/T2 signal lesions suggesting multiple brain abscesses on the 24th day ( Figures 1C, F ). We suspected the patient had the brain Nocardia or Aspergillus infections. Unfortunately, he refused further medication and died after auto discharge.\n\nLiterature Review\n\nSeventeen CS with nocardiosis patients from 15 published reports (8, 10–23) were reviewed. Together with our case, 18 CS patients (11 male, 7 female) were identified. Patients were HIV negative and had no history of organ transplantation, no use of immunosuppression therapy. The clinical characteristics were summarized in Table 1 . The average age of patients was 41.9 ± 5.0 years. Eight patients (44.4%) had hypertension and 14 patients (77.8%) had diabetes mellitus. The causes of CS were all ACTH-dependent. Two patients (11.1%) were diagnosed as CD while nine patients (50.0%) diagnosed as EAS and seven patients (38.9%) with suspected as EAS of unknown origin including our patient. The ectopic ATCH originated from bronchial carcinoid (3/18), pancreatic neuroendocrine tumor (2/18), small cell lung carcinoma (1/18), paraganglioma (1/18), neuroblastoma (1/18), and small cell carcinoma in rib (1/18). The average 24hrUFC was 7,587.1 ± 2,772.0 μg/d. The average serum total cortisol and ACTH (8 AM) was 80.2 ± 18.7 μg/dl and 441.8 ± 131.8 pg/ml, respectively. Serum cortisol levels of 11 EAS and 2 CD were above 43.1 μg/dl. The 24hrUFC levels of 11 EAS were above 2,000 μg/d. Totally, serum cortisol or 24hrUFC levels were above these levels in 83.3% (15/18) patients.\n\nTable 1 Clinical characteristics, diagnosis, treatments, and outcomes of 18 patients of Cushing’s syndrome with nocardiosis.\n\nAuthors\tCountry\tAge (year)\tGender\tHTN\tDM\t24hr UFC (μg)\tACTH (pg/mL)\tSerum total cortisol (μg/dl)\tCause of Cushing’s syndrome\tInfection sites\tChest imaging\tCo-infection\tAntibiotics\tTreatment of Cushing’s syndrome\tOutcome\t\nPetersen DP, 1981 (10)\tU.S.\t72\tF\tNo\tNo\tNA\televated\televated\tEAS origin from pulmonary carcinoid tumor\tlung and skin\tnodules\tnone\tTMP-SMZ\tMitotane\tmortality\t\nNatale RB, 1981 (11)\tU.S.\t24\tM\tNo\tYes\t1,1820\t902\t110\tEAS origin from bronchial carcinoid\tlung\tinfiltrated and cavitary lesion\tPneumocystis carinii\tTMP-SMZ\tmetapyrone and bilateral adrenalectomy\tmortality\t\nHiggins TL, 1982 (12)\tU.S.\t47\tM\tNo\tYes\t882\t1,128\t44\tEAS origin from pancreatic neuroendocrine tumor\tlung\tnodules\tE. coli and Pseudomonas\tintravenous sulfadiazine and oral cycloserine\tmetyrapone, aminoglutethimide,5-fluorouracil, streptozocin, and Cytoxan\tmortality\t\nFindlay JC, 1992 (13)\tU.S.\t71\tF\tYes\tYes\tNA\tNA\t47.8\tCushing’s disease\tlung and brain\tcavitary lesion\tnone\tsulfadiazine\taminoglutethimide and metyrapone\tmortality\t\nBoscaro M, 1994 (14)\tItaly\t27\tM\tNo\tNo\t980\t48.5\t27\toccult EAS\tlung, brain, and abdomen\tinfiltration\tnone\tTMP-SMZ\tmetyrapone + aminoglutethimide followed by bilateral adrenalectomy\tsurvival\t\nHuang TP, 1994 (15)\tChina\t25\tM\tNo\tYes\t8,454\t725\t62\tEAS origin from rib small cell carcinoma\tlung\tnodules and cavitary lesion\tnone\tNA\tketoconazole\tmortality\t\nBeinart GA, 2003 (16)\tU.S.\t68\tM\tYes\tYes\t4,322\t519\t82\tEAS origin from metastatic small cell lung carcinoma\tlung\tconsolidation and cavitary lesion\tAspergillus, Clostridium difficile colitis, enterococcal bacteremia\tTMP-SMZ\tcarboplatin, etoposide, ketoconazole\tmortality\t\nChrysanthidis T, 2010 (17)\tGreece\t52\tF\tNo\tYes\t>1812\t79\t20.3\toccult EAS\tlung, brain, and skin\tinfiltration\tnone\tmeropenem, gentamicin, and minocycline\tketoconazole\tmortality\t\nSutton BJ, 2011 (18)\tU.S.\t42\tF\tNo\tNo\tNA\t152\tNA\tEAS origin from pulmonary carcinoid tumor\tlung\tnodules\tnone\tTMP-SMZ\tRFA of the carcinoid tumor\tsurvival\t\nChowdry RP, 2012 (19)\tU.S.\t48\tF\tNo\tYes\t16,340\t296\t106.2\tEAS origin from pancreatic neuroendocrine cancer\tlung and blood\tnodules and pleural effusion\tE. coli and Pneumocystis jirovechi\tTMP-SMZ\tketoconazole\tmortality\t\nMomah N, 2012 (20)\tU.S.\t42\tM\tYes\tYes\t21,469\t1,013\t130\toccult EAS\tlung and brain\tcavitary lesion\tmethicillin-sensitive Staphylococcus aureus, Pneumocystosis and brain aspergillosis\tTMP-SMZ\tketoconazole, octreotide, and radical thymectomy and mediastinectomy\tmortality\t\nRizwan A, 2014 (21)\tPakistan\t53\tM\tYes\tYes\t2,000\t68.5\t20\toccult EAS\tlung\tcavitary lesion\tnone\tTMP-SMZ\tbilateral adrenalectomy\tsurvival\t\nRizwan A, 2014 (21)\tPakistan\t54\tM\tYes\tYes\t27,216\t159\t134\toccult EAS with multiple metastasis\tlung\tcavitary lesion\tnone\tTMP-SMZ\tnone\tmortality\t\nRizwan A, 2014 (21)\tPakistan\t38\tM\tYes\tYes\t9,088\t255\t192\toccult EAS\tlung\tconsolidation and pleural effusion\tnone\tTMP-SMZ\tketoconazole\tsurvival\t\nXu L, 2016 (8)\tChina\t35\tM\tYes\tYes\t3,118.08\t372\t>50\tEAS origin from mediastinal paraganglioma\tlung\tnodules and cavitary lesion\tnone\tTMP-SMZ\tresection of the mediastinal tumor\tsurvival\t\nKobayashi K, 2018 (22)\tJapan\t52\tF\tNo\tNo\tNA\t469\t59.6\tEAS origin from olfactory neuroblastoma\tlung\tnodules\tnone\tTMP-SMZ\tmetyrapone and mitotane\tsurvival\t\nMylonas CC, 2019 (23)\tGreece\t40\tF\tYes\tYes\tNA\t126.9\t61.5\tCushing’s disease\tlung\tnodules and cavitary lesion\tnone\tTMP-SMZ\ttranssphenoidal pituitary surgery\tsurvival\t\nOur case, 2020\tChina\t41\tM\tNo\tYes\t3,522\t171\t51.2\toccult EAS\tlung and brain\tcavitary lesion\tAspergillus\tTMP-SMZ, ceftriaxone and amphotericin B\tnone\tmortality\t\n\nThe pulmonary nocardiosis related symptoms varied including fever, cough, expectoration, dyspnea, chest pain, and hemoptysis. Seven patients were confused and six patients progressed to respiratory failure that required intubation and mechanical ventilation. Three patients had only chest imaging changes with no fever or any pulmonary symptoms. The pulmonary radiologic findings included cavitary lesions (10/18), nodules (8/18), infiltration (3/18), consolidation (2/18), and pleural effusion (2/18) ( Table 1 ). Multiple pulmonary radiologic findings manifested in one patient. The diagnosis of nocardiosis was established by modified acid-fast and/or methenamine silver stain and culture from sputum, bronchoalveolar lavage fluid (BALF), or biopsy tissues of lung, skin, and brain lesions. Pulmonary nocardiosis was diagnosed in all patients. Other infection sites of Nocardia were brain (5/18), skin (2/18), blood (1/18), and paravertebral site (1/18). Co-infections were found in 33.3% (6/18) patients. Co-infected microorganisms included Pneumocystis jirovechi (3/18), Aspergillus (3/18), Escherichia coli (2/18), Clostridium difficile (1/18), Enterococcus (1/18), Pseudomonas (1/18), and Staphylococcus aureus (1/18) ( Table 1 ). Diagnosis time of Nocardia was variant. The shortest time for identification of Nocardia was 3 days after symptoms onset. In some patients, the Nocardia identification time lasted for several weeks, even after the patients’ death.\n\nFourteen patients were treated with TMP-SMZ for nocardiosis. Due to the resistance of TMP-SMZ, one patient was treated with meropenem and gentamicin. The duration of antibiotic therapy lasted from 3 days to 1 year. The treatment of CS included surgery and medical therapy. Transsphenoidal pituitary surgery was performed in one patient, resection or radiofrequency ablation (RFA) of EAS tumor in three patients, bilateral adrenalectomy in three patients. Drugs that reduced cortisol levels, including ketoconazole, metapyrone, mitotane, and cytotoxic drugs, were used in 12 patients. In terms of prognosis, 11/18 (61.1%) patients died. Eight patients died of infections and three patients died of progression of malignancy. The average ACTH, cortisol, and 24hr UFC level of mortality and survival were 554.7 ± 401.0 and 213.1 ± 159.0 pg/ml (P = 0.04), 78.8 ± 39.5 and 72.0 ± 69.6 μg/dl, 9,369.3 ± 9,560.8 μg, and 3,796.5 ± 3,634.1 μg, respectively. The patients that had co-infections had higher ACTH level (671.5 ± 398.2 vs 245.5 ± 217.1 pg/ml, P = 0.047). Patients with lower level of ACTH, no co-infection, underwent CS surgery and received antibiotic therapy for more than 6 months had more possibilities to survive ( Table 2 ).\n\nTable 2 Comparison of clinical characteristics between distinct outcomes of patients of Cushing’s syndrome with nocardiosis.\n\n\t\tSurvival\tMortality\tP value\t\nn\t\t7\t11\t\t\nAge (year)\t41.0 ± 9.2\t49.5 ± 16.5\t0.24\t\nGender\tFemale\t3\t4\t0.78\t\n\tMale\t4\t7\t\n24hrUFC (μg)\t3,796.5 ± 3,634.1 (n = 4)\t9,369.3 ± 9,560.8 (n = 6)\t0.31\t\nF (μg/dl)\t72.0 ± 69.6 (n = 5)\t78.8 ± 39.5 (n = 10)\t0.81\t\nACTH (pg/ml)\t213.1 ± 159.0 (n = 7)\t554.7 ± 401.0 (n = 9)\t0.04\t\nCause of Cushing’s syndrome\tCD\t1\t1\t1.00\t\n\tEAS\t6\t10\t\nDM\tYes\t4\t10\t0.25\t\n\tNo\t3\t1\t\nExtrapulmonary\tYes\t1\t6\t0.09\t\nnocardiosis\tNo\t6\t5\t\nCo-infections\tYes\t0\t6\t0.02\t\n\tNo\t7\t5\t\nSurgery of CS\tYes\t5\t2\t0.02\t\n\tNo\t2\t9\t\nTreatment duration\t≥6 months\t6\t2\t0.002\t\nof antibiotics\t<6 months\t0\t8\t\n\nDiscussion\n\nAlthough nocardiosis in EAS patients has been reported, our review presented 18 nocardiosis with CS patients (16 EAS and 2 CD) and emphasized the possibility of Nocardia infection in other forms of CS. In addition, according to the clinical characteristics, treatments, and prognosis of these 18 patients, we put forward the risk factors for mortality in CS patients with nocardiosis.\n\nOpportunistic infections in endogenous CS were predominantly observed in patients with severe cortisol excess (24). Previous reports (16, 25) had shown that high levels of endogenous glucocorticoids above the cut-off levels of serum cortisol, 43.1 μg/dl and 24hrUFC, 2,000 μg/d, were reliable indicators for severe infections in EAS patients. Fifteen of 18 (83.3%) patients including 13 EAS and 2 CD patients in our series were detected of high levels of serum cortisol or 24hrUFC exceeded these cut-off values. In addition, our review showed that CS patients with higher level of ACTH had more risks for co-infections and mortality. It was suggested that we should give more concern to avoiding infections in CS patients with extremely high ACTH concentrations. We did not find the difference in serum cortisol or 24hrUFC between patients of survival and mortality maybe because of the relatively small sample size. Hypercortisolism impaired cellular and humoral immunity. CS patients show significant lymphopenia, especially the reduction in the CD4+ subset, the reduction in the CD4/CD8 ratio are predictors for opportunistic infections (26). However, there was no record of lymphocytes subsets analysis in our review.\n\nPulmonary infection was the most common manifestation in nocardiosis. The clinical characteristics and symptoms of pulmonary nocardiosis were non-specific. Some patients had no pulmonary symptoms while some patients experienced respiratory failure rapidly. The radiologic findings were variable. Nodules, masses, cavitations, infiltration, consolidation, and pleural effusion could be radiographic presentations of pulmonary nocardiosis. Xu L. et al. (8) proposed cavity lesions, consolidation/infiltration, and nodule/mass were the major findings for EAS patients. The most common findings were cavitary lesion and nodules in our review. It was noted that these radiologic findings could also be the presentation of fungal, mycobacterial infections, and malignancies including both primary and metastatic lung cancers. Lung nodules were suspected to be tumors of EAS in five patients (27.7%) (19, 21–23) in our series including our patient. Biopsies of suspicious lung nodules were performed. Histological and cytologic examination of the biopsy showed no evidence of malignancy but inflammation. Nocardia infection was confirmed by the biopsy. Therefore, rapid changes of chest imagings indicated an infective etiology rather than malignancy and Nocardia infection should be carefully cautioned (19).\n\nAggressive diagnostic approaches were warranted in individuals suspected of infections. Broncho-alveolar lavage (BAL), brushing by bronchoscopy, or percutaneous lung fine-needle aspiration from the cavitated nodule might be the drawing location for cytology examinations and culture to establish the diagnosis of pulmonary nocardiosis. We should pay adequate attention in order to make early etiological diagnosis.\n\nIn our CS review, 11 of 18 patients (61.1%) died. The mortality rate was similar with that reported in EAS patients of 66.7% (8). It is seemed that the mortality rate of nocardiosis in CS patients is higher than that in other immunocompromised patients of 34.5–40% (3, 4). Mortality appeared to be correlated with multiple sites of infections and was reported as high as 100% in patients with disseminated diseases (4, 27). We did not find the extrapulmonary nocardiosis had impacts on mortality. The reason might be the small sample of our case series. Co-infections with other microorganisms have been found to attribute to mortality in nocardiosis (28). Our patients and the other two patients (16, 20) with nocardia and aspergillus co-infections had bad outcomes. Moreover, 33.3% (6/18) patients had co-infections in our series. All of them died afterwards. CS patients with marked high levels of ACTH are prone to have co-infections. Clinicians need to be mindful of opportunistic co-infections in patients with CS.\n\nReducing the cortisol level was essential for the treatment of CS with nocardiosis (29, 30). Resection of primary tumor that induced over-secretion of ACTH was an efficient and rapid strategy. However, EAS can be a diagnostic challenge with the hormonal source difficult to find. Seven patients (38.9%) had occult EAS in our series. 68Ga-conjugated somatostatin receptor targeting peptide positron emission tomography (68Ga-SSTR-PET/CT) contributes to localization of primary tumor of EAS (31). If the primary tumor couldn’t be found, bilateral adrenalectomy might be of value (32). Anticortisolic drugs also provided decrease of hypercorticism (33).Patients who underwent CS surgery had better prognosis than those treated by medicines only. Moreover, it was worth mentioning that patients with nocardiosis generally needed 6 to 12 months of antibiotic therapy, depending on their immunological status and the organs infected (34). The survived patients received antibiotic drugs for more than 6 months in our review.\n\nThere are some limitations in this study. Firstly, EAS was suspected without definite localization of primary tumor produced excess hormone in our patient. Secondly, this is a retrospective study. In addition, the sample size is relatively small as Nocardia infection in CS is incredibly rare reported. Future research is required to improve the prognosis of CS with nocardiosis.\n\nIn conclusion, Nocardia infection should be cautioned when a patient with CS presents abnormal chest radiographs. The mortality risk factors of CS with nocardiosis are high level of ACTH and co-infections. We should endeavor to make early etiological diagnosis. Long-term application of sensitive antibiotics and aggressive treatments of CS are beneficial for prognosis.\n\nData Availability Statement\n\nThe original contributions presented in the study are included in the article. Further inquiries can be directed to the corresponding author.\n\nEthics Statement\n\nThe studies involving human participants were reviewed and approved by Peking Union Medical College Hospital. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.\n\nAuthor Contributions\n\nDZ and YJ designed the study, and DZ and HF participated in data collection. DZ performed the systematic review and drafted the manuscript. YJ edited and reviewed the manuscript. LL, ZL, WX, and XX partially conceived the research idea. All authors contributed to the article and approved the submitted version.\n\nFunding\n\nThis study was supported by grant from the Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences (2018PT32001) and grant from Peking Union Medical College Hospital (ZC201904197).\n\nConflict of Interest\n\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n==== Refs\nReferences\n\n1 Hayes AR Grossman AB . The Ectopic Adrenocorticotropic Hormone Syndrome: Rarely Easy, Always Challenging. Endocrinol Metab Clin North Am (2018) 47 :409–25. 10.1016/j.ecl.2018.01.005\n2 Beaman BL Beaman L . Nocardia species: host-parasite relationships. Clin Microbiol Rev (1994) 7 :213–64. 10.1128/cmr.7.2.213\n3 Williams E Jenney AW Spelman DW . Nocardia bacteremia: A single-center retrospective review and a systematic review of the literature. Int J Infect Dis (2020) 92 :197–207. 10.1016/j.ijid.2020.01.011 31978577\n4 Zia K Nafees T Faizan M Salam O Asad SI Khan YA . Ten Year Review of Pulmonary Nocardiosis: A Series of 55 Cases. Cureus (2019) 11 :e4759. 10.7759/cureus.4759 31363440\n5 Wilson JW . Nocardiosis: updates and clinical overview. Mayo Clin Proc (2012) 87 :403–7. 10.1016/j.mayocp.2011.11.016\n6 Fareau GG Vassilopoulou-Sellin R . Hypercortisolemia and infection. Infect Dis Clin North Am (2007) 21 :639–57. 10.1016/j.idc.2007.06.001\n7 Graham BS Tucker WJ . Opportunistic infections in endogenous Cushing’s syndrome. Ann Intern Med (1984) 101 :334–8. 10.7326/0003-4819-101-3-334\n8 Xu L Xu Q Yang M Gao H Xu M Ma W . Nocardiosis in ectopic ACTH syndrome: A case report and review of 11 cases from the literature. Exp Ther Med (2016) 12 :3626–32. 10.3892/etm.2016.3846\n9 Nieman LK Biller BM Findling JW Newell-Price J Savage MO Stewart PM . The diagnosis of Cushing’s syndrome: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab (2008) 93 :1526–40. 10.1210/jc.2008-0125\n10 Petersen DP Wong LB . Nocardia infection of the hand-case report. J Handb Surg Am (1981) 6 :502–5. 10.1016/s0363-5023(81)80112-8\n11 Natale RB Yagoda A Brown A Singer C Stover D Bajorunas D . Combined Pneumocystis carinii and Nocardia asteroides pneumonitis in a patient with an ACTH-producing carcinoid. Cancer (1981) 47 :2933–5. 10.1002/1097-0142(19810615)47:12<2933::aid-cncr2820471233>3.0.co;2-g\n12 Higgins TL Calabrese LH Sheeler LR . Opportunistic infections in patients with ectopic ACTH-secreting tumors. Cleve Clin Q (1982) 49 :43–9. 10.3949/ccjm.49.1.43\n13 Findlay JC Arafah BM Silverman P Aron DC . Cushing’s syndrome with cranial and pulmonary lesions: necessity for tissue diagnosis. South Med J (1992) 85 :204–6. 10.1097/00007611-199202000-00022\n14 Boscaro M Fallo F Sonino N . Disseminated nocardiosis in a patient with Cushing’s syndrome. J Endocrinol Invest (1994) 17 :443–5. 10.1007/BF03347735\n15 Huang TP Wang PW Liu RT Tung SC Jean WY Lu YC . Ectopic ACTH syndrome with nocardiosis–a case report. Changgeng Yi Xue Za Zhi (1994) 17 :371–7.\n16 Beinart GA Rao RK Hollander H . Ectopic ACTH syndrome resulting in nocardiosis and acute respiratory failure. Hosp Physician (2003) 39 :49–54.\n17 Chrysanthidis T Yavropoulou M Metallidis S . Disseminated Nocardiosis in Ectopic Adrenocorticotropic Hormone Syndrome-A Case Report. Endocrinol (2010) 6 :286–7. 10.1097/TEN.0b013e3181fcff16\n18 Sutton BJ Parks GE Manavi CK Palavecino EL Geisinger KR . Cushing’s syndrome and nocardiosis associated with a pulmonary carcinoid tumor: report of a case and review of the literature. Diagn Cytopathol (2011) 39 :359–62. 10.1002/dc.21428\n19 Chowdry RP Bhimani C Delgado MA Lee DJ Dayamani P Sica GL . Unusual suspects: pulmonary opportunistic infections masquerading as tumor metastasis in a patient with adrenocorticotropic hormone-producing pancreatic neuroendocrine cancer. Ther Adv Med Oncol (2012) 4 :295–300. 10.1177/1758834012456415 23118805\n20 Momah N Koroscil T . Occult ectopic adrenocorticotropic hormone secretion: diagnostic dilemma and infective consequence. Clin Pract (2012) 2 :e82. 10.4081/cp.2012.e82 24765481\n21 Rizwan A Sarfaraz A Jabbar A Akhter J Islam N . Case report: nocardia infection associated with ectopic cushings. BMC Endocr Disord (2014) 14 :51. 10.1186/1472-6823-14-51 24950706\n22 Kobayashi K Asakura T Ishii M Akhter J Islam N . Pulmonary nocardiosis mimicking small cell lung cancer in ectopic ACTH syndrome associated with transformation of olfactory neuroblastoma: a case report. BMC Pulm Med (2018) 18 (1 ):142. 10.1186/1472-6823-14-51 30134888\n23 Mylonas CC Gomatou G Asimakopoulou A Masaoutis C Kyriakopoulos G Kopelia M . Pulmonary nocardiosis associated with Cushing’s disease: a case report. Monaldi Arch Chest Dis (2019) 89 (3 ). 10.4081/monaldi.2019.1130\n24 Bakker RC Gallas PR Romijn JA Wiersinga WM . Cushing’s syndrome complicated by multiple opportunistic infections. J Endocrinol Invest (1998) 21 :329–33. 10.1007/BF03350337\n25 Sarlis NJ Chanock SJ Nieman LK . Cortisolemic indices predict severe infections in Cushing syndrome due to ectopic production of adrenocorticotropin. J Clin Endocrinol Metab (2000) 85 :42–7. 10.1210/jcem.85.1.6294\n26 Hasenmajer V Sbardella E Sciarra F Minnetti M Isidori AM Venneri MA . The Immune System in Cushing’s Syndrome. Trends Endocrinol Metab (2020) 31 :655–69. 10.1016/j.tem.2020.04.004\n27 Lerner PI . Nocardiosis. Clin Infect Dis (1996) 22 :891–903. 10.1093/clinids/22.6.891 8783685\n28 Huang L Sun L Yan Y . Characteristics of nocardiosis patients with different immune status from a Chinese tertiary general hospital during 8-year period: A STROBE-compliment observational study. Med (Baltimore) (2019) 98 :e17913. 10.1097/MD.0000000000017913\n29 Lionakis MS Kontoyiannis DP . Glucocorticoids and invasive fungal infections. Lancet (2003) 362 :1828–38. 10.1016/S0140-6736(03)14904-5\n30 Lutgers HL Vergragt J Dong PV de Vries J Dullaart RP van den Berg G . Severe hypercortisolism: a medical emergency requiring urgent intervention. Crit Care Med (2010) 38 :1598–601. 10.1097/CCM.0b013e3181e47b7a\n31 Isidori AM Sbardella E Zatelli MC Boschetti M Vitale G Colao A . Conventional and Nuclear Medicine Imaging in Ectopic Cushing’s Syndrome: A Systematic Review. J Clin Endocrinol Metab (2015) 100 :3231–44. 10.1210/JC.2015-1589\n32 Joubert M Reznik Y Verdon R . “Rescue” bilateral adrenalectomy in paraneoplastic Cushing’s syndrome with invasive Aspergillus fumigatus infection. Am J Med Sci (2007) 334 :497–8. 10.1097/MAJ.0b013e3180a5e924\n33 Kamenicky P Droumaguet C Salenave S Blanchard A Jublanc C Gautier JF . Mitotane, metyrapone, and ketoconazole combination therapy as an alternative to rescue adrenalectomy for severe ACTH-dependent Cushing’s syndrome. J Clin Endocrinol Metab (2011) 96 :2796–804. 10.1210/jc.2011-0536\n34 Martinez R Reyes S Menendez R . Pulmonary nocardiosis: risk factors, clinical features, diagnosis and prognosis. Curr Opin Pulm Med (2008) 14 :219–27. 10.1097/MCP.0b013e3282f85dd3\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1664-2392",
"issue": "12()",
"journal": "Frontiers in endocrinology",
"keywords": "Cushing’s disease; Cushing’s syndrome; ectopic ACTH syndrome; infection; nocardiosis",
"medline_ta": "Front Endocrinol (Lausanne)",
"mesh_terms": null,
"nlm_unique_id": "101555782",
"other_id": null,
"pages": "640998",
"pmc": null,
"pmid": "33854481",
"pubdate": "2021",
"publication_types": "D002363:Case Reports; D013485:Research Support, Non-U.S. Gov't",
"references": "14654323;21752886;29754641;18334580;23118805;7930389;31702669;24950706;7020921;28105096;6268699;31631643;18091374;10634361;18427245;9648056;30134888;32387195;8783685;17826616;24765481;26158607;7850654;7094331;1738892;22469352;6331781;31978577;8055469;20495451;20857397;31363440",
"title": "Cushing's Syndrome With Nocardiosis: A Case Report and a Systematic Review of the Literature.",
"title_normalized": "cushing s syndrome with nocardiosis a case report and a systematic review of the literature"
} | [
{
"companynumb": "CN-GILEAD-2021-0552829",
"fulfillexpeditecriteria": "1",
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"activesubstance": {
"activesubstancename": "AMPHOTERICIN B"
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{
"abstract": "BACKGROUND\nCarisoprodol, a centrally acting muscle relaxant with a high abuse potential, has barbiturate-like properties at the GABA-A receptor, leading to central nervous system depression and desired effects. Its tolerance and dependence has been previously demonstrated in an animal model, and withdrawal has been described in several recent case reports. Many cases can be effectively managed with a short course of benzodiazepines or antipsychotic agents. However, abrupt cessation in a patient with a history of long-term and high-dose carisoprodol abuse may result in symptoms that are more difficult for providers to treat.\n\n\nMETHODS\nWe present a case of a 34-year-old man with a long history of carisoprodol abuse who was found unresponsive after having ingested 7.5 grams of carisoprodol. He was intubated and admitted to the intensive care unit. He was given propofol, dexmedetomidine, fentanyl, ketamine, lorazepam, midazolam, quetiapine, and haloperidol, some at high-dose infusions, before his agitation and ventilator asynchrony could be controlled. His improvement coincided with the addition of carisoprodol and phenobarbital to his treatment regimen. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Trends show increasing emergency department presentations for drug-related disorders and treatment. This case highlights an uncommon case of carisoprodol withdrawal that may be encountered by emergency physicians, and demonstrates that benzodiazepines may not be sufficient to suppress severe withdrawal symptoms. Treatment with carisoprodol and phenobarbital provided additional benefit and can be considered in cases of severe carisoprodol withdrawal.",
"affiliations": "Department of Emergency Medicine, University of California, San Francisco, San Francisco, California; California Poison Control System, San Francisco Division, San Francisco, California.;Department of Laboratory Medicine, University of California, San Francisco, San Francisco, California.;Department of Emergency Medicine, University of California, San Francisco, San Francisco, California; California Poison Control System, San Francisco Division, San Francisco, California.;California Poison Control System, San Francisco Division, San Francisco, California; Department of Clinical Pharmacy, University of California, San Francisco, San Francisco, California.",
"authors": "Vo|Kathy T|KT|;Horng|Howard|H|;Smollin|Craig G|CG|;Benowitz|Neal L|NL|",
"chemical_list": "D006993:Hypnotics and Sedatives; D002328:Carisoprodol; D000069348:Quetiapine Fumarate; D020927:Dexmedetomidine; D007649:Ketamine; D006220:Haloperidol; D008140:Lorazepam; D008874:Midazolam; D005283:Fentanyl; D015742:Propofol",
"country": "United States",
"delete": false,
"doi": "10.1016/j.jemermed.2016.11.015",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0736-4679",
"issue": "52(5)",
"journal": "The Journal of emergency medicine",
"keywords": "addiction; carisoprodol; withdrawal",
"medline_ta": "J Emerg Med",
"mesh_terms": "D000328:Adult; D002328:Carisoprodol; D020927:Dexmedetomidine; D062787:Drug Overdose; D005283:Fentanyl; D006220:Haloperidol; D006801:Humans; D006993:Hypnotics and Sedatives; D007362:Intensive Care Units; D007649:Ketamine; D008140:Lorazepam; D008297:Male; D008874:Midazolam; D015742:Propofol; D000069348:Quetiapine Fumarate; D012121:Respiration, Artificial; D013375:Substance Withdrawal Syndrome; D019966:Substance-Related Disorders",
"nlm_unique_id": "8412174",
"other_id": null,
"pages": "680-683",
"pmc": null,
"pmid": "27979642",
"pubdate": "2017-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Severe Carisoprodol Withdrawal After a 14-Year Addiction and Acute Overdose.",
"title_normalized": "severe carisoprodol withdrawal after a 14 year addiction and acute overdose"
} | [
{
"companynumb": "US-TEVA-733860USA",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
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{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CARISOPRODOL"
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"drugadditional": null,
"d... |
{
"abstract": "Tofacitinib is an oral Janus kinase inhibitor that is under investigation for the treatment of psoriatic arthritis. We evaluated tofacitinib in patients with active psoriatic arthritis who had previously had an inadequate response to tumor necrosis factor (TNF) inhibitors.\n\n\n\nIn this 6-month randomized, placebo-controlled, double-blind, phase 3 trial, we randomly assigned 395 patients, in a 2:2:1:1 ratio, to four regimens: 5 mg of tofacitinib administered orally twice daily (132 patients); 10 mg of tofacitinib twice daily (132 patients); placebo, with a switch to 5 mg of tofacitinib twice daily at 3 months (66 patients); or placebo, with a switch to 10 mg of tofacitinib twice daily at 3 months (65 patients). Data from the patients who received placebo during the first 3 months of the trial were pooled. The primary end points were the percentage of patients who had at least 20% improvement according to the criteria of the American College of Rheumatology (ACR20 response) and the change from baseline score on the Health Assessment Questionnaire-Disability Index (HAQ-DI; scores range from 0 to 3, with higher scores indicating greater disability) at the month 3 analysis.\n\n\n\nAt 3 months, the rates of ACR20 response were 50% with the 5-mg dose of tofacitinib and 47% with the 10-mg dose, as compared with 24% with placebo (P<0.001 for both comparisons); the corresponding mean changes from baseline in HAQ-DI score were -0.39 and -0.35, as compared with -0.14 (P<0.001 for both comparisons). Serious adverse events occurred in 4% of the patients who received the 5-mg dose of tofacitinib continuously and in 6% who received the 10-mg dose continuously. Over the course of 6 months, there were four serious infections, three herpes zoster infections, one myocardial infarction, and one ischemic stroke among the patients who received tofacitinib continuously. Elevations of aspartate and alanine aminotransferase concentrations of three or more times the upper limit of the normal range occurred in more patients who received tofacitinib continuously than in patients who received placebo followed by tofacitinib.\n\n\n\nIn this trial involving patients with active psoriatic arthritis who had had an inadequate response to TNF inhibitors, tofacitinib was more effective than placebo over 3 months in reducing disease activity. Adverse events were more frequent with tofacitinib than with placebo. (Funded by Pfizer; OPAL Beyond ClinicalTrials.gov number, NCT01882439 .).",
"affiliations": "From the University of Toronto, Toronto Western Hospital, Toronto (D.G.); Geisel School of Medicine at Dartmouth, Dartmouth-Hitchcock Medical Center, Lebanon, NH (W.R.); Universidade Federal do Paraná, Curitiba, Brazil (V.F.A.); Goethe University and Fraunhofer Institute for Molecular Biology and Applied Ecology Project Group Translational Medicine and Pharmacology (TMP), Frankfurt, Germany (F.B.); Hospital Universitario Marqués de Valdecilla, Instituto de Investigación Marqués de Valdecilla, Santander, Spain (R.B.); Specjalistyczne Gabinety Lekarskie DERMED, Lodz, Poland (A.K.); Pfizer, Groton, CT (E.K., C.W., S.M., K.S.K.); and Pfizer, Collegeville, PA (T.H.).;From the University of Toronto, Toronto Western Hospital, Toronto (D.G.); Geisel School of Medicine at Dartmouth, Dartmouth-Hitchcock Medical Center, Lebanon, NH (W.R.); Universidade Federal do Paraná, Curitiba, Brazil (V.F.A.); Goethe University and Fraunhofer Institute for Molecular Biology and Applied Ecology Project Group Translational Medicine and Pharmacology (TMP), Frankfurt, Germany (F.B.); Hospital Universitario Marqués de Valdecilla, Instituto de Investigación Marqués de Valdecilla, Santander, Spain (R.B.); Specjalistyczne Gabinety Lekarskie DERMED, Lodz, Poland (A.K.); Pfizer, Groton, CT (E.K., C.W., S.M., K.S.K.); and Pfizer, Collegeville, PA (T.H.).;From the University of Toronto, Toronto Western Hospital, Toronto (D.G.); Geisel School of Medicine at Dartmouth, Dartmouth-Hitchcock Medical Center, Lebanon, NH (W.R.); Universidade Federal do Paraná, Curitiba, Brazil (V.F.A.); Goethe University and Fraunhofer Institute for Molecular Biology and Applied Ecology Project Group Translational Medicine and Pharmacology (TMP), Frankfurt, Germany (F.B.); Hospital Universitario Marqués de Valdecilla, Instituto de Investigación Marqués de Valdecilla, Santander, Spain (R.B.); Specjalistyczne Gabinety Lekarskie DERMED, Lodz, Poland (A.K.); Pfizer, Groton, CT (E.K., C.W., S.M., K.S.K.); and Pfizer, Collegeville, PA (T.H.).;From the University of Toronto, Toronto Western Hospital, Toronto (D.G.); Geisel School of Medicine at Dartmouth, Dartmouth-Hitchcock Medical Center, Lebanon, NH (W.R.); Universidade Federal do Paraná, Curitiba, Brazil (V.F.A.); Goethe University and Fraunhofer Institute for Molecular Biology and Applied Ecology Project Group Translational Medicine and Pharmacology (TMP), Frankfurt, Germany (F.B.); Hospital Universitario Marqués de Valdecilla, Instituto de Investigación Marqués de Valdecilla, Santander, Spain (R.B.); Specjalistyczne Gabinety Lekarskie DERMED, Lodz, Poland (A.K.); Pfizer, Groton, CT (E.K., C.W., S.M., K.S.K.); and Pfizer, Collegeville, PA (T.H.).;From the University of Toronto, Toronto Western Hospital, Toronto (D.G.); Geisel School of Medicine at Dartmouth, Dartmouth-Hitchcock Medical Center, Lebanon, NH (W.R.); Universidade Federal do Paraná, Curitiba, Brazil (V.F.A.); Goethe University and Fraunhofer Institute for Molecular Biology and Applied Ecology Project Group Translational Medicine and Pharmacology (TMP), Frankfurt, Germany (F.B.); Hospital Universitario Marqués de Valdecilla, Instituto de Investigación Marqués de Valdecilla, Santander, Spain (R.B.); Specjalistyczne Gabinety Lekarskie DERMED, Lodz, Poland (A.K.); Pfizer, Groton, CT (E.K., C.W., S.M., K.S.K.); and Pfizer, Collegeville, PA (T.H.).;From the University of Toronto, Toronto Western Hospital, Toronto (D.G.); Geisel School of Medicine at Dartmouth, Dartmouth-Hitchcock Medical Center, Lebanon, NH (W.R.); Universidade Federal do Paraná, Curitiba, Brazil (V.F.A.); Goethe University and Fraunhofer Institute for Molecular Biology and Applied Ecology Project Group Translational Medicine and Pharmacology (TMP), Frankfurt, Germany (F.B.); Hospital Universitario Marqués de Valdecilla, Instituto de Investigación Marqués de Valdecilla, Santander, Spain (R.B.); Specjalistyczne Gabinety Lekarskie DERMED, Lodz, Poland (A.K.); Pfizer, Groton, CT (E.K., C.W., S.M., K.S.K.); and Pfizer, Collegeville, PA (T.H.).;From the University of Toronto, Toronto Western Hospital, Toronto (D.G.); Geisel School of Medicine at Dartmouth, Dartmouth-Hitchcock Medical Center, Lebanon, NH (W.R.); Universidade Federal do Paraná, Curitiba, Brazil (V.F.A.); Goethe University and Fraunhofer Institute for Molecular Biology and Applied Ecology Project Group Translational Medicine and Pharmacology (TMP), Frankfurt, Germany (F.B.); Hospital Universitario Marqués de Valdecilla, Instituto de Investigación Marqués de Valdecilla, Santander, Spain (R.B.); Specjalistyczne Gabinety Lekarskie DERMED, Lodz, Poland (A.K.); Pfizer, Groton, CT (E.K., C.W., S.M., K.S.K.); and Pfizer, Collegeville, PA (T.H.).;From the University of Toronto, Toronto Western Hospital, Toronto (D.G.); Geisel School of Medicine at Dartmouth, Dartmouth-Hitchcock Medical Center, Lebanon, NH (W.R.); Universidade Federal do Paraná, Curitiba, Brazil (V.F.A.); Goethe University and Fraunhofer Institute for Molecular Biology and Applied Ecology Project Group Translational Medicine and Pharmacology (TMP), Frankfurt, Germany (F.B.); Hospital Universitario Marqués de Valdecilla, Instituto de Investigación Marqués de Valdecilla, Santander, Spain (R.B.); Specjalistyczne Gabinety Lekarskie DERMED, Lodz, Poland (A.K.); Pfizer, Groton, CT (E.K., C.W., S.M., K.S.K.); and Pfizer, Collegeville, PA (T.H.).;From the University of Toronto, Toronto Western Hospital, Toronto (D.G.); Geisel School of Medicine at Dartmouth, Dartmouth-Hitchcock Medical Center, Lebanon, NH (W.R.); Universidade Federal do Paraná, Curitiba, Brazil (V.F.A.); Goethe University and Fraunhofer Institute for Molecular Biology and Applied Ecology Project Group Translational Medicine and Pharmacology (TMP), Frankfurt, Germany (F.B.); Hospital Universitario Marqués de Valdecilla, Instituto de Investigación Marqués de Valdecilla, Santander, Spain (R.B.); Specjalistyczne Gabinety Lekarskie DERMED, Lodz, Poland (A.K.); Pfizer, Groton, CT (E.K., C.W., S.M., K.S.K.); and Pfizer, Collegeville, PA (T.H.).;From the University of Toronto, Toronto Western Hospital, Toronto (D.G.); Geisel School of Medicine at Dartmouth, Dartmouth-Hitchcock Medical Center, Lebanon, NH (W.R.); Universidade Federal do Paraná, Curitiba, Brazil (V.F.A.); Goethe University and Fraunhofer Institute for Molecular Biology and Applied Ecology Project Group Translational Medicine and Pharmacology (TMP), Frankfurt, Germany (F.B.); Hospital Universitario Marqués de Valdecilla, Instituto de Investigación Marqués de Valdecilla, Santander, Spain (R.B.); Specjalistyczne Gabinety Lekarskie DERMED, Lodz, Poland (A.K.); Pfizer, Groton, CT (E.K., C.W., S.M., K.S.K.); and Pfizer, Collegeville, PA (T.H.).;From the University of Toronto, Toronto Western Hospital, Toronto (D.G.); Geisel School of Medicine at Dartmouth, Dartmouth-Hitchcock Medical Center, Lebanon, NH (W.R.); Universidade Federal do Paraná, Curitiba, Brazil (V.F.A.); Goethe University and Fraunhofer Institute for Molecular Biology and Applied Ecology Project Group Translational Medicine and Pharmacology (TMP), Frankfurt, Germany (F.B.); Hospital Universitario Marqués de Valdecilla, Instituto de Investigación Marqués de Valdecilla, Santander, Spain (R.B.); Specjalistyczne Gabinety Lekarskie DERMED, Lodz, Poland (A.K.); Pfizer, Groton, CT (E.K., C.W., S.M., K.S.K.); and Pfizer, Collegeville, PA (T.H.).",
"authors": "Gladman|Dafna|D|;Rigby|William|W|;Azevedo|Valderilio F|VF|;Behrens|Frank|F|;Blanco|Ricardo|R|;Kaszuba|Andrzej|A|;Kudlacz|Elizabeth|E|;Wang|Cunshan|C|;Menon|Sujatha|S|;Hendrikx|Thijs|T|;Kanik|Keith S|KS|",
"chemical_list": "D018501:Antirheumatic Agents; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011758:Pyrroles; D014409:Tumor Necrosis Factor-alpha; C479163:tofacitinib; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D053612:Janus Kinases",
"country": "United States",
"delete": false,
"doi": "10.1056/NEJMoa1615977",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0028-4793",
"issue": "377(16)",
"journal": "The New England journal of medicine",
"keywords": null,
"medline_ta": "N Engl J Med",
"mesh_terms": "D000284:Administration, Oral; D000328:Adult; D000410:Alanine Transaminase; D018501:Antirheumatic Agents; D015535:Arthritis, Psoriatic; D001219:Aspartate Aminotransferases; D004185:Disability Evaluation; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D053612:Janus Kinases; D008297:Male; D008875:Middle Aged; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011758:Pyrroles; D017211:Treatment Failure; D014409:Tumor Necrosis Factor-alpha",
"nlm_unique_id": "0255562",
"other_id": null,
"pages": "1525-1536",
"pmc": null,
"pmid": "29045207",
"pubdate": "2017-10-19",
"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": "Tofacitinib for Psoriatic Arthritis in Patients with an Inadequate Response to TNF Inhibitors.",
"title_normalized": "tofacitinib for psoriatic arthritis in patients with an inadequate response to tnf inhibitors"
} | [
{
"companynumb": "DE-PFIZER INC-2015161462",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "METHOTREXATE SODIUM"
},
"drugadditional": null... |
{
"abstract": "BACKGROUND\nIn addition to other treatments, patients with prostate cancer (pCA) and bone metastasis receive bisphosphonates. Since 2003, a previously unknown side-effect of bisphosphonates-bisphosphonate-associated osteonecrosis of the jaws (BP-ONJ)-has been described, and frequency has since increased. An exact incidence is still unknown.\n\n\nOBJECTIVE\nThe aim of this study was to assess the incidence and additional factors in the development of BP-ONJ.\n\n\nMETHODS\nFrom July 2006 to October 2007, patients with advanced pCA and osseous metastasis receiving bisphosphonate therapy in the Department of Urology or Haematology and Oncology at the Johannes-Gutenberg-University Mainz, Germany, received a dental examination. In all, 43 patients were included.\n\n\nMETHODS\nPatients were checked for exposed bone, osteonecrosis, mucosal defects, inflammation, and oral hygiene. Further points were the applied bisphosphonate, co-medication, the duration of application, and possible trigger factors for BP-ONJ.\n\n\nCONCLUSIONS\nEight of 43 patients developed BP-ONJ (18.6%). All patients had received zoledronate at least 14 times. Two patients had received bondronate, and one patient had received pamidronate before switching to zoledronate. All patients had had a previous tooth extraction or a denture pressure sore, and all patients had received additional chemotherapy and corticosteroids.\n\n\nCONCLUSIONS\nThe reason for this relatively high incidence compared to other studies might be the prospective study design and thorough dental examination. In studies with such small numbers as have been published to date, nondetection or nonreported cases of BP-ONJ have an influence on the outcome. The incidence of BP-ONJ in patients with pCA might be an underestimated problem.",
"affiliations": "Klinik für Mund-, Kiefer- und Gesichtschirurgie, Johannes Gutenberg-Universität Mainz, Mainz, Germany. walter@mkg.klinik.uni-mainz.de",
"authors": "Walter|Christian|C|;Al-Nawas|Bilal|B|;Grötz|Knut A|KA|;Thomas|Christian|C|;Thüroff|Joachim W|JW|;Zinser|Viktoria|V|;Gamm|Heinold|H|;Beck|Joachim|J|;Wagner|Wilfried|W|",
"chemical_list": "D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D007093:Imidazoles; D000077211:Zoledronic Acid",
"country": "Switzerland",
"delete": false,
"doi": "10.1016/j.eururo.2008.06.070",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0302-2838",
"issue": "54(5)",
"journal": "European urology",
"keywords": null,
"medline_ta": "Eur Urol",
"mesh_terms": "D000368:Aged; D050071:Bone Density Conservation Agents; D001859:Bone Neoplasms; D003430:Cross-Sectional Studies; D004164:Diphosphonates; D005500:Follow-Up Studies; D005858:Germany; D006801:Humans; D007093:Imidazoles; D007275:Injections, Intravenous; D007571:Jaw Diseases; D008297:Male; D008875:Middle Aged; D010020:Osteonecrosis; D015995:Prevalence; D011379:Prognosis; D011471:Prostatic Neoplasms; D012189:Retrospective Studies; D012307:Risk Factors; D000077211:Zoledronic Acid",
"nlm_unique_id": "7512719",
"other_id": null,
"pages": "1066-72",
"pmc": null,
"pmid": "18602738",
"pubdate": "2008-11",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": null,
"title": "Prevalence and risk factors of bisphosphonate-associated osteonecrosis of the jaw in prostate cancer patients with advanced disease treated with zoledronate.",
"title_normalized": "prevalence and risk factors of bisphosphonate associated osteonecrosis of the jaw in prostate cancer patients with advanced disease treated with zoledronate"
} | [
{
"companynumb": "DE-ROCHE-605222",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ZOLEDRONIC ACID"
},
"drugadditional": "3",
"d... |
{
"abstract": "OBJECTIVE\nPrimary central nervous system lymphoma (PCNSL) is rare disease and shows poor prognosis although methotrexate-based chemotherapy is used. Here, we present our experiences with high-dose methotrexate (HD-MTX) monotherapy for immunocompetent patients with PCNSL at three institutions and investigate factors related to survival.\n\n\nMETHODS\nPCNSL patients, who were histologically confirmed with diffuse large B cells and treated with HD-MTX monotherapy from 2001 to 2016, were retrospectively reviewed. Patients underwent induction chemotherapy with 8 g/m2 of MTX every 10 days (maximum three cycles). Maintenance chemotherapy of 3.5 g/m2 of MTX (maximum six cycles) was selectively performed depending on the response to induction chemotherapy.\n\n\nRESULTS\nA total of 67 patients were included. Although seven patients discontinued induction chemotherapy because of MTX toxicity, 40 (59.7%) patients showed a complete response (CR) to induction chemotherapy. Twenty-six (38.8%) and three (4.5%) patients showed a CR and partial response, respectively, after maintenance chemotherapy. Forty-one patients with recurrence or progression following HD-MTX underwent second-line treatment. Progression-free survival rates were 43% and 24% at 1 and 2 years, respectively. The median overall survival was 40.3 months. In a multivariate analysis, a radiological CR to induction chemotherapy was a significant factor related to prolonged progression-free survival and overall survival (P < 0.05).\n\n\nCONCLUSIONS\nMTX-monotherapy is tolerable in terms of adverse effects and still considered as a treatment option in patients with PCNSL. However, an additional therapeutic option should be prepared for non-CR responders to induction chemotherapy.",
"affiliations": "Department of Neurosurgery, Incheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Incheon, Korea.;Department of Neurosurgery, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.;Department of Neurosurgery, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, Suwon, Korea.;Department of Neurosurgery, Incheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Incheon, Korea.;Department of Neurosurgery, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.;Department of Neurosurgery, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.;Department of Neurosurgery, St. Vincent's Hospital, Cell Death Disease Research Center, College of Medicine, The Catholic University of Korea, Suwon, Korea.",
"authors": "Yoon|Wan-Soo|WS|https://orcid.org/0000-0002-2504-4734;Park|Jae-Sung|JS|;Kim|Young-Il|YI|;Chung|Dong-Sup|DS|;Jeun|Sin-Soo|SS|;Hong|Yong-Kil|YK|;Yang|Seung Ho|SH|",
"chemical_list": "D008727:Methotrexate",
"country": "Australia",
"delete": false,
"doi": "10.1111/ajco.13427",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1743-7555",
"issue": "17(1)",
"journal": "Asia-Pacific journal of clinical oncology",
"keywords": "central nervous system; drug therapy; lymphoma; methotrexate; survival",
"medline_ta": "Asia Pac J Clin Oncol",
"mesh_terms": "D000328:Adult; D000368:Aged; D016543:Central Nervous System Neoplasms; D005260:Female; D006801:Humans; D008228:Lymphoma, Non-Hodgkin; D008297:Male; D008727:Methotrexate; D008875:Middle Aged; D012008:Recurrence; D012074:Remission Induction; D012189:Retrospective Studies",
"nlm_unique_id": "101241430",
"other_id": null,
"pages": "123-130",
"pmc": null,
"pmid": "32978898",
"pubdate": "2021-02",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "High-dose methotrexate monotherapy for newly diagnosed primary central nervous system lymphoma: 15-year multicenter experience.",
"title_normalized": "high dose methotrexate monotherapy for newly diagnosed primary central nervous system lymphoma 15 year multicenter experience"
} | [
{
"companynumb": "KR-PFIZER INC-2020380388",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHOTREXATE SODIUM"
},
"drugadditional": "3",... |
{
"abstract": "Blastic plasmacytoid dendritic cell neoplasm (LPDC) is a rare and aggressive leukemia entity with cutaneous and extracutaneous involvement, reaching most often lymph, blood and bone marrow. Two cases of LPDC diagnosed in Hospital Center of Le Mans are reported, a 78 year old woman (case 1) and a 82 year old man (case 2), and have been clinically, biologically and histologically documented. The clinical presentation, diagnostic difficulties are reminded, as well as the pathogenesis and therapeutic aspect.",
"affiliations": "Laboratoire d'hématologie, Centre hospitalier du Mans, France.;Laboratoire d'hématologie, Centre hospitalier du Mans, France.;Laboratoire d'hématologie, Centre hospitalier du Mans, France.;Laboratoire d'anatomocytopathologie, Centre hospitalier du Mans, France.;Laboratoire d'hématologie, Centre hospitalier du Mans, France.",
"authors": "Kaabar|Mohamed|M|;Lemaire|Pierre|P|;Laribi|Kamel|K|;Sandrini|Jérémy|J|;Pineau-Vincent|Fabienne|F|",
"chemical_list": null,
"country": "France",
"delete": false,
"doi": "10.1684/abc.2015.1094",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0003-3898",
"issue": "73(6)",
"journal": "Annales de biologie clinique",
"keywords": "5-azacytidine; leukemia; plasmocytoid dendritic cell",
"medline_ta": "Ann Biol Clin (Paris)",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D003713:Dendritic Cells; D017809:Fatal Outcome; D005260:Female; D019337:Hematologic Neoplasms; D006801:Humans; D007938:Leukemia; D008297:Male; D012878:Skin Neoplasms",
"nlm_unique_id": "2984690R",
"other_id": null,
"pages": "733-6",
"pmc": null,
"pmid": "26553703",
"pubdate": "2015",
"publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "Blastic plasmacytoid dendritic cell neoplasm: two case reports.",
"title_normalized": "blastic plasmacytoid dendritic cell neoplasm two case reports"
} | [
{
"companynumb": "FR-CELGENE-FRA-2015114188",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "AZACITIDINE"
},
"drugadditional": null,
... |
{
"abstract": "Infections of the adrenal glands remain an important cause of adrenal insufficiency, especially in the developing world. Indeed, when Thomas Addison first described the condition that now bears his name over 150 years ago, the vast majority of cases were attributable to tuberculosis. Here we describe a classic, but relatively uncommon, presentation in the United States of adrenal insufficiency followed by a review of the current literature pertaining to adrenal infections.",
"affiliations": "Department of Internal Medicine, Saint Vincent Hospital, Worcester, MA 01760, USA.;Department of Internal Medicine, Saint Vincent Hospital, Worcester, MA 01760, USA.;Department of Internal Medicine, Saint Vincent Hospital, Worcester, MA 01760, USA.;Department of Internal Medicine, Saint Vincent Hospital, Worcester, MA 01760, USA.",
"authors": "Upadhyay|Jagriti|J|;Sudhindra|Praveen|P|;Abraham|George|G|;Trivedi|Nitin|N|",
"chemical_list": null,
"country": "Egypt",
"delete": false,
"doi": "10.1155/2014/876037",
"fulltext": "\n==== Front\nInt J EndocrinolInt J EndocrinolIJEInternational Journal of Endocrinology1687-83371687-8345Hindawi Publishing Corporation 10.1155/2014/876037Review ArticleTuberculosis of the Adrenal Gland: A Case Report and Review of the Literature of Infections of the Adrenal Gland Upadhyay Jagriti *Sudhindra Praveen Abraham George Trivedi Nitin Department of Internal Medicine, Saint Vincent Hospital, Worcester, MA 01760, USA*Jagriti Upadhyay: jagriti.upadhyay@gmail.comAcademic Editor: Gian Paolo Rossi\n\n2014 6 8 2014 2014 8760374 4 2014 15 7 2014 16 7 2014 Copyright © 2014 Jagriti Upadhyay et al.2014This 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.Infections of the adrenal glands remain an important cause of adrenal insufficiency, especially in the developing world. Indeed, when Thomas Addison first described the condition that now bears his name over 150 years ago, the vast majority of cases were attributable to tuberculosis. Here we describe a classic, but relatively uncommon, presentation in the United States of adrenal insufficiency followed by a review of the current literature pertaining to adrenal infections.\n==== Body\n1. Introduction\nA 46-year-old man presented to his physician with a 3-month history of generalized weakness and 15-pound unintentional weight loss. He also reported mild dyspnea on exertion and decreased appetite. His past medical history was significant for hypertriglyceridemia, primary hypothyroidism, and vitamin D deficiency. He had emigrated from the Philippines 6 years prior and had been working as a nurse at a skilled nursing facility. He had not left the country since his initial arrival. He denied sick contacts, specifically exposure to tuberculosis, smoking, alcohol consumption, or the use of illicit substances. A tuberculin skin test performed in 2007 resulted in induration (diameter unknown) and it was attributed to prior BCG vaccine. There was no evidence of pulmonary tuberculosis on a chest radiograph. Physical examination revealed abdominal distension and free fluid but was otherwise unremarkable. A diagnostic paracentesis revealed an exudative effusion with a positive Ziehl Neelsen stain for acid fast bacilli. The patient was started on treatment (Isoniazid, rifampicin, pyrazinamide, and ethambutol) for presumed extrapulmonary tuberculosis which was later confirmed by culture.\n\nOne month after starting antitubercular therapy he presented to the hospital with worsening fatigue, salt craving, vomiting, loss of libido, and erectile dysfunction. On examination, he had low blood pressure and appeared cachectic. In addition he had bitemporal muscle wasting and hyperpigmentation of skin, oral mucosa, and nails. Laboratory evaluation was significant for hyponatremia, hyperkalemia, and mild hypercalcemia. A random cortisol was 2.5 mcg/dL with an ACTH of 531.2 pcg/mL. The basal and cosyntropin stimulated serum cortisol were, respectively 1.8 mcg/dL and 2.0 mcg/dL, which was consistent with the diagnosis of primary adrenal insufficiency most likely due to tuberculosis. A computed tomography scan of the abdomen with intravenous contrast revealed bilaterally enlarged adrenal glands (4 cm × 3.3 cm on the right, 2.3 cm × 2.1 cm on the left) (Figure 1). On review of his prior CT scan of the abdomen, the patient had bilaterally enlarged adrenal glands at the time of his initial presentation as well.\n\nWith the background of tuberculosis and acute adrenal insufficiency diagnosed by laboratory test, bilateral enlargement of adrenal glands was considered most consistent with tuberculosis in our patient. Deterioration of his clinical status following antitubercular treatment could be attributed to accelerated cortisol metabolism by induction of CYP 3A4 by rifampicin. He was initially treated with intravenous hydrocortisone and was subsequently discharged on hydrocortisone and fludrocortisone. His symptoms have improved significantly. However, he is requiring slightly higher dose of hydrocortisone, which could be due to CYP 3A4 induction by rifampicin. He is likely to require lifelong treatment for adrenal insufficiency. A study that looked at tuberculosis patients with bilaterally enlarged adrenal glands found that treatment with antituberculosis drugs does not improve or help recover adrenal functionality [1]. Adrenal biopsy was not performed because the presentation was strongly suggestive of adrenal tuberculosis with active extra-adrenal tuberculosis.\n\n\nComment. It is to be noted that BCG vaccine received at birth has no impact on PPD test result 10 years later [2]. The presumption made by the other hospital that this patient's positive TST is secondary to a vaccination at birth was incorrect. Positive PPD in this patient should have prompted further investigations.\n\n2. Background\nIt is interesting to note that Thomas Addison was in fact seeking an anatomic basis for pernicious anemia rather than the biochemical effects of adrenal insufficiency when he published his seminal paper on the subject. The eleven patients he described in his report all had tuberculosis of the adrenal glands [3]. This consumption has since receded to the background of ailments that afflict the Western world and today is generally considered a disease of immigrants from endemic areas, the immunocompromised or the destitute. In the developing world, however, tuberculosis continues to account for about 20–30% of cases of Addison's disease [4].\n\nThe clinical presentation of primary adrenal insufficiency is protean, and an underlying infectious etiology can further obscure the manifestations. The most frequent manifestations are weakness, fatigue, anorexia, weight loss, nausea, vomiting, hypotension, and skin hyperpigmentation (present in 60–100% of patients) [5, 6]. Understandably any of the above symptoms or signs could be easily missed or attributed to the primary infectious process itself.\n\nIn the developed world, about 10% of cases of Addison's disease have an infectious etiology; however there are few data available regarding the frequency of organisms that cause clinical adrenal insufficiency. HIV/AIDS and opportunistic infections like cytomegalovirus are the most commonly cited causes following tuberculosis. Various fungi like Cryptococcus, Histoplasma, Coccidioides, Paracoccidioides are also described to involve the adrenal glands in several case reports (Table 1).\n\n3. Tuberculosis\n\nMycobacterium tuberculosis complex spreads to the adrenal glands hematogenously. Clinical manifestations may take years to become apparent, and asymptomatic infection is not uncommon. Adrenal involvement was found in 6% of patients with active tuberculosis in an autopsy series [7]. More than 90% of the gland must be destroyed before insufficiency appears [8]. The widespread use of computed tomography has improved our understanding of the patterns of involvement of the adrenal gland in tuberculosis. The majority of patients with active or recently acquired disease (<2 years) have bilateral adrenal enlargement, while calcification and atrophy are the norm with more remote infection or inactive disease [8, 9].\n\nThat the adrenals can be enlarged in patients with pulmonary tuberculosis without active involvement of the glands has been demonstrated in various studies. Stress and inflammation could be potential reasons. The activity of the hypothalamic pituitary axis (HPA) has been the subject of numerous studies. The lack of a uniform definition of a “normal cortisol response” to ACTH stimulation has perhaps contributed to some of the heterogeneity in the results. Keleştimur et al. studied the HPA axis in 27 patients with active pulmonary tuberculosis. They also compared responses to 1 mcg and 250 mcg ACTH stimulation. Cortisol responses were consistently higher in the cases when compared to controls [10]. A more recent study by Laway et al. found significantly lower basal and stimulated cortisol levels in active pulmonary tuberculosis when compared to controls, as well as enlarged adrenal glands. None of the patients had clinical adrenal insufficiency. Both of these findings improved after successful antituberculous treatment [4]. However, the absence of serum albumin levels and the lack of adrenal biopsies in the cases limit the interpretation of the results. Other studies have also demonstrated a reduction in adrenal gland size after successful treatment of pulmonary tuberculosis [11].\n\nWhen tuberculosis results in overt adrenal insufficiency, antituberculous chemotherapy does not appear to restore function. One must also be cognizant of the effect of rifampin, a potent hepatic enzyme inducer on the metabolism of glucocorticoids. Failure to increase the dose of steroid replacement therapy may result in the development of adrenal crisis [1]. Adrenal biopsy is not necessary for primary adrenal insufficiency with bilateral adrenal enlargement in a patient with proven extra-adrenal tuberculosis. However, about 12% of patients with adrenal tuberculosis have no evidence of active extra-adrenal tuberculosis [12]. Adrenal biopsy is generally necessary in these patients to prove adrenal involvement by tuberculosis.\n\n4. HIV Infection\nHIV infection affects the adrenal gland in multiple ways. Apart from direct infection, opportunistic infections and antiretroviral medications also have a significant effect on the adrenal glands.\n\nAdrenal insufficiency is prevalent in 17% of patients admitted with AIDS [13]. Due to its high prevalence, recommendations have been made to screen for adrenal insufficiency in HIV patients with symptoms [14]. Most common causes of adrenal insufficiency are infections like CMV, Mycobacterium tuberculosis and MAI, Cryptococcus neoformans, Histoplasma capsulatum, Pneumocystis jirovecii, and Toxoplasma gondii, neoplastic diseases (Kaposi's sarcoma and lymphoma), and bilateral adrenal hemorrhage [15, 16]. Few drugs used for the treatment of HIV infection (protease inhibitors) and drugs used to treat opportunistic infections like rifampicin, ketoconazole, and cotrimoxazole may exacerbate manifestations of primary adrenal insufficiency [17, 18]. Studies have shown decreased level of cortisol, adrenal androgens, and mineralocorticoids in patients infected with HIV [19].\n\nHIV infection can also lead to secondary adrenal insufficiency in advanced stages of the disease by decreasing pituitary and adrenal responses to CRH [20]. Opportunistic infections like CMV, Mycobacterium tuberculosis, Toxoplasma gondii, Cryptococcus neoformans, and Pneumocystis jirovecii can also infiltrate the pituitary leading to multiple endocrinopathies.\n\nTreatment of adrenal insufficiency in HIV infection includes hydrocortisone and fludrocortisone (if there is evidence of mineralocorticoid insufficiency).\n\nThere are cases of Cushing's like phenotype in patients treated with antiretroviral drugs (protease inhibitors and NNRTIs) often referred to as “pseudo-Cushing's” [21]. A normal cortisol response to the dexamethasone suppression test differentiates pseudo-Cushing's from Cushing's syndrome. Studies have also shown elevated levels of basal plasma cortisol in untreated HIV patients when compared to healthy individuals. The postulated mechanisms include stress due to HIV infection, increased cytokines resulting in stimulation of HPA axis, and reduction in cortisol catabolism [22].\n\nAdrenal tumors found almost exclusively in HIV patients include Kaposi's sarcoma which is secondary to coinfection with the oncogenic human herpes virus type 8 (HHV8) and non-Hodgkin's lymphoma (high-grade malignant B phenotype) which could be secondary to Epstein-Barr virus (EBV) [23, 24].\n\n5. Human Cytomegalovirus Infection\nHuman cytomegalovirus (HCMV) has been frequently identified as a cause of adrenal insufficiency, especially in patients with HIV/AIDS. The virus has been shown by Trevisan et al. to infect normal human adrenocortical cells and induce cytopathic changes [25]. It also acts as an inducer of steroidogenesis which may explain the discordance between the high rates of CMV adrenalitis in immune suppressed patients in autopsy studies and the relatively rare diagnosis of adrenal insufficiency ante mortem. The virus causes the greatest damage at the cortex-medulla junction [26]. While adrenalitis may be the sole manifestation, the disease is usually disseminated. There have been case reports of exacerbation of CMV infection in patients of adrenal insufficiency after starting glucocorticoids most likely due to the immunosuppressive effect [27, 28].\n\n6. Histoplasma capsulatum\n\nAdrenal involvement is typically seen with disseminated chronic histoplasmosis. In one report, primary adrenal insufficiency occurred in 41.3% of adrenal histoplasmosis cases [29]. Histoplasmosis often coexists with HIV-AIDS and is more commonly seen in the immunocompromised, posttransplant and elderly populations [30]. Histoplasmosis presents with similar constellation of clinical features as tuberculosis and is often missed. Furthermore, it also shares pathological characteristics of necrotizing granulomas and caseous necrosis with tuberculosis. Adrenal glands have bilaterally enlarged radiographic appearance and CT guided biopsy often confirms the diagnosis of adrenal histoplasmosis [31, 32]. In addition to tuberculosis, it can also be often mistaken for a lymphoma, underlining the importance of biopsy in these cases. Management includes treatment with amphotericin B followed by itraconazole (for disseminated disease) and replacement of glucocorticoid and mineralocorticoid if there is evidence of adrenal insufficiency.\n\n7. Paracoccidioidomycosis\nParacoccidioides, a thermal dimorphic fungus, causes infection through the inhalation of infectious conidia. It is endemic in several South American countries. Two species, P. braziliensis and P. lutzi, are pathogenic in humans. While the acute form usually appears as progressive lymphadenopathy, the chronic form affects the skin, lungs, mucous membranes, and the adrenal glands [33]. Adrenal insufficiency occurs in a large number of patients (2.9%–48.2%) and has even been reported as the initial presenting feature [34, 35]. Autopsy series have demonstrated adrenal involvement in 85–90% of cases [35]. Clinical manifestations range from the asymptomatic to frank Addisonian crisis. This correlates with the extent of granulomatous involvement of the adrenal glands. Similar to tuberculosis, adrenal insufficiency typically persists even after treatment of the infection [35].\n\n8. Other Causes of Adrenal Infections\n8.1. Viruses\nMany of the herpes viruses infect the adrenal gland including herpes simplex virus types 1 and 2, Epstein-Barr virus, and HCMV. This occurs usually in the setting of disseminated disease and may appear as adrenalitis. Disseminated HSV type 1 and 2 infections in neonates can be fulminant [36]. Murine models suggest the possibility of the adrenals being the initial seat of multiplication of these viruses [37].\n\nEBV, HCMV, and Polyoma BK virus have been identified in resected adrenocortical tumors; the former has also been associated with lymphoma of the adrenal gland [38, 39].\n\nOther commonly occurring viruses that can infect the adrenal glands include echoviruses which can lead to adrenal hemorrhage and necrosis in neonates [40].\n\nThe hemorrhagic fever viruses, although rare, can cause devastating damage to the adrenal glands. The Ebola virus, a filovirus, has been shown to cause liquefaction of the adrenals [41]. Other filoviruses and arenaviruses can also damage the adrenals by direct infection [42].\n\n8.2. Fungi\nAdrenal cryptococcosis occurs in disseminated cryptococcal infection, usually in the immunocompromised; however, there are case reports of adrenal cryptococcosis in healthy individuals as well. Pneumonia and meningitis are the most common presentations [43]. Like any other fungal infection, the adrenal glands are enlarged on CT scan and the diagnosis is confirmed by a CT guided biopsy [44]. Cryptococcal antigen titers are invariably high and can be used as a biomarker for disease resolution on follow-up [45]. A 6-month course of fluconazole appears to be effective [46]. In contrast to tuberculosis and histoplasmosis, adrenal insufficiency is often improved with resolution of the disease. Adrenal cryptococcal infection resistant to antifungal therapy may respond to adrenalectomy [47].\n\n\nPneumocystis jirovecii is an infrequent cause of adrenal insufficiency even in patients with defective cell mediated immunity such as patients with HIV/AIDS. However, it has been known to cause fatal adrenal crisis in the apparently immunocompetent host as well [48].\n\n\nBlastomyces dermatitidis is a thermal dimorphic fungus that is the North American counterpart of Paracoccidioides in terms of its pathogenesis and propensity for establishing chronic systemic infection. Although pulmonary infection is the most common presentation, it frequently affects the skin, bones, adrenal glands, and the genitourinary system. Almost any organ system may be involved. It appears that subclinical infection of the adrenal glands is more common than overt insufficiency [49]. About 10% of cases in autopsy series revealed adrenal gland infection [50]. Amphotericin B and itraconazole are the drugs of choice in disseminated disease.\n\n8.3. Bacteria\nAtypical mycobacteria have been isolated from adrenal glands in patients with HIV/AIDS, however, given the multiple etiologies for adrenal insufficiency and frequent coinfection with other organisms that are known to cause destruction of the adrenal glands; however, it is difficult to establish a causal relationship [15].\n\nThe Waterhouse-Friedrichsen syndrome deserves special mention. It is a form of acute adrenal insufficiency that occurs in the setting of bacterial sepsis resulting in adrenal hemorrhage. A number of bacteria are associated with this entity including N. meningitidis, H. influenza, pneumococcus, P. multocida, K. oxytoca, S. aureus, Capnocytophaga canimorsus, Ewingella, and group A streptococcal infections. The organisms are rarely isolated from the adrenal glands at autopsy [51–54].\n\n8.4. Parasites\nOf all the organisms mentioned in this review, parasites are perhaps the least commonly reported causes of adrenal infection in the United States. Microsporidia have been reported to cause necrotic lesions in the adrenal glands, particularly in patients with AIDS [55]. Echinococcosis (hydatid disease) is responsible for about 7% of all adrenal cysts. Treatment is surgical excision followed by several months of chemotherapy with oral albendazole to prevent recurrence [56, 57]. Visceral leishmaniasis is another cause of cystic adrenal disease. Trypanosoma cruzi, the causative agent of Chagas' disease, has been shown to infect the adrenal gland. Studies have postulated that the adrenals may serve as a reservoir for T. cruzi and parasitemia in the central adrenal vein has been correlated with the development of chronic chagasic cardiomyopathy [58, 59]. African trypanosomiasis has been associated with polyendocrinopathies including hypogonadism, hypothyroidism, and adrenal insufficiency. This can result from a primary glandular or secondary (central) involvement. In one case series of 137 Ugandan patients, treatment of the infection resulted in recovery of adrenal and thyroid function, but hypogonadism tended to persist for years [60].\n\n9. Conclusion\nThe adrenal glands can be affected by a wide range of organisms through multiple mechanisms including direct infection as well as disturbance of the HPA axis due to physiologic stress and cytokine release being the most common. Many of the diseases described in this review appear as chronic illnesses that have manifestations similar to adrenal insufficiency; therefore, very high index of suspicion is required for making the diagnosis of adrenal insufficiency in these patients. Bilateral adrenal enlargement is a feature of a number of these illnesses, especially the granulomatous infections. It is interesting to note that bilateral adrenal enlargement does not necessarily indicate adrenal infection but may be merely reflective of the response to stress. Successful treatment often results in the reduction of gland size. Once adrenal insufficiency has set in, however, the adrenal hypofunction tends to persist despite appropriate treatment of the underlying infection.\n\nThe biochemical diagnosis of adrenal insufficiency is often complicated by acute illness, which ironically is often the setting for it. Lack of uniform definitions and availability of reliability of assays used to measure ACTH and cortisol levels were the limitations encountered in a number of studies. Current guidelines recommend using a 250 mcg postintravenous corticotropin stimulated cortisol level of >18 mcg/dL as a cut-off to rule out primary adrenal insufficiency. In the setting of critical illness a serum cortisol level less than 25 mcg/dL or an increment of less than 9 mcg/dL 30 minutes after a 1 mcg intravenous corticotropin injection may be suggestive of adrenal insufficiency [61].\n\nSteroid replacement strategies are the same irrespective of the etiology, but special attention must be paid to patients on rifampin, isoniazid, azole antifungal agents, and certain antiretroviral agents (ritonavir). These agents significantly impact steroid catabolism by interfering with the cytochrome P 450 system [62].\n\n“The leading and characteristic features which merit attention are anemia, general languor and debility, remarkable feebleness of the heart's action, irritability of the stomach and a peculiar change of the color in the skin, occurring in connection with a diseased condition of the suprarenal capsules.” Dr. Addison's classic description can scarcely be improved upon today. It cannot be emphasized enough that the diagnosis of adrenal insufficiency is a clinical challenge and requires a high index of suspicion, especially in the setting of an infectious process [3].\n\nConflict of Interests\nThe authors declare that there is no conflict of interests regarding the publication of this paper.\n\nFigure 1 CT scan of the abdomen and pelvis with oral and intravenous contrast showing bilateral adrenal enlargement (black arrows).\n\nTable 1 Salient features of various adrenal infections.\n\nOrganism\tImaging findings\tComments\t\n\nMycobacterium tuberculosis \n\tBilateral adrenal enlargement \n(active infection). Atrophy and calcification in remote infection\tAdrenal enlargement improves with treatment; adrenal insufficiency does not. Steroid dose should be increased if on rifampin\t\n\n\n\t\nHIV\tDepends on the etiology \n(multiple OIs can involve the adrenals)\tAdrenal insufficiency due to viral, fungal, mycobacterial infiltration. “Pseudo-Cushing's” due to antiretroviral drugs and impaired cortisol metabolism\t\n\n\n\t\n\nHistoplasma capsulatum \n\tBilateral adrenal enlargement\tNearly 50% have adrenal involvement \t\n\n\n\t\n\nParacoccidioides \n\tBilateral adrenal enlargement\tEndemic in South America. Adrenal insufficiency does not always improve with treatment of the infection\t\n\n\n\t\n\nBlastomyces dermatitidis \n\tBilateral adrenal enlargement\tSimilar to paracoccidioidomycosis, overt adrenal insufficiency is less common\t\n\n\n\t\nHuman cytomegalovirus infection\tVariable\tOne of the most common adrenal infections in patients with AIDS. Insufficiency can manifest even when the patient is on glucocorticoid replacement\t\n\n\n\t\nBacterial sepsis\tAdrenal hemorrhage\tA number of bacteria are associated with the Waterhouse-Friderichsen syndrome. Most commonly seen when encapsulated organisms cause overwhelming sepsis\t\n\n\n\t\n\nEchinococcus sp.\tAdrenal cysts\tCauses 6-7% of all adrenal cysts. Treatment is with surgery and albendazole\t\n\n\n\t\n\nTrypanosoma sp.\tVariable\tAdrenals may be the reservoir for T.cruzi while T.brucei (African sleeping sickness) causes mixed central/peripheral adrenal insufficiency\n==== Refs\n1 Bhatia E Jain SK Gupta RK Pandey R Tuberculous Addison's disease: Lack of normalization of adrenocortical function after anti-tuberculous chemotherapy Clinical Endocrinology 1998 48 3 355 359 2-s2.0-0031882477 9578827 \n2 Farhat M Greenaway C Pai M Menzies D False-positive tuberculin skin tests: What is the absolute effect of BCG and non-tuberculous mycobacteria? International Journal of Tuberculosis and Lung Disease 2006 10 11 1192 1204 2-s2.0-33750796878 17131776 \n3 Pearce JM Thomas Addison (1793–1860) Journal of the Royal Society of Medicine 2004 97 6 297 300 2-s2.0-3442893004 15173338 \n4 Laway BA Khan I Shah BA Choh NA Bhat MA Shah ZA Pattern of adrenal morphology and function in pulmonary tuberculosis: response to treatment with antitubercular therapy Clinical Endocrinology 2013 79 3 321 325 2-s2.0-84880835674 23414172 \n5 Charmandari E Nicolaides NC Chrousos GP Adrenal Insufficiency 2014 Lancet \n6 Brandao Neto RA Carvalho JF Diagnosis and classification of Addison's disease (autoimmune adrenalitis) Autoimmunity Reviews 2014 13 4-5 408 411 24424183 \n7 Lam KY Lo CY A critical examination of adrenal tuberculosis and a 28-year autopsy experience of active tuberculosis Clinical Endocrinology 2001 54 5 633 639 2-s2.0-0035724629 11380494 \n8 Kelestimur F The endocrinology of adrenal tuberculosis: The effects of tuberculosis on the hypothalamo-pituitary-adrenocortical function Journal of Endocrinological Investigation 2004 27 4 380 386 2-s2.0-2942615151 15233561 \n9 McMurry JF Jr. Long D McClure R Kotchen TA Addison's disease with adrenal enlargement on computed tomographic scanning. Report of two cases of tuberculosis and review of the literature The American Journal of Medicine 1984 77 2 365 368 2-s2.0-0021230247 6087660 \n10 Keleştimur F Göktaş Z Gülmez I Low dose (1 μ g) adrenocorticotropin stimulation test in the evaluation of hypothalamo-pituitary-adrenal axis in patients with active pulmonary tuberculosis Journal of Endocrinological Investigation 2000 23 4 235 239 2-s2.0-0342369504 10853709 \n11 Gülmez I Keleştimur F Durak AC Özesmi M Changes in the size of adrenal glands in acute pulmonary tuberculosis with therapy Endocrine Journal 1996 43 5 573 576 2-s2.0-0029911947 8980899 \n12 Kelestimur F Unlu Y Ozesmi M Tolu I A hormonal and radiological evaluation of adrenal gland in patients with acute or chronic pulmonary tuberculosis Clinical Endocrinology 1994 41 1 53 56 2-s2.0-0028070212 8050132 \n13 Hofbauer LC Heufelder AE Endocrine implications of human immunodeficiency virus infection Medicine 1996 75 5 262 278 2-s2.0-0029815082 8862348 \n14 Al-Harthi L Voris J Patterson BK Evaluation of the impact of highly active antiretroviral therapy on immune recovery in antiretroviral naive patients HIV Medicine 2004 5 1 55 65 2-s2.0-10744222905 14731171 \n15 Glasgow BJ Steinsapir KD Anders K Layfield LJ Adrenal pathology in the acquired immune deficiency syndrome American Journal of Clinical Pathology 1985 84 5 594 597 2-s2.0-0022377907 3904401 \n16 Bricaire F Marche C Zoubi D Regnier B Saimot AG Adrenocortical lesions and AIDS The Lancet 1988 1 8590 article 881 2-s2.0-0023928437 \n17 Lo J Grinspoon SK Adrenal function in HIV infection Current Opinion in Endocrinology, Diabetes and Obesity 2010 17 3 205 209 2-s2.0-77951804292 \n18 Pont A Williams PL Loose DS Ketoconazole blocks adrenal steroid synthesis Annals of Internal Medicine 1982 97 3 370 372 2-s2.0-0019980296 6287893 \n19 Findling JW Buggy BP Gilson IH Brummitt CF Bernstein BM Raff H Longitudinal evaluation of adrenocortical function in patients infected with the human immunodeficiency virus The Journal of Clinical Endocrinology & Metabolism 1994 79 4 1091 1096 2-s2.0-0028102977 7962279 \n20 Lortholary O Christeff N Casassus P Hypothalamo-pituitary-adrenal function in human immunodeficiency virus-infected men Journal of Clinical Endocrinology and Metabolism 1996 81 2 791 796 2-s2.0-0030020560 8636305 \n21 Miller KK Daly PA Sentochnik D Pseudo-Cushing's syndrome in human immunodeficiency virus-infected patients Clinical Infectious Diseases 1998 27 1 68 72 2-s2.0-0031829526 9675454 \n22 Sutinen J Kannisto K Korsheninnikova E In the lipodystrophy associated with highly active antiretroviral therapy, pseudo-Cushing's syndrome is associated with increased regeneration of cortisol by 11β -hydroxysteroid dehydrogenase type 1 in adipose tissue Diabetologia 2004 47 10 1668 1671 2-s2.0-19944417900 15455200 \n23 Mastorakos G Magiakou M-A Chrousos GP Effects of the immune/inflammatory reaction on the hypothalamic-pituitary-adrenal axis Annals of the New York Academy of Sciences 1995 771 438 448 2-s2.0-0029552068 8597420 \n24 Grulich AE Li Y McDonald AM Correll PK Law MG Kaldor JM Decreasing rates of Kaposi's sarcoma and non-Hodgkin's lymphoma in the era of potent combination antiretroviral therapy AIDS 2001 15 5 629 633 2-s2.0-0035970668 11317001 \n25 Trevisan M Matkovic U Cusinato R Toppo S Palù G Barzon L Human cytomegalovirus productively infects adrenocortical cells and induces an early cortisol response Journal of Cellular Physiology 2009 221 3 629 641 2-s2.0-70449729513 19688782 \n26 Rodrigues D Reis M Teixeira V Pathologic findings in the adrenal glands of autopsied patients with acquired immunodeficiency syndrome Pathology Research and Practice 2002 198 1 25 30 2-s2.0-0036175716 \n27 Ardalan M Shoja MM Cytomegalovirus-induced adrenal insufficiency in a renal transplant recipient Transplantation Proceedings 2009 41 7 2915 2916 2-s2.0-70149089908 19765472 \n28 Uno K Konishi M Yoshimoto E Fatal cytomegalovirus-associated adrenal insufficiency in an AIDS patient receiving corticosteroid therapy Internal Medicine 2007 46 9 617 620 2-s2.0-34249688491 17473501 \n29 Koene RJ Catanese J Sarosi GA Adrenal hypofunction from histoplasmosis: a literature review from 1971 to 2012 Infection 2013 41 4 757 759 2-s2.0-84881090170 23771479 \n30 Kauffman CA Fungal infections in older adults Clinical Infectious Diseases 2001 33 4 550 555 2-s2.0-0035882402 11462194 \n31 Goodwin RA Jr. Shapiro JL Thurman GH Thurman SS Des Prez RM Disseminated histoplasmosis: clinical and pathologic correlations Medicine 1980 59 1 1 33 2-s2.0-0018890577 7356773 \n32 Mukherjee JJ Villa ML Tan L Lee KO Image in endocrinology: bilateral adrenal masses due to histoplasmosis The Journal of Clinical Endocrinology & Metabolism 2005 90 12 6725 6726 2-s2.0-28744432354 16330806 \n33 Bocca AL Amaral AC Teixeira MM Paracoccidioidomycosis: eco-epidemiology, taxonomy and clinical and therapeutic issues Future Microbiology 2013 8 9 1177 1191 24020744 \n34 Agudelo CA Muñoz C Ramírez A Identification of Paracoccidioides brasiliensis in adrenal glands biopsies of two patients with paracoccidioidomycosis and adrenal insufficiency Revista do Instituto de Medicina Tropical de Sao Paulo 2009 51 1 45 48 2-s2.0-60849122551 19229390 \n35 Tobon AM Agudelo CA Restrepo CA Adrenal function status in patients with paracoccidioidomycosis after prolonged post-therapy follow-up The American Journal of Tropical Medicine and Hygiene 2010 83 1 111 114 20595488 \n36 Nakamura Y Yamamoto S Tanaka S Herpes simplex viral infection in human neonates: an immunohistochemical and electron microscopic study Human Pathology 1985 16 11 1091 1097 2-s2.0-0022356943 2997017 \n37 Potratz D Brake B Dienes HP Herpes simplex virus type 1 and 2 in the adrenal glands: replication and histopathology Archives of Virology 1986 90 3-4 207 222 2-s2.0-0022471970 3015081 \n38 Pomara G Cappello F Barzon L Cytomegalovirus and BK-Virus co-infection of a clinically non-functioning adrenal adenoma: Innocent bystanders or new pathogenetic agents? European Journal of Histochemistry 2006 50 2 131 132 2-s2.0-38749121017 16864124 \n39 Ohsawa M Tomita Y Hashimoto M Yasunaga Y Kanno H Aozasa K Malignant lymphoma of the adrenal gland: its possible correlation with the Epstein-Barr virus Modern Pathology 1996 9 5 534 543 2-s2.0-0029951565 8733769 \n40 Ventura KC Hawkins H Smith MB Walker DH Fatal neonatal echovirus 6 infection: autopsy case report and review of the literature Modern Pathology 2001 14 2 85 90 2-s2.0-0035108106 11235909 \n41 Mahanty S Bray M Pathogenesis of filoviral haemorrhagic fevers The Lancet Infectious Diseases 2004 4 8 487 498 2-s2.0-4043053773 15288821 \n42 Edington GM White HA The pathology of Lassa fever Transactions of the Royal Society of Tropical Medicine and Hygiene 1972 66 3 381 389 5046378 \n43 Subramanian S Mathai D Clinical manifestations and management of cryptococcal infection Journal of Postgraduate Medicine 2005 51 supplement 1 S21 S26 2-s2.0-33645544832 16519251 \n44 Walker BF Gunthel CJ Bryan JA Watts NB Clark RV Disseminated cryptococcosis in an apparently normal host presenting as primary adrenal insufficiency: diagnosis by fine needle aspiration The American Journal of Medicine 1989 86 6, part 1 715 717 2-s2.0-0024390467 2658577 \n45 Hung Z-S Lai Y-H Hsu Y-H Wang C-H Fang T-C Hsu B-G Disseminated cryptococcosis causes adrenal insufficiency in an immunocompetent individual Internal Medicine 2010 49 11 1023 1026 2-s2.0-77953355641 20519820 \n46 Huston SM Mody CH Cryptococcosis: an Emerging Respiratory Mycosis Clinics in Chest Medicine 2009 30 2 253 264 2-s2.0-64249107091 19375632 \n47 Takeshita A Nakazawa H Akiyama H Disseminated cryptococcosis presenting with adrenal insufficiency and menigitis: resistant to prolonged antifungal therapy but responding to bilateral adrenalectomy Internal Medicine 1992 31 12 1401 1405 2-s2.0-0026989211 1300177 \n48 Agarwal J Agarwal G Ayyagari A Kar DK Mishra SK Bhatia E Isolated Pneumocystis carinii infection of adrenal glands causing Addison's disease in a non-immunocompromised adult Endocrine Pathology 2001 12 1 87 91 2-s2.0-0034965814 11478273 \n49 Rimondi AP Bianchini E Barucchello G Panzavolta R Addison's disease caused by adrenal blastomycosis: a case report with fine needle aspiration (FNA) cytology Cytopathology 1995 6 4 277 279 2-s2.0-0029094576 8520008 \n50 Chandler PT Addison's disease secondary to North American blastomycosis Southern Medical Journal 1977 70 7 863 864 2-s2.0-0017398922 877650 \n51 Tormos LM Schandl CA The significance of adrenal hemorrhage: undiagnosed waterhouse-friderichsen syndrome, a case series Journal of Forensic Sciences 2013 58 4 1071 1074 2-s2.0-84880142165 23458363 \n52 Kamio M Hibino T Matsumori K Case report: a case of invasive pneumococcal disease with purpura fulminans and Waterhouse-Friderichsen syndrome Nihon Naika Gakkai Zasshi 2012 101 5 1382 1385 2-s2.0-84866159715 22693858 \n53 Shimizu S Tahara Y Atsumi T Waterhouse-Friderichsen syndrome caused by invasive Haemophilus influenzae type B infection in a previously healthy young man Anaesthesia and Intensive Care 2010 38 1 214 215 2-s2.0-75749112046 20191807 \n54 Adem PV Montgomery CP Husain AN Staphylococcus aureus sepsis and the Waterhouse-Friderichsen syndrome in children The New England Journal of Medicine 2005 353 12 1245 1251 2-s2.0-25144473101 16177250 \n55 Mertens RB Didier ES Fishbein MC Bertucci DC Rogers LB Orenstein JM \nEncephalitozoon cuniculi microsporidiosis: infection of the brain, heart, kidneys, trachea, adrenal glands, and urinary bladder in a patient with AIDS Modern Pathology 1997 10 1 68 77 2-s2.0-0031040281 9021729 \n56 Ozarmagan S ErbilI Y BarbarosI U Salmaslioglu A Bozbora A Primary hydatid disease in the adrenal gland: a case report Brazilian Journal of Infectious Diseases 2006 10 5 362 363 17293927 \n57 Akçay MN Akçay G Balik AA Böyük A Hydatid cysts of the adrenal gland: review of nine patients World Journal of Surgery 2004 28 1 97 99 2-s2.0-17744412292 14639487 \n58 de Paula Antunes Teixeira V Hial V da Silva Gomes RA Correlation between adrenal central vein parasitism and heart fibrosis in chronic chagasic myocarditis The American Journal of Tropical Medicine and Hygiene 1997 56 2 177 180 2-s2.0-1842365470 9080877 \n59 Teixeira de VPA Araujo MBM Dos Reis MA Possible role of an adrenal parasite reservoir in the pathogenesis of chronic Trypanosoma cruzi myocarditis Transactions of the Royal Society of Tropical Medicine and Hygiene 1993 87 5 552 554 2-s2.0-0027507680 8266407 \n60 Reincke M Arlt W Heppner C Petzke F Chrousos GP Allolio B Neuroendocrine dysfunction in African trypanosomiasis: the role of cytokines Annals of the New York Academy of Sciences 1998 840 809 821 2-s2.0-0032078327 9629307 \n61 Bornstein SR Predisposing factors for adrenal insufficiency The New England Journal of Medicine 2009 360 22 2328 2339 2-s2.0-66249120658 19474430 \n62 McAllister WAC Thompson PJ Al Habet SM Rogers HJ Rifampicin reduces effectiveness and bioavailability of prednisolone British Medical Journal 1983 286 6369 923 925 2-s2.0-0020695718 6403136\n\n",
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"pubdate": "2014",
"publication_types": "D016428:Journal Article; D016454:Review",
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"title": "Tuberculosis of the adrenal gland: a case report and review of the literature of infections of the adrenal gland.",
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"abstract": "This is the first report on safety and efficacy of intravenous bisphosphonates (IV BP) for treatment of disuse osteoporosis and low bone mineral density (BMD) in children with spinal muscular atrophy (SMA). IV BP appears to be safe and effective in fracture rate reduction. However, caution is necessary given the occurrence of an atypical femur fracture.\n\n\nBACKGROUND\nChildren with SMA are at high risk for fragility fractures and low BMD. IV BP have been used for treatment of disuse osteoporosis in pediatrics. However, safety and efficacy of IV BP in the SMA population has not been reported.\n\n\nMETHODS\nRetrospective chart review of IV BP for treatment of disuse osteoporosis and low BMD in children with SMA at a tertiary pediatric center from 2010 to 2018 RESULTS: Eight patients (50% female; 75% SMA type 1; median age at first infusion 6.7 years) receiving a total of 39 infusions (54% pamidronate, 46% zoledronic acid) were included in this report. Acute phase reactions occurred following 38% and 3% of initial and subsequent infusions, respectively. BMD trended toward improvement at 1 year post-treatment. Among six patients who had > 2 years of follow-up, fracture rate decreased from 1.4 to 0.1 fracture/year. An atypical femur fracture was observed in one patient.\n\n\nCONCLUSIONS\nThese findings suggest that in children with SMA, IV BP therapy appears to be safe with minimal acute side effects and effective to reduce fracture rate. Caution is still needed given the occurrence of an atypical femur fracture in SMA population.",
"affiliations": "Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, 45267, USA.;Division of Biostatistics and Epidemiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, USA.;Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, 45267, USA. halley.wasserman@cchmc.org.",
"authors": "Nasomyont|N|N|https://orcid.org/0000-0001-8996-8760;Hornung|L N|LN|;Wasserman|H|H|https://orcid.org/0000-0002-8309-6321",
"chemical_list": "D050071:Bone Density Conservation Agents; D004164:Diphosphonates",
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"doi": "10.1007/s00198-019-05227-9",
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"issue": "31(5)",
"journal": "Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA",
"keywords": "Atypical femur fracture, bisphosphonates; DXA; osteoporosis; pediatrics; spinal muscular atrophy",
"medline_ta": "Osteoporos Int",
"mesh_terms": "D015519:Bone Density; D050071:Bone Density Conservation Agents; D002648:Child; D004164:Diphosphonates; D005260:Female; D050723:Fractures, Bone; D006801:Humans; D008297:Male; D009134:Muscular Atrophy, Spinal; D010024:Osteoporosis; D012189:Retrospective Studies",
"nlm_unique_id": "9100105",
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"pubdate": "2020-05",
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"title": "Intravenous bisphosphonate therapy in children with spinal muscular atrophy.",
"title_normalized": "intravenous bisphosphonate therapy in children with spinal muscular atrophy"
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"abstract": "BACKGROUND\nPatients who undergo allogeneic stem cell transplantation and subsequent radiation therapy uncommonly develop graft-versus-host disease within the irradiated area. We quantified the incidence of this complication, which is a novel contribution to the field. From 2010 to 2014, 1849 patients underwent allogeneic stem cell transplantation, and 41 (2 %) received radiation therapy afterward. Of these, two patients (5 %) developed graft-versus-host disease within the irradiated tissues during or immediately after radiation therapy.\n\n\nMETHODS\nThe first patient is a 37-year-old white man who had Hodgkin lymphoma; he underwent allogeneic stem cell transplantation from a matched unrelated donor and received radiation therapy for an abdominal and pelvic nodal recurrence. After 28.8 Gy, he developed grade 4 gastrointestinal graft-versus-host disease, refractory to tacrolimus and steroids, but responsive to pentostatin and photopheresis. The other patient is a 24-year-old white man who had acute leukemia; he underwent allogeneic stem cell transplantation from a matched related donor and received craniospinal irradiation for a central nervous system relapse. After 24 cobalt Gy equivalent, he developed severe cutaneous graft-versus-host disease, sharply delineated within the radiation therapy field, which was responsive to tacrolimus and methylprednisolone.\n\n\nCONCLUSIONS\nWe conclude that graft-versus-host disease within irradiated tissues is an uncommon but potentially serious complication that may follow radiation therapy in patients who have undergone allogeneic stem cell transplantation. Clinicians must be aware of this complication and prepared with strategies to mitigate risk. Patients who have undergone allogeneic stem cell transplantation represent a unique population that may offer novel insight into the pathways involved in radiation-related inflammation.",
"affiliations": "Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas, USA. samilgrom@mdanderson.org.;Department of Stem Cell Transplantation, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas, USA.;Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas, USA.;Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas, USA.;Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas, USA.;Department of Stem Cell Transplantation, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas, USA.;Department of Pathology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas, USA.;Department of Stem Cell Transplantation, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas, USA.;Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas, USA.",
"authors": "Milgrom|Sarah A|SA|;Nieto|Yago|Y|;Pinnix|Chelsea C|CC|;Smith|Grace L|GL|;Wogan|Christine F|CF|;Rondon|Gabriela|G|;Medeiros|L Jeffrey|LJ|;Kebriaei|Partow|P|;Dabaja|Bouthaina S|BS|",
"chemical_list": "D000893:Anti-Inflammatory Agents; D000970:Antineoplastic Agents; D007166:Immunosuppressive Agents; D015649:Pentostatin; D016559:Tacrolimus; D008775:Methylprednisolone",
"country": "England",
"delete": false,
"doi": "10.1186/s13256-016-0999-z",
"fulltext": "\n==== Front\nJ Med Case RepJ Med Case RepJournal of Medical Case Reports1752-1947BioMed Central London 99910.1186/s13256-016-0999-zCase ReportGraft-versus-host disease after radiation therapy in patients who have undergone allogeneic stem cell transplantation: two case reports Milgrom Sarah A. samilgrom@mdanderson.org 1Nieto Yago ynieto@mdanderson.org 2Pinnix Chelsea C. ccpinnix@mdanderson.org 1Smith Grace L. glsmith@mdanderson.org 1Wogan Christine F. cwogan@mdanderson.org 1Rondon Gabriela grondon@mdanderson.org 2Medeiros L. Jeffrey ljmedeiros@mdanderson.org 3Kebriaei Partow pkebriae@mdanderson.org 2Dabaja Bouthaina S. bdabaja@mdanderson.org 11 Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas USA 2 Department of Stem Cell Transplantation, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas USA 3 Department of Pathology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas USA 28 7 2016 28 7 2016 2016 10 20927 10 2015 6 7 2016 © The Author(s). 2016\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nPatients who undergo allogeneic stem cell transplantation and subsequent radiation therapy uncommonly develop graft-versus-host disease within the irradiated area. We quantified the incidence of this complication, which is a novel contribution to the field. From 2010 to 2014, 1849 patients underwent allogeneic stem cell transplantation, and 41 (2 %) received radiation therapy afterward. Of these, two patients (5 %) developed graft-versus-host disease within the irradiated tissues during or immediately after radiation therapy.\n\nCase presentation\nThe first patient is a 37-year-old white man who had Hodgkin lymphoma; he underwent allogeneic stem cell transplantation from a matched unrelated donor and received radiation therapy for an abdominal and pelvic nodal recurrence. After 28.8 Gy, he developed grade 4 gastrointestinal graft-versus-host disease, refractory to tacrolimus and steroids, but responsive to pentostatin and photopheresis. The other patient is a 24-year-old white man who had acute leukemia; he underwent allogeneic stem cell transplantation from a matched related donor and received craniospinal irradiation for a central nervous system relapse. After 24 cobalt Gy equivalent, he developed severe cutaneous graft-versus-host disease, sharply delineated within the radiation therapy field, which was responsive to tacrolimus and methylprednisolone.\n\nConclusions\nWe conclude that graft-versus-host disease within irradiated tissues is an uncommon but potentially serious complication that may follow radiation therapy in patients who have undergone allogeneic stem cell transplantation. Clinicians must be aware of this complication and prepared with strategies to mitigate risk. Patients who have undergone allogeneic stem cell transplantation represent a unique population that may offer novel insight into the pathways involved in radiation-related inflammation.\n\nKeywords\nGraft-versus-host diseaseGVHDRadiation therapyRTAllogeneic stem cell transplantissue-copyright-statement© The Author(s) 2016\n==== Body\nBackground\nThe management of hematologic malignancies is complex, often involving several types of therapies with toxicities that are heavily influenced by other treatments administered. Allogeneic stem cell transplantation (ASCT) is an important form of treatment for some hematologic cancers. A significant cause of morbidity and mortality after ASCT is graft-versus-host disease (GVHD), an immune response mounted by donor cells against recipient tissues. Several risk factors for GVHD have been identified [1, 2], among them radiation therapy (RT). Our group and others have reported rare cases of GVHD arising within irradiated tissues in patients who have undergone ASCT [3–5]. In this study, we aimed to assess the frequency of this complication.\n\nWith the approval of our institutional review board, we retrospectively reviewed records of patients who had undergone ASCT at our institution from 1 January 2010 to 31 December 2014. Those who had received at least one course of RT after ASCT comprised the study population. Disease characteristics, treatment details, and clinical outcomes were retrieved from electronic medical records. GVHD was defined and graded by treating physicians based on clinical and pathologic findings. The RT plans were reviewed to determine the dose that had been delivered to the affected organs.\n\nDuring the study interval, 1849 patients underwent an ASCT at our institution, 41 (2 %) of whom also received at least one course of RT after ASCT. The baseline characteristics of this cohort are summarized in Table 1. Of these 41 patients, 17 (41 %) experienced acute GVHD (four grade 1, 11 grade 2, and two grade 3); in four cases, the diagnosis of acute GVHD was made after RT (range 21 to 204 days after initiation of RT). In this cohort, nine patients (22 %) developed chronic GVHD (one limited and eight extensive); in four cases, chronic GVHD was diagnosed after treatment with RT (range 22 to 238 days after initiation of RT).Table 1 Patient, disease, and treatment characteristics\n\nCharacteristic\tValue or number of patients (%)\t\nAge at allogeneic stem cell transplantation, years\t\t\n Median (range)\t40 (21–69)\t\nSex\t\t\n Male\t32 (78 %)\t\n Female\t9 (22 %)\t\nEthnicity\t\t\n White\t26 (63 %)\t\n Hispanic\t10 (24 %)\t\n Black\t5 (12 %)\t\nDiagnosis\t\t\n Acute myeloid leukemia\t9 (22 %)\t\n Acute lymphocytic leukemia\t7 (17 %)\t\n Acute biphenotypic leukemia\t1 (2 %)\t\n Chronic myeloid leukemia\t3 (7 %)\t\n Chronic lymphoid leukemia\t1 (2 %)\t\n Mantle cell lymphoma\t2 (5 %)\t\n Classical Hodgkin lymphoma\t7 (17 %)\t\n Mycosis fungoides\t6 (15 %)\t\n Diffuse large B-cell lymphoma\t4 (10 %)\t\n Peripheral T-cell lymphoma\t1 (2 %)\t\nDonor\t\t\n Matched unrelated donor\t21 (51 %)\t\n Matched related donor\t18 (44 %)\t\n Cord blood\t2 (5 %)\t\nConditioning regimen\t\t\n Busulfan/fludarabine\t11 (27 %)\t\n Busulfan/clofarabine\t5 (12 %)\t\n Busulfan/fludarabine/clofarabine\t1 (2 %)\t\n Fludarabine/melphalan\t13 (32 %)\t\n Fludarabine/melphalan/rituximab\t1 (2 %)\t\n Fludarabine/bendamustine/rituximab\t1 (2 %)\t\n Fludarabine/bendamustine/ibritumomab\t1 (2 %)\t\n Fludarabine/melphalan/alemtuzumab\t2 (5 %)\t\n Melphalan/thiotepa/fludarabine/cyclophosphamide\t1 (2 %)\t\n Busulfan/clofarabine/gemcitabine\t4 (10 %)\t\n Fludarabine/cyclophosphamide/2 Gy TBI\t1 (2 %)\t\nTime from ASCT to RT, days\t\t\n Median (range)\t299 (45–1715)\t\nRT dose, Gy\t\t\n Median (range)\t23.4 (2–44)\t\nNumber of RT fractions\t\t\n Median (range)\t12 (1–22)\t\n\nASCT allogeneic stem cell transplantation, RT radiation therapy, TBI total body irradiation\n\n\n\nIn two patients (5 % of the cohort), GVHD developed during or immediately after RT within the irradiated tissues. In a third case, hemorrhagic esophagitis developed 7 days after completion of craniospinal irradiation (CSI). Although an esophageal biopsy was morphologically suggestive of GVHD, the clinical presentation was not consistent with this diagnosis, and the symptoms resolved with steroids alone. Therefore, the symptoms were attributed to RT-induced inflammation, and this case was not included. The two cases of GVHD following RT are described below.\n\nCase presentation\nCase 1\nAn otherwise healthy 37-year-old white man had chemorefractory classic Hodgkin lymphoma, treated with the following regimens: (1) doxorubicin, bleomycin, vinblastine, and dacarbazine; (2) ifosfamide, carboplatin, and etoposide; (3) brentuximab; (4) gemcitabine and vinorelbine; (5) bendamustine; (6) everolimus; (7) sirolimus and vorinostat; (8) lenalidomide; and (9) dexamethasone, cytarabine, and cisplatin. He then underwent an ASCT from a 10/10 matched unrelated donor, with a fludarabine and melphalan conditioning regimen.\n\nThree months after the ASCT, the disease relapsed in his abdominal and pelvic lymph nodes. He was treated with intensity-modulated RT to his para-aortic and pelvic lymph nodes, starting on day 119 after the ASCT. At that time, no evidence of GVHD was present, and the tacrolimus was tapered off. The plan was to treat his abdominal and pelvic lymph nodes with a total dose of 39.6 Gy in 22 fractions. However, after completing 28.8 Gy in 16 fractions, he experienced severe abdominal pain, nausea, vomiting, and copious watery diarrhea. An endoscopy revealed an erythematous gastrointestinal mucosa with superficial ulcers. Biopsies taken throughout his gastrointestinal tract were consistent with GVHD. In his stomach and duodenum, the mucosa showed loss of glands, dilated glands with eosinophilic and granular debris, and increased apoptotic cells (Fig. 1). In his colon, increased apoptotic cells and loss of glands were identified.Fig. 1 \na Full thickness of gastric antrum showing denuded epithelium, loss of glands, dilated glands, and relatively few inflammatory cells in the lamina propria. b High magnification showing dilated gastric glands with eosinophilic granular debris and apoptotic nuclear fragments. These findings support grade 4 graft-versus-host disease\n\n\n\nThese findings led to a diagnosis of grade 4 GVHD of the gastrointestinal tract, experienced after 28.8 Gy. His bowel, contoured as “bowel space,” received a maximum dose of 31.8 Gy and mean dose of 14.8 Gy. The volume of bowel space that received ≥30 Gy was 39 cc, ≥20 Gy was 1400 cc, and ≥10 Gy was 2450 cc. His stomach received a maximum dose of 25 Gy and mean dose of 2.9 Gy. The volume of stomach that received ≥20 Gy was 4.3 cc and ≥10 Gy was 31 cc (Fig. 2). Initial treatment with tacrolimus and steroids (2 mg/kg/day) had no effect, but subsequent pentostatin and photopheresis produced a good response. At last follow-up, 6 months after RT had been stopped, his GVHD was quiescent on photopheresis and tacrolimus, with no evidence of active Hodgkin lymphoma in his abdomen or pelvis.Fig. 2 Intensity-modulated radiation therapy plan for Case 1 shows the 28.8 Gy that had been delivered when graft-versus-host symptoms appeared. Green color wash indicates clinical target volume; blue color wash indicates planning target volume\n\n\n\nCase 2\nAs previously reported [4], an otherwise healthy 24-year-old white man with relapsed Philadelphia-positive B-cell acute lymphocytic leukemia was treated initially with cyclophosphamide, vincristine, doxorubicin, dexamethasone, cytarabine, and methotrexate (hyper-CVAD) with dasatinib. Disease relapse in his central nervous system (CNS) and bone marrow during maintenance therapy was salvaged with augmented hyper-CVAD and dasatinib, followed by a 10/10 human leukocyte antigen (HLA)-matched related ASCT from his sister, with a busulfan and clofarabine conditioning regimen.\n\nOn day 82 after the ASCT, he presented with a headache; he was diagnosed as having an isolated CNS relapse and was treated with rituximab, asparaginase, dasatinib, high-dose methotrexate, and intrathecal cytarabine, followed by consolidative CSI. The CSI was with proton therapy, to a total dose of 24 cobalt Gy equivalent (CGE) in 12 fractions. His brain was treated with right and left posterior oblique beams, and his spine was treated with three posterior-anterior beams. The CSI was begun on day 197 after the ASCT, and no evidence of GVHD was present at that time. The tacrolimus dose was reduced during RT.\n\nOne month after completing CSI, he developed severe dermatitis within the RT portals and conjunctivitis, keratopathy, and conjunctival ulceration. The dose delivered to his skin had been 22 CGE [4]. A skin biopsy showed inflammatory cell-poor interface dermatitis with vacuolar alterations of the basal keratinocytes and dyskeratotic cells, consistent with grade 2 to 3 GVHD. Treatment with tacrolimus and methylprednisolone (2 mg/kg/day) resulted in resolution of his cutaneous GVHD; however, keratoconjunctivitis sicca persisted despite prednisolone ophthalmic drops. His cutaneous GVHD returned several months later, both within and outside the RT field. This extensive chronic GVHD progressed despite steroids, tacrolimus, and photopheresis, manifesting as ulcerations, scleroderma-like changes, and chronic osteomyelitis that necessitated bilateral above-the-knee amputations. He died of aspiration pneumonia and respiratory failure 4.5 years after the ASCT, with no evidence of leukemia.\n\nConclusions\nGVHD is a potentially serious complication that may follow RT in patients who have undergone ASCT. Cases have been reported [4–6]; however, the incidence of this complication was unknown previously. We identified 41 sequential patients who received RT after ASCT, two (5 %) of whom developed clinically significant GVHD within the irradiated tissues during or immediately after RT, despite delivery of relatively low doses to the affected organs. Radiation-induced inflammation was an alternative diagnosis that was considered; however, both the clinical and pathological findings were consistent with GVHD. We conclude that GVHD following RT is uncommon; however, this diagnosis should be considered in patients who have undergone ASCT and who develop RT-related side effects that are more severe than expected.\n\nDiscussion\nGiven the study design, conclusive demonstration of a causal relationship between RT and GVHD is not possible. However, GVHD developed within the irradiated tissues during or immediately following RT, in patients who were without evidence of GVHD previously. Furthermore, in Case 2, cutaneous GVHD was strictly demarcated within the irradiated area [4]. These findings strongly suggest a causal relationship.\n\nThe small number of events in this study precludes the identification of factors that might modify the risk of GVHD. It is notable, however, that the doses of immunosuppressive agents were tapered around the time of RT in both cases. This observation suggests that immunosuppressive therapy should not be reduced during this period, even if patients are free of clinically apparent GVHD at the time of RT.\n\nTheoretically, RT can trigger GVHD via local cellular damage and induction of pro-inflammatory pathways. Multiple inflammatory mediators are activated, upregulated, or released in response to ionizing radiation, such as NF-kB, TNF-α, TGF-β, GM-CSF, COX-2, ICAM-1, IL-1, IL-6, IL-8, IFN, c-Fos, c-Myc, c-Jun, and extracellular nucleotides [6–11]. The resulting chemotactic signals lead to rapid recruitment of diverse leukocyte subgroups into the irradiated area [12–14]. RT also upregulates expression of major histocompatibility complex (MHC) class I/II antigens by cancer cells, rendering them more sensitive to T cell recognition through antigen presentation by dendritic cells [13, 15, 16]. RT may well have similar effects on normal tissues. For patients who have had an ASCT, this immune stimulation may cause dendritic cells to present host antigens to donor T cells, predisposing to the development of GVHD.\n\nThe immune response induced by ionizing radiation is an area of fervent study, both in the laboratory and in the clinic. Patients who have undergone ASCT represent a unique population that may offer additional insight into the pathways involved in radiation-related inflammation. Furthermore, clearer understanding of the mechanisms by which RT induces GVHD may enable the development of therapeutic interventions. RT is a highly effective form of treatment for hematologic malignancies, but clinicians must be able to recognize risk factors for toxicity, including GVHD, and strive to develop strategies to mitigate morbidity.\n\nAbbreviations\nASCT, allogeneic stem cell transplantation; CGE, cobalt Gray equivalent; CNS, central nervous system; CSI, craniospinal irradiation; GVHD, graft-versus-host disease; HLA, human leukocyte antigen; hyper-CVAD, cyclophosphamide, vincristine, doxorubicin, dexamethasone, cytarabine, and methotrexate; MHC, major histocompatibility complex; RT, radiation therapy\n\nAcknowledgements\nThe authors would like to thank Dr Valerie Reed for her thoughtful review of the manuscript.\n\nFunding\nThere was no source of funding for this research.\n\nAvailability of data and materials\nThe datasets upon which the conclusions of the manuscript are based have been made available at zenodo.org (doi:10.5281/zenodo.53915).\n\nAuthors’ contributions\nSAM drafted the manuscript. All authors revised it critically, gave approval of the final version to be published, and agree to be accountable for all aspects of the work.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nConsent for publication\nWritten informed consent was obtained from the patient (Case 1) for publication of the case and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nWritten informed consent was obtained from the patient’s next of kin (Case 2) for publication of the case. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nEthics approval and consent to participate\nApproval was obtained from our institutional review board to conduct this study (MDACC protocol ID #PA13-0947).\n==== Refs\nReferences\n1. Flowers ME Inamoto Y Carpenter PA Lee SJ Kiem HP Petersdorf EW Comparative analysis of risk factors for acute graft-versus-host disease and for chronic graft-versus-host disease according to National Institutes of Health consensus criteria Blood 2011 117 11 3214 9 10.1182/blood-2010-08-302109 21263156 \n2. Jagasia M Arora M Flowers ME Chao NJ McCarthy PL Cutler CS Risk factors for acute GVHD and survival after hematopoietic cell transplantation Blood 2012 119 1 296 307 10.1182/blood-2011-06-364265 22010102 \n3. Okamoto S Takahashi S Inoue T Tojo A Tani K Kikuchi A Cutaneous chronic graft-versus-host disease localized to the field of total lymphoid irradiation Bone Marrow Transplant 1996 17 1 111 3 8673042 \n4. Sharp H, Grosshans D, Kadia T, Dabaja BS. Cutaneous graft-versus-host disease after proton-based craniospinal irradiation for recurrent Philadelphia-positive acute lymphoblastic leukaemia. BMJ Case Reports. 2012;2012. doi:10.1136/bcr.02.2012.5742.\n5. Socie G Gluckman E Cosset JM Devergie A Girinski T Esperou H Unusual localization of cutaneous chronic graft-versus-host disease in the radiation fields in four cases Bone Marrow Transplant 1989 4 1 133 5 2924034 \n6. Hong JH Chiang CS Sun JR Withers HR McBride WH Induction of c-fos and junB mRNA following in vivo brain irradiation Brain Res Mol Brain Res 1997 48 2 223 8 10.1016/S0169-328X(97)00095-8 9332719 \n7. Akashi M Hachiya M Koeffler HP Suzuki G Irradiation increases levels of GM-CSF through RNA stabilization which requires an AU-rich region in cancer cells Biochem Biophys Res Commun 1992 189 2 986 93 10.1016/0006-291X(92)92301-D 1472071 \n8. Steinauer KK Gibbs I Ning S French JN Armstrong J Knox SJ Radiation induces upregulation of cyclooxygenase-2 (COX-2) protein in PC-3 cells Int J Radiat Oncol Biol Phys 2000 48 2 325 8 10.1016/S0360-3016(00)00671-4 10974444 \n9. Son EW Rhee DK Pyo S Gamma-irradiation-induced intercellular adhesion molecule-1 (ICAM-1) expression is associated with catalase: activation of Ap-1 and JNK J Toxicol Environ Health A 2006 69 24 2137 55 10.1080/15287390600747759 17062505 \n10. Pasi F Facoetti A Nano R IL-8 and IL-6 bystander signalling in human glioblastoma cells exposed to gamma radiation Anticancer Res 2010 30 7 2769 72 20683011 \n11. Zhang JS Nakatsugawa S Niwa O Ju GZ Liu SZ Ionizing radiation-induced IL-1 alpha, IL-6 and GM-CSF production by human lung cancer cells Chin Med J (Engl) 1994 107 9 653 7 7805455 \n12. Shiao SL Coussens LM The tumor-immune microenvironment and response to radiation therapy J Mammary Gland Biol Neoplasia 2010 15 4 411 21 10.1007/s10911-010-9194-9 21161342 \n13. Gupta A Probst HC Vuong V Landshammer A Muth S Yagita H Radiotherapy promotes tumor-specific effector CD8+ T cells via dendritic cell activation J Immunol 2012 189 2 558 66 10.4049/jimmunol.1200563 22685313 \n14. Burnette BC Liang H Lee Y Chlewicki L Khodarev NN Weichselbaum RR The efficacy of radiotherapy relies upon induction of type i interferon-dependent innate and adaptive immunity Cancer Res 2011 71 7 2488 96 10.1158/0008-5472.CAN-10-2820 21300764 \n15. Abdel-Wahab Z Dar MM Hester D Vervaert C Gangavalli R Barber J Effect of irradiation on cytokine production, MHC antigen expression, and vaccine potential of interleukin-2 and interferon-gamma gene-modified melanoma cells Cell Immunol 1996 171 2 246 54 10.1006/cimm.1996.0200 8806794 \n16. Ciernik IF Romero P Berzofsky JA Carbone DP Ionizing radiation enhances immunogenicity of cells expressing a tumor-specific T-cell epitope Int J Radiat Oncol Biol Phys 1999 45 3 735 41 10.1016/S0360-3016(99)00226-6 10524430\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1752-1947",
"issue": "10()",
"journal": "Journal of medical case reports",
"keywords": "Allogeneic stem cell transplant; GVHD; Graft-versus-host disease; RT; Radiation therapy",
"medline_ta": "J Med Case Rep",
"mesh_terms": "D000328:Adult; D000893:Anti-Inflammatory Agents; D000970:Antineoplastic Agents; D017809:Fatal Outcome; D006086:Graft vs Host Disease; D018380:Hematopoietic Stem Cell Transplantation; D006689:Hodgkin Disease; D006801:Humans; D007166:Immunosuppressive Agents; D015456:Leukemia, Biphenotypic, Acute; D008297:Male; D008775:Methylprednisolone; D015649:Pentostatin; D017893:Photopheresis; D018714:Radiotherapy, Adjuvant; D016559:Tacrolimus; D014184:Transplantation, Homologous; D055815:Young Adult",
"nlm_unique_id": "101293382",
"other_id": null,
"pages": "209",
"pmc": null,
"pmid": "27465468",
"pubdate": "2016-07-28",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "22010102;21161342;10974444;17062505;8806794;20683011;21300764;21263156;22685313;8673042;9332719;22787181;1472071;2924034;7805455;10524430",
"title": "Graft-versus-host disease after radiation therapy in patients who have undergone allogeneic stem cell transplantation: two case reports.",
"title_normalized": "graft versus host disease after radiation therapy in patients who have undergone allogeneic stem cell transplantation two case reports"
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"companynumb": "US-PFM-US-2016-2552",
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"abstract": "BACKGROUND\nPrucalopride is a selective, high-affinity, 5-hydroxytryptamine 4 (5-HT4) receptor agonist, which is approved for the symptomatic treatment of chronic constipation in women in whom laxatives fail to provide adequate relief. Women of childbearing potential, many of whom will be using oral contraceptives, comprise a large proportion of patients seeking medical therapy for constipation.\n\n\nOBJECTIVE\nThe aim of this study was to evaluate the effect of prucalopride on the absorption and steady-state pharmacokinetics of oral contraceptives in healthy women.\n\n\nMETHODS\nSixteen women (aged 18-45 years) were enrolled in this open-label, two-way crossover trial (ClinicalTrials.gov identifier: NCT01036893) and given two 5-day treatments with a once-daily oral contraceptive (ethinylestradiol 0.035 mg + norethisterone 1 mg), alone and in combination with prucalopride 2 mg once daily. Treatments were separated by a 7 ± 2-day washout period. On days 1 and 5, blood samples were obtained pre-dose and at regular intervals post-dose up to 24 and 48 hours, respectively, to determine ethinylestradiol and norethisterone plasma concentrations. Prucalopride plasma concentrations were determined pre-dose and 3 hours post-dose on days 1 and 5, and 24 hours post-dose on day 6. Safety was assessed.\n\n\nRESULTS\nThirteen participants completed the study. One participant was thought to be non-compliant on days 3 and/or 4, and was excluded from the day 5 analysis. On days 1 and 5, maximum plasma concentrations of both oral contraceptive constituents were attained in ~1 hour and were unaffected by prucalopride administration. On day 5, steady-state prucalopride and oral contraceptive concentrations had been achieved. Prucalopride did not affect the pharmacokinetics of the oral contraceptives: point estimates for the maximum plasma concentration and area under the plasma concentration-time curve values and their associated 90 % confidence intervals were contained within predefined equivalence limits (80-125 %). Prucalopride was well tolerated, with a safety profile consistent with those observed in previous studies.\n\n\nCONCLUSIONS\nCo-administration of prucalopride with an oral contraceptive did not result in any clinically meaningful pharmacokinetic interactions and was well tolerated.",
"affiliations": "Clinical Pharmacokinetics, Princeton, NJ, USA.",
"authors": "Van de Velde|Vera|V|;Vandeplassche|Lieve|L|;Hoppenbrouwers|Mieke|M|;Boterman|Mark|M|;Ausma|Jannie|J|",
"chemical_list": "D001572:Benzofurans; D003277:Contraceptives, Oral, Combined; C406662:prucalopride",
"country": "New Zealand",
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"doi": "10.1007/s40268-013-0008-6",
"fulltext": "\n==== Front\nDrugs R D\nDrugs R D\nDrugs in R&D\n1174-5886\n1179-6901\nSpringer International Publishing AG Cham\n\n23539257\n8\n10.1007/s40268-013-0008-6\nOriginal Research Article\nEffect of Prucalopride on the Pharmacokinetics of Oral Contraceptives in Healthy Women\nVan de Velde Vera\nVandeplassche Lieve\nHoppenbrouwers Mieke\nBoterman Mark\nAusma Jannie\nClinical Pharmacokinetics, Princeton, NJ USA\nShire-Movetis NV, Veedijk 58 (1004), 2300 Turnhout, Belgium\nAnalytisch Biochemisch Laboratorium BV, Assen, The Netherlands\n29 3 2013\n29 3 2013\n3 2013\n13 1 4351\n© The Author(s) 2013\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.\nBackground\n\nPrucalopride is a selective, high-affinity, 5-hydroxytryptamine 4 (5-HT4) receptor agonist, which is approved for the symptomatic treatment of chronic constipation in women in whom laxatives fail to provide adequate relief. Women of childbearing potential, many of whom will be using oral contraceptives, comprise a large proportion of patients seeking medical therapy for constipation.\n\nObjective\n\nThe aim of this study was to evaluate the effect of prucalopride on the absorption and steady-state pharmacokinetics of oral contraceptives in healthy women.\n\nMethods\n\nSixteen women (aged 18–45 years) were enrolled in this open-label, two-way crossover trial (ClinicalTrials.gov identifier: NCT01036893) and given two 5-day treatments with a once-daily oral contraceptive (ethinylestradiol 0.035 mg + norethisterone 1 mg), alone and in combination with prucalopride 2 mg once daily. Treatments were separated by a 7 ± 2-day washout period. On days 1 and 5, blood samples were obtained pre-dose and at regular intervals post-dose up to 24 and 48 hours, respectively, to determine ethinylestradiol and norethisterone plasma concentrations. Prucalopride plasma concentrations were determined pre-dose and 3 hours post-dose on days 1 and 5, and 24 hours post-dose on day 6. Safety was assessed.\n\nResults\n\nThirteen participants completed the study. One participant was thought to be non-compliant on days 3 and/or 4, and was excluded from the day 5 analysis. On days 1 and 5, maximum plasma concentrations of both oral contraceptive constituents were attained in ~1 hour and were unaffected by prucalopride administration. On day 5, steady-state prucalopride and oral contraceptive concentrations had been achieved. Prucalopride did not affect the pharmacokinetics of the oral contraceptives: point estimates for the maximum plasma concentration and area under the plasma concentration–time curve values and their associated 90 % confidence intervals were contained within predefined equivalence limits (80–125 %). Prucalopride was well tolerated, with a safety profile consistent with those observed in previous studies.\n\nConclusion\n\nCo-administration of prucalopride with an oral contraceptive did not result in any clinically meaningful pharmacokinetic interactions and was well tolerated.\n\nissue-copyright-statement© Springer International Publishing Switzerland 2013\n==== Body\nIntroduction\n\nThe dihydrobenzofuran-carboxamide derivative prucalopride is the first selective, high-affinity, 5-hydroxytryptamine 4 (5-HT4) receptor agonist with potent gastrointestinal prokinetic activity [1, 2]. Prucalopride, at a standard dose of 2 mg once daily, is approved for the symptomatic treatment of chronic constipation in women in whom laxatives fail to provide adequate relief [1]. In three identical pivotal phase III trials in patients with chronic constipation, prucalopride 2 mg once daily for 12 weeks increased the frequency of spontaneous complete bowel movements, improved patient satisfaction with treatment and bowel function, and improved patient perception of constipation severity and constipation-related quality of life [3–5]. In these studies, prucalopride was generally well tolerated, with most adverse events (AEs) being mild to moderate in severity and transient in nature. Across the pivotal trials, the most frequently reported AEs associated with therapy were headache (25 % of patients) and gastrointestinal symptoms (nausea [19 %], diarrhea [12 %], or abdominal pain [12 %]) [3, 4]. AEs occurred predominantly at the start of therapy and usually disappeared within a few days with continued treatment [3, 4].\n\nThe prevalence of chronic constipation in the general population is relatively high, with 5–18 % of individuals reporting some form of constipation [6], although the actual numbers may be underestimated because a large proportion do not seek medical attention for their condition [7]. Women, particularly those younger than 50 years, present with constipation more commonly than men (prevalence ratio 2.2:1) [8–10]. Women of childbearing potential, many of whom will be using oral contraceptives, therefore comprise a large proportion of those seeking medical therapy for constipation. It is thus important to understand whether treatments for chronic constipation interact with the pharmacokinetics of oral contraceptives.\n\nPrucalopride has an established pharmacokinetic profile [2]. In summary, the maximum plasma concentration (Cmax) is reached within 2–3 hours of a single 2 mg oral dose. Absolute oral bioavailability is greater than 90 %, and absorption is not influenced by concomitant food intake, which indicates that the drug can be taken with or without meals. Prucalopride undergoes limited metabolism and is largely eliminated unchanged in the urine via passive renal filtration and active secretion. The elimination half-life (t½) of prucalopride is approximately 24–30 hours, supporting once-daily administration.\n\nCompounds that induce cytochrome P450 (CYP) 3A4 (such as estrogen-2-hydroxylase) have been shown to reduce systemic exposure to contraceptive steroids such as ethinylestradiol and norethisterone [11], which carries with it the risks of spotting, breakthrough bleeding, and ultimately contraceptive failure [12]. Currently available data indicate that prucalopride does not act as an inducer of CYP3A4—in vivo studies of prucalopride administered for 1 week or more showed that it did not lower plasma concentrations of erythromycin or R-warfarin (data on file). However, interference with the absorption of oral contraceptives could theoretically result in considerably reduced plasma concentrations, with contraceptive failure as a consequence. In this study of healthy women, we therefore investigated the effects of prucalopride on the pharmacokinetics of the estrogen ethinylestradiol and the progestogen norethisterone, which are the active constituents of several oral contraceptives.\n\nMethods\n\nStudy Design\n\nThis randomized, open-label, two-way crossover, phase I trial (ClinicalTrials.gov identifier: NCT01036893) was designed to evaluate both the effect of single-dose prucalopride 2 mg (Resolor®;1 prucalopride succinate tablets) on the absorption of ethinylestradiol and norethisterone, and the effect of 5 or 6 days of treatment with prucalopride 2 mg once daily on the steady-state pharmacokinetics of ethinylestradiol and norethisterone in healthy women. The trial was carried out at a single center in Germany (FOCUS Clinical Drug Development GmbH, Neuss, Germany) from December 17, 2009, until February 10, 2010, in accordance with the Declaration of Helsinki and the International Conference on Harmonisation Good Clinical Practice guidelines [13, 14], and was approved by the relevant independent ethics committees. All participants provided written informed consent before screening.\n\nParticipants\n\nEligibility was assessed at a screening visit, which took place within the 4 weeks before the first drug administration. Healthy women (in the age group of 18–45 years) who had regular menstrual cycles of 28 ± 3 days in the previous 6 months were eligible for inclusion in the study if they had a body mass index (BMI) of 18–27 kg/m2; had not smoked in the 6 months before screening; and were using adequate non-hormonal birth control such as the double-barrier method (e.g. a condom and spermicide, a cervical cap and spermicide), were practicing abstinence, or had a partner who was sterile (e.g. had undergone vasectomy).\n\nIndividuals were excluded from the study if they had a history or evidence of drug or alcohol abuse; had abnormal electrocardiogram (ECG) intervals or morphology (e.g. QT interval >500 ms or corrected QT interval using Bazett’s formula [QTcB] >470 ms) that were considered to be clinically significant; had a history or evidence of cardiac arrhythmias, bronchospastic disease, or cardiovascular disease; or had a history or evidence of psychiatric, gynecological, hepatic, gastrointestinal, renal, endocrine, neurological, or dermatological disease. Individuals with drug allergies, those who had contraindications for the use of oral contraceptives (e.g. known or suspected active venous thromboembolic disorders, hormone-dependent malignancies, coagulation disorders, menstrual cycle-dependent migraines, lipid metabolism disorders, or hepatic disorders), and those who had used other medications, oral contraceptives, or any hormonal depot device in the 6 months before screening were also excluded. In addition, individuals were excluded if they had participated in an investigational drug study or had donated blood in the 30 days before the first visit, had positive blood test results for human immunodeficiency virus (HIV) or hepatitis B or C at screening, or were pregnant or breastfeeding.\n\nTreatments\n\nIn accordance with a two-way randomized crossover study design, participants were given two 5-day treatments (days 1–5 of each crossover phase; Fig. 1) with a once-daily oral contraceptive, once as monotherapy (treatment A) and once with once-daily prucalopride on days 1–6 of the treatment phase (treatment B). The washout period between the two contraceptive treatments was 7 ± 2 days. The stage of the patient’s menstrual cycle was not taken into account in the timings of these treatments. The oral contraceptive Trinovum® (ethinylestradiol 0.035 mg and norethisterone 1 mg; Janssen-Cilag Ltd) was used; prucalopride was administered as 2 mg film-coated tablets containing prucalopride succinate, equivalent to 2.0 mg prucalopride base.Fig. 1 Overview of the trial design. OC oral contraceptive\n\nThe oral contraceptive dose was taken at 0800 hours. For the combination treatment, prucalopride was administered immediately before the oral contraceptive. The drugs were taken with a total of 200 mL of non-carbonated water. On days 1 and 5 of each treatment period, the study medication was administered in the clinic following an overnight fast of at least 10 hours, and participants were not permitted to eat or drink until 2 hours after receiving the medication, at which time they received a standard breakfast. On all other days, participants took the study treatments either at the clinic (days 2 and 6) or at home (days 3 and 4) 30 minutes before breakfast. Compliance was assessed by investigator supervision of dosing (except on days 3 and 4) and daily diary entries.\n\nDuring the study, participants were not permitted to take medication other than the study drugs, with the exception of as-needed paracetamol/acetaminophen (up to a maximum of three 500 mg tablets per day, and no more than 3 g during the study).\n\nPharmacokinetic Assessments\n\nSerial blood samples for the determination of ethinylestradiol and norethisterone concentrations in plasma were taken on day 1 pre-dose and then at 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post-dose, and on day 5 pre-dose and then at 1, 2, 3, 4, 6, 8, 10, 12, 24, 36, and 48 hours post-dose. Participants receiving treatment B had serial blood samples collected for the determination of plasma concentrations of prucalopride on days 1 and 5 pre-dose and then at 3 hours post-dose, and on day 6 pre-dose and then at 24 hours post-dose. No pharmacokinetic parameters were calculated for prucalopride.\n\nAssay Validation\n\nPlasma samples were analyzed for prucalopride, ethinylestradiol, and norethisterone, using validated liquid chromatography–tandem mass spectrometry (LC–MS/MS) methods. Assay methods were validated in accordance with the US Food and Drug Administration (FDA) Guidance for Industry: Bioanalytical Method Validation [15] and the Good Laboratory Practice regulations of the Organisation for Economic Co-operation and Development [16]. Validation parameters, including accuracy (expressed as bias), precision (percentage coefficient of variation), recovery, specificity, dilution, and stability were evaluated and amply met the acceptance criteria outlined in the FDA guidance [15].\n\nThe method for the determination of prucalopride in human heparin plasma was linear in the range of 0.200–100 ng/mL, with a lower limit of quantification (LLQ) of 0.200 ng/mL. Briefly, prucalopride was extracted from 50 μL plasma by liquid–liquid extraction with tertiary butyl methyl ether under alkaline conditions, using an analog (SSP-002392) as the internal standard. High-performance liquid chromatography–tandem mass spectrometry (HPLC–MS/MS) analysis was carried out with an API-4000 mass spectrometer (AB Sciex, Toronto, ON, Canada) coupled with an Agilent 1100 HPLC system (Agilent, Santa Clara, CA, USA). The mass spectrometer was operating in positive electrospray ionization (ESI) mode, and the chromatographic separation was achieved on a Zorbax Extend-C18 3.5 μm HPLC column, 4.6 × 75 mm, with a mobile-phase gradient.\n\nFor ethinylestradiol, the method was linear in the range of 3.00–600 pg/mL, with an LLQ of 3.00 pg/mL, using 500 μL of plasma. Ethinylestradiol and its deuterated internal standard (ethinylestradiol-d4) were extracted from plasma by solid-phase extraction on Isolute C18 (EC) cartridges (Biotage, Uppsala, Sweden). Subsequently, ethinylestradiol was derivatized with dansyl chloride and the derivate was extracted using liquid–liquid extraction with a mixture of tertiary butyl methyl ether and pentane. HPLC–MS/MS analysis was performed using the API-4000 mass spectrometer coupled with the Agilent 1100 HPLC system. The mass spectrometer was operating in positive atmospheric pressure chemical ionization (APCI) mode, and the chromatographic separation was achieved on a Hypersil C8 BDS HPLC column (3.0 μm, 4.6 × 150 mm), with a mobile-phase gradient.\n\nFor norethisterone, the method was linear in the range of 0.0500–20.0 ng/mL, with an LLQ of 0.0500 ng/mL, using 500 μL of plasma. In summary, norethisterone and its stable isotope-labeled internal standard (13C2-norethisterone) were extracted from plasma by online solid-phase extraction on HySphere C8 EC-SE cartridges, using a Symbiosis Pharma system (Spark Holland BV, Emmen, The Netherlands), which was preceded by liquid–liquid extraction with a mixture of chloroform and pentane. Chromatographic separation was achieved on a Zorbax XDB-C8 HPLC column (3.5 μm, 75 × 4.6 mm), with a mobile-phase gradient. The API-4000 mass spectrometer was operating in positive APCI mode.\n\nIn the current study, each analytical run consisted of a freshly prepared calibration curve, using blank human heparin plasma for all three analytes. Quality control (QC) samples were prepared at three different concentrations (prucalopride: 0.600, 6.00, and 80.0 ng/mL; ethinylestradiol: 9.00, 50.0, and 150 pg/mL; norethisterone: 0.150, 1.00, and 16.0 ng/mL), stored with the study samples, and analyzed in duplicate divided over the analytical run. Run acceptance was performed in accordance with the FDA Guidance for Industry: Bioanalytical Method Validation [15]. In this study, the overall accuracy of the QC samples ranged from −0.4 % to 3.4 % for prucalopride, from 1.1 % to 2.4 % for ethinylestradiol, and from 0.0 % to 0.4 % for norethisterone. The precision ranged from 2.9 % to 4.2 % for prucalopride, from 2.9 % to 8.3 % for ethinylestradiol, and from 1.9 % to 5.8 % for norethisterone. In all methods, no interference was observed at the retention time of the analytes and their internal standards. Moreover, >66 % of 48 re-analyzed plasma samples (for ethinylestradiol and norethisterone) or 12 re-analyzed plasma samples (for prucalopride) showed differences of ≤20 % compared with the original result, therefore demonstrating incurred sample reproducibility for all three analytes.\n\nPharmacokinetic Analysis\n\nPharmacokinetic analyses were performed using WinNonlin® software (version 5.20; Pharsight Corporation, Mountain View, CA, USA) and Statistical Analysis System (SAS®) software (version 9.1.3; SAS® Institute Inc., Cary, NC, USA). The following pharmacokinetic parameters were determined on day 1 for norethisterone and ethinylestradiol: Cmax, time to reach Cmax (tmax), and area under the plasma concentration–time curve (AUC) during the first 24-hour dosing interval (AUC24) calculated by linear trapezoidal summation. On day 5, the following parameters were determined: the minimum plasma concentration during a 24-hour dosing interval (Cmin), Cmax, AUC during a 24-hour dosing interval (AUCτ) calculated by linear trapezoidal summation, and t½, defined as 0.693/λ, where λ is the elimination rate constant determined by linear regression of the terminal points of the log-linear plasma concentration–time curve.\n\nSafety Assessments\n\nSafety was assessed by AEs (recorded throughout the study); clinical laboratory measurements (performed at screening, pre-dose on day 1 and day 7 of each treatment period, and at the final visit or discontinuation); physical examinations (at screening, on day 1 of each treatment period, and at the final visit or discontinuation); assessments of vital signs (at screening, pre-dose on day 1, at the end of each treatment period, and at the final visit or discontinuation); and 12-lead ECGs (at screening, on day 1 of each treatment period, and at the final visit or discontinuation). A blood sample for serology testing (HIV and hepatitis B and C) was obtained at screening, and samples for hematology and coagulation tests were obtained at screening, on days 1 and 7 of each treatment period, and at the final visit or discontinuation. Drug and alcohol screening (at screening and on day −1 of each treatment period) and pregnancy testing (at screening, on day −1 of each treatment period, and at the final visit or discontinuation) were also performed.\n\nStatistical Analysis\n\nNo formal sample size calculation was performed. A sample size of 16 participants (in order to have at least 12 individuals completing the trial) with a crossover design was considered sufficient to determine relevant changes in the plasma concentrations of ethinylestradiol and norethisterone.\n\nDescriptive statistics were calculated for the plasma concentrations of norethisterone and ethinylestradiol at each sampling time and for the derived pharmacokinetic parameters. Mixed effects modeling (with the participant as the random effect and with the sequence, period, and treatment as fixed effects) was used to compare natural log-transformed Cmax and AUC24 values between treatments on day 1, and to compare natural log-transformed Cmin, Cmax, and AUCτ values, and untransformed t½ values between treatments on day 5. Using the mean squared error from the model, 90 % confidence intervals (CIs) were calculated for the treatment difference (B − A) of the log-transformed bioavailability parameters Cmax and AUC24 on day 1, and Cmin, Cmax, and AUCτ values on day 5. Classical 90 % CIs for the ratios of treatment B (oral contraceptive plus prucalopride) to treatment A (oral contraceptive alone) were then obtained by exponentiation and expressed as percentages. The absence of an interaction was declared if the 90 % CIs were contained within the range of 80–125 %. The non-parametric Koch procedure was used to compare tmax values on day 1 and day 5 between treatments. A non-parametric 90 % CI for the treatment difference (B − A) was calculated using a distribution-free procedure adapted to two-way crossover designs. Descriptive statistics were calculated for the prucalopride plasma concentrations at each sampling time. Safety data were analyzed descriptively and comprised data from all participants who had taken study medication, including those not included in the pharmacokinetic analysis.\n\nResults\n\nParticipants\n\nSixteen individuals were enrolled in the study, all of whom were Caucasian women. Their mean age was 35.5 years (range 19–44 years), their mean body weight was 65.9 kg (range 51–80 kg), their mean height was 169 cm (range 163–180 cm), and their mean BMI was 23.0 kg/m2 (range 19.0–27.0 kg/m2). At screening, all participants had a regular menstrual cycle and there were no abnormal findings.\n\nThree participants discontinued the trial, all of whom were withdrawn because of AEs. These AEs (vomiting, dental pulpitis, and headache; all moderate in intensity) occurred with oral contraceptive plus prucalopride (treatment B) in the group that received this treatment combination first. These three participants therefore did not receive oral contraceptive alone. In total, 14 individuals reported protocol deviations, of which only two were major (prohibited concomitant medications used: ibuprofen 150 mg and metoclopramide 8 mg); both participants with major protocol deviations were among those who were withdrawn because of AEs. On day 5 of the oral contraceptive plus prucalopride period, one participant had pre-dose concentrations of prucalopride, ethinylestradiol, and norethisterone that were much lower than would be theoretically expected and much lower than the pre-dose concentrations measured on other days of the same treatment period in this participant. On day 3 this individual had reported nausea and vomiting, and on days 3 and 4 she had not reported intake of trial medication in her participant diary (although later she stated that she had taken the trial medication). After supervised drug intake on day 5, drug absorption appeared normal (as evidenced by the ethinylestradiol and norethisterone profiles on day 5, and the day 6 prucalopride pre-dose and 24-hour post-dose concentrations), which strongly suggests that this individual did not take the study medication on days 3 and/or 4. Therefore, statistical comparison of the day 5 pharmacokinetic parameters was also performed on a subset of 12 participants, excluding this suspected non-compliant participant.\n\nEthinylestradiol Pharmacokinetics\n\nOn day 1, Cmax was reached at a median time of 1 hour after dosing with both treatments (Fig. 2 and Table 1). There were no statistically significant differences in Cmax, tmax, or AUC24 between treatments (oral contraceptive vs. oral contraceptive plus prucalopride; Table 1). The geometric mean treatment ratios for Cmax and AUC24 were 110.37 % and 95.52 %, respectively, and the associated 90 % CIs were within the predefined equivalence limits of 80–125 % (Table 1).Fig. 2 Mean ethinylestradiol plasma concentration–time profiles on day 1 and day 5 (n = 13). OC oral contraceptive\n\nTable 1 Pharmacokinetic parameters and summary of the equivalence analysis for ethinylestradiol\n\nParameter\tTreatment A\tTreatment B\tOC + prucalopride versus OC alone\t\nOC alonea\tOC + prucalopridea\tPE (%)\t90 % CI\tp value\t\nDay 1 (n = 13)\t\n tmax (h)\t1.0 [1.0–2.0]\t1.0 [1.0–2.0]\t0.00\t−0.50, 0.00\t0.4224\t\n Cmax (pg/mL)\t90.5 ± 21.8\t103 ± 32.0\t110.37\t99.74, 122.13\t0.1079\t\n AUC24 (pg·h/mL)\t727 ± 156\t720 ± 204\t95.52\t90.70, 100.61\t0.1409\t\nDay 5 (n = 13)b\t\n tmax (h)\t1.0 [1.0–3.0]\t1.0 [1.0–3.0]\t−0.50\t−1.00, 0.00\t0.0644\t\n Cmin (pg/mL)\t18.6 ± 7.4\t17.8 ± 8.1\t83.00\t65.43, 105.29\t0.1872\t\n Cmax (pg/mL)\t130 ± 34\t123 ± 27\t96.07\t89.37, 103.28\t0.3412\t\n AUCτ (pg·h/mL)\t1,153 ± 323\t1,090 ± 296\t92.54\t85.07, 100.66\t0.1260\t\n t½ (h)\t17.1 ± 2.4\t15.0 ± 3.2\t–\t–\t0.0154\t\nDay 5 (n = 12)b\t\n tmax (h)\t1.0 [1.0–3.0]\t1.0 [1.0–3.0]\t−0.25\t−0.50, 0.00\t0.1530\t\n Cmin (pg/mL)\t19.4 ± 7.0\t19.3 ± 6.3\t97.10\t86.83, 108.59\t0.6438\t\n Cmax (pg/mL)\t132 ± 35\t126 ± 27\t99.12\t92.80, 105.88\t0.8140\t\n AUCτ (pg·h/mL)\t1,135 ± 331\t1,119 ± 288\t97.65\t93.36, 102.14\t0.3605\t\n t½ (h)\t17.4 ± 2.2\t15.3 ± 3.1\t–\t–\t0.0305\t\naValues are expressed as means ± standard deviations, except for tmax, for which median [range] values are given\n\nbResults are based on all data (n = 13) and on n = 12 after exclusion of one participant because circumstantial evidence indicated that her medication was not taken on days 3 and/or 4\n\nAUC τ area under the plasma concentration–time curve during a 24-hour dosing interval, AUC 24 area under the plasma concentration–time curve during the first 24-hour dosing interval, CI confidence interval, C max maximum plasma concentration, C min minimum plasma concentration, OC oral contraceptive, PE point estimate of the geometric mean treatment ratio, t ½ elimination half-life, t max time to reach Cmax\n\nEthinylestradiol steady state was reached on day 5, with similar plasma concentrations of ethinylestradiol observed before and 24 hours after administration of oral contraceptive alone (20.7 ± 8.1 pg/mL and 20.5 ± 6.7 pg/mL, respectively) and oral contraceptive plus prucalopride (18.5 ± 8.5 pg/mL and 19.2 ± 6.7 pg/mL, respectively) [Fig. 2]. On day 5, Cmax was reached at a median time of 1 hour after dosing and there were no statistically significant differences in tmax, Cmin, Cmax, or AUCτ between treatments (Table 1). There was a statistically significant difference in t½, but this difference was considered too small to be clinically meaningful. The geometric mean treatment ratios for Cmax and AUCτ were 96.07 % and 92.54 %, respectively, and the associated 90 % CIs were within the predefined equivalence limits of 80–125 % (Table 1). The lower limit of the 90 % CI was well below 80 % for Cmin when all participants were included in the analysis, but fell within the predefined equivalence limits when the data from the suspected non-compliant participant were omitted (Table 1).\n\nNorethisterone Pharmacokinetics\n\nOn day 1, Cmax was reached at a median time of 1 hour after administration (Fig. 3 and Table 2); there were no statistically significant differences in Cmax, tmax, or AUC24 between treatments (Table 2). The geometric mean treatment ratio for Cmax was 94.14 %, and the associated 90 % CI was within the predefined equivalence limits (Table 2). The geometric mean treatment ratio for AUC24 was 90.29 %, and the lower limit of the 90 % CI (79.12 %) was very slightly below the pre-set lower limit of 80 % (Table 2). However, this difference was considered too small to be clinically relevant.Fig. 3 Mean norethisterone plasma concentration–time profiles on day 1 and day 5 (n = 13). OC oral contraceptive\n\nTable 2 Pharmacokinetic parameters and summary of the equivalence analysis for norethisterone\n\nParameter\tTreatment A\tTreatment B\tOC + prucalopride versus OC alone\t\nOC alonea\tOC + prucalopridea\tPE (%)\t90 % CI\tp value\t\nDay 1 (n = 13)\t\n tmax (h)\t1.0 [1.0–2.0]\t1.0 [1.0–2.0]\t0.00\t−0.03, 0.00\t0.3210\t\n Cmax (ng/mL)\t12.6 ± 5.0\t12.4 ± 4.4\t94.14\t81.02, 109.37\t0.4845\t\n AUC24 (ng·h/mL)\t61.1 ± 30.7\t58.2 ± 26.2\t90.29\t79.12, 103.02\t0.1918\t\nDay 5 (n = 13)b\t\n tmax (h)\t1.0 [1.0–2.0]\t1.0 [1.0–2.0]\t0.00\t0.00, 0.00\t0.7261\t\n Cmin (ng/mL)\t0.93 ± 0.45\t0.92 ± 0.50\t73.92\t49.05, 111.39\t0.2125\t\n Cmax (ng/mL)\t17.1 ± 4.6\t17.0 ± 4.7\t98.07\t88.37, 108.84\t0.7434\t\n AUCτ (ng·h/mL)\t105 ± 39\t98.9 ± 33.7\t91.36\t82.58, 101.09\t0.1370\t\n t½ (h)\t10.2 ± 2.0\t9.8 ± 1.8\t–\t–\t0.1858\t\nDay 5 (n = 12)b\t\n tmax (h)\t1.0 [1.0–2.0]\t1.0 [1.0–2.0]\t0.00\t−0.50, 0.00\t0.6000\t\n Cmin (ng/mL)\t0.97 ± 0.45\t1.00 ± 0.44\t97.94\t84.37, 113.70\t0.8059\t\n Cmax (ng/mL)\t17.0 ± 4.8\t17.1 ± 4.9\t99.00\t88.02, 111.35\t0.8801\t\n AUCτ (ng·h/mL)\t100 ± 37\t100 ± 35\t96.04\t88.28, 104.47\t0.4045\t\n t½ (h)\t10.3 ± 2.0\t9.9 ± 1.9\t–\t–\t0.1637\t\naValues are expressed as means ± standard deviations, except for tmax, for which median [range] values are given\n\nbResults are based on all data (n = 13) and on n = 12 after exclusion of one participant because circumstantial evidence indicated that her medication was not taken on days 3 and/or 4\n\nAUC τ area under the plasma concentration–time curve during a 24-hour dosing interval, AUC 24 area under the plasma concentration–time curve during the first 24-hour dosing interval, CI confidence interval, C max maximum plasma concentration, C min minimum plasma concentration, OC oral contraceptive, PE point estimate of the geometric mean treatment ratio, t ½ elimination half-life, t max time to reach Cmax\n\nNorethisterone steady state was reached on day 5, with plasma concentrations of norethisterone being similar before and 24 hours after administration of oral contraceptive alone (0.97 ± 0.47 ng/mL and 1.13 ± 0.51 ng/mL, respectively) and oral contraceptive plus prucalopride (0.92 ± 0.51 ng/mL and 1.11 ± 0.48 ng/mL, respectively) [Fig. 3]. On day 5, Cmax was reached at a median time of 1 hour after dosing. There were no statistically significant differences in tmax, Cmin, Cmax, AUCτ, or t½ between treatments (Table 2). The geometric mean treatment ratios for Cmax and AUCτ were 98.07 % and 91.36 %, respectively, and the associated 90 % CIs were within the predefined equivalence limits of 80–125 % for Cmax and AUCτ (Table 2). For Cmin, the geometric mean treatment ratio and the lower limit of the 90 % CI were below 80 % when all participants were included in the analysis. However, these parameters fell within the predefined equivalence limits when the data from the suspected non-compliant participant were omitted (Table 2).\n\nPrucalopride Pharmacokinetics\n\nOn day 1, the mean near-peak (3-hour) concentration of prucalopride was 4.56 ± 0.87 ng/mL. On day 5, prucalopride steady state was reached, with similar plasma concentrations pre-dose on days 5 and 6 and at 24 hours post-dose on day 6 (3.00 ± 1.16 ng/mL, 3.20 ± 0.84 ng/mL, and 3.13 ± 0.58 ng/mL, respectively). On day 5, the mean near-peak (3-hour) steady-state plasma concentration of prucalopride was 8.18 ± 1.64 ng/mL.\n\nPrucalopride Safety and Tolerability\n\nNo unexpected safety findings for prucalopride were identified on administration with ethinylestradiol and norethisterone. No deaths or serious or severe treatment-emergent AEs were reported. Treatment-emergent AEs were more common in participants receiving prucalopride plus oral contraceptive (39 events, n = 15 [93.8 %]) than in those receiving oral contraceptive alone (4 events, n = 4 [30.8 %]). The most common AEs that occurred with oral contraceptive plus prucalopride were headache (11 events, n = 11 [68.8 %]), nausea (11 events, n = 10 [62.5 %]), vomiting (7 events, n = 6 [37.5 %]), and diarrhea (4 events, n = 4 [25.0 %]). All cases of headache and diarrhea started on day 1, as did eight of the cases of nausea. Five participants experienced vomiting on day 1 (one of whom also experienced vomiting on day 7), and a sixth participant reported vomiting on day 3. Three of the episodes of vomiting occurred 1.5–3.5 hours post-dose, while the other four episodes occurred 9–21 hours post-dose. The four AEs that were reported in participants receiving oral contraceptive alone were all moderate cases of headache, three of which occurred on day 1 and one that occurred on day 8. One episode of palpitations was reported, but this did not result in drug discontinuation and was not associated with other serious cardiovascular events. No clinically relevant abnormalities or trends were observed in the laboratory data, vital signs, ECGs, or physical examinations.\n\nDiscussion\n\nPrucalopride was developed for the treatment of chronic constipation, which tends to be more common in women than in men. A high proportion of patients taking prucalopride are therefore also likely to be taking oral contraceptives. Several oral contraceptives (including ethinylestradiol and norethisterone) are metabolized by CYP3A4, induction of which can reduce exposure to the components of the oral contraceptives and risk contraceptive failure. Although there is no indication that prucalopride has CYP3A4-inducing properties, and it has a very low potential for enzyme inhibition, the pharmacodynamic properties of prucalopride may theoretically lead to reduced absorption of concomitantly used drugs. However, the findings of the current study indicate that prucalopride has no clinically relevant effects on the pharmacokinetics of either ethinylestradiol or norethisterone.\n\nSingle-dose prucalopride had no effect on the rate or extent of ethinylestradiol and norethisterone absorption, despite a number of participants reporting diarrhea on day 1 of treatment. Thus, the faster transit associated with diarrhea and the known prokinetic effects of prucalopride appear not to have been associated with any clinically relevant effects in terms of drug absorption. This suggests that the absorption of oral contraceptives is unaffected by the changes in transit time evoked by prucalopride, and points to the limited importance of enterohepatic circulation (with possible second-pass absorption as a consequence) in the absorption of oral steroids in humans [17]. In addition, prucalopride did not affect the pharmacokinetics of ethinylestradiol and norethisterone once steady-state concentrations of prucalopride and oral contraceptive were achieved, indicating that there was no metabolic interaction of prucalopride with the oral contraceptive constituents.\n\nPrucalopride was well tolerated, and the safety profile was consistent with observations from previous studies of prucalopride in adult populations [3, 18, 19]. The most frequent treatment-emergent AEs were gastrointestinal symptoms (nausea, vomiting, and diarrhea), which were predominantly limited to day 1 of drug administration. These findings are in agreement with those of previous studies, in which diarrhea and nausea were more frequently reported with prucalopride treatment than with placebo, with most cases occurring during the first 1–2 days of treatment [3, 4]. Importantly, the present study was performed in healthy volunteers who were not constipated, which might have been an influencing factor in the occurrence of gastrointestinal-related AEs due to the potent gastrointestinal prokinetic activity of prucalopride. Nonetheless, these events did not affect the pharmacokinetics of the oral contraceptive. In particular, the vomiting did not occur at a time that would affect absorption of the oral contraceptive. However, as with all drugs, if vomiting were to occur very soon after oral contraceptive administration, then full absorption of the drug(s) could not be guaranteed.\n\nConsistent with the high affinity and selectivity of prucalopride for 5-HT4 receptors [20, 21], there were no clinically relevant changes in vital signs or ECG parameters, and no significant cardiovascular AEs were observed.\n\nThis is the first study to look at the interaction between prucalopride and oral contraceptives. However, a number of limitations should be noted. First, the findings are applicable only to the oral contraceptives evaluated in the study, and may not be generalizable to other oral contraceptives. A second potential limitation is that women with a BMI greater than 27 kg/m2 were excluded from the study, and therefore the findings may not be applicable to obese women.\n\nConclusion\n\nAdministering prucalopride with an oral contraceptive containing ethinylestradiol and norethisterone is not associated with any clinically meaningful drug–drug interactions or safety concerns. These findings are important because oral contraceptive therapy often combines the estrogen ethinylestradiol and the progestogen norethisterone, and these constituents are likely to be among concomitant medications used by women taking prucalopride.\n\nThe authors thank Dr Andreas Schrödter (of FOCUS Clinical Drug Development GmbH) for his invaluable assistance in performing the study, and Matthias Gurniak (of FOCUS Clinical Drug Development GmbH) for additional operational support. This clinical research was funded by the sponsor, Shire-Movetis NV. Under the direction of the authors, Tom Potter and Catherine Hill (employees of Oxford PharmaGenesis™ Ltd [Oxford, UK] and PharmaGenesis™ London [London, UK]) provided writing assistance for this publication. Editorial assistance in formatting, proofreading, copy editing, and fact checking was also provided by Oxford PharmaGenesis™ Ltd. Slavka Baronikova and David Pierce from Shire-Movetis NV reviewed and edited the manuscript for scientific accuracy. Shire-Movetis NV provided funding to Oxford PharmaGenesis™ Ltd for support in writing and editing this manuscript. Although the sponsor was involved in the design, collection, analysis, interpretation, and fact checking of information, the content of this manuscript, the ultimate interpretation, and the decision to submit it for publication in Drugs in R&D was made by the authors independently. The authors confirm that the data presented provide an accurate representation of the study results.\n\nAuthor Contributions\n\nVera Van de Velde and Lieve Vandeplassche were involved in the conception of the study and interpretation of the data. Mieke Hoppenbrouwers was involved in conception, analysis, and interpretation. Mark Boterman was involved in laboratory testing and analysis of the data. Jannie Ausma was responsible for coordinating the study and was also involved in the conception, analysis, and interpretation of the data. All authors were involved throughout the development of the manuscript.\n\nConflict of Interest Disclosures\n\nVera Van de Velde has received consultancy fees from Shire-Movetis NV. Mark Boterman’s institution (Analytisch Biochemisch Laboratorium BV) received a grant from Shire-Movetis NV for analysis of the study samples. Lieve Vandeplassche, Mieke Hoppenbrouwers, and Jannie Ausma are employees of Shire-Movetis NV and hold stock/stock options in Shire. The authors have no other conflicts of interest that are directly relevant to the content of this article.\n\n1 Resolor® is a CTM registered trademark of Shire-Movetis NV.\n==== Refs\nReferences\n\n1. European Medicines Agency. Resolor (prucalopride): summary of product characteristics. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/001012/WC500053998.pdf. Accessed 26 March 2012.\n2. Frampton JE Prucalopride Drugs 2009 69 17 2463 2476 10.2165/11204000-000000000-00000 19911858\n3. Camilleri M Kerstens R Rykx A A placebo-controlled trial of prucalopride for severe chronic constipation N Engl J Med 2008 358 22 2344 2354 10.1056/NEJMoa0800670 18509121\n4. Quigley EM Vandeplassche L Kerstens R Clinical trial: the efficacy, impact on quality of life, and safety and tolerability of prucalopride in severe chronic constipation: a 12-week, randomized, double-blind, placebo-controlled study Aliment Pharmacol Ther 2009 29 3 315 328 10.1111/j.1365-2036.2008.03884.x 19035970\n5. Tack J van Outryve M Beyens G Prucalopride (Resolor) in the treatment of severe chronic constipation in patients dissatisfied with laxatives Gut 2009 58 3 357 365 10.1136/gut.2008.162404 18987031\n6. Wald A Scarpignato C Mueller-Lissner S A multinational survey of prevalence and patterns of laxative use among adults with self-defined constipation Aliment Pharmacol Ther 2008 28 7 917 930 18644012\n7. Tack J Muller-Lissner S Stanghellini V Diagnosis and treatment of chronic constipation: a European perspective Neurogastroenterol Motil 2011 23 8 697 710 10.1111/j.1365-2982.2011.01709.x 21605282\n8. Pare P Ferrazzi S Thompson WG An epidemiological survey of constipation in Canada: definitions, rates, demographics, and predictors of health care seeking Am J Gastroenterol 2001 96 11 3130 3137 10.1111/j.1572-0241.2001.05259.x 11721760\n9. Higgins PD Johanson JF Epidemiology of constipation in North America: a systematic review Am J Gastroenterol 2004 99 4 750 759 10.1111/j.1572-0241.2004.04114.x 15089911\n10. Choung RS Locke GR 3rd Schleck CD Cumulative incidence of chronic constipation: a population-based study 1988–2003 Aliment Pharmacol Ther 2007 26 11–12 1521 1528 10.1111/j.1365-2036.2007.03540.x 17919271\n11. Barditch-Crovo P Trapnell CB Ette E The effects of rifampin and rifabutin on the pharmacokinetics and pharmacodynamics of a combination oral contraceptive Clin Pharmacol Ther 1999 65 4 428 438 10.1016/S0009-9236(99)70138-4 10223781\n12. Bolt HM Interactions between clinically used drugs and oral contraceptives Environ Health Perspect 1994 102 Suppl 9 35 38 10.1289/ehp.94102s935 7698081\n13. European Medicines Agency. ICH harmonised tripartite guidelines for good clinical practice, 1996. http://www.emea.europa.eu/pdfs/human/ich/013595en.pdf. Accessed 11 June 2012.\n14. World Medical Association. Declaration of Helsinki: ethical principles for medical research involving human subjects. http://www.wma.net/en/30publications/10policies/b3/. Accessed 12 August 2009.\n15. US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Center for Veterinary Medicine (CVM). Guidance for industry: bioanalytical method validation, 2001. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm070107.pdf. Accessed 14 December 2011.\n16. Organisation for Economic Co-operation and Development. OECD principles of good laboratory practice (GLP). http://www.oecd.org/document/63/0,3746,en_2649_34377_2346175_1_1_1_1,00.html. Accessed 13 April 2012.\n17. Hanker JP Gastrointestinal disease and oral contraception Am J Obstet Gynecol 1990 163 6 Pt 2 2204 2207 10.1016/0002-9378(90)90562-L 2256527\n18. Camilleri M Van Outryve MJ Beyens G Clinical trial: the efficacy of open-label prucalopride treatment in patients with chronic constipation: follow-up of patients from the pivotal studies Aliment Pharmacol Ther 2010 32 9 1113 1123 10.1111/j.1365-2036.2010.04455.x 21039673\n19. Quigley EM Tack J Kerstens R The efficacy and safety of oral prucalopride in female patients with chronic constipation who had failed laxative therapy (EMA-authorised population) is similar to that of the ITT population in the initial pivotal trials: pooled data analysis Gastroenterology 2012 142 Suppl I S820 S821\n20. De Maeyer JH Aerssens J Verhasselt P Alternative splicing and exon duplication generates 10 unique porcine 5-HT 4 receptor splice variants including a functional homofusion variant Physiol Genomics 2008 34 1 22 33 10.1152/physiolgenomics.00038.2008 18430808\n21. De Maeyer JH Prins NH Schuurkes JA Differential effects of 5-hydroxytryptamine4 receptor agonists at gastric versus cardiac receptors: an operational framework to explain and quantify organ-specific behavior J Pharmacol Exp Ther 2006 317 3 955 964 10.1124/jpet.106.101329 16501067\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1174-5886",
"issue": "13(1)",
"journal": "Drugs in R&D",
"keywords": null,
"medline_ta": "Drugs R D",
"mesh_terms": "D000328:Adult; D001572:Benzofurans; D003277:Contraceptives, Oral, Combined; D018592:Cross-Over Studies; D004347:Drug Interactions; D005260:Female; D006801:Humans; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "100883647",
"other_id": null,
"pages": "43-51",
"pmc": null,
"pmid": "23539257",
"pubdate": "2013-03",
"publication_types": "D017426:Clinical Trial, Phase I; D016428:Journal Article; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": "18644012;19035970;18509121;21605282;21039673;18430808;19911858;11721760;2256527;17919271;10223781;19886379;18987031;7698081;16501067;15089911",
"title": "Effect of prucalopride on the pharmacokinetics of oral contraceptives in healthy women.",
"title_normalized": "effect of prucalopride on the pharmacokinetics of oral contraceptives in healthy women"
} | [
{
"companynumb": "US-JNJFOC-20130503312",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PRUCALOPRIDE SUCCINATE"
},
"drugadditional": null... |
{
"abstract": "Demodex spp. mites are a common colonizer of sebaceous adult skin. Though usually clinically insignificant, demodicosis may be associated with a wide spectrum of skin diseases in immunocompetent hosts, such as erythematotelangiectatic and papulopustular rosacea, Demodex folliculorum, and blepharitis. We present a case of a healthy 9-year-old boy with an exuberant, inflammatory, Demodex-associated pustular eruption of the face, induced by the use of a high-potency topical steroid and successfully treated with oral ivermectin.",
"affiliations": "Division of Dermatology, Department of Internal Medicine, Albert Einstein College of Medicine, Bronx, NY, USA.;Division of Dermatology, Department of Internal Medicine, Albert Einstein College of Medicine, Bronx, NY, USA.;Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, USA.;Division of Dermatology, Department of Internal Medicine, Albert Einstein College of Medicine, Bronx, NY, USA.;Division of Dermatology, Department of Internal Medicine, Albert Einstein College of Medicine, Bronx, NY, USA.",
"authors": "Guzman|Anthony K|AK|https://orcid.org/0000-0002-2624-1852;Gittler|Julia K|JK|;Amin|Bijal|B|;Srikantha|Rithu|R|;Balagula|Yevgeniy|Y|",
"chemical_list": "D013256:Steroids",
"country": "United States",
"delete": false,
"doi": "10.1111/pde.14315",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0736-8046",
"issue": "37(5)",
"journal": "Pediatric dermatology",
"keywords": "corticosteroid-topical; demodex; dermatopathology; infestations; therapy-systemic",
"medline_ta": "Pediatr Dermatol",
"mesh_terms": "D000818:Animals; D001762:Blepharitis; D002648:Child; D006801:Humans; D008297:Male; D008924:Mite Infestations; D008925:Mites; D012393:Rosacea; D013256:Steroids",
"nlm_unique_id": "8406799",
"other_id": null,
"pages": "985-986",
"pmc": null,
"pmid": "32729151",
"pubdate": "2020-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Acute inflammatory Demodex-induced pustulosis in an immunocompetent patient related to topical steroid use.",
"title_normalized": "acute inflammatory demodex induced pustulosis in an immunocompetent patient related to topical steroid use"
} | [
{
"companynumb": "US-009507513-2011USA010639",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MOMETASONE FUROATE"
},
"drugadditional": "3"... |
{
"abstract": "A 65-year-old Japanese woman with Parkinson's disease, later diagnosed with Lewy body disease, presented with a 2-day history of systemic tremors. She also had fever without rigidity or creatine kinase (CK) elevation. She was diagnosed with sepsis caused by pyelonephritis with acute kidney injury and parkinsonism exacerbation. Although antibiotic and fluid therapy improved her pyuria and renal function, her fever and tremors persisted. On the fourth day, her symptoms worsened and resulted in cardiopulmonary arrest; however, quick resuscitation allowed the return of spontaneous circulation. Simultaneously, hyperthermia, altered consciousness, extrapyramidal symptoms, dysautonomia and CK elevation were noted. Thus, dantrolene administration was initiated with a tentative diagnosis of neuroleptic malignant syndrome (NMS). This caused her fever to subside, and her symptoms gradually improved. It was difficult to distinguish between parkinsonism exacerbation associated with sepsis and NMS. Physicians should consider NMS early on, even if the patient does not fulfil the diagnostic criteria.",
"affiliations": "Division of General Internal Medicine, School of Medicine, Tokai University, Isehara, Japan.;Division of General Internal Medicine, School of Medicine, Tokai University, Isehara, Japan.;Division of General Internal Medicine, School of Medicine, Tokai University, Isehara, Japan.;Division of General Internal Medicine, School of Medicine, Tokai University, Isehara, Japan.",
"authors": "Manabe|Saki|S|;Yanagi|Hidetaka|H|;Ozawa|Hideki|H|;Takagi|Atsushi|A|",
"chemical_list": "D000900:Anti-Bacterial Agents; D009125:Muscle Relaxants, Central; D003620:Dantrolene",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2018-227216",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "12(2)",
"journal": "BMJ case reports",
"keywords": "intensive care; neurology; primary care; psychiatry; unwanted effects / adverse reactions",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000368:Aged; D000900:Anti-Bacterial Agents; D003620:Dantrolene; D003937:Diagnosis, Differential; D005260:Female; D005440:Fluid Therapy; D006801:Humans; D020961:Lewy Body Disease; D009125:Muscle Relaxants, Central; D009459:Neuroleptic Malignant Syndrome; D018805:Sepsis; D016896:Treatment Outcome",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "30824461",
"pubdate": "2019-02-28",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "23271911;11145488;15824341;12735913;16237129;20082998;9330840;17541044;17802712;2863986;26223336;15264967;16682107;27068351;30346242;29494265",
"title": "Neuroleptic malignant syndrome as part of an akinetic crisis associated with sepsis in a patient with Lewy body disease.",
"title_normalized": "neuroleptic malignant syndrome as part of an akinetic crisis associated with sepsis in a patient with lewy body disease"
} | [
{
"companynumb": "JP-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2019-BI-013210",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PRAMIPEXOLE"
},
... |
{
"abstract": "BACKGROUND\nOpen fetal myelomeningocele (MMC) surgery is currently the standard of care option for prenatal MMC repair. We described the population referred to our center and reviewed outcome after open fetal MMC repair.\n\n\nMETHODS\nAll patients referred to our center for MMC were reviewed from July 2014 to June 2020. For all the patients who underwent fetal MMC repair, surgical details, maternal characteristics and data from the neonatal to the three-years-old evaluations were collected.\n\n\nRESULTS\nAmong the 126 patients referred to our center, 49.2% were eligible and 27.4% (n = 17) of them underwent fetal MMC repair. Average gestational age at fetal surgery was 24+6 weeks. There was no case of fetal complication and the only maternal complication was one case of transfusion. We recorded 70% of premature rupture of membranes and 47% of premature labor. Average gestational age at delivery was 34+2 weeks and no patient delivered before 30 weeks. There was no case of uterine scar dehiscence or maternal complication during cesarean section. After birth, 59% of the children had a hindbrain herniation reversal. At 1-year-old, 42% were assigned a functional level of one or more better than expected according to the prenatal anatomic level and 25% required a ventriculoperitoneal shunt. At 3-year-old, all the children attended school and 75% were able to walk with orthotics or independently.\n\n\nCONCLUSIONS\nOpen fetal surgery enables anatomical repair of the MMC lesion, a potential benefit on cerebral anomalies and motor function, with a low rate of perinatal and maternal complications.",
"affiliations": "Sorbonne University, AP-HP, Trousseau Hospital, DMU ORIGYNE, Department of Fetal Medicine, 26 Avenue du Dr Arnold Netter, 75012 Paris, France; National Reference Center for Rare Disease: Vertebral and Spinal Cord Anomalies (MAVEM Center), AP-HP, Trousseau Hospital, 26 Avenue du Dr Arnold Netter, 75012 Paris, France. Electronic address: lucie.guilbaud@aphp.fr.;Sorbonne University, AP-HP, Trousseau Hospital, DMU ORIGYNE, Department of Fetal Medicine, 26 Avenue du Dr Arnold Netter, 75012 Paris, France; National Reference Center for Rare Disease: Vertebral and Spinal Cord Anomalies (MAVEM Center), AP-HP, Trousseau Hospital, 26 Avenue du Dr Arnold Netter, 75012 Paris, France.;National Reference Center for Rare Disease: Vertebral and Spinal Cord Anomalies (MAVEM Center), AP-HP, Trousseau Hospital, 26 Avenue du Dr Arnold Netter, 75012 Paris, France; Sorbonne University, AP-HP, Trousseau Hospital, Department of Physical Medicine and Rehabilitation, 26 Avenue du Dr Arnold Netter, 75012 Paris, France.;National Reference Center for Rare Disease: Vertebral and Spinal Cord Anomalies (MAVEM Center), AP-HP, Trousseau Hospital, 26 Avenue du Dr Arnold Netter, 75012 Paris, France; Paris University, AP-HP, Necker Enfants Malades Hospital, Department of Pediatric Neurosurgery, 149 Rue de Sèvres, 75015 Paris, France.;Sorbonne University, AP-HP, Trousseau Hospital, DMU ORIGYNE, Department of Fetal Medicine, 26 Avenue du Dr Arnold Netter, 75012 Paris, France; National Reference Center for Rare Disease: Vertebral and Spinal Cord Anomalies (MAVEM Center), AP-HP, Trousseau Hospital, 26 Avenue du Dr Arnold Netter, 75012 Paris, France.;Sorbonne University, AP-HP, Trousseau Hospital, DMU ORIGYNE, Department of Fetal Medicine, 26 Avenue du Dr Arnold Netter, 75012 Paris, France; National Reference Center for Rare Disease: Vertebral and Spinal Cord Anomalies (MAVEM Center), AP-HP, Trousseau Hospital, 26 Avenue du Dr Arnold Netter, 75012 Paris, France.;Sorbonne University, AP-HP, Trousseau Hospital, DMU ORIGYNE, Department of Fetal Medicine, 26 Avenue du Dr Arnold Netter, 75012 Paris, France; National Reference Center for Rare Disease: Vertebral and Spinal Cord Anomalies (MAVEM Center), AP-HP, Trousseau Hospital, 26 Avenue du Dr Arnold Netter, 75012 Paris, France.;Lyon Claude Bernard University, hôpital Femme-Mère-Enfant, Department of Pediatric Neurosurgery, 59 Boulevard Pinel, 69500 Bron, France.;National Reference Center for Rare Disease: Vertebral and Spinal Cord Anomalies (MAVEM Center), AP-HP, Trousseau Hospital, 26 Avenue du Dr Arnold Netter, 75012 Paris, France; Sorbonne University, AP-HP, Trousseau Hospital, Department of Pediatric Radiology, 26 Avenue du Dr Arnold Netter, 75012 Paris, France.;National Reference Center for Rare Disease: Vertebral and Spinal Cord Anomalies (MAVEM Center), AP-HP, Trousseau Hospital, 26 Avenue du Dr Arnold Netter, 75012 Paris, France; Sorbonne University, AP-HP, Trousseau Hospital, DMU ORIGYNE, Department of Pediatric Neurology, 26 Avenue du Dr Arnold Netter, 75012 Paris, France.;Sorbonne University, AP-HP, Trousseau Hospital, DMU ORIGYNE, Neonatal Intensive Care Unit, 26 Avenue du Dr Arnold Netter, 75012 Paris, France.;Sorbonne University, AP-HP, Trousseau Hospital, Department of Anesthesiology, 26 Avenue du Dr Arnold Netter, 75012 Paris, France.;National Reference Center for Rare Disease: Vertebral and Spinal Cord Anomalies (MAVEM Center), AP-HP, Trousseau Hospital, 26 Avenue du Dr Arnold Netter, 75012 Paris, France; Sorbonne University, AP-HP, Trousseau Hospital, Department of Physical Medicine and Rehabilitation, 26 Avenue du Dr Arnold Netter, 75012 Paris, France.;National Reference Center for Rare Disease: Vertebral and Spinal Cord Anomalies (MAVEM Center), AP-HP, Trousseau Hospital, 26 Avenue du Dr Arnold Netter, 75012 Paris, France; Paris University, AP-HP, Necker Enfants Malades Hospital, Department of Pediatric Neurosurgery, 149 Rue de Sèvres, 75015 Paris, France.;Sorbonne University, AP-HP, Trousseau Hospital, DMU ORIGYNE, Department of Fetal Medicine, 26 Avenue du Dr Arnold Netter, 75012 Paris, France; National Reference Center for Rare Disease: Vertebral and Spinal Cord Anomalies (MAVEM Center), AP-HP, Trousseau Hospital, 26 Avenue du Dr Arnold Netter, 75012 Paris, France.",
"authors": "Guilbaud|Lucie|L|;Maurice|Paul|P|;Lallemant|Pauline|P|;De Saint-Denis|Timothée|T|;Maisonneuve|Emeline|E|;Dhombres|Ferdinand|F|;Friszer|Stéphanie|S|;Di Rocco|Federico|F|;Garel|Catherine|C|;Moutard|Marie-Laure|ML|;Lachtar|Mohamed-Ali|MA|;Rigouzzo|Agnès|A|;Forin|Véronique|V|;Zérah|Michel|M|;Jouannic|Jean-Marie|JM|",
"chemical_list": null,
"country": "France",
"delete": false,
"doi": "10.1016/j.jogoh.2021.102155",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2468-7847",
"issue": "50(9)",
"journal": "Journal of gynecology obstetrics and human reproduction",
"keywords": "Dysraphism; Fetal surgery; Myelomeningocele; Myeloschisis; Open maternal fetal surgery; Spina bifida",
"medline_ta": "J Gynecol Obstet Hum Reprod",
"mesh_terms": null,
"nlm_unique_id": "101701588",
"other_id": null,
"pages": "102155",
"pmc": null,
"pmid": "33915336",
"pubdate": "2021-11",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Open fetal surgery for myelomeningocele repair in France.",
"title_normalized": "open fetal surgery for myelomeningocele repair in france"
} | [
{
"companynumb": "FR-NOVARTISPH-NVSC2021FR281931",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "VANCOMYCIN"
},
"drugadditional": "4",
... |
{
"abstract": "Immune-mediated adverse effects of immune checkpoint inhibitors are rather common, but neuromyopathic immune-related adverse events are very rare. In this report, we present a unique case of a patient with a complex neuromyopathic syndrome with axonal neuropathy and inflammatory myopathy after a single dose of pembrolizumab. An 82-year-old patient with a previously untreated stage IIIc melanoma developed ptosis in the left eye, generalized weakness, and neck and shoulder pain 15 days after pembrolizumab administration. He had left-sided ptosis and miosis, with a normal pupillary light reflex, horizontal diplopia, and voice hoarseness, along with weakness of the neck muscles and a hypokinetic right vocal cord at laryngoscopy. The laboratory evaluation was remarkable for the marked increase in the serum lactate dehydrogenase and creatine phosphokinase levels. Further evaluation revealed findings compatible with axonal neuropathy and inflammatory myopathy. The patient was treated with corticosteroids, immunoglobulin, and plasmapheresis, with a minor response; the patient eventually died. This case represents a newly described syndrome probably associated with pembrolizumab administration.",
"affiliations": "*First Department of Internal Medicine, Laikon General Hospital, National and Kapodistrian University of Athens †Neurology Department, Laikon General Hospital, Athens, Greece.",
"authors": "Diamantopoulos|Panagiotis T|PT|;Tsatsou|Katerina|K|;Benopoulou|Olga|O|;Anastasopoulou|Amalia|A|;Gogas|Helen|H|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D000074322:Antineoplastic Agents, Immunological; D061026:Programmed Cell Death 1 Receptor; C582435:pembrolizumab",
"country": "United States",
"delete": false,
"doi": "10.1097/CJI.0000000000000172",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1524-9557",
"issue": "40(6)",
"journal": "Journal of immunotherapy (Hagerstown, Md. : 1997)",
"keywords": null,
"medline_ta": "J Immunother",
"mesh_terms": "D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized; D000074322:Antineoplastic Agents, Immunological; D001369:Axons; D001763:Blepharoptosis; D064420:Drug-Related Side Effects and Adverse Reactions; D017809:Fatal Outcome; D006801:Humans; D007167:Immunotherapy; D008297:Male; D008545:Melanoma; D009220:Myositis; D009367:Neoplasm Staging; D010523:Peripheral Nervous System Diseases; D061026:Programmed Cell Death 1 Receptor",
"nlm_unique_id": "9706083",
"other_id": null,
"pages": "221-223",
"pmc": null,
"pmid": "28498142",
"pubdate": "2017",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Inflammatory Myopathy and Axonal Neuropathy in a Patient With Melanoma Following Pembrolizumab Treatment.",
"title_normalized": "inflammatory myopathy and axonal neuropathy in a patient with melanoma following pembrolizumab treatment"
} | [
{
"companynumb": "GR-009507513-1707GRC007432",
"fulfillexpeditecriteria": "1",
"occurcountry": "GR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ASPIRIN"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nAnxiety and depression are common among psoriasis and psoriatic arthritis (PsA) patients, but rates may differ by treatment.\n\n\nOBJECTIVE\nTo quantify the risk of incident treated anxiety, depression and mixed anxiety + depression in users of apremilast compared with users of other treatments for psoriasis and PsA.\n\n\nMETHODS\nWe conducted two separate cohort studies of psoriasis and PsA patients treated with apremilast, tumour necrosis factor inhibitor biologics, interleukin-17, -23 or -12/23 inhibitor biologics, conventional DMARDs or systemic corticosteroids in the United States MarketScan database. Cohort entry was date of first study drug after 21 March 2014. We identified cases who had a depression and/or anxiety diagnosis with a prescription for antidepressant/antianxiety medication within 30 days of the diagnosis code. We calculated incidence rates (IRs) and incidence rate ratios with 95% confidence intervals (CIs) for treated anxiety, treated depression and treated anxiety + depression per 1000 patient-years (PY) among patients.\n\n\nRESULTS\nAmong the psoriasis cohort, IRs for each outcome were similar between exposure categories and highest among users of systemic corticosteroids alone. IRs (95% CI) for apremilast alone were 9.2 (6.6-12.5), 4.6 (2.8-7.1) and 4.6 (2.8-7.1) per 1000 PY for treated anxiety, treated depression and treated anxiety + depression, respectively. In the PsA cohort, the rate of anxiety was highest among users of apremilast alone; rates of depression and anxiety + depression were similar for apremilast compared with other PsA treatments. IRs for each outcome were also high for users of corticosteroids in both the psoriasis and PsA cohorts.\n\n\nCONCLUSIONS\nAmong patients with psoriasis, users of apremilast had similar rates of anxiety and depression as users of other non-corticosteroid systemic psoriasis treatments. Among PsA patients, users of apremilast had similar rates of depression and anxiety + depression compared with users of other systemic non-corticosteroid PsA drugs; however, the rate of anxiety was slightly higher.",
"affiliations": "Boston Collaborative Drug Surveillance Program, Lexington, MA, USA.;Boston Collaborative Drug Surveillance Program, Lexington, MA, USA.;Boston Collaborative Drug Surveillance Program, Lexington, MA, USA.;Boston Collaborative Drug Surveillance Program, Lexington, MA, USA.",
"authors": "Vasilakis-Scaramozza|C|C|;Persson|R|R|;Hagberg|K W|KW|;Jick|S|S|https://orcid.org/0000-0002-2215-1067",
"chemical_list": "D000305:Adrenal Cortex Hormones; D018501:Antirheumatic Agents; D001688:Biological Products; D013792:Thalidomide; C505730:apremilast",
"country": "England",
"delete": false,
"doi": "10.1111/jdv.16231",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0926-9959",
"issue": "34(8)",
"journal": "Journal of the European Academy of Dermatology and Venereology : JEADV",
"keywords": null,
"medline_ta": "J Eur Acad Dermatol Venereol",
"mesh_terms": "D000305:Adrenal Cortex Hormones; D018501:Antirheumatic Agents; D001007:Anxiety; D015535:Arthritis, Psoriatic; D001688:Biological Products; D015331:Cohort Studies; D003863:Depression; D006801:Humans; D011565:Psoriasis; D013792:Thalidomide; D014481:United States",
"nlm_unique_id": "9216037",
"other_id": null,
"pages": "1755-1763",
"pmc": null,
"pmid": "31981426",
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"abstract": "Eosinophilia has been reported as a rare, new biological effect of immune checkpoint inhibition that may be associated with improved treatment response and the development of immune-related adverse events.\n\n\n\nWe report a case of dual checkpoint inhibitor-associated hypereosinophilia and eosinophilic enteritis in a patient with advanced cutaneous melanoma. Rapid resolution of peripheral eosinophilia and associated symptoms was achieved with steroids alone.\n\n\n\nImmune checkpoint inhibition can trigger inflammation in virtually any organ in the body, leading to diverse clinical manifestations. To our knowledge, this is the first case report of eosinophilic enteritis due to ipilimumab plus nivolumab.",
"affiliations": "Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.;Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA.;Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.;Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. rdc2150@cumc.columbia.edu.",
"authors": "Yang|J|J|;Lagana|S M|SM|;Saenger|Y M|YM|;Carvajal|R D|RD|0000-0002-3796-1118",
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"fulltext": "\n==== Front\nJ Immunother CancerJ Immunother CancerJournal for Immunotherapy of Cancer2051-1426BioMed Central London 74310.1186/s40425-019-0743-5Case ReportDual checkpoint inhibitor-associated eosinophilic enteritis Yang J. 1Lagana S. M. 2Saenger Y. M. 13http://orcid.org/0000-0002-3796-1118Carvajal R. D. rdc2150@cumc.columbia.edu 131 0000 0001 2171 9952grid.51462.34Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY USA 2 0000000419368729grid.21729.3fDepartment of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY USA 3 0000000419368729grid.21729.3fHerbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY USA 15 11 2019 15 11 2019 2019 7 31026 6 2019 16 9 2019 © The Author(s). 2019Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nEosinophilia has been reported as a rare, new biological effect of immune checkpoint inhibition that may be associated with improved treatment response and the development of immune-related adverse events.\n\nCase presentation\nWe report a case of dual checkpoint inhibitor-associated hypereosinophilia and eosinophilic enteritis in a patient with advanced cutaneous melanoma. Rapid resolution of peripheral eosinophilia and associated symptoms was achieved with steroids alone.\n\nConclusions\nImmune checkpoint inhibition can trigger inflammation in virtually any organ in the body, leading to diverse clinical manifestations. To our knowledge, this is the first case report of eosinophilic enteritis due to ipilimumab plus nivolumab.\n\nKeywords\nMelanomaCheckpoint inhibitionEosinophiliaEosinophilic enteritisissue-copyright-statement© The Author(s) 2019\n==== Body\nIntroduction\nImmune checkpoint inhibition with anti-PD-1 (programmed death 1) and anti-CLTA-4 (cytotoxic T-lymphocyte associated protein 4) agents has revolutionized the treatment of various cancers, but can be associated with a diverse range of immune-related adverse events including pneumonitis, colitis, and rare cases of myocarditis. Eosinophilic enteritis is a rare primary eosinophilic gastrointestinal disorder, first described in 1937, characterized by gastrointestinal symptoms in the presence of pathological eosinophilic infiltration of the intestinal wall without secondary causes of gut eosinophilia. To our knowledge, this is the first reported case of eosinophilic enteritis associated with ipilimumab plus nivolumab.\n\nCase presentation\nA 68-year old Caucasian man was referred to our medical oncology clinic in August 2017 for management of a stage IIIB (AJCC version 7) cutaneous melanoma. He was diagnosed with a 2 mm thick melanoma over the right scalp in December 2012 that was excised. Sentinel lymph node biopsy was negative. He remained disease-free until August 2017 when he noticed a pruritic scalp nodule located approximately 2 cm from the prior skin graft that was biopsy-proven to be an in-transit recurrence of the melanoma. He underwent repeat excision, with pathological staging demonstrating a stage IIIB (pT4apN2cM0) melanoma. Molecular testing was notable for a GNA11 Q209L mutation that was also found in the previous specimen from 2012. MRI brain and CT chest, abdomen, and pelvis were negative for distant metastases. He was started on adjuvant pembrolizumab on 12/14/2017. Shortly after the first dose, he developed an enlarging right supraclavicular lymph node. Fine needle aspiration of the lymph node revealed metastatic melanoma. Repeat scans after 3 additional doses of pembrolizumab demonstrated new hepatic lesions. Treatment was intensified with the addition of talimogene laherparepvec (T-VEC) injections into the supraclavicular lymph node. He developed a maculopapular rash that was managed with topical hydrocortisone. There was significant decrease in the size of the injected lymph node with initially stable visceral disease, but MRI abdomen on 6/8/2018 after 5 concurrent doses of T-VEC and pembrolizumab showed interval growth in several hepatic lesions.\n\nHe was transitioned to dual checkpoint inhibition with ipilimumab 3 mg/kg plus nivolumab 1 mg/kg and received his first dose on 6/21/2018. Blood work on 7/9/2018 was notable for an absolute eosinophil count (AEC) of 700/mm3 [normal range 30–350; peripheral eosinophilia defined as AEC > 500/mm3] (Fig. 1). He received 2 additional doses of ipilimumab plus nivolumab on 7/12/2018 and 8/1/2018 with concurrent stereotactic body radiation therapy (SBRT) to 2 liver lesions (50 Gy over 5 fractions to each lesion). He returned for his final dose of combination therapy on 8/23/18, but treatment was held for worsening pruritus, rash, non-productive cough, and new transaminitis (AST 60, ALT 151). Around this time, he also developed vague gastrointestinal symptoms consisting of abdominal pain, bloating, nausea, and diarrhea. His AEC continued to rise, peaking at 3600/mm3 on 8/21/2018. He did not have rectal bleeding or ascites. Stool and serologic studies were negative for parasitic infection. Restaging scans on 8/27/2018 showed further disease progression in the liver and the development of a new soft tissue paraspinal lesion. He was evaluated by a gastroenterologist and underwent an upper endoscopy which revealed no gross abnormalities, but biopsy of the duodenum revealed a prominent eosinophilic infiltrate (80–100 eosinophils per HPF) consistent with eosinophilic enteritis (Fig. 2).\nFig. 1 Absolute eosinophil count over treatment course. First black arrow – initiation of prednisone 1 mg/kg. Red arrow – steroid dose tapered down to prednisone 5 mg daily. Second black arrow – steroid dose increased to prednisone 15 mg daily. Asterisk – unknown eosinophil count\n\n\nFig. 2 Duodenal biopsy showed extensive eosinophilic infiltrate. A – Greater than 100 eosinophils per high-power field, predominantly in lamina propria (hematoxylin and eosin, 40X view). B – Eosinophilic infiltration within duodenal crypts as indicated by black arrows (60X view)\n\n\n\nHe was started on prednisone 1 mg/kg daily with rapid improvement in his peripheral eosinophilia, rash, cough, and gastrointestinal symptoms. When the prednisone was tapered off, he developed recurrent symptoms with a concomitant rise in his AEC. He was restarted on prednisone 15 mg daily with normalization of his AEC. Subsequent scans demonstrated essentially stable disease for three months, although minor growth was noted in several cutaneous lesions. He received additional lines of therapy including off-label trametinib for GNA11-mutant melanoma, nivolumab monotherapy, and combination chemotherapy with carboplatin, vinblastine, and dacarbazine. The most recent AEC was normal off prednisone. Most recent imaging showed disease progression in the lung, and he was restarted on ipilimumab plus nivolumab in combination with T-VEC injections.\n\nDiscussion\nPrimary eosinophilic gastrointestinal disorders encompass a group of rare diseases characterized by pathologic eosinophilic infiltration of the gastrointestinal tract in the absence of other identifiable causes of gut eosinophilia. Eosinophilic gastritis, enteritis, and gastroenteritis are generally grouped together due to clinical similarities, but it is unclear whether these represent distinct entities or share a common pathological process [1]. Abdominal pain, nausea, and vomiting are common presenting symptoms, and the majority of patients have peripheral eosinophilia. There are no consensus histopathologic criteria for diagnosis, but experts have proposed guidelines suggesting that greater than 25 eosinophils per high power field (HPF), in conjunction with eosinophilic acute cryptitis, is abnormal [2]. The diagnosis of eosinophilic enteritis additionally requires the exclusion of secondary causes of intestinal eosinophilia such as parasitic infections, inflammatory bowel disease, autoimmune vasculitides, and culprit drugs e.g., gold therapy, oral hypoglycemic agents, and non-steroidal anti-inflammatory drugs (NSAIDs) [3].\n\nThe molecular pathogenesis of eosinophilic gastroenteritis is thought to be mediated by a type 2 helper T cell (Th2)-driven immune response that triggers eosinophil chemotaxis and activation. Transcriptomic analysis of gastric biopsies obtained from patients with eosinophilic gastroenteritis reveals activation of the Th2 cytokine signaling pathways IL-4, IL-5, and IL-13. Upregulation of the chemokine CCL26 (eotaxin-3), a known eosinophil chemoattractant and downstream target of IL-4 and IL-13, further corroborates the central role of Th2-driven immunity [4–7]. Similar to our patient who has a history of multiple allergies to dust, pollen, latex, and several medications (penicillin, pregabalin, ibuprofen), affected individuals tend to have atopic phenotypes consisting of asthma, eczema, and allergies to food or medicine. In the case we present, checkpoint inhibition may have provoked a similar immune response in the duodenum leading to eosinophilic inflammation. Indeed, T cell co-stimulation through CD28 and B7–2 plays an important role in the Th2-mediated immune response that promotes bronchial asthma. Administration of a CTLA-4 immunoglobulin (fusion protein consisting of extracellular domain of CTLA-4 and a human γ-1 constant region) blocks this interaction and reduces eosinophil accumulation and Th2 cytokine production [8]. Thus, we may surmise that checkpoint inhibition with ipilimumab could trigger allergic conditions such as eosinophilic enteritis. Alternatively, the accumulation of gut eosinophils may have been secondary to a hypereosinophilic syndrome-like condition induced by immunotherapy.\n\nPeripheral eosinophilia, long observed during the course of IL-2 therapy due to induction of IL-4 and IL-5 [9–11], was recently documented as a new, rare biological effect of checkpoint inhibition. A retrospective case series based on a French pharmacovigilance registry included 909 patients who received anti-PD-1 or anti-PD-L1 therapy between 2013 and 2016 [12]. A total of 26 patients (2.8%) were deemed to have immune-related eosinophilia, the majority of whom were treated for advanced melanoma. The median time to increase in eosinophil count was 3.0 months after the first cycle of therapy, with peak eosinophilia (median peak 1000/mm3) occurring after a median of 6.4 months. Notably, no patient developed any clinical manifestations related to eosinophilia. Our patient experienced a mild increase in AEC from 160/mm3 to > 300/mm3 approximately 1 month after initiating pembrolizumab monotherapy and had a second increase to 700/mm3 roughly 2 weeks after receiving the first dose of ipilimumab plus nivolumab. The peak AEC of 3600/mm3 occurred 2 months after dual checkpoint inhibitor treatment (Fig. 1). Two cases of drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome due to immune checkpoint inhibition have also been reported [13, 14]. Although our patient did present with rash and systemic symptoms including cough and gastrointestinal complaints, DRESS syndrome seemed less likely in the absence of fever, lymphadenopathy, extensive rash covering the face and greater than 50% of the body surface area, and typical involvement of the kidney or liver. He had a mild transaminitis attributed to radiation therapy that resolved prior to initiation of steroids.\n\nPrior reports additionally suggest that baseline elevation in eosinophil count [15, 16] or increase during treatment with checkpoint inhibition [17] may serve as predictive biomarkers of improved response and survival outcomes as well as increased risk of immune-related adverse events in melanoma patients. For example, in a retrospective analysis of 616 patients with advanced melanoma treated with pembrolizumab, baseline relative eosinophil count (REC) > 1.5% was an independent prognosticator of improved overall survival (median OS 19.6 months vs 5.8 months in patients with REC > 1.5 and < 1.5% respectively) [15]. Similarly, improved response rates and long-term disease control were observed in metastatic melanoma patients who experienced an increase in AEC of > 100/mm3 or had an AEC > 400/mm3 at 12 weeks after initiating anti-PD-1 therapy [17]. 22 of 73 patients (30%) with advanced melanoma treated with ipilimumab at a single institution developed hypereosinophilia (defined as an AEC > 400/mm3) during the course of their treatment [18]. An increase in AEC of greater than 100/mm3 between the first and second infusions was associated with longer survival (median OS 11.3 months versus 6.8 months, p = 0.012), and 73% of these patients had immune-related adverse events primarily involving the gastrointestinal tract. None of these adverse events were thought to be directly related to the hypereosinophilia, though biopsies of the affected organ were not obtained in all cases. Our patient had initial radiographic progression followed by several months of stable disease, but whether disease control was secondary to delayed immunotherapy response or receipt of other regimens such as trametinib and chemotherapy is unclear. Interestingly, a recent case report of hypereosinophilia in a non-small cell lung cancer patient who had lethal, hyperprogressive disease after a single dose of nivolumab highlights a more complex, context-specific role for eosinophils in which the immune modulatory effects of eosinophils may depend on which cytokines are present in the immediate surroundings [19]. TNF-α and IFN-у appear to enhance eosinophilic production of pro-inflammatory Th1-type chemokines such as CXCL9 and CXCL10 whereas TNF-α and IL-4 stimulate eosinophilic production of Th2-type chemokines, which sustain a more immunosuppressive tumor microenvironment.\n\nThe immunological role of eosinophils is not fully understood, but they are implicated in various immune processes including host immune response to helminthic infections, pathogenesis of atopic conditions, and tumor surveillance. Eosinophils may promote antitumor immunity by recruiting CD8+ T cells to the tumor microenvironment via secretion of chemoattractants (CCL5, CXCL9, and CXCL10) and normalization of tumor vasculature, thereby allowing for increased effector T cell infiltration [20]. Moreover, eosinophils may polarize tumor-associated macrophages toward an M1 phenotype [20] and mediate direct tumor cell lysis via the release of granule-associated cytotoxic proteins including major basic protein, eosinophil peroxidase, and eosinophil-derived neurotoxin. Indeed, IL-5 transgenic mice expressing high endogenous levels of eosinophils displayed resistance to the development of methylcholanthrene (MCA)-induced fibrosarcomas [21]. In the case we present, it remains unclear whether there was any correlation between the eosinophilia and period of stable disease given the patient received multiple subsequent lines of therapy.\n\nConclusion\nWe present a case of dual checkpoint inhibitor-associated hypereosinophilia and eosinophilic enteritis in a patient with advanced cutaneous melanoma. Rapid resolution of peripheral eosinophilia and associated symptoms was achieved with steroids alone. To our knowledge, this is the first case report of a direct clinical manifestation of hypereosinophilia due to immunotherapy.\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAcknowledgements\nN/A\n\nAuthors’ contributions\nJY, SML, YMS, and RDC contributed to the writing of the manuscript. SL contributed pathology images. All authors read and approved the final manuscript.\n\nFunding\nN/A\n\nAvailability of data and materials\nN/A\n\nEthics approval and consent to participate\nColumbia University requirements (http://www.cumc.columbia.edu/dept/irb/policies/docs/Case_Report_ Policy.doc):\n\nCase report on a single patient: A case report describing the treatment of a single patient does not meet the federal definition of human subjects research on the basis that the information in the case report is not generalizable knowledge. Therefore, clinicians at the University are not required to obtain IRB approval for case reports of a single patient. Investigators who are asked by a journal or other entity to provide documentation from the IRB that such a case report was either approved by the IRB or did not require review by the IRB may present the Columbia Univesity IRB/Privacy Board Policy on Case Reports as evidence that the case report does not require IRB approval.\n\nConsent for publication\nConsent was obtained.\n\nCompeting interests\nRDC serves as a consultant to Array, BMS, Castle Biosciences, Compugen, Foundation Medicine, Immunocore, I-Mab, Incyte, Merck, Roche/Genentech, PureTech Health, Sanofi Genzyme, and Sorrento Therapeutics. RC is also on the advisory board for Aura Biosciences, Chimeron, and Rgenix and receives research funding (to Columbia University) from Amgen, Astellis, AstraZeneca, Bayer, Bellicum, BMS, Corvus, Eli Lilly, Immunocore, Incyte, Macrogenics, Merck, Mirati, Novartis, Pfizer, Plexxikon, and Roche/Genentech. YMS receives research and travel funding from Amgen. JY and SML declare that they have no competing interests.\n==== Refs\nReferences\n1. Rothenberg ME Eosinophilic gastrointestinal disorders (EGID) J Allergy Clin Immunol 2004 113 11 28 10.1016/j.jaci.2003.10.047 14713902 \n2. Lwin T Melton SD Genta RM Eosinophilic gastritis: histopathological characterization and quantification of the normal gastric eosinophil content Mod Pathol 2011 24 556 563 10.1038/modpathol.2010.221 21169993 \n3. Pineton de Chambrun G, Dufour G, Tassy B, et al. Diagnosis, Natural History and Treatment of Eosinophilic Enteritis: a Review. Curr Gastroenterol Rep 2018;20:37.\n4. Khan S Orenstein SR Eosinophilic gastroenteritis Gastroenterol Clin N Am 2008 37 333 348 10.1016/j.gtc.2008.02.003 \n5. Khan S Eosinophilic gastroenteritis Best Pract Res Clin Gastroenterol 2005 19 177 198 10.1016/j.bpg.2005.01.009 15833687 \n6. Caldwell JM Collins MH Stucke EM Histologic eosinophilic gastritis is a systemic disorder associated with blood and extragastric eosinophilia, TH2 immunity, and a unique gastric transcriptome J Allergy Clin Immunol 2014 134 1114 1124 10.1016/j.jaci.2014.07.026 25234644 \n7. Zhang M Li Y Eosinophilic gastroenteritis: a state-of-the-art review J Gastroenterol Hepatol 2017 32 64 72 10.1111/jgh.13463 \n8. Tsuyuki S Tsuyuki J Einsle K Kopf M Coyle AJ Costimulation through B7-2 (CD86) is required for the induction of a lung mucosal T helper cell 2 (TH2) immune response and altered airway responsiveness J Exp Med 1997 185 1671 1679 10.1084/jem.185.9.1671 9151904 \n9. Macdonald D Gordon AA Kajitani H Enokihara H Barrett AJ Interleukin-2 treatment-associated eosinophilia is mediated by interleukin-5 production Br J Haematol 1990 76 168 173 10.1111/j.1365-2141.1990.tb07867.x 2094320 \n10. van Haelst PC Kovach JS Kita H Administration of interleukin-2 (IL-2) results in increased plasma concentrations of IL-5 and eosinophilia in patients with cancer Blood 1991 78 1538 1544 10.1182/blood.V78.6.1538.1538 1884020 \n11. Sosman JA Bartemes K Offord KP Evidence for eosinophil activation in cancer patients receiving recombinant interleukin-4: effects of interleukin-4 alone and following interleukin-2 administration Clinical cancer research : an official journal of the American Association for Cancer Research 1995 1 805 812 9816049 \n12. Bernard-Tessier A Jeanville P Champiat S Immune-related eosinophilia induced by anti-programmed death 1 or death-ligand 1 antibodies Eur J Cancer 2017 81 135 137 10.1016/j.ejca.2017.05.017 28624693 \n13. Voskens CJ Goldinger SM Loquai C The price of tumor control: an analysis of rare side effects of anti-CTLA-4 therapy in metastatic melanoma from the ipilimumab network PLoS One 2013 8 e53745 10.1371/journal.pone.0053745 23341990 \n14. Mirza S Hill E Ludlow SP Nanjappa S Checkpoint inhibitor-associated drug reaction with eosinophilia and systemic symptom syndrome Melanoma Res 2017 27 271 273 10.1097/CMR.0000000000000326 28146044 \n15. Weide B Martens A Hassel JC Baseline biomarkers for outcome of melanoma patients treated with Pembrolizumab Clinical cancer research : an official journal of the American Association for Cancer Research 2016 22 5487 5496 10.1158/1078-0432.CCR-16-0127 27185375 \n16. Rosner S Kwong E Shoushtari AN Peripheral blood clinical laboratory variables associated with outcomes following combination nivolumab and ipilimumab immunotherapy in melanoma Cancer medicine 2018 7 690 697 10.1002/cam4.1356 29468834 \n17. Gaba Lydia Victoria Iván Pineda Estela Fernandez Aranzazu Aya Francisco Prat Aleix Arance Ana M Changes in blood eosinophilia during anti-PD1 therapy as a predictor of long term disease control in metastatic melanoma Journal of Clinical Oncology 2015 33 15_suppl 9069 9069 10.1200/jco.2015.33.15_suppl.9069 \n18. Delyon J Mateus C Lefeuvre D Experience in daily practice with ipilimumab for the treatment of patients with metastatic melanoma: an early increase in lymphocyte and eosinophil counts is associated with improved survival Annals of oncology : official journal of the European Society for Medical Oncology 2013 24 1697 1703 10.1093/annonc/mdt027 23439861 \n19. Occhipinti M Falcone R Onesti CE Marchetti P Hyperprogressive disease and early Hypereosinophilia after anti-PD-1 treatment: a case report Drug safety - case reports 2018 5 12 10.1007/s40800-018-0078-z 29536185 \n20. Carretero R Sektioglu IM Garbi N Salgado OC Beckhove P Hammerling GJ Eosinophils orchestrate cancer rejection by normalizing tumor vessels and enhancing infiltration of CD8(+) T cells Nat Immunol 2015 16 609 617 10.1038/ni.3159 25915731 \n21. Simson L Ellyard JI Dent LA Regulation of carcinogenesis by IL-5 and CCL11: a potential role for eosinophils in tumor immune surveillance J Immunol 2007 178 4222 4229 10.4049/jimmunol.178.7.4222 17371978\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2051-1426",
"issue": "7(1)",
"journal": "Journal for immunotherapy of cancer",
"keywords": "Checkpoint inhibition; Eosinophilia; Eosinophilic enteritis; Melanoma",
"medline_ta": "J Immunother Cancer",
"mesh_terms": "D000368:Aged; D000074322:Antineoplastic Agents, Immunological; D000971:Antineoplastic Combined Chemotherapy Protocols; D004751:Enteritis; D004802:Eosinophilia; D005756:Gastritis; D006801:Humans; D000074324:Ipilimumab; D008297:Male; D008545:Melanoma; D000077594:Nivolumab; D011241:Prednisone; D012878:Skin Neoplasms",
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"title": "Dual checkpoint inhibitor-associated eosinophilic enteritis.",
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"abstract": "BACKGROUND\nLocal anesthesia could result in lethal complications if injected in highly vascularized area. Dentist should take care to avoid such complications.\n\n\nMETHODS\nWe present a case of 15 year old girl with a coma following convulsive status epilepticus which developed after inferior alveolar nerve blockade by a dentist. The patient was admitted to the intensive care unit ICU and recovered within several days.\n\n\nCONCLUSIONS\nThis case is reported to tell both of dentists and medical staff that although it is uncommon, such complications of local anesthesia should be in mind to be avoided and managed promptly if happened.",
"affiliations": "Division of Neurology, Department of Internal Medicine, Aleppo University Hospital, Aleppo, Syria. iamrana13@yahoo.com.;Division of General Internal Medicine, Aleppo University Hospital, Aleppo, Syria.;Head of Neurology Unit, Aleppo University Hospital, Aleppo, Syria.;Division of Neurology, Department of Internal Medicine, Aleppo University Hospital, Aleppo, Syria.",
"authors": "Alsukhni|Rana Alnasser|RA|;Ghoubari|Mohamed Sourat|MS|;Farfouti|M Taher|MT|;Aboras|Yasmin Adib|YA|",
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"fulltext": "\n==== Front\nBMC Res NotesBMC Res NotesBMC Research Notes1756-0500BioMed Central London 210010.1186/s13104-016-2100-9Case ReportStatus epilepticus following local anesthesia in a previously healthy adult Alsukhni Rana Alnasser iamrana13@yahoo.com Ghoubari Mohamed Sourat M.Sourat.Ghoubari@hotmail.com Farfouti M.Taher dr.taherfarfouti@gmail.com Aboras Yasmin Adib dr.yasa233@yahoo.com Division of Neurology, Department of Internal Medicine, Aleppo University Hospital, Aleppo, Syria Division of General Internal Medicine, Aleppo University Hospital, Aleppo, Syria Head of Neurology Unit, Aleppo University Hospital, Aleppo, Syria 10 6 2016 10 6 2016 2016 9 30012 10 2015 24 5 2016 © The Author(s) 2016\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nLocal anesthesia could result in lethal complications if injected in highly vascularized area. Dentist should take care to avoid such complications.\n\nCase presentation\nWe present a case of 15 year old girl with a coma following convulsive status epilepticus which developed after inferior alveolar nerve blockade by a dentist. The patient was admitted to the intensive care unit ICU and recovered within several days.\n\nConclusion\nThis case is reported to tell both of dentists and medical staff that although it is uncommon, such complications of local anesthesia should be in mind to be avoided and managed promptly if happened.\n\nKeywords\nStatus epilepticusLocal anesthesiaHealthy adultissue-copyright-statement© The Author(s) 2016\n==== Body\nBackground\nSystemic toxicity of local anesthesia can occur after administration of an excessive dose, with rapid absorption, or occur because of accidental intravascular injection [1, 2].\n\nOf these, intravascular injection is probably now the most common cause of systemic toxicity and the only one that cannot always be prevented by proper dosage selection and administration technique [3].\n\nSystemic toxicity of local anesthetics is typically manifested as central nervous system (CNS) toxicity (tinnitus, disorientation, and ultimately, seizures) or cardiovascular toxicity (hypotension, dysrhythmias, and cardiac arrest).\n\nTrue overdosage is quite rare in dentistry, except in small children, because of the low doses employed. Nevertheless, case reports have documented unexpected convulsions and death in healthy adult patients receiving routine intraoral injections [4].\n\nDeToledo reported a case of lidocaine-induced seizures in patients with history of epilepsy [5]. Brown DL1 reported several cases for seizures and cardiovascular changes resulting from local anesthetic in patients undergoing brachial plexus, epidural, and caudal regional anesthetics [6].\n\nMenif reported three cases of lidocaine toxicity in infants secondary to local anesthesia administered in the community for elective circumcision [7].\n\nThis case, however, describes a status epilepticus in a previously healthy young female after a probable intra-arterial injection of lidocaine and adrenaline for local intraoral anesthesia.\n\nCase presentation\nA 15 year old girl presented to the ER with coma following several tonic–clonic convulsions.\n\nThe patient was previously healthy with no personal or familial medical history. During her visit to a dentist for endodontic treatment, the dentist injected 1.5 ml of 2 % lidocaine (the total dose was 30 mg) and epinephrine 1:100,000 for local anesthesia. The solution was injected on the left side by an expert hand without prior aspiration.\n\nThe injection lasted about 2 min. By the end of the injection, the girl collapsed and several intermittent tonic–clonic convulsions ensued. These lasted about 30 min and were followed by deep coma.\n\nOn examination\nGlasgow coma scale (GCS) was three, brainstem reflexes were intact, and no fever was noticed. Vital signs were within normal limits.\n\nHer left cheek and gingiva were edematous and a giant gingival hematoma was noticed.\n\nOptic disc examination showed no edema.\n\nElectrocardiogram (ECG) was normal except for sinus tachycardia (120 beat per minute).\n\nElectroencephalography (EEG) showed diffuse slow activity, predominately theta rhythms, with no signs of continuous status epilepticus.\n\nBrain computed tomography (CT) revealed reduced white–gray matter differentiation with effacement of cerebral sulci which was compatible with cerebral edema.\n\nBrain magnetic resonance imaging with venogram (Fig. 1) and angiogram (Fig. 2) MRI + MRV + MRA showed cerebral edema, bilateral and almost symmetric hyperintense T2 lesions with restricted diffusion in both frontal and occipital lobes (Fig. 3), and no underlying cerebral venous thrombosis CVT.Fig. 1 Magnetic resonance venogram demonstrates patent cerebral venous sinuses\n\n\n\nLumbar puncture was performed and revealed the following results: 10 lymphocytes, elevated protein (50 mg/dl), no RBCs, and negative gram stain. Whereas blood glucose was 50 mg/dl, CSF glucose was 70.\n\nOrdinary labs including Calcium, Albumin, MG, Na, K, creatinine, urea, LFTs, CBC, Plt, PT, PTT, and INR were all normal and troponin was negative.\n\nThe patient was admitted to the ICU and intubated.\n\nPhenytoin at dose 15 mg/kg was loaded with close cardiac monitoring, and a maintenance dose of 100 mg twice daily was initiated in the second day.\n\nA bolus (1 g/kg) of Mannitol was given intravenously, followed by a maintenance dose of 0.5 g/kg/8 h. GCS, consequently, improved to nine in 2 days.\n\nThe patient recovered completely and was discharged after a week of admission.\n\nDiscussion\nLidocaine causes reversible blockade of impulse propagation along nerve fibers by preventing the inward movement (Fig. 2) of sodium ions through the nerve membrane. Local anesthetics of the amide type are thought to act at sodium channels of the nerve membrane. The addition of adrenaline (a vasopressor that works by stimulating both α- and β-adrenergic receptors) decreases the rate of absorption of lidocaine from the site of injection, increasing the duration of effect.Fig. 2 Magnetic resonance angiogram (MRA) shows normal cerebral arteries\n\n\n\nIt has been proven that lidocaine has a dose dependent vascular effect. While low doses of lidocaine may cause vasoconstriction, moderate or high doses cause vasodilation and decreased SVR.\n\nLocal anesthetic medicines may have similar effects on excitable membranes in the brain and myocardium. However, central nervous system toxicity usually precedes the cardiovascular effects since it occurs at lower plasma concentrations.\n\nThe earliest signs of systemic toxicity are usually caused by blockade of inhibitory pathways in the cerebral cortex [8]. This allows for disinhibition of facilitator neurons resulting in excitatory cell overactivity and unopposed (generally enhanced) excitatory nerve activity, as a result, initial subjective symptoms of CNS toxicity include signs of excitation (Fig. 3) such as lightheadedness and dizziness, difficulty focusing, tinnitus, confusion, and circumoral numbness [9, 10]. Likewise, the objective signs of local anesthetic CNS toxicity are excitatory, for example, shivering, myoclonus, tremors, and sudden muscular contractions [11]. As the local anesthetic level rises, tonic–clonic convulsions occur. Symptoms of CNS excitations typically are followed by signs of CNS depression. Seizures activity ceases rapidly and ultimately is succeeded by respiratory depression and respiratory arrest.Fig. 3 Axial diffusion weighted and ADC magnetic resonance imaging of the brain demonstrates bilateral cortical diffusion restriction in frontal, parietal and occipital lobes\n\n\n\nSystemic toxicity could be precipitated not only by over dose or elevated injection rate, but also by accidentally injecting the local anesthetic into a highly vascularized area (intra arterial or intravenous accidental injection), which may have caused the toxicity in our patient as the gingival hematoma indicated.\n\nThe blood supply to the head and face comes partly via the external carotid artery, which branches off to form the internal maxillary artery. There are many proposals which advocate that accidentally injected local anesthetics into a branch of the external carotid artery may result in serious adverse effects by flowing in retrograde fashion down to the internal carotid artery and then directly to the brain.\n\nAldrete and Narang proposed that anesthetic solution injected accidentally into a branch of the external carotid artery could flow in a retrograde fashion so as to enter the internal carotid artery and gain direct access to the brain without having to pass first through the systemic circulation [12].\n\nAldrete and co-workers marshaled considerable evidence to support their “reverse carotid flow” theory. They found, for example, high concentrations of lidocaine in the internal carotid artery immediately after injecting the drug into the facial artery of dogs [13].\n\nSeveral case reports have described such anesthetic toxicity in infants, experimental animals, and even in human adults after local anesthesia of brachial plexus, unintended intracarotid lidocaine injection during carotid endarterectomy surgery as well as after either epidural or caudal anesthetic injection. However, this is the first reported case of a status epilepticus developing after a dental procedure in a previously healthy patient.\n\nSeveral differential diagnoses were plausible in this case. When in fact the paradox of CSF/serum glucose was explained by the effect of adrenaline, other CSF findings were compatible with either aseptic meningitis or encephalitis. Nonetheless, the absence of fever, the extremely acute presentation of seizures, the incompatibility of MRI findings, and the rapid spontaneous recovery made both of these differential diagnoses improbable. Thus, no further investigations like PCR were conducted.\n\nAnother important differential diagnosis was air embolism. However, there were many issues which argue against this diagnosis:The injected size of anesthetic solution was 1.5 ml, as a result, bubbles with a significant size were not bound to exist.\n\nIf the solution had been injected intra arterially, repetitive seizures rather than a single seizure during the following half an hour would have been unlikely due to the little size and short lasted injection.\n\nIf the solution had been injected intra venously, it would have been improbable that bubbles have overwhelmed the air-filtering capacity of the pulmonary vessels (>0.30 ml/kg/min) [14].\n\n\n\nThough titration of serum level of lidocaine could have been beneficial, the small total injected dose −20 mg was too small to cause systemic toxicity in a previously healthy adult.\n\nNo follow up MRI was requested. However, a follow up brain CT scan was performed a week later and was completely normal. Consequently, MRI changes were probably transient changes due to the status epilepticus rather than stroke. Lidocaine induced vasoconstriction following distribution through systemic circulation was another possible mechanism of bilaterally restricted diffusion.\n\nIn this case, phenytoin was used safely to control seizures in spite of its potential for synergistic effect with lidocaine toward cardiac toxicity. Thus, phenytoin may be optimally avoided in such circumstances. Diazepam, however, represents the first line treatment while Phenobarbital comes second [15].\n\nConclusion\nIt is vital for dentists to avoid injection of local anesthetics by aspirating before the injection and noting anatomical structures. They are also supposed to deeply understand the possible mechanisms of systemic toxicity. Dental professionals should recognize early signs of CNS toxicity of local anesthetics, including seizures and be prepared to manage them to optimize the patient outcome. Therefore, they should be well trained to do CPR, and it is recommended that suitable resuscitation equipment is available in dentistry clinics.\n\nWe have adhered to the CARE guidelines for completeness, transparency and data analysis in case reports.\n\nAbbreviations\nCNScentral nervous system\n\nICUintensive care unit\n\nGCSglasgow coma scale\n\nECGelectrocardiography\n\nEEGelectroencephalography\n\nCTcomputed tomography\n\nMRImagnetic resonance imaging\n\nMRVmagnetic resonance venography\n\nCVTcerebral venous thrombosis\n\nCSFcerebrospinal fluid\n\nMGmagnesium\n\nNasodium\n\nKpotassium\n\nLFTsliver function tests\n\nCBCcomplete blood count\n\nPltplatelets\n\nPTprothrombin time\n\nPTTpartial thromboplastin time\n\nINRinternational normalized ratio\n\nAuthors’ contributions\nRAA and MSG: Substantial contributions to the conception of the manuscript. MTF and YAA: revised the manuscript critically for important intellectual content. All authors read and approved the final manuscript.\n\nAcknowledgements\nNone.\n\nThis article is a case report that describes a status epilepticus after administration of local anesthetic for dental procedure in a healthy adult.\n\nAvailability of data and materials\nAll available data are included within the manuscript.\n\nCompeting interest\nThe authors declare that they have no competing interests.\n\nConsent to publish\nWritten informed consent was obtained from the patient for publication of this case report and any accompanying images.\n==== Refs\nReferences\n1. Weinberg GL Current concept in resuscitation of patients with local anesthesic cardiac toxicity Reg Anesth Pain Med 2002 27 568 575 \n2. Long WB Rosenblum S Grady IP Successful rescuscitation of bupivacaine induced cardiac arrest using cardiopulmonary bypass Amesth Analg. 1989 69 403 406 \n3. Moore DC Bridenbaugh LD Thompson GE Balfour RI Horton WG Bupivacaine: a review of 11,080 cases Anesth Analg 1978 57 42 53 10.1213/00000539-197801000-00009 564643 \n4. Tomlin PJ Death in outpatient dental anaesthetic practice Anaesthesia 1974 29 551 570 10.1111/j.1365-2044.1974.tb00718.x 4433014 \n5. DeToledo JC Minagar A Lowe MR Lidocaine-induced seizures in patients with history of epilepsy Anesthesiology. 2002 97 3 737 739 10.1097/00000542-200209000-00031 12218544 \n6. Brown DL Ransom DM Hall JA Leicht CH Schroeder DR Offord KP Regional anesthesia and local anesthetic-induced systemic toxicity Anesth Analg. 1995 81 2 321 328 7618723 \n7. Menif K Khaldi A Bouziri A Hamdi A Belhadj S Ben Jaballah N Lidocaine toxicity secondary to local anesthesia administered in the community for elective circumcision Fetal Pediatr Pathol. 2011 30 6 359 362 10.3109/15513815.2011.555813 22059457 \n8. Scott DB Toxic effects of local anesthetic agents on the central nervous system Br J Anaesth. 1986 48 732 735 10.1093/bja/58.7.732 3730224 \n9. Scott BD Evaluation of the toxicity of local anesthetic agents in man Br J Anesth. 1975 47 56 61 10.1093/bja/47.1.56 \n10. Mather LE Tucker GT Murphy TM Stanton Hicks MD Bonica JJ Cardiovascular and subjective central nervous system effects of long acting local anaesthetics in man Anaesth Intensive Care 1979 7 215 221 \n11. Scott DB Evaluation of clinical tolerance of local anaesthetic agents Br J Anaesth 1979 7 215 221 \n12. Aldrete JA Narang R Deaths due to local analgesia in dentistry Anaesthesia 1975 30 685 686 10.1111/j.1365-2044.1975.tb00932.x 1190406 \n13. Aldrete JA Nicholson J Sada T Davidson W Garrastasu G Cephalic kinetics of intra-arterially injected lidocaine Oral Surg 1977 44 167 172 10.1016/0030-4220(77)90263-8 268567 \n14. Van Hulst RA Klein J Lachmann B Gas embolism: pathophysiology and treatment Clin Physiol Funct Imaging 2003 23 5 237 246 10.1046/j.1475-097X.2003.00505.x 12950319 \n15. Drug toxcicity and metabolism in pediatrics. P88. 18, 19.\n\n",
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"keywords": "Healthy adult; Local anesthesia; Status epilepticus",
"medline_ta": "BMC Res Notes",
"mesh_terms": "D000293:Adolescent; D000772:Anesthesia, Local; D000779:Anesthetics, Local; D003128:Coma; D005260:Female; D006801:Humans; D007362:Intensive Care Units; D007902:Length of Stay; D008012:Lidocaine; D013226:Status Epilepticus",
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"pubdate": "2016-06-10",
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"title": "Status epilepticus following local anesthesia in a previously healthy adult.",
"title_normalized": "status epilepticus following local anesthesia in a previously healthy adult"
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"abstract": "BACKGROUND\nMetastatic spread to the pancreas is a rare event. Renal cell carcinoma represents one possible site of origin of pancreatic metastases. Renal cell carcinoma often metastasizes late and exclusively to the pancreas, suggesting a special role of renal cell carcinoma among primaries metastasizing to the pancreas. Even rarer, renal cell carcinoma may occur simultaneously with pancreatic ductal adenocarcinoma.\n\n\nMETHODS\nWe present the case of a 78-year-old male Caucasian patient with a history of clear-cell renal cell carcinoma treated with oncological left nephrectomy 20 years before. The patient was diagnosed with pancreatic ductal adenocarcinoma by fine-needle aspiration cytology. At our institution, he received neoadjuvant therapy with folic acid, fluorouracil, irinotecan, oxaliplatin for borderline-resectable pancreatic ductal adenocarcinoma, and subsequently underwent total pancreatectomy. Upon resection, pancreatic ductal adenocarcinoma as well as two metachronous metastases of clear-cell renal cell carcinoma occurring simultaneously and cospatially with pancreatic ductal adenocarcinoma were diagnosed in the pancreatic body.\n\n\nCONCLUSIONS\nRenal cell carcinoma metastases of the pancreas are rare and often occur decades after the initial diagnosis of renal cell carcinoma. The combination of renal cell carcinoma metastases and pancreatic ductal adenocarcinoma is even rarer. However, the possibility should be considered by clinicians, radiologists, and pathologists. The special role of renal cell carcinoma as a site of origin of pancreatic metastasis should be further elucidated.",
"affiliations": "Institute of Pathology, Heinrich Heine University and University Hospital Duesseldorf, Moorenstr. 5, 40225, Duesseldorf, Germany.;Institute of Pathology, Heinrich Heine University and University Hospital Duesseldorf, Moorenstr. 5, 40225, Duesseldorf, Germany.;Department of Diagnostic and Interventional Radiology, Heinrich Heine University and University Hospital Duesseldorf, Duesseldorf, Germany.;Department of General, Visceral and Pediatric Surgery, Heinrich Heine University and University Hospital Duesseldorf, Duesseldorf, Germany.;Department of Diagnostic and Interventional Radiology, Heinrich Heine University and University Hospital Duesseldorf, Duesseldorf, Germany.;Department of General, Visceral and Pediatric Surgery, Heinrich Heine University and University Hospital Duesseldorf, Duesseldorf, Germany.;Institute of Pathology, Heinrich Heine University and University Hospital Duesseldorf, Moorenstr. 5, 40225, Duesseldorf, Germany. irene.esposito@med.uni-duesseldorf.de.",
"authors": "Haeberle|Lena|L|;Busch|Melanie|M|;Kirchner|Julian|J|;Fluegen|Georg|G|;Antoch|Gerald|G|;Knoefel|Wolfram Trudo|WT|;Esposito|Irene|I|",
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"fulltext": "\n==== Front\nJ Med Case Rep\nJ Med Case Rep\nJournal of Medical Case Reports\n1752-1947\nBioMed Central London\n\n2768\n10.1186/s13256-021-02768-8\nCase Report\nPancreatic ductal adenocarcinoma concomitant with pancreatic metastases of clear-cell renal cell carcinoma: a case report\nHaeberle Lena 1\nBusch Melanie 1\nKirchner Julian 2\nFluegen Georg 3\nAntoch Gerald 2\nKnoefel Wolfram Trudo 3\nEsposito Irene irene.esposito@med.uni-duesseldorf.de\n\n1\n1 grid.411327.2 0000 0001 2176 9917 Institute of Pathology, Heinrich Heine University and University Hospital Duesseldorf, Moorenstr. 5, 40225 Duesseldorf, Germany\n2 grid.411327.2 0000 0001 2176 9917 Department of Diagnostic and Interventional Radiology, Heinrich Heine University and University Hospital Duesseldorf, Duesseldorf, Germany\n3 grid.411327.2 0000 0001 2176 9917 Department of General, Visceral and Pediatric Surgery, Heinrich Heine University and University Hospital Duesseldorf, Duesseldorf, Germany\n31 5 2021\n31 5 2021\n2021\n15 3145 1 2021\n1 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/. 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\nMetastatic spread to the pancreas is a rare event. Renal cell carcinoma represents one possible site of origin of pancreatic metastases. Renal cell carcinoma often metastasizes late and exclusively to the pancreas, suggesting a special role of renal cell carcinoma among primaries metastasizing to the pancreas. Even rarer, renal cell carcinoma may occur simultaneously with pancreatic ductal adenocarcinoma.\n\nCase presentation\n\nWe present the case of a 78-year-old male Caucasian patient with a history of clear-cell renal cell carcinoma treated with oncological left nephrectomy 20 years before. The patient was diagnosed with pancreatic ductal adenocarcinoma by fine-needle aspiration cytology. At our institution, he received neoadjuvant therapy with folic acid, fluorouracil, irinotecan, oxaliplatin for borderline-resectable pancreatic ductal adenocarcinoma, and subsequently underwent total pancreatectomy. Upon resection, pancreatic ductal adenocarcinoma as well as two metachronous metastases of clear-cell renal cell carcinoma occurring simultaneously and cospatially with pancreatic ductal adenocarcinoma were diagnosed in the pancreatic body.\n\nConclusions\n\nRenal cell carcinoma metastases of the pancreas are rare and often occur decades after the initial diagnosis of renal cell carcinoma. The combination of renal cell carcinoma metastases and pancreatic ductal adenocarcinoma is even rarer. However, the possibility should be considered by clinicians, radiologists, and pathologists. The special role of renal cell carcinoma as a site of origin of pancreatic metastasis should be further elucidated.\n\nKeywords\n\nPancreatic cancer\nClear-cell renal cell carcinoma\nPancreatic metastases\nSynchronous\nMetachronous\nCase report\nUniversitätsklinikum Düsseldorf. Anstalt öffentlichen Rechts (8911)Open Access funding enabled and organized by Projekt DEAL.\n\nissue-copyright-statement© The Author(s) 2021\n==== Body\nBackground\n\nPancreatic ductal adenocarcinoma (PDAC) is the most frequent form of pancreatic neoplasm, accounting for approximately 85% of pancreatic tumors, and is most commonly localized in the pancreatic head [1]. Neoadjuvant therapy is emerging in PDAC treatment, especially in the context of borderline-resectable PDAC [2].\n\nPancreatic metastases are generally uncommon, with the most frequent sites of origin being lung cancer and gastrointestinal (GI) cancers [3]. More rarely, renal cell carcinoma (RCC) can spread to the pancreas, accounting for approximately 5% of all pancreatic metastases [3].\n\nHere, we report the rare case of concomitant neoadjuvant-treated PDAC and two clear-cell RCC (ccRCC) metastases in the pancreas of a 78-year-old male patient and present a brief review of literature.\n\nCase presentation\n\nA 78-year-old male Caucasian patient presented at our hospital with PDAC of the pancreatic body that had been diagnosed cytologically at a different institution. Due to newly occurring jaundice, he had received stenting of the distal bile duct and pancreatic fine needle aspiration (FNA) cytology. The patient had a history of oncological left nephrectomy for ccRCC 20 years prior. Relevant secondary diagnoses included permanent atrial fibrillation, hypertension, coronary artery disease, and chronic kidney failure. When the patient initially presented at our institution, he reported unintentional weight loss of 3–4 kg and a lack of appetite. Physical examination showed no remarkable findings.\n\nDuring staging, abdominal sonography, computed tomography (CT), and chest x-ray demonstrated no distant metastases of PDAC. Multiple space-occupying masses in the pancreas were found on CT scans (Fig. 1). Due to radiologically suspected infiltration of the portal vein and possible abutment of the celiac trunk, the PDAC was classified as borderline resectable.Fig. 1 Computed tomography scans of the pancreas. a Hypervascular lesion in the body/tail of the pancreas (arrow), highly suspicious for a renal cell cancer metastasis or neuroendocrine tumor. b Hypodense, more proximally located lesion in the pancreas (arrow), suspicious for adenocarcinoma\n\nThe patient received neoadjuvant chemotherapy with folic acid, fluorouracil, irinotecan, oxaliplatin (FOLFIRINOX) regimen because of good Eastern Cooperative Oncology Group (ECOG) performance status and borderline resectability of the PDAC. However, after the second FOLFIRINOX cycle, he developed a non-ST-segment elevating myocardial infarction (NSTEMI). Consequently, treating physicians decided to stop chemotherapy and proceed to surgical resection.\n\nSubsequent positron emission tomography-computed tomography (PET-CT) scans showed the already known space-occupying masses in the body and tail of the pancreas. An additional, morphologically distinct area of high metabolic activity was seen in the pancreatic head.\n\nThe patient underwent total pancreatectomy with splenectomy and segmental portal/superior mesenteric vein resection and reconstruction, hemigastrectomy, and cholecystectomy.\n\nUpon pathological examination of the resection specimen, two well-defined tumors (1.8 cm in diameter and 0.4 cm in diameter, respectively) with inhomogeneous yellow and brown cut surface were found in the pancreatic body, encompassed by another ill-defined solid white-yellowish tumor with a diameter of 2.8 cm, extending to the pancreatic tail (Fig. 2).Fig. 2 Macroscopic section of the pancreatic body. The two well-defined RCC metastases (white asterisks) as well as the ill-defined white-yellowish PDAC in between (black asterisk) can be seen. Axial slicing technique was used for grossing of the pancreatic head (not shown), while the pancreatic body and tail were sectioned parallel to the pancreatic neck margin\n\nUpon microscopic examination, tumor cell formations with different histomorphology were found in the pancreatic body/tail (Fig. 3a). The two well-defined tumors shared an identical histomorphology displaying nodular growth of uniform tumor cells with transparent cytoplasm and small nuclei (Fig. 3b). Upon immunohistochemistry, the tumor cells stained positive for vimentin and Pax-8 (Fig. 3c, d), whereas they were negative for CK7 and Ca19-9, and were therefore diagnosed as ccRCC metastases. The larger, ill-defined tumor extending to the pancreatic tail showed a more heterogeneous histomorphology. While some areas displayed small- to medium-sized irregular tubular glands embedded in a desmoplastic stroma, other areas showed a cribriform to solid growth pattern and consisted of tumor cells with prominent eosinophilic cytoplasm, sometimes containing cytoplasmic vacuoles and highly pleomorphic enlarged nuclei (Fig. 3e). Upon immunohistochemistry, these tumor cells expressed Ca19-9 and CK7 (Fig. 3f, g), while staining negative for vimentin and Pax-8, thereby representing PDAC. Adenosquamous differentiation was excluded by p40 immunohistochemistry (not shown). Hypereosinophilic cytoplasm and cytoplasmic vacuoles were interpreted as regressive cytopathic changes following preoperative chemotherapy. The tumor regression was classified as grade 3 (poor response) according to the College of American Pathologists (CAP) tumor regression grading system [4]. Moreover, numerous venous and perineural infiltrations, six regional lymph node metastases, and peritoneal carcinomatosis were found. The final TNM stage of the PDAC was ypT2 ypN2 (6/45) ypM1 (PER) L0 V1 Pn1 R1. Fig. 3 Histomorphology and immunohistochemistry of the pancreatic body/tail lesions. a Microscopic overview of ccRCC metastasis (bottom left) and PDAC (upper right) in immediate juxtaposition to one another (hematoxylin and eosin [H&E], 20×). b Higher magnification of ccRCC metastasis displaying its typical histomorphology with a solid growth of tumor cells with clear cytoplasm (H&E, 80×). c Immunohistochemistry for vimentin showing membranous positivity, confirming ccRCC metastasis (100×). d ccRCC metastasis also verified by nuclear positivity for Pax-8 in immunohistochemistry (200×). e Higher magnification of PDAC, containing irregular tubuli (bottom left), but also solid areas with vacuolized eosinophilic cytoplasm and highly pleomorphic nuclei, accounting for regressive changes after neoadjuvant therapy (upper right) (H&E, 80×). f, g PDAC tumor cell complexes showing characteristic positivity for Ca19-9 (f) and CK7 (g) on immunohistochemistry (80×)\n\nThe patient initially recovered steadily after surgery. However, approximately 2 weeks after surgery, he suffered from pulmonary aspiration and had to receive CPR and bronchoscopic suctioning. In a subsequent abdominal CT scan, free intraabdominal gas was detected, prompting surgery including atypical partial resection of the stomach due to ischemic perforation. Although surgery was successful, the patient developed septic shock with disseminated intravascular coagulation the following day. Despite further surgery, including subtotal colectomy due to ischemia, the patient passed away one day later as a result of refractory shock and multiple organ failure.\n\nAn overview of the clinical course is given in Table 1.Table 1 Overview of the clinical course in the present case\n\nTime point\tEvent\t\nT = 0\tERCP with stenting of distal bile duct and EUS-FNA cytology of the pancreatic body due to painless jaundice (ex domo)\t\nT = 5 days\tDiagnosis of G2 PDAC of the pancreatic body in EUS-FNA cytology material (ex domo)\t\nT = 5 weeks\tBegin of FOLFIRINOX chemotherapy with neoadjuvant intent due to borderline resectability of PDAC and patient’s good general condition\t\nT = 7 weeks\tNSTEMI with subsequent coronary artery stenting and stop of FOLFIRINOX therapy\t\nT = 8 weeks\tInterdisciplinary decision for surgical therapy\t\nT = 10 weeks\tTotal pancreatectomy with splenectomy and segmental portal/superior mesenteric vein resection and reconstruction, hemigastrectomy and cholecystectomy\t\nT = 12 weeks\tWorsening postoperative condition, including ischemic perforation of the stomach, colon ischemia, refractory shock, and multiple organ failure, leading to the patient’s death\t\nERCP endoscopic retrograde cholangiopancreatography, EUS-FNA endoscopic ultrasound-guided fine-needle aspiration, FOLFIRINOX folinic acid, fluorouracil, irinotecan, oxaliplatin, NSTEMI non-ST-segment elevating myocardial infarction, PDAC pancreatic ductal adenocarcinoma\n\nDiscussion\n\nMetastases to the pancreas are rare and are often not clinically apparent. In a study considering surgical specimens and autopsy data, most resected pancreatic tumors were primary pancreatic tumors (such as PDAC), while only 3.9% of pancreatic surgical specimens harbored tumors of extrapancreatic origin, involving the pancreas secondarily [3]. However, 43% of the pancreatic tumors found in autopsy cases were found to be secondary tumors, suggesting that secondary tumors in the pancreas are often clinically inapparent [3]. While in the autopsy series, lung cancer (42%) and GI cancers (25%) were the most frequent sites of origin for metastases in the pancreas, the surgical series contained mainly lymphomas (29%) and carcinomas of the stomach (18%) and kidney (16%) as sites of origin of pancreatic metastases [3]. A systematic literature review found that, among patients who received pancreatectomy for metastases, RCC metastases were the most frequent (63%) [5].\n\nThe median interval between primary RCC and metastasis to the pancreas is approximately 7 years, and pancreatic metastasis has been shown to occur as late as 20 years after the primary diagnosis of RCC [6]. The fact that pancreatic metastases of RCC often occur late, taken together with the fact that the pancreas is frequently the only organ to be affected by metachronous RCC metastases, has prompted authors to suggest a “seed and soil” theory in the context of RCC metastases to the pancreas. Accordingly, disseminated tumor cells spread through the vascular system and may only develop into metastases at locations where specific interactions between tumor cells and host tissue allow for maturation to metastases, for example, facilitated by the formation of a premetastatic niche, specific chemokine interactions between tumor cells and host tissue, and tumor-cell-favoring immunoediting in/of the host tissue [7]. However, the exact reasons for the “pancreatotropism” of RCC cells remains unknown. Patients resected for pancreas metastases from RCC seem to have a significantly more favorable prognosis compared with patients resected for pancreas metastases of other origin [5]. This is in line with findings indicating that ccRCC with pancreatic metastasis is characterized by high vascularization, homogeneous growth pattern, and low-grade nuclei in histopathology as well as a less aggressive molecular profile compared with ccRCC with nonpancreatic metastases [8]. This suggests that ccRCC with (exclusive) metastases to the pancreas represent a specific rather indolent subset of ccRCC. The above-described histomorphological aspects can also be found in the present case (Fig. 3).\n\nIn the present case, late metachronous RCC metastasis were found concomitant with PDAC. Patients with RCC generally seem to have a significantly higher risk of developing various other primary malignancies [9]. As chemotherapy and/or radiation are usually not part of the initial therapy of RCC, it can be hypothesized that these additional primary malignancies in RCC patients are not therapy induced, but rather linked to exogenous and/or genetic factors. For example, tobacco smoking is a risk factor shared by various cancers, including RCC and PDAC. Pathogenic variants of VHL (Von Hippel–Lindau tumor suppressor) are a major genetic parameter linked to ccRCC. Patients with VHL disease harbor an increased risk of developing ccRCC, among other tumors [10]. In addition, 46–82% of sporadic ccRCC contain pathogenic mutations of VHL [10]. Patients with VHL disease are also prone to develop serous cystic neoplasms (SCN) of the pancreas and pancreatic neuroendocrine neoplasms (pNEN); however, neither VHL disease and nor sporadic VHL variants are linked to PDAC [11].\n\nCases of synchronous or metachronous RCC and PDAC in the pancreas have rarely been reported in the literature. In 2012, a retrospective study of 1178 patients with pancreatic cancer found 16 cases of PDAC or intraductal papillary mucinous neoplasm (IPMN) in the pancreas with synchronous or metachronous RCC. Among 12 PDAC patients, 9 patients with metachronous RCC, but only 3 patients with synchronous RCC, were identified [12]. In Table 2, an overview is given of the available cases in the English-speaking literature, with detailed information on simultaneously occurring PDAC and RCC.Table 2 Overview of literature on simultaneously occurring pancreatic ductal adenocarcinoma (PDAC) and renal cell carcinoma (RCC)\n\nAge\tSex\tSubtype and localization of RCC\tProcedure for RCC\tLocalization of PDAC\tProcedure for PDAC\tFollow-up\tSource\t\n78\tM\tccRCC, two pancreas body metastases\tTotal pancreatectomy\tPancreatic body/tail\tTotal pancreatectomy\tPerioperative death*\tPresent case\t\n70\tM\tccRCC, kidney (exact site unknown)\tPartial nephrectomy\tProximal pancreas\tppWhipple\t35 months, alive\t[12]\t\n70\tM\tccRCC, kidney (exact site unknown)\tPartial nephrectomy\tProximal pancreas\tppWhipple\t5.25 months, dead\t[12]\t\n71\tM\tPapillary RCC, kidney (exact site unknown)\tPartial nephrectomy\tProximal pancreas\tppWhipple\t3.25 months, dead\t[12]\t\n67\tM\tccRCC, left kidney\tLeft nephrectomy\tPancreas head\tppWhipple\t15 months, dead\t[13]\t\n62\tM\tPapillary RCC, right kidney\tRadical right nephrectomy\tPancreas body\tUnknown; not resected\tUnknown\t[14]\t\n70\tF\tccRCC, right kidney\tChemotherapy\tPancreas body\tChemotherapy\t13 months, dead\t[15]\t\nPDAC pancreatic ductal adenocarcinoma, (cc)RCC (clear-cell) renal cell carcinoma, F female, M male, pp pylorus-preserving\n\n*Death 15 days after surgery\n\nThe strength of our case report resides in the detailed radiological and pathological evaluation of the simultaneously and cospatially occurring PDAC and pancreatic ccRCC metastases. However, its limitation is the short follow-up period due to the patient’s postoperative death. Of course, reasons for and against surgery must be carefully weighed in a case with extensive involvement of the pancreas by multiple masses in a patient with relevant comorbidities and reduced general health condition. Decision for surgery was made in the present case in an interdisciplinary tumor board despite the patient’s advanced age and recent myocardial infarction during FOLFIRINOX therapy, as PDAC was classified as borderline resectable, he was in stable general condition, and he expressed an explicit wish to undergo surgery.\n\nIn the present case, the primary RCC occurred antecedent to the primary PDAC; however, RCC metastases and PDAC occurred simultaneously and in the same location. It is speculative whether in this case the presence of PDAC might have played a role in the development of pancreatic RCC metastasis, for example, by creating a favorable local immune environment, or vice versa.\n\nGenerally, the case presented here illustrates that, although preoperative diagnostic tools have reached a high standard of quality, the validity of a preoperative diagnosis can still be limited, underlining the importance of pathological examination in the diagnostic process.\n\nConclusions\n\nAlthough RCC metastases in the pancreas are rare, and their combination with PDAC even more so, clinicians, radiologists, and pathologists should be aware of this possibility. Interpretation of imaging in such cases may be highly challenging, especially after preoperative treatment. Hence, close interdisciplinary collaboration is essential in the diagnostic process.\n\nAbbreviations\n\nCa 19-9 Carbohydrate antigen 19-9\n\n(cc)RCC (Clear-cell) renal cell carcinoma\n\nCK7 Cytokeratin 7\n\nCPR Cardiopulmonary resuscitation\n\n(PET-)CT (Positron emission tomography-)computed tomography\n\nECOG Eastern Cooperative Oncology Group\n\nERCP Endoscopic retrograde cholangiopancreatography\n\n(EUS-)FNA (Endoscopic ultrasound-guided) fine-needle aspiration\n\nFOLFIRINOX Folic acid, fluorouracil, irinotecan, oxaliplatin\n\nGI Gastrointestinal\n\nIPMN Intraductal papillary-mucinous neoplasm\n\nNSTEMI Non-ST-segment elevating myocardial infarction\n\nPax-8 Paired box protein 8\n\npNEN Pancreatic neuroendocrine neoplasm\n\nPDAC Pancreatic ductal adenocarcinoma\n\nSCN Serous cystic neoplasm\n\nVHL Von Hippel–Lindau\n\nAcknowledgements\n\nNot applicable.\n\nAuthors’ contributions\n\nLH: acquisition and interpretation of pathological patient data, drafting, critical revision, and approval of the manuscript; MB: general data collection, drafting, critical revision, and approval of the manuscript; JK: acquisition and interpretation of radiological patient data, critical revision, and approval of the manuscript; GF: acquisition and interpretation of clinical/surgical patient data, critical revision, and approval of the manuscript; GA: acquisition and interpretation of radiological patient data, critical revision, and approval of the manuscript; WTK: acquisition and interpretation of clinical/surgical patient data, critical revision, and approval of the manuscript; IE: acquisition and interpretation of pathological patient data, drafting, critical revision, and approval of the manuscript. All authors read and approved the final manuscript.\n\nFunding\n\nOpen Access funding enabled and organized by Projekt DEAL.\n\nAvailability of data and materials\n\nAll data generated or analyzed during this study are included in this published article.\n\nDeclarations\n\nEthics approval and consent to participate\n\nThe patient received standard-of-care diagnostics and therapy. No experimental treatment was applied.\n\nConsent for publication\n\nWritten informed consent was obtained from the next of kin of the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nCompeting interests\n\nThe authors declare no competing interests.\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Hruban RH, Pitman MB, Klimstra DS. Tumors of the pancreas: In: AFIP Atlas of Tumor Pathology, series 4, fascicle 6. Washington, DC; 2007.\n2. Verbeke CS Haeberle L Lenggenhager D Esposito I Pathology assessment of pancreatic cancer following neoadjuvant treatment: time to move on Pancreatology 2018 18 467 476 10.1016/j.pan.2018.04.010 29843972\n3. Adsay NV Andrea A Basturk O Kilinc N Nassar H Cheng JD Secondary tumors of the pancreas: an analysis of a surgical and autopsy database and review of the literature Virchows Arch 2004 444 527 535 10.1007/s00428-004-0987-3 15057558\n4. Kakar S, Shi C, Adsay NV, Fitzgibbons P, Frankel WL, Klimstra DS, et al. Protocol for the examination of specimens from patients with carcinoma of the pancreas version 4.0.0.1. College of American Pathologists. 2017. https://documents.cap.org/protocols/cp-pancreas-exocrine-17protocol-4001.pdf. Accessed 29 Nov 2020.\n5. Adler H Redmond CE Heneghan HM Swan N Maguire D Traynor O Pancreatectomy for metastatic disease: a systematic review Eur J Surg Oncol 2014 40 379 386 10.1016/j.ejso.2013.12.022 24462547\n6. Wente MN Kleeff J Esposito I Hartel M Müller MW Fröhlich BE Renal cancer cell metastasis into the pancreas: a single-center experience and overview of the literature Pancreas 2005 30 218 222 10.1097/01.mpa.0000153337.58105.47 15782097\n7. Sellner F Observations on solitary versus multiple isolated pancreatic metastases of renal cell carcinoma: another indication of a seed and soil mechanism? Cancers (Basel) 2019 11 1379 10.3390/cancers11091379\n8. Singla N, Xie Z, Zhang Z, Gao M, Yousuf Q, Onabolu O, et al. Pancreatic tropism of metastatic renal cell carcinoma. JCI Insight. 2020;5:e134564.\n9. Beisland C Talleraas O Bakke A Norstein J Multiple primary malignancies in patients with renal cell carcinoma: a national population-based cohort study BJU Int 2006 97 698 702 10.1111/j.1464-410X.2006.06004.x 16536756\n10. Cowey CL Rathmell WK VHL gene mutations in renal cell carcinoma: role as biomarker of disease outcome and drug efficacy Curr Oncol Rep 2010 11 94 101 10.1007/s11912-009-0015-5\n11. Lonser RR Glenn GM Walther M Chew EY Libutti SK Linehan WM Von Hippel-Lindau disease Lancet 2003 361 2059 2067 10.1016/S0140-6736(03)13643-4 12814730\n12. Müller SA Pahernik S Hinz U Martin DJ Wente MN Hackert T Renal tumors and second primary pancreatic tumors: a relationship with clinical impact? Patient Saf Surg 2012 6 18 10.1186/1754-9493-6-18 22873581\n13. Alexakis N Bosonnet L Connor S Ellis I Sutton R Campbell F Double resection for patients with pancreatic cancer and a second primary renal cell cancer Dig Surg 2003 20 428 432 10.1159/000072711 12900534\n14. Ismail TO, Janane A, Hajji F, Dekkak Y, Bekkali S, Sossa J, et al. Synchronous primary tumor of kidney and pancreas: case report. Afr J Urol. 2010;16:128–31.\n15. Mahfoud T Tanz R Khmamouche MR Allaoui M Belbaraka R Khouchani M Ichou M Synchronous primary renal cell carcinoma and pancreatic ductal adenocarcinoma: case report and literature review Case Rep Oncol. 2017 10 1050 1056 10.1159/000484552 29515395\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1752-1947",
"issue": "15(1)",
"journal": "Journal of medical case reports",
"keywords": "Case report; Clear-cell renal cell carcinoma; Metachronous; Pancreatic cancer; Pancreatic metastases; Synchronous",
"medline_ta": "J Med Case Rep",
"mesh_terms": "D000230:Adenocarcinoma; D000368:Aged; D002292:Carcinoma, Renal Cell; D006801:Humans; D007680:Kidney Neoplasms; D008297:Male; D010180:Pancreatectomy; D010190:Pancreatic Neoplasms",
"nlm_unique_id": "101293382",
"other_id": null,
"pages": "314",
"pmc": null,
"pmid": "34059139",
"pubdate": "2021-05-31",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "29843972;16536756;22873581;15057558;31533220;12900534;12814730;24462547;19216840;32271170;29515395;15782097",
"title": "Pancreatic ductal adenocarcinoma concomitant with pancreatic metastases of clear-cell renal cell carcinoma: a case report.",
"title_normalized": "pancreatic ductal adenocarcinoma concomitant with pancreatic metastases of clear cell renal cell carcinoma a case report"
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"companynumb": "DE-HIKMA PHARMACEUTICALS USA INC.-DE-H14001-21-54700",
"fulfillexpeditecriteria": "1",
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"activesubstancename": "FLUOROURACIL"
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"abstract": "OBJECTIVE\nHyperkalemia is an electrolyte disorder that may occur during the first few months after a renal transplant, in patients undergoing cyclosporine immunosuppression. We present our experience with cyclosporine-associated hyperkalemia in living-donor renal transplant recipients, with isolated clinically relevant hyperkalemia soon after surgery.\n\n\nMETHODS\nWe report 4 living-donor renal recipients with hyperkalemia soon after transplant.\n\n\nRESULTS\nSevere unexpected hyperkalemia (7.5- 9.4 mmol/L) was noted in our patients 12, 20, 22, and 34 days after transplant. The C2 cyclosporine concentration was within recommended range or slightly greater than 1200 ng/mL. The hypertonic glucose/insulin treatment along with potassium diet was without results. A reduction in daily cyclosporine dosages, along with 1- to 2-week administration of fludrocortisone was effective. The patients became normokalemic taking a standard, triple-drug immunosuppression protocol, and were discharged home with normal renal function. There were no repeat episodes of hyperkalemia in any of the patients during 12 months of follow-up.\n\n\nCONCLUSIONS\nCyclosporine should be considered a cause of hyperkalemia in renal transplant recipients. Successful treatment with fludrocortisone confirms that transitional pseudohypoaldosteronism has a potential nephrotoxic effect of cyclosporine. We recommend close monitoring of the cyclosporine concentration and administering fludrocortisone when treating hyperkalemia in renal transplant recipients.",
"affiliations": "From the University Clinic of Nephrology, Medical Faculty, University \"Ss Cyril and Methodius,\" R. of Macedonia.",
"authors": "Pavleska-Kuzmanovska|Svetlana|S|;Popov|Zivko|Z|;Ivanovski|Ognen|O|;Ristovska|Vesna|V|;Masin-Spasovska|Jelka|J|;Rambabova-Busljetic|Irena|I|;Ivanovski|Ninoslav|N|",
"chemical_list": "D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D005438:Fludrocortisone",
"country": "Turkey",
"delete": false,
"doi": "10.6002/ect.2013.0159",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1304-0855",
"issue": "12(5)",
"journal": "Experimental and clinical transplantation : official journal of the Middle East Society for Organ Transplantation",
"keywords": null,
"medline_ta": "Exp Clin Transplant",
"mesh_terms": "D000328:Adult; D000368:Aged; D065095:Calcineurin Inhibitors; D016572:Cyclosporine; D016903:Drug Monitoring; D005438:Fludrocortisone; D006801:Humans; D006947:Hyperkalemia; D007166:Immunosuppressive Agents; D007674:Kidney Diseases; D016030:Kidney Transplantation; D019520:Living Donors; D008297:Male; D011237:Predictive Value of Tests; D011546:Pseudohypoaldosteronism; D012307:Risk Factors; D012720:Severity of Illness Index; D013997:Time Factors; D066027:Transplant Recipients; D016896:Treatment Outcome",
"nlm_unique_id": "101207333",
"other_id": null,
"pages": "479-83",
"pmc": null,
"pmid": "24417207",
"pubdate": "2014-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Cyclosporine nephrotoxicity and early posttransplant hyperkalemia in living-donor renal recipients: report of 4 cases.",
"title_normalized": "cyclosporine nephrotoxicity and early posttransplant hyperkalemia in living donor renal recipients report of 4 cases"
} | [
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"companynumb": "PHHY2014MK133563",
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"abstract": "Convulsive status epilepticus is the most common neurological emergency in children. Its management is important to avoid or minimise neurological morbidity and death. The current first-choice second-line drug is phenytoin (Epanutin, Pfizer Inc., New York, NY, USA), for which there is no robust scientific evidence.\n\n\n\nTo determine whether phenytoin or levetiracetam (Keppra, UCB Pharma, Brussels, Belgium) is the more clinically effective intravenous second-line treatment of paediatric convulsive status epilepticus and to help better inform its management.\n\n\n\nA multicentre parallel-group randomised open-label superiority trial with a nested mixed-method study to assess recruitment and research without prior consent.\n\n\n\nParticipants were recruited from 30 paediatric emergency departments in the UK.\n\n\n\nParticipants aged 6 months to 17 years 11 months, who were presenting with convulsive status epilepticus and were failing to respond to first-line treatment.\n\n\n\nIntravenous levetiracetam (40 mg/kg) or intravenous phenytoin (20 mg/kg).\n\n\n\nPrimary outcome - time from randomisation to cessation of all visible signs of convulsive status epilepticus. Secondary outcomes - further anticonvulsants to manage the convulsive status epilepticus after the initial agent, the need for rapid sequence induction owing to ongoing convulsive status epilepticus, admission to critical care and serious adverse reactions.\n\n\n\nBetween 17 July 2015 and 7 April 2018, 286 participants were randomised, treated and consented. A total of 152 participants were allocated to receive levetiracetam and 134 participants to receive phenytoin. Convulsive status epilepticus was terminated in 106 (70%) participants who were allocated to levetiracetam and 86 (64%) participants who were allocated to phenytoin. Median time from randomisation to convulsive status epilepticus cessation was 35 (interquartile range 20-not assessable) minutes in the levetiracetam group and 45 (interquartile range 24-not assessable) minutes in the phenytoin group (hazard ratio 1.20, 95% confidence interval 0.91 to 1.60; p = 0.2). Results were robust to prespecified sensitivity analyses, including time from treatment commencement to convulsive status epilepticus termination and competing risks. One phenytoin-treated participant experienced serious adverse reactions.\n\n\n\nFirst, this was an open-label trial. A blinded design was considered too complex, in part because of the markedly different infusion rates of the two drugs. Second, there was subjectivity in the assessment of 'cessation of all signs of continuous, rhythmic clonic activity' as the primary outcome, rather than fixed time points to assess convulsive status epilepticus termination. However, site training included simulated demonstration of seizure cessation. Third, the time point of randomisation resulted in convulsive status epilepticus termination prior to administration of trial treatment in some cases. This affected both treatment arms equally and had been prespecified at the design stage. Last, safety measures were a secondary outcome, but the trial was not powered to demonstrate difference in serious adverse reactions between treatment groups.\n\n\n\nLevetiracetam was not statistically superior to phenytoin in convulsive status epilepticus termination rate, time taken to terminate convulsive status epilepticus or frequency of serious adverse reactions. The results suggest that it may be an alternative to phenytoin in the second-line management of paediatric convulsive status epilepticus. Simple trial design, bespoke site training and effective leadership were found to facilitate practitioner commitment to the trial and its success. We provide a framework to optimise recruitment discussions in paediatric emergency medicine trials.\n\n\n\nFuture work should include a meta-analysis of published studies and the possible sequential use of levetiracetam and phenytoin or sodium valproate in the second-line treatment of paediatric convulsive status epilepticus.\n\n\n\nCurrent Controlled Trials ISRCTN22567894 and European Clinical Trials Database EudraCT number 2014-002188-13.\n\n\n\nThis project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 58. See the NIHR Journals Library website for further project information.",
"affiliations": "The Roald Dahl Neurophysiology Department, Alder Hey Children's Hospital, Liverpool, UK.;Liverpool Clinical Trials Centre, University of Liverpool, Liverpool, UK.;Liverpool Clinical Trials Centre, University of Liverpool, Liverpool, UK.;Emergency Department, Alder Hey Children's Hospital, Liverpool, UK.;Liverpool Clinical Trials Centre, University of Liverpool, Liverpool, UK.;Liverpool Clinical Trials Centre, University of Liverpool, Liverpool, UK.;Institute of Population Health, University of Liverpool, Liverpool, UK.;Institute of Population Health, University of Liverpool, Liverpool, UK.;Emergency Department, Alder Hey Children's Hospital, Liverpool, UK.;Emergency Department, Alder Hey Children's Hospital, Liverpool, UK.;Faculty of Health and Applied Sciences, University of the West of England, Bristol, UK.;Liverpool Clinical Trials Centre, University of Liverpool, Liverpool, UK.;Liverpool Clinical Trials Centre, University of Liverpool, Liverpool, UK.;The Roald Dahl Neurophysiology Department, Alder Hey Children's Hospital, Liverpool, UK.;Patient and public involvement representative, Wrexham, UK.;Faculty of Health and Applied Sciences, University of the West of England, Bristol, UK.",
"authors": "Appleton|Richard E|RE|0000-0002-0742-2113;Rainford|Naomi Ea|NE|0000-0002-5876-3946;Gamble|Carrol|C|0000-0002-3021-1955;Messahel|Shrouk|S|0000-0003-0645-3070;Humphreys|Amy|A|0000-0002-5996-2613;Hickey|Helen|H|0000-0003-0467-0362;Woolfall|Kerry|K|0000-0002-5726-5304;Roper|Louise|L|0000-0002-2918-7628;Noblet|Joanne|J|0000-0001-5232-8495;Lee|Elizabeth|E|0000-0002-2846-2448;Potter|Sarah|S|0000-0003-1463-279X;Tate|Paul|P|0000-0002-4246-1409;Al Najjar|Nadia|N|0000-0002-2851-0913;Iyer|Anand|A|0000-0002-3932-4729;Evans|Vicki|V|;Lyttle|Mark D|MD|0000-0002-8634-7210",
"chemical_list": "D000927:Anticonvulsants; D000077287:Levetiracetam; D010672:Phenytoin",
"country": "England",
"delete": false,
"doi": "10.3310/hta24580",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1366-5278",
"issue": "24(58)",
"journal": "Health technology assessment (Winchester, England)",
"keywords": "CONVULSIVE; EPILEPSY; LEVETIRACETAM; PAEDIATRIC; PHENYTOIN; RANDOMISED; SEIZURE; STATUS EPILEPTICUS; TRIA",
"medline_ta": "Health Technol Assess",
"mesh_terms": "D061605:Administration, Intravenous; D000293:Adolescent; D000927:Anticonvulsants; D002648:Child; D002675:Child, Preschool; D000074099:Equivalence Trials as Topic; D005260:Female; D006801:Humans; D007223:Infant; D000077287:Levetiracetam; D008297:Male; D010672:Phenytoin; D013226:Status Epilepticus; D006113:United Kingdom",
"nlm_unique_id": "9706284",
"other_id": null,
"pages": "1-96",
"pmc": null,
"pmid": "33190679",
"pubdate": "2020-11",
"publication_types": "D017429:Clinical Trial, Phase IV; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": "29320603;26088885;31005385;14974641;19520272;17872937;16247069;19364625;21180643;19458986;26898705;21898137;22321334;30845977;31005386;24431415;12190265;16886975;18291724;19898966;31774955;20534046;27736657;19264738;26384724;17292636;16023510;24615624;24433665;25678575;21098797;16174888;17898030;16844492;16235337;28629473;22722010;17954477;15489391;24342374;18571898;28640109;30090128;32203691;3294743;19194344;26464416;29937585;30087153;24001084;18852834;21765898;15705666;28641582;25899652;24363651;21477994;24979285;12915082;30898169;20801389;14768461;24833694",
"title": "Levetiracetam as an alternative to phenytoin for second-line emergency treatment of children with convulsive status epilepticus: the EcLiPSE RCT.",
"title_normalized": "levetiracetam as an alternative to phenytoin for second line emergency treatment of children with convulsive status epilepticus the eclipse rct"
} | [
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"companynumb": "GB-PFIZER INC-2019187609",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PHENYTOIN SODIUM"
},
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... |
{
"abstract": "BACKGROUND\nAmiodarone is a highly effective treatment for supraventricular and ventricular tachyarrhythmia; however, it could be associated with several serious adverse effects, including liver injury.\n\n\nMETHODS\nWe report the clinical and histological features of two contrasting Japanese patients with amiodarone-induced reversible and irreversible hepatotoxicity. One patient with amiodarone-induced irreversible hepatotoxicity showed liver cirrhosis during treatment with amiodarone and died of hepatic failure; the other patient, who had reversible hepatotoxicity, showed a reversible course of liver function and imaging after discontinuation of amiodarone.\n\n\nCONCLUSIONS\nWe emphasize the importance of close monitoring of liver enzymes and evaluation of liver computed tomographic imaging as well as liver biopsy during treatment with amiodarone, and discontinuation should be considered when amiodarone-induced hepatotoxicity is suspected.",
"affiliations": "Division of Cardiovascular and Internal Medicine, Kanazawa University Graduate School of Medical Sciences, 13-1 Takara-machi, Kanazawa, 920-8640, Japan.;Division of Cardiovascular and Internal Medicine, Kanazawa University Graduate School of Medical Sciences, 13-1 Takara-machi, Kanazawa, 920-8640, Japan. ht240z@sa3.so-net.ne.jp.;Division of Cardiovascular and Internal Medicine, Kanazawa University Graduate School of Medical Sciences, 13-1 Takara-machi, Kanazawa, 920-8640, Japan.;Division of Cardiovascular and Internal Medicine, Kanazawa University Graduate School of Medical Sciences, 13-1 Takara-machi, Kanazawa, 920-8640, Japan.;Division of Cardiovascular and Internal Medicine, Kanazawa University Graduate School of Medical Sciences, 13-1 Takara-machi, Kanazawa, 920-8640, Japan.;Division of Cardiovascular and Internal Medicine, Kanazawa University Graduate School of Medical Sciences, 13-1 Takara-machi, Kanazawa, 920-8640, Japan.;Division of Cardiovascular and Internal Medicine, Kanazawa University Graduate School of Medical Sciences, 13-1 Takara-machi, Kanazawa, 920-8640, Japan.;Division of Cardiovascular and Internal Medicine, Kanazawa University Graduate School of Medical Sciences, 13-1 Takara-machi, Kanazawa, 920-8640, Japan.;Division of Cardiovascular and Internal Medicine, Kanazawa University Graduate School of Medical Sciences, 13-1 Takara-machi, Kanazawa, 920-8640, Japan.;Department of Molecular and Cellular Pathology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan.;Department of Human Pathology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan.;Department of Pathology and Laboratory Medicine, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan.;Division of Cardiovascular and Internal Medicine, Kanazawa University Graduate School of Medical Sciences, 13-1 Takara-machi, Kanazawa, 920-8640, Japan.",
"authors": "Tsuda|Toyonobu|T|;Tada|Hayato|H|;Tanaka|Yoshihiro|Y|;Nishida|Naoto|N|;Yoshida|Taiji|T|;Sawada|Takeshi|T|;Sakata|Kenji|K|;Hayashi|Kenshi|K|;Kawashiri|Masa-Aki|MA|;Oyama|Takeru|T|;Sasaki|Motoko|M|;Kurose|Nozomu|N|;Yamagishi|Masakazu|M|",
"chemical_list": "D000889:Anti-Arrhythmia Agents; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D000638:Amiodarone",
"country": "England",
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"doi": "10.1186/s13256-018-1629-8",
"fulltext": "\n==== Front\nJ Med Case RepJ Med Case RepJournal of Medical Case Reports1752-1947BioMed Central London 162910.1186/s13256-018-1629-8Case ReportAmiodarone-induced reversible and irreversible hepatotoxicity: two case reports Tsuda Toyonobu ttsuda0329@yahoo.co.jp 1Tada Hayato +81-76-265-2251ht240z@sa3.so-net.ne.jp 1Tanaka Yoshihiro littlechild0626@gmail.com 1Nishida Naoto abcing4410@gmail.com 1Yoshida Taiji tjyd27@gmail.com 1Sawada Takeshi sawada1046@gmail.com 1Sakata Kenji kenjis@yu.incl.ne.jp 1Hayashi Kenshi kenshi@med.kanazawa-u.ac.jp 1Kawashiri Masa-aki mk@med.kanazawa-u.ac.jp 1Oyama Takeru takeruoyama@staff.kanazawa-u.ac.jp 2Sasaki Motoko m8sasaki@med.kanazawa-u.ac.jp 3Kurose Nozomu k-nozomu@kanazawa-med.ac.jp 4Yamagishi Masakazu myamagi@med.kanazawa-u.ac.jp 11 0000 0001 2308 3329grid.9707.9Division of Cardiovascular and Internal Medicine, Kanazawa University Graduate School of Medical Sciences, 13-1 Takara-machi, Kanazawa, 920-8640 Japan 2 0000 0001 2308 3329grid.9707.9Department of Molecular and Cellular Pathology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan 3 0000 0001 2308 3329grid.9707.9Department of Human Pathology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan 4 0000 0001 2308 3329grid.9707.9Department of Pathology and Laboratory Medicine, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan 14 4 2018 14 4 2018 2018 12 9526 1 2018 21 2 2018 © The Author(s). 2018Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nAmiodarone is a highly effective treatment for supraventricular and ventricular tachyarrhythmia; however, it could be associated with several serious adverse effects, including liver injury.\n\nCase presentation\nWe report the clinical and histological features of two contrasting Japanese patients with amiodarone-induced reversible and irreversible hepatotoxicity. One patient with amiodarone-induced irreversible hepatotoxicity showed liver cirrhosis during treatment with amiodarone and died of hepatic failure; the other patient, who had reversible hepatotoxicity, showed a reversible course of liver function and imaging after discontinuation of amiodarone.\n\nConclusions\nWe emphasize the importance of close monitoring of liver enzymes and evaluation of liver computed tomographic imaging as well as liver biopsy during treatment with amiodarone, and discontinuation should be considered when amiodarone-induced hepatotoxicity is suspected.\n\nKeywords\nAmiodaroneHepatotoxicityissue-copyright-statement© The Author(s) 2018\n==== Body\nBackground\nAmiodarone is a highly effective treatment for supraventricular and ventricular tachyarrhythmia; however, it could be associated with several serious adverse effects, including pulmonary toxicity [1], thyroid dysfunction [2], and liver injury [3]. Serious adverse effects sometimes result in a poor prognosis because of the very long plasma half-life of amiodarone. Amiodarone-induced hepatotoxicity can progress to cirrhosis, resulting in decompensated hepatic failure, although this rarely happens [4]. In this report, we present the clinical features of two patients with amiodarone-induced reversible and irreversible hepatotoxicity, highlighting the importance of close monitoring of liver enzymes and evaluation of liver computed tomographic (CT) images as well as liver biopsy during treatment with amiodarone.\n\nCase presentation\nPatient 1\nPatient 1 was a 62-year-old Japanese man admitted to our hospital for general malaise and systemic edema. He had been an office worker, had a history of smoking, and had no history of alcohol intake. He had no apparent family history of cardiovascular and liver diseases. He had been diagnosed with cardiac sarcoidosis complicated with ventricular tachycardia (VT) when he was 49 years old. Since then, he had been treated with corticosteroids (prednisolone 10 mg/day) and amiodarone (150 mg/day), in addition to enalapril (5 mg/day), metoprolol (20 mg/day), and lansoprazole (15 mg/day). After the initiation of amiodarone, the patient’s liver enzymes were gradually as well as intermittently exacerbated to elevated over the course of 13 years (peak aspartate aminotransferase 161 IU/L [normal range 9–32 IU/L]; peak alanine aminotransferase 106 IU/L [normal range 4–37 IU/L]); however, the treating physician decided to continue amiodarone to control the patient’s VT. During the follow-up period, the patient’s mean plasma level of amiodarone was 1.8 μg/ml and that of desethylamiodarone was 1.1 μg/ml. An abdominal plain CT scan showed diffuse high attenuation of the liver parenchyma (Fig. 1a). The patient had no history of hospitalization for heart failure after the introduction of amiodarone. However, general malaise and systemic edema occurred, and abdominal ultrasound showed liver cirrhosis, splenomegaly, and massive ascites.Fig. 1 a Computed tomographic scan shows diffuse high attenuation of the liver parenchyma (96 Hounsfield units). b Massive ascites and splenomegaly were found, in addition to diffuse high attenuation of the liver parenchyma. c Regenerative nodules and well-developed bridging fibrosis were observed (hematoxylin and eosin stain, magnification × 20), as were marked neutrophilic infiltration, a remarkable amount of Mallory bodies (arrowheads), and ballooned hepatocytes (arrow) (hematoxylin and eosin stain, magnification × 200). d Numerous whorled or lamellar inclusions in lysosomes were detected by electron microscopy\n\n\n\nAt admission, the patient’s blood pressure was 95/66 mmHg, his heart rate was 69 beats/minute, and his body temperature was 35.6 °C. His consciousness was clear, and his respiratory sounds were normal. Marked distention of the abdomen was observed, and the liver and spleen were palpable from the abdominal wall. No abnormal neurological finding was observed.\n\nA chest x-ray revealed mild cardiomegaly (cardiothoracic ratio 50%) without marked congestion and pleural effusion. Echocardiography showed mild left ventricular systolic dysfunction (ejection fraction 45%) and mild mitral and tricuspid regurgitation without a finding of pulmonary hypertension. Blood tests showed thrombocytopenia (81 × 103/μl), elevations of liver and ductal enzymes (aspartate aminotransferase 135 IU/L, alanine aminotransferase 91 IU/L, γ-glutamyl transpeptidase [γ-GTP] 202 IU/L, total bilirubin 2.4 md/dl), and hypoalbuminemia (serum albumin 3.1 g/dl). The patient’s brain natriuretic peptide level was mildly elevated (136 pg/ml), which showed no change during follow-up. Other serologic study results were negative for chronic viral hepatitis and other liver diseases. An abdominal plain CT scan showed massive ascites and splenomegaly, in addition to diffuse high attenuation of the liver parenchyma (Fig. 1b). At that time, amiodarone was discontinued because amiodarone-induced hepatotoxicity was suspected. However, the patient died of hepatic insufficiency during hospitalization. An autopsy revealed yellow liver specimens with a rough surface that suggested cirrhotic changes. Hematoxylin and eosin staining showed regenerative nodules and well-developed bridging fibrosis. Marked neutrophilic infiltrates, a remarkable amount of Mallory bodies, and hepatocellular ballooning were observed (Fig. 1c). Moreover, electron microscopic examination detected numerous whorled or lamellar bodies in the lysosomes (Fig. 1d). These findings helped diagnose amiodarone-induced hepatotoxicity associated with irreversible liver cirrhosis.\n\nPatient 2\nPatient 2 was a 74-year-old Japanese man who underwent hemodialysis for chronic renal failure and was admitted to our hospital because of asymptomatic liver enzyme elevation. He had been working for the government, had never smoked, and had no history of alcohol abuse. He had no apparent family history of cardiovascular or liver diseases. At admission, his blood pressure was 126/52 mmHg, his heart rate was 46 beats/minute, and his body temperature was 36.4 °C. Physical and neurological examinations yielded no abnormal findings. Blood tests showed anemia (hemoglobin 11.5 g/dl), elevations of liver and ductal enzymes (aspartate aminotransferase 189 IU/L, alanine aminotransferase 150 IU/L, γ-GTP 1009 IU/L), elevation of C-reactive protein (1.04 mg/dl), and renal dysfunction (creatinine 3.34 mg/dl at 1 day after his regular hemodialysis). A chest x-ray revealed no abnormal findings. Echocardiography showed mild left ventricular systolic dysfunction (ejection fraction 48%) without any apparent structural diseases.\n\nAmiodarone (200 mg/day), in addition to enalapril (5 mg/day), spironolactone (25 mg/day), bisoprolol (2.5 mg/day), and lansoprazole (15 mg/day), was introduced when the patient was age 71 because of ventricular arrhythmia, including sustained VT, although no structural heart disease was observed. After the introduction of amiodarone, no ventricular arrhythmia was documented during follow-up. However, the patient’s liver enzymes were gradually exacerbated to elevated after beginning amiodarone over 1 year (peak aspartate aminotransferase 189 IU/L, peak alanine aminotransferase 150 IU/L). He had no clinical or laboratory evidence of congestive heart failure or other liver diseases. An abdominal plain CT scan showed diffuse high attenuation of the liver parenchyma, as seen in patient 1 (Fig. 2a). To investigate the cause of liver dysfunction, a liver biopsy was performed. Histologically, the liver showed steatohepatitis with severe perivenular, pericellular, and chicken wire–like periportal fibrosis (Fig. 2b); numerous Mallory bodies; hepatocellular ballooning; and mild macrovesicular and microvesicular fatty changes (Fig. 2b). Mild lymphocytic and neutrophilic infiltration was also observed. Bridging fibrosis divided the hepatic parenchyma, but regenerative nodules were not formed. These histological findings suggested amiodarone-induced nonalcoholic steatohepatitis. We decided to discontinue amiodarone. A cardioverter defibrillator implant was performed to prevent sudden cardiac death due to ventricular arrhythmia. After discontinuation of amiodarone, the patient’s plasma concentration of amiodarone gradually decreased from 1.4 to 0.07 μg/ml during 9 months, followed by improvement in liver enzymes. Notably, the patient’s liver enzymes and fibrosis markers, such as hyaluronic acid and type IV collagen, started to improve 2 months later, after the discontinuation of amiodarone. Under these conditions, a follow-up plain CT scan showed marked improvement of the liver parenchyma density (Fig. 2c). The patient’s liver enzymes decreased to within normal range 8 months after discontinuation of amiodarone.Fig. 2 a Computed tomogram shows diffuse high attenuation of the liver parenchyma (120 Hounsfield units). b Distinct collagen deposition is seen in the periportal, perivenular, and pericellular locations, which formed bridging fibrosis (Azan stain, magnification × 100). There were numerous Mallory bodies (arrowheads) as well as hepatocellular ballooning (arrows) and mild macrovesicular and microvesicular fatty changes. Mild lymphocytic and neutrophilic infiltration was also observed (hematoxylin and eosin stain, magnification × 400). c After discontinuation of amiodarone, the patient’s liver density dramatically improved to a normal level (45 Hounsfield units) during the course of 9 months\n\n\n\nDiscussion\nIn this report, we present the clinical features of two patients with amiodarone-induced reversible and irreversible hepatotoxicity, highlighting the importance of close monitoring of liver enzymes and evaluation of liver CT imaging as well as liver biopsy during treatment with amiodarone. Approximately 25% of patients using amiodarone develop a transient asymptomatic increase in serum aminotransferase levels that resolves spontaneously or after dose reduction [4]. Amiodarone-induced symptomatic hepatitis, cirrhosis, and fatal hepatic failure are extremely rare (0–3%) [4, 5]. However, when the diagnosis is established, the mortality risk may be as high as 60% at 5 months [6]. Histological features of amiodarone-induced hepatotoxicity are similar to alcoholic hepatitis and characterized by Mallory bodies, leukocyte infiltration, steatosis, and ballooning of hepatocytes [7]. Amiodarone and its metabolites accumulate in lysosomes of hepatocytes and lead to inhibition of phospholipase A1 and A2, which inhibits removal of lysosomal lipids and leads to phospholipidosis [8]. As with our patients, this mechanism leads to steatohepatitis and finally to irreversible liver cirrhosis. The presence of lamellar lysosomal inclusion bodies visualized by electron microscopy is a typical pathological finding of amiodarone-induced hepatotoxicity [7]. In patient 1, amiodarone was continued under the conditions of elevated liver enzymes in addition to the use of corticosteroids that could cause liver injury or accelerate his underlying liver injury, and it led to irreversible fatal hepatic failure. However, in patient 2, amiodarone was discontinued immediately after the detection of liver enzyme elevation and led to improvement of liver function. According to these two clinical courses, amiodarone should be discontinued immediately if amiodarone-induced liver injury is suspected.\n\nAmiodarone is a lipophilic agent and tends to accumulate in lipid-laden organelles such as the liver. It is reported that a concentration of amiodarone and its metabolite, N-desethylamiodarone, in the liver may be as high as 500-fold of the serum level [9].\n\nPrevious reports showed that the plasma amiodarone level may be poorly correlated with its toxicity [10]. However, high liver density seen on CT scans, which is secondary to increased iodine content of amiodarone and reflects the tissue level of amiodarone, may be useful to detect the toxicity [11]. In this regard, it is important to evaluate elevations of liver enzymes, liver CT imaging (high attenuation of the liver parenchyma), and histology, and discontinuation should be considered when amiodarone-induced hepatotoxicity is suspected. Alternative strategies, such as catheter ablation and/or an implantable cardioverter defibrillator implant could be considered for such patients.\n\nConclusions\nAmiodarone-induced hepatotoxicity showed a reversible or irreversible course, depending on when or if the drug was discontinued. Close monitoring of liver enzymes and evaluation of liver CT imaging and liver biopsy results should be considered, and amiodarone should be discontinued when amiodarone-induced hepatotoxicity is suspected.\n\nAcknowledgements\nNone.\n\nAvailability of data and materials\nAll data generated or analyzed during this study are included in this published article.\n\nAuthors’ contributions\nAll authors contributed to the patients’ care, preparation of the images, and writing/reviewing of the manuscript. All authors read and approved the final manuscript.\n\nEthics approval and consent to participate\nThe publication of this case report was approved by the clinical research ethics committees of Kanazawa University Hospital.\n\nConsent for publication\nWritten informed consent was obtained from the patients or their relatives for publication of this case report and any accompanying images. A copy of the written consents is available for review by the Editor-in-Chief of this journal.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Dusman RE Stanton MS Miles WM Clinical features of amiodarone-induced pulmonary toxicity Circulation 1990 82 51 59 10.1161/01.CIR.82.1.51 2364524 \n2. Shiga T Wakaumi M Matsuda N Amiodarone-induced thyroid dysfunction and ventricular tachyarrhythmias during long-term therapy in Japan Jpn Circ J 2001 65 958 960 10.1253/jcj.65.958 11716246 \n3. Mason JW Amiodarone N Engl J Med 1987 316 455 466 10.1056/NEJM198702193160807 3543680 \n4. Lewis JH Ranard RC Caruso A Amiodarone hepatotoxicity: prevalence and clinicopathologic correlations among 104 patients Hepatology 1989 9 679 685 10.1002/hep.1840090504 2785079 \n5. Richer M Robert S Fatal hepatotoxicity following oral administration of amiodarone Ann Pharmacother 1995 29 582 586 10.1177/106002809502900605 7663029 \n6. Hussain N Bhattacharyya A Prueksaritanond S Amiodarone-induced cirrhosis of liver: what predicts mortality? ISRN Cardiol 2013 2013 617943 23577267 \n7. Lewis JH Mullick F Ishak KG Histopathologic analysis of suspected amiodarone hepatotoxicity Hum Pathol 1990 21 59 67 10.1016/0046-8177(90)90076-H 2403975 \n8. Martin WJ 2nd Kachel DL Vilen T Natarajan V Mechanism of phospholipidosis in amiodarone pulmonary toxicity J Pharmacol Exp Ther 1989 251 272 278 2795460 \n9. Brien JF Jimmo S Brennan FJ Ford SE Armstrong PW Distribution of amiodarone and its metabolite, desethylamiodarone, in human tissues Can J Physiol Pharmacol 1987 65 360 364 10.1139/y87-062 3580958 \n10. Goldschlager N Epstein AE Naccarelli G Olshansky B Singh B Practice Guidelines Subcommittee, North American Society of Pacing and Electrophysiology Practical guidelines for clinicians who treat patients with amiodarone Arch Intern Med 2000 160 1741 1748 10.1001/archinte.160.12.1741 10871966 \n11. Kim BB Kim DM Choi DH Amiodarone toxicity showing high liver density on CT scan with normal liver function and plasma amiodarone levels in a long-term amiodarone user Int J Cardiol 2014 172 494 495 10.1016/j.ijcard.2014.01.020 24485640\n\n",
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"abstract": "Worldwide, tuberculosis is the leading cause of death from an infectious disease. Ocular involvement can cause significant and permanent vision loss. Ocular manifestations of tuberculosis often present with visual symptoms. Asymptomatic ocular tuberculosis is uncommon and yet can have serious consequences if missed.\nAn immunocompetent 26-year-old Filipino man living in regional Australia who was diagnosed with active pulmonary tuberculosis and started on antitubercular therapy. He was referred to an ophthalmologist for baseline ethambutol screening to exclude pre-existing optic neuropathy. Despite having no visual symptoms, when examined, the patient had vision threatening occlusive retinal vasculitis. He was initially commenced on localised therapy via bevacizumab intravitreal injections and retinal photocoagulation. Following completion of antitubercular therapy, high dose prednisone was commenced and slowly tapered.\nWe present the case of an asymptomatic sight threatening occlusive vasculitis that was discovered on pre-treatment ophthalmology review. This case emphasises the need for referral for full ophthalmic screening in newly diagnosed tuberculosis to exclude vision-threatening complications.",
"affiliations": "Ophthalmology, Royal North Shore Hospital, Sydney, Australia.;Ophthalmology, Royal North Shore Hospital, Sydney, Australia.;Port Macquarie Eye Centre, Port Macquarie, Australia.",
"authors": "Bartimote|Christopher|C|;Fraser-Bell|Samantha|S|;Dunn|Hamish|H|",
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"fulltext": "\n==== Front\nRespir Med Case Rep\nRespir Med Case Rep\nRespiratory Medicine Case Reports\n2213-0071\nElsevier\n\nS2213-0071(21)00118-0\n10.1016/j.rmcr.2021.101456\n101456\nCase Report\nAsymptomatic occlusive retinal vasculitis in newly diagnosed active tuberculosis\nBartimote Christopher cbar5910@uni.sydney.edu.au\nad∗\nFraser-Bell Samantha abd\nDunn Hamish cd\na Ophthalmology, Royal North Shore Hospital, Sydney, Australia\nb Ophthalmology, Sydney Eye Hospital, Sydney, Australia\nc Port Macquarie Eye Centre, Port Macquarie, Australia\nd The University of Sydney, Sydney, Australia\n∗ Corresponding author. Royal North Shore Hospital, Reserve Rd, St Leonards, NSW, Australia. cbar5910@uni.sydney.edu.au\n24 6 2021\n2021\n24 6 2021\n33 10145619 1 2021\n23 4 2021\n15 6 2021\n© 2021 The Authors\n2021\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).\nIntroduction\n\nWorldwide, tuberculosis is the leading cause of death from an infectious disease. Ocular involvement can cause significant and permanent vision loss. Ocular manifestations of tuberculosis often present with visual symptoms. Asymptomatic ocular tuberculosis is uncommon and yet can have serious consequences if missed.\n\nCase report\n\nAn immunocompetent 26-year-old Filipino man living in regional Australia who was diagnosed with active pulmonary tuberculosis and started on antitubercular therapy. He was referred to an ophthalmologist for baseline ethambutol screening to exclude pre-existing optic neuropathy. Despite having no visual symptoms, when examined, the patient had vision threatening occlusive retinal vasculitis. He was initially commenced on localised therapy via bevacizumab intravitreal injections and retinal photocoagulation. Following completion of antitubercular therapy, high dose prednisone was commenced and slowly tapered.\n\nConclusions\n\nWe present the case of an asymptomatic sight threatening occlusive vasculitis that was discovered on pre-treatment ophthalmology review. This case emphasises the need for referral for full ophthalmic screening in newly diagnosed tuberculosis to exclude vision-threatening complications.\n\nKeywords\n\nTuberculosis\nVasculitis\nRetina\nOphthalmology\n==== Body\n1 Introduction\n\nTuberculosis infects over a third of the world's population and is the leading cause of death by an infectious disease [[1], [2], [3]]. It is caused by Mycobacterium tuberculosis, an intracellular bacillus [1,2] that leads to a granulomatous pulmonary infection. Due to the haematogenous spread of the bacteria, however, tuberculosis can infect any structure in the body [4]. Ocular tuberculosis can cause significant morbidity from the active infection and subsequent inflammatory response. It often presents with visual symptoms, such as blurry vision, diplopia flashes and/or floaters [2,3,5]. Asymptomatic ocular manifestations of tuberculosis have been described [4], although it usually occurs in immunocompromised patients or where the lesions develop in the periphery of the retina [5,6]. Treatment of ocular tuberculosis involves anti-tubercular treatment (ATT) combined with local and/or systemic immunosuppression [2,7]. We present the case of an asymptomatic sight threatening occlusive retinal vasculitis presenting soon after an active tuberculosis diagnosis.\n\n2 Case report\n\nAn immunocompetent 26-year-old Phillipino man living in regional Australia was diagnosed with active pulmonary tuberculosis and was commenced on ATT consisting of 2 months of ethambutol and pyrazinamide with 6 months of isoniazid and rifampicin (2HRZE/4HR). After 2 weeks of ATT, he presented to the local ophthalmologist for baseline ethambutol screening. At the time of review, he did not report any visual symptoms. Physical examination demonstrated visual acuity of 20/20 in each eye. Corneae and anterior chamber examination was normal. However, fundal examination revealed temporal blot haemorrhages and multiple inferior and superonasal nodules at the veins that were suspicious for occlusive retinal vasculitis (Fig. 1). Fundus fluorescein angiography (FFA) confirmed periphlebitis with staining of the vessel walls, and a secondary branch retinal vein occlusion (BRVO) with diffuse areas of capillary non-perfusion indicating retinal ischaemia (Fig. 2).Fig. 1 Colour fundus photograph demonstrating Occlusive Vasculitis with retinal nodules (blue arrow) and temporal blot haemorrhages (red arrow). (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)\n\nFig. 1\n\nFig. 2 Fundus fluorescein angiography demonstrating Branch Retinal Vein Occlusion with surrounding capillary non-perfusion (blue arrow). (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)\n\nFig. 2\n\nTo combat the immunoreaction causing the vasculitis a systemic steroid is often used. In discussion with the treating respiratory physician, the use of systemic steroids was avoided to prevent immunosuppression in active tuberculosis. Instead, the off-label use of bevacizumab 4mg as an intravitreal injection (IVI) was utilised to provide localised treatment for the vasculitis. With the IVI, the periphlebitis and temporal haemorrhages were settling, however, extensive whitening of the retina developed from the BRVO. Sectoral scatter laser therapy was applied to the areas of retinal ischaemia to prevent extension and the risk of retinal detachment. Throughout this period, visual acuity remained normal and the patient asymptomatic.\n\nSix weeks after the initiation of ATT, systemic steroids (1mg/kg) were initiated with gastric protection (pantoprazole 40mg). In the preceding reviews of the eye, peripheral whitening and vascular sheathing reduced but remained present until the cessation of the 6 months of ATT. There was a recurrence of retinal whitening and perivascular nodules when the prednisone dose was reduced after 3 weeks, but abated following medical retina subspecialty advice of a small increase in steroids and a prolonged wean. The slow wean of steroids was conducted over 4 months after the cessation of ATT. Over 28 months of follow-up there were no further recurrences of ocular inflammation or signs of vasculitis after completing the 9 months total of systemic steroids.\n\n3 Discussion\n\nMycobacterium tuberculosis can infect all parts of the eye leading to a myriad of presentations known as ocular tuberculosis. Ocular tuberculosis, however, can range from cutaneous nodules and abscesses on the eyelids, mucopurulent and chronic conjunctivitis, choroiditis, uveitis and endophthalmitis [8]. The seemingly localised infections may initially present in a single area of the eye but can spread haematogenously or by local extension to other ocular structures [8]. Additionally, the spread of M tuberculosis can trigger an immunoreaction to tuberculosis antigens with an unclear pathophysiology as it can be seen in both active and latent tuberculosis. It has been found to cause anterior uveitis, anterior scleritis, serpiginoid choroiditis, occlusive vasculitis and severe vitritis [9,10]. Therefore, therapies must target M. tuberculosis infection as well as suppress the immune response [3,9].\n\nUnfortunately, the complications of these pathologies can be devastating, increasing the likelihood of poor visual outcomes [8,9,11]. For example, occlusive retinal vasculitis predominantly affects retinal venules [9] and can be complicated by retinal vein occlusion, such as BRVO as seen in this case. In turn, the associated ischaemia can lead to retinal neovascularisation and its complications [11]. Although the effect on vision may initially be minimal, it can progress to permanent vision loss [6]. Yaacob et al. reported the only other case of an asymptomatic occlusive retinal vasculitis caused by tuberculosis [12]. The vasculitis occurred in the periphery of the retina which can often present with no symptoms [6]. In our case, however, the vasculitis was sight threatening on presentation leading to our concern, as it was an asymptomatic vasculitis with the potential for severe morbidity.\n\nThe collaborative ocular tuberculosis study developed a guideline for treatment of ocular tuberculosis based on tuberculosis community prevalence and the results of radiologic and immunologic tests [13]. Using these guidelines, instituting ATT in the treatment of ocular tuberculosis is a calculated decision based on the risk of disease progression and the likelihood of a poor prognosis [7,9,13]. Additionally, systemic steroid regimes or the localised use of vascular endothelial growth factor inhibitors, such as the off-label use of intravitreal bevacizumab as in our case, can be used to minimise the severe visual complications from vasculitis caused by tuberculosis [3,14,15].\n\nIt is important to note, however, that numerous other entities may present with similar retinal and/or choroidal pathology [16,17]. Agarwal et al. characterised the aetiology and epidemiology of occlusive retinal vasculitis from two tertiary institutions [16]. Forty-three percent were caused by tuberculosis, however, there were a multitude of other aetiologies including Systemic Lupus Erythematosus, Bechet's disease, Sarcoidosis, Eales disease, Herpes simplex and zoster viruses [16]. Differentiating the aetiology of the ocular disease is extremely important as without appropriate treatment the prognosis is very poor [16,17].\n\nThe prognosis of retinal vasculitis in tuberculosis patients usually depends on the risk of that pathology developing complications [[14], [15], [16], [17]]. Pathologies that are prone to develop ischaemia, such as occlusive retinal vasculitis as seen in our case, have a very guarded prognosis as the neovascularisation and retinal ischaemia can lead to irreparable damage to the retina [14,16]. Aggressive and novel treatments are indicated in these circumstances due to the high risk of poor visual outcomes [14]. Early assessment and diagnosis is paramount to maximise recovery and minimise complications.\n\nIn the management of tuberculosis, however, visually asymptomatic patients are usually only referred to an ophthalmologist for Ethambutol screening to document a baseline assessment of the optic nerve before or soon after the initiation of ATT, as the doses of ethambutol utilised can lead to optic nerve toxicity [7,[17], [18]]. The examination will concentrate on the appearance of the optic nerve and functional tests of the eye such as visual field and colour vision [[17], [18]]. From this case, we demonstrate the value of a full ocular examination and fundus imaging regardless of whether visual symptoms are present. Further health economic research is indicated to determine the public health value of such practice.\n\n4 Conclusions\n\nWe present the case of an asymptomatic sight threatening occlusive vasculitis caused by active tuberculosis. Although asymptomatic ocular manifestations of tuberculosis are uncommon, the consequences of missed diagnoses can be devastating. By incorporating referrals for full retinal examination and investigation into practice, it would allow for early detection and treatment of ocular tuberculosis complications.\n\nDeclaration of competing interest\n\nWe declare no competing or conflicts of interests.\n\nAll authors were involved in conception, writing and critical review of the report.\n\nInformed consent was obtained from the patient for the publication of the clinical pictures and case report.\n\nThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit-sectors.\n==== Refs\nReferences\n\n1 Global Tuberculosis Report 2019 2019 World Health Organisation Geneva\n2 Gupta Amod Bansal Reema Gupta Vishali Sharma Aman Bambery Pradeep Ocular signs predictive of tubercular uveitis Am. J. Ophthalmol. 149 4 2010 562 570 20149341\n3 Sanghvi C. Bell C. Woodhead M. Hardy C. Jones N. Presumed tuberculous uveitis: diagnosis, management, and outcome Eye 25 4 2011 475 480 21293496\n4 Ray S. Talukdar A. Kundu S. Khanra D. Sonthalia N. Diagnosis and Management of Miliary Tuberculosis: Current State and Future Perspective vol. 9 2013 9 26\n5 Gupta V. Shoughy S. Khairallah M. Rosenbaum J.T. Curi A. Tabbara K.F. Clinics of ocular tuberculosis Ocul. Immunol. Inflamm. 23 1 2015 14 24 25615807\n6 Rosenbaum J.T. Sibley C.H. Lin P. Retinal vasculitis Curr. Opin. Rheumatol. 28 3 2016 228 235 26945335\n7 Bansal R. Gupta A. Gupta V. Role of anti-tubercular therapy in uveitis with latent/manifest tuberculosis Am. J. Ophthalmol. 146 2008 772 779 18708180\n8 Thompson M.J. Albert D.M. Ocular tuberculosis Arch. Ophthalmol. 123 6 2005 844 849 15955987\n9 Ng Ken K. Nisbet Mitzi Damato Erika M. Sims Joanne L. Presumed tuberculous uveitis in non-endemic country for tuberculosis: case series from a New Zealand tertiary uveitis clinic Clin. Exp. Ophthalmol. 45 4 2017 357 365 27896896\n10 Ang Marcus Hedayatfar Alireza Zhang Rongli Chee Soon-Phaik Clinical signs of uveitis associated with latent tuberculosis Clin. Exp. Ophthalmol. 40 7 2012 689 696 22299676\n11 Manousaridis K. Ong E. Stenton C. Gupta R. Browning A.C. Pandit R. Clinical presentation, treatment, and outcomes in presumed intraocular tuberculosis: experience from newcastle upon tyne, UK Eye 27 4 2013 480 486 23429412\n12 Yaacob N. Yaakob M. Mustari Z. Hussein A. Silent occlusive retinal vasculitis in a patient with pulmonary Tuberculosis J. of Biomed & Clin. Sci. 3 1 2018 31 34\n13 Agrawal R. Testi I. Bodaghi B. Collaborative ocular tuberculosis study consensus guidelines on the management of tubercular uveitis – report 2: guidelines for initiating antitubercular therapy in anterior uveitis, intermediate uveitis, panuveitis, and retinal vasculitis Ophthalmology 128 2 2021 277 287 32603726\n14 Ali A. Ku J. Suhler E. The course of retinal vasculitis Br. J. Ophthalmol. 98 2014 785 789 24511084\n15 Agrawal R. Gunasekeran D.V. Grant R. Clinical features and outcomes of patients with tubercular uveitis treated with antitubercular therapy in the collaborative ocular tuberculosis study (COTS)–1 JAMA Ophthalmol. 135 12 2017 1318 1327 29075752\n16 Agarwal A. Karkhur S. Aggarwal K. Epidemiology and clinical features of inflammatory retinal vascular occlusions: pooled data from two tertiary-referral institutions Clin. Exp. Ophthalmol. 46 1 2018 62 74 28557287\n17 Rosenbaum J. Sibley C. Lin P. Retinal vasculitis Curr. Opin. Rheumatol. 28 3 2016 228 235 26945335\n18 Chamberlain P.D. Sadaka A. Berry S. Lee A.G. Ethambutol optic neuropathy Curr. Opin. Ophthalmol. 28 6 2017 545 551 28759559\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2213-0071",
"issue": "33()",
"journal": "Respiratory medicine case reports",
"keywords": "Ophthalmology; Retina; Tuberculosis; Vasculitis",
"medline_ta": "Respir Med Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101604463",
"other_id": null,
"pages": "101456",
"pmc": null,
"pmid": "34401294",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "28759559;28557287;27896896;23429412;18708180;20149341;15955987;26945335;24511084;21293496;25615807;29075752;22299676;32603726;23326198",
"title": "Asymptomatic occlusive retinal vasculitis in newly diagnosed active tuberculosis.",
"title_normalized": "asymptomatic occlusive retinal vasculitis in newly diagnosed active tuberculosis"
} | [
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"companynumb": "AU-SUN PHARMACEUTICAL INDUSTRIES LTD-2022R1-323384",
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"abstract": "Rabies is a fatal disease. Saliva of a rabid dog is a rich source of rabies virus. We report a patient who suffered of rabies, who was infected by abrasion caused by the nails of a rabid dog. Dogs often lick their nails and thereby transfer the rabies virus-contaminated saliva to their claws. Despite treatment in our Intensive Care Unit and application of various pharmacological antidotes, we were unable to prevent the fatal outcome.",
"affiliations": "Bawaskar Hospital and Research Center, Mahad, Maharashtra, India.;Bawaskar Hospital and Research Center, Mahad, Maharashtra, India.;Bawaskar Hospital and Research Center, Mahad, Maharashtra, India.",
"authors": "Bawaskar|Himmatrao S|HS|;Bawaskar|Pramodini H|PH|;Bawaskar|Parag H|PH|",
"chemical_list": null,
"country": "India",
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"doi": "10.4103/ijccm.IJCCM_245_13",
"fulltext": "\n==== Front\nIndian J Crit Care MedIndian J Crit Care MedIJCCMIndian Journal of Critical Care Medicine : Peer-reviewed, Official Publication of Indian Society of Critical Care Medicine0972-52291998-359XMedknow Publications & Media Pvt Ltd India IJCCM-21-87210.4103/ijccm.IJCCM_245_13Case ReportRabies: A Novel Clinical Presentation Bawaskar Himmatrao S. Bawaskar Pramodini H. Bawaskar Parag H. Bawaskar Hospital and Research Center, Mahad, Maharashtra, IndiaAddress for correspondence: Dr. Himmatrao S. Bawaskar, Bawaskar Hospital and Clinical Research Center, Mahad, Raigad - 402 301, Maharashtra, India. E-mail: himmatbawaskar@rediffmail.com12 2017 21 12 872 874 Copyright: © 2017 Indian Journal of Critical Care Medicine2017This 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.Rabies is a fatal disease. Saliva of a rabid dog is a rich source of rabies virus. We report a patient who suffered of rabies, who was infected by abrasion caused by the nails of a rabid dog. Dogs often lick their nails and thereby transfer the rabies virus-contaminated saliva to their claws. Despite treatment in our Intensive Care Unit and application of various pharmacological antidotes, we were unable to prevent the fatal outcome.\n\nElapid venomGABAglycoproteinNMDArabies\n==== Body\nINTRODUCTION\nRabies a fatal neurological disease caused by lassavirus. Virus is transmitted through the infected saliva of canine animals. Prevention of this grave disease is achived by pre and post exposure immunization, and rabies immunoglobulin against rabies when it required. Irrespective of freely and free available rabies vaccine at government hospital including primary health centers. Still we witness the grave disease with fatal outcome, because of century old myth deeply rooted amongst villagers that dog bite only village healers (Tantrik, Mantrika and ozas) or herbal remedies can cure and protect from rabies. Rabies virus outer cover is glycoprotein responsible to induce slow apoptosis of infected brain neuron. Rabies encephalitis is easy to diagnose. Even at advanced tertiary care center the fatality of rabies victim is 100%, only in a immunized victim there are chances of recovery with neurologoical deficit.[1] Irrespective of raised titer of rabies antibodies in a infected victim with disease did not arrest the severity of disease. In rabies prevention is a mother of cure.\n\nCASE REPORT\nOn May 3, 2011, at 10 AM, a 50-year-old female was admitted to an outpatient department hospital at Mahad in the district of Raigad. She complained of insomnia, suffocation, fever, severe whole-body pain, and malaise over the past 4 days. On April 30, she had been examined by her family doctor. She received an unidentified injection, acetaminophen tablets, and oral chloroquine. There was no improvement of symptoms.\n\nSince she additionally complained of chest pain, she was admitted to the Intensive Care Unit (ICU) on May 2, where her pain was attributed to unstable angina. She was closely monitored and was given nasal oxygen, intravenous fluids, a nitroglycerin drip and furosemide. In addition, a treatment with low-molecular-weight heparin 60 mg every 12 h digoxin, aspirin, clopidogrel and statin was started. There was no clinical improvement. On the 3rd day, the ICU doctor transferred her to a tertiary care hospital for further cardiac investigation to rule out ischemic cardiomyopathy.\n\nInstead of going to Mumbai, the relatives brought the patient to the clinic at Mahad. On admission, she was fully conscious. She presented with a history of mitral valve replacement in 1994. She complained of excessive thirst and being unable to drink water for 2 days. While examining her, we asked for a glass of water. Simple by hearing the word water (Pani in vernacular language), she suddenly developed severe laryngeal spasm [Figure 1, Video 1]. This repeated laryngeal spasm in response to the word “water” confirmed that she was suffering from rabies. We asked her and the relatives regarding any history of a dog bite. She reported that 4 months ago, a furious dog had bitten four persons from her village. All of them were treated with immunization as exposure prevention by the government hospital. All the four are healthy at present. The furious dog had caught her sari (cloth), and with its claws, it caused multiple abrasions at her right foot. She cleaned the blood and the abrasions by rubbing it with her sari. She and her relatives believed that only the bite of a dog can cause the disease and hence avoided postexposure rabies immunization though it is free and freely available at the primary health center, which is 5 km away from her village. However, she reported that instead of visiting the hospital, she visited a Tantrik (village healer) who gave her some herbal medicine.\n\nFigure 1 The patient developed laryngopharyngeal spasm just by hearing the word “water” (Pani in vernacular language)\n\n Her blood pressure was 140/80, she had no signs of myocardial failure, a grade 3/6 systolic murmur was heard at over the aortic root area, and an ejection click of the mitral valve was heard over the apex. The respiratory rate was 14/min and no pathological breathing sounds were heard over her chest. Her body temperature was 99°F. There was no any neurological deficit except laryngeal spasm.\n\nAs major symptom, she described that she experienced tingling and numbness and heaviness in her right lower limb. Troponin T was negative, and serum sodium was 128 mEq/l. Electrocardiogram showed a heart rate of 75 beats/min with minor ST-T changes [Figure 2]. Hemoglobin level was 14.6 g/dl, leukocyte count was 11,100 cu.mm, and blood sugar was 105 mg/dl.\n\nFigure 2 Electrocardiogram – normal sinus rhythm minor ST-T changes\n\nShe was isolated in a dark room. Very carefully, we placed a nasogastric feeding tube. She was given intravenous fluids, intravenous atropine 3 mg, magnesium sulfate (MgSO4) 2 g, midazolam 1 mg/kg body weight, and sustained acting zolpidem 12.5 mg through the nasal tube. The next day she developed a mixed form of delirium with being fully conscious in-between (lucid interval). She still occasionally developed laryngeal spasms. On the 3rd day, she presented with tachycardia, delirium, internuclear ophthalmoplegia, and plantar flexion, and the strength in all limbs was grade 5/5, but she had no neck rigidity. Moist rales were heard over the chest, and she became tachypnoeic. At 3 AM on the 4th day, she developed pulmonary edema and massive hematemesis and died of respiratory arrest. She was conscious till death. No attempt to resuscitate her was initiated following the decision of seniors and relatives.\n\nDISCUSSION\nYearly 30,000 victims die of rabies in India alone. The high incidence of rabies in a developing country is due to the mere neglect of rabies immunization after dog bites. This is explained by false beliefs and lack of social awareness though the rabies immunization is given free at primary health centers. Moreover, medical professionals maintain false silence react restrainedly toward this century-old grave disease as seen in the present case.[1] Rabies is a 100% fatal disease; up till now, only 7 cases recovered with prolonged intensive care, irrespective of treatment with antiserum, antiviral, interferon-alpha, corticosteroids, and other immunosuppressant drugs.[1] Dogs often lick their nails and claws where the virus-contaminated saliva remains and can cause severe infections with rabies by abrasions as observed in the present case.[1]\n\nCellular receptor dysfunctions caused by the virus play an important role in the pathogenesis of rabies encephalitis.[1] Datura seeds (atropine) counteract the rabies virus action as mentioned in Ayurveda.[2] In the present case, atropine prevents the development of recurrent severe spasm due to the attempt to swallow the accumulated saliva in the mouth cavity.\n\nThe rabies virus binds to the postsynaptic acetylcholine receptors and competitively blocks cholinergic ligands. The chemical and structural sequence homology of the glycoprotein of rabies viruses is similar to the elapid venom neurotoxin alpha-bungarotoxin; it is not available. Molecular scientists should search out the chemical structure from alpha_bungarotoxin, which may competitively inhibit the action of virus glycoprotein or immunoglobulin against alpha-bungarotoxin may neutralize the action of glycoprotein on infected brain neuron and upgrade the neuronal apoptosis, which is downgraded by virus glycoprotein. The virulence of virus inversely related to the neuronal apoptosis.[134]\n\nN-methyl-D-aspartate (NMDA) subtype R1 and gamma-aminobutyric acid (GABA) have been suggested as possible rabies virus receptors in the central nervous system. MgSO4, a selective noncompetitive antagonist of NMDA receptors, may prevent cellular injury. MgSO4 prevented sudden cardiac arrest due to cardiac arrhythmias, convulsions, and hypertension in the present case. Zolpidem induces selective inhibition of the normal GABAergic inhibitory neuron. Pathophysiology evoked by rabies virus is its action on NMDA and GABA receptors. Hence, we used these Zolpidem and also MgSO4 as an antagonist to the NMDA receptors.[5]\n\nThe chemical sequence homology of the glycoprotein of the rabies virus mimics the krait venom, a neurotoxin called alpha-bungarotoxin, a presynaptic acetylcholine receptor destructor. It is possible that a drug derived from krait venom may act as a competitive antagonist of the rabies virus glycoprotein evokes potent lethal action in central nervous system and peripheral nicotinic receptors. It so might help to inhibit the progress of rabies. However, monovalent krait antivenom is a rich source of alpha-bungarotoxin antibodies, may help to neutralize the rabies virus glycoprotein.[67]\n\nImmediate wound cleaning by soap and water and active immunization prevent this grave disease. Chances of development of mild diseases and recovery are higher in partially immunized victim.[1]\n\nDeclaration of patient consent\nThe authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n\nVideo Available on: www.ijccm.org\n==== Refs\nREFERENCES\n1 Warrell MJ Warrell DA Rabies and other lyssavirus diseases Lancet 2004 363 959 69 15043965 \n2 Agnihotri P Guru LV Sushrutsanhita Kashi Sankrut Granthmala 1968 156 Varanasi Chourvamma Sanskut Sansthan 56 63 \n3 Lentz TL Burrage TG Smith AL Crick J Tignor GH Is the acetylcholine receptor a rabies virus receptor? Science 1982 215 182 4 7053569 \n4 Warrell DA The clinical management of snake bite in the Southeast Asian Region South Asian J Trop Med Public Health 1999 30 1 84 \n5 Standaert DG Young AB Hardman JG Limbird LE Treatment of central nervous system degenerative disorders Goodman and Gilman's The Pharmacological Basis of Therapeutics 2001 10th ed Ch. 22 New York McGraw-Hill 549 51 \n6 Bawaskar HS Bawaskar PH Bawaskar PH Premonitory signs and symptoms of envenoming by common krait (Bungarus caeruleus ) Trop Doct 2014 44 82 5 24549631 \n7 Hemachudha T Laothamatas J Rupprecht CE Human rabies: A disease of complex neuropathogenetic mechanisms and diagnostic challenges Lancet Neurol 2002 1 101 9 12849514\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0972-5229",
"issue": "21(12)",
"journal": "Indian journal of critical care medicine : peer-reviewed, official publication of Indian Society of Critical Care Medicine",
"keywords": "Elapid venom; GABA; NMDA; glycoprotein; rabies",
"medline_ta": "Indian J Crit Care Med",
"mesh_terms": null,
"nlm_unique_id": "101208863",
"other_id": null,
"pages": "872-874",
"pmc": null,
"pmid": "29307972",
"pubdate": "2017-12",
"publication_types": "D002363:Case Reports",
"references": "12849514;15043965;24549631;7053569",
"title": "Rabies: A Novel Clinical Presentation.",
"title_normalized": "rabies a novel clinical presentation"
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"companynumb": "IN-CIPLA LTD.-2018IN00767",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ZOLPIDEM TARTRATE"
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"drugadditional": null,... |
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"abstract": "BACKGROUND\nFindings from observational studies have suggested a delay in nursing home placement with dementia drug treatment, but findings from a previous randomised trial of patients with mild-to-moderate Alzheimer's disease showed no effect. We investigated the effects of continuation or discontinuation of donepezil and starting of memantine on subsequent nursing home placement in patients with moderate-to-severe Alzheimer's disease.\n\n\nMETHODS\nIn the randomised, double-blind, placebo-controlled Donepezil and Memantine in Moderate to Severe Alzheimer's Disease (DOMINO-AD) trial, community-living patients with moderate-to-severe Alzheimer's disease (who had been prescribed donepezil continuously for at least 3 months at a dose of 10 mg for at least the previous 6 weeks and had a score of between 5 and 13 on the Standardised Mini-Mental State Examination) were recruited from 15 secondary care memory centres in England and Scotland and randomly allocated to continue donepezil 10 mg per day without memantine, discontinue donepezil without memantine, discontinue donepezil and start memantine 20 mg per day, or continue donepezil 10 mg per day and start memantine 20 mg per day, for 52 weeks. After 52 weeks, choice of treatment was left to participants and their physicians. Place of residence was recorded during the first 52 weeks of the trial and then every 26 weeks for a further 3 years. A secondary outcome of the trial, reported in this study, was nursing home placement: an irreversible move from independent accommodation to a residential caring facility. Analyses restricted to risk of placement in the first year of follow-up after the patients had completed the double-blind phase of the trial were post-hoc. The DOMINO-AD trial is registered with the ISRCTN Registry, number ISRCTN49545035.\n\n\nRESULTS\nBetween Feb 11, 2008, and March 5, 2010, 73 (25%) patients were randomly assigned to continue donepezil without memantine, 73 (25%) to discontinue donepezil without memantine, 76 (26%) to discontinue donepezil and start memantine, and 73 (25%) to continue donepezil and start memantine. 162 (55%) patients underwent nursing home placement within 4 years of randomisation, with similar numbers for all groups (36 [49%] in patients who continued donepezil without memantine, 42 [58%] who discontinued donepezil without memantine, 41 [54%] who discontinued donepezil and started memantine, and 43 [59%] who continued donepezil and started memantine). We noted significant (p=0·010) heterogeneity of treatment effect over time, with significantly more nursing home placements in the combined donepezil discontinuation groups during the first year (hazard ratio 2·09 [95% CI 1·29-3·39]) than in the combined donepezil continuation groups, and no difference during the next 3 years (0·89 [0·58-1·35]). We noted no effect of patients starting memantine compared with not starting memantine during the first year (0·92 [0·58-1·45]) or the next 3 years (1·23 [0·81-1·87]).\n\n\nCONCLUSIONS\nWithdrawal of donepezil in patients with moderate-to-severe Alzheimer's disease increased the risk of nursing home placement during 12 months of treatment, but made no difference during the following 3 years of follow-up. Decisions to stop or continue donepezil treatment should be informed by potential risks of withdrawal, even if the perceived benefits of continued treatment are not clear.\n\n\nBACKGROUND\nMedical Research Council and UK Alzheimer's Society.",
"affiliations": "Division of Psychiatry, University College London, London, UK; Department of Old Age Psychiatry, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK. Electronic address: robert.howard@ucl.ac.uk.;Oxford Health NHS Foundation Trust, Warneford Hospital, Headington, Oxford, UK.;Health Sciences, University of Leicester, Leicester, UK.;Centre for Brain Sciences, University of Edinburgh, Edinburgh, UK.;Five Boroughs Partnership NHS Foundation Trust, Winwick, Warrington, UK.;Centre for Ageing and Vitality, Newcastle upon Tyne, UK.;Institute of Brain, Behaviour and Mental Health, University of Manchester, Manchester, UK.;Institute of Mental Health, University of Nottingham, Nottingham, UK.;Kingsway Care Centre, Dundee, UK.;Faculty of Medicine, University of Southampton, Southampton, UK.;Department of Pyschiatry, University of Nottingham, Nottingham, UK.;Research Institute for the Care of Older People, Bath, UK.;Newcastle; University Institute for Ageing, Newcastle University, Newcastle Upon Tyne, UK.;Ayrshire and Arran NHS, University Hospital Crosshouse, Crosshouse, Kilmarnock, UK.;Department of Psychiatry, University of Cambridge, Cambridge, UK.;Oxford University Hospitals NHS Trust, Headington, Oxford, UK.;National Perinatal Epidemiology Unit Clinical Trials Unit, University of Oxford, Oxford, UK.;Division of Psychiatry, University College London, London, UK.;Cardiff University School of Medicine, Cardiff, UK.;London School of Economics, London, UK.;Wolfson Centre for Age Related Disorders, King's College London, London, UK.;Department of Psychology, King's College London, London, UK.;Brighton and Sussex Medical School, University of Sussex, Brighton, East Sussex, UK.;Department of Old Age Psychiatry, King's College London, London, UK.;Medical Research Council Clinical Trials Unit, University College London, London, UK.;Birmingham and Solihull Mental Health NHS Foundation Trust, Birmingham, UK.;Medical Research Council Clinical Trials Unit, University College London, London, UK.",
"authors": "Howard|Robert|R|;McShane|Rupert|R|;Lindesay|James|J|;Ritchie|Craig|C|;Baldwin|Ashley|A|;Barber|Robert|R|;Burns|Alistair|A|;Dening|Tom|T|;Findlay|David|D|;Holmes|Clive|C|;Jones|Robert|R|;Jones|Roy|R|;McKeith|Ian|I|;Macharouthu|Ajay|A|;O'Brien|John|J|;Sheehan|Bart|B|;Juszczak|Edmund|E|;Katona|Cornelius|C|;Hills|Robert|R|;Knapp|Martin|M|;Ballard|Clive|C|;Brown|Richard G|RG|;Banerjee|Sube|S|;Adams|Jessica|J|;Johnson|Tony|T|;Bentham|Peter|P|;Phillips|Patrick P J|PP|",
"chemical_list": "D007189:Indans; D018697:Nootropic Agents; D010880:Piperidines; D000077265:Donepezil; D008559:Memantine",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1474-4422",
"issue": "14(12)",
"journal": "The Lancet. Neurology",
"keywords": null,
"medline_ta": "Lancet Neurol",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease; D003071:Cognition; D000077265:Donepezil; D004311:Double-Blind Method; D005260:Female; D006707:Homes for the Aged; D006801:Humans; D007189:Indans; D008297:Male; D008559:Memantine; D009483:Neuropsychological Tests; D018697:Nootropic Agents; D009735:Nursing Homes; D010880:Piperidines; D012720:Severity of Illness Index",
"nlm_unique_id": "101139309",
"other_id": null,
"pages": "1171-81",
"pmc": null,
"pmid": "26515660",
"pubdate": "2015-12",
"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Nursing home placement in the Donepezil and Memantine in Moderate to Severe Alzheimer's Disease (DOMINO-AD) trial: secondary and post-hoc analyses.",
"title_normalized": "nursing home placement in the donepezil and memantine in moderate to severe alzheimer s disease domino ad trial secondary and post hoc analyses"
} | [
{
"companynumb": "GB-CIPLA LTD.-2015GB09203",
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"occurcountry": "GB",
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"activesubstancename": "DONEPEZIL"
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{
"abstract": "BACKGROUND\nNegative myoclonus is a jerky, brief, and sudden interruption of voluntary muscle contraction. Although gabapentin and pregabalin have been reported to induce positive myoclonus in some patients with impaired renal function, there are only a few studies describing pregabalin- or gabapentin-induced negative myoclonus. This study reviewed patients who had developed pregabalin- or gabapentin-induced negative myoclonus.\n\n\nMETHODS\nWe collected the patients with negative myoclonus who were referred to the department of neurology at a university-affiliated hospital and selected pregabalin- or gabapentin-induced negative myoclonus. Then reviewed the literature with respect to pregabalin- or gabapentin-induced negative myoclonus.\n\n\nRESULTS\nA total of 77 patients with negative myoclonus were reviewed. Among them, 21 neuropathic pain patients who were prescribed and developed negative myoclonus induced by pregabalin (9 cases) or gabapentin (12 cases). To prove causality of the drug, probable and certain level of category according to the WHO-UMC criteria were recruited. Of the 21 patients, 3 had impaired renal function, while 18 had normal renal function. Review of the literature identified 7 further cases (6 had normal renal function) with pregabalin- or gabapentin-induced negative myoclonus.\n\n\nCONCLUSIONS\nPregabalin- and gabapentin-induced negative myoclonus can develop even in patients with normal renal function. Physicians should keep in mind the possibility of patients developing negative myoclonus under treatment of pregabalin or gabapentin even in short period of time and with low dosage, and in the normal range of renal function. Further prospective study investigating incidence and risk factors is warranted.",
"affiliations": "Department of Neurology, Korea University Anam Hospital, Korea University College of Medicine, Seoul, South Korea.;Department of Neurology, Korea University Ansan Hospital, Korea University College of Medicine, Ansan, South Korea.;Department of Neurology, Korea University Ansan Hospital, Korea University College of Medicine, Ansan, South Korea.;Medical Library, Korea University, Seoul, South Korea.;Department of Neurology, Korea University Ansan Hospital, Korea University College of Medicine, Ansan, South Korea. Electronic address: kwondoya@korea.ac.kr.",
"authors": "Kim|Jung Bin|JB|;Jung|Jin-Man|JM|;Park|Moon-Ho|MH|;Lee|Eun Ju|EJ|;Kwon|Do-Young|DY|",
"chemical_list": "D000588:Amines; D000700:Analgesics; D003509:Cyclohexanecarboxylic Acids; D000069583:Pregabalin; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.jns.2017.09.019",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0022-510X",
"issue": "382()",
"journal": "Journal of the neurological sciences",
"keywords": "Gabapentin; Negative myoclonus; Pregabalin; Renal function; T-type calcium channel",
"medline_ta": "J Neurol Sci",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000588:Amines; D000700:Analgesics; D003509:Cyclohexanecarboxylic Acids; D005260:Female; D000077206:Gabapentin; D006801:Humans; D008297:Male; D008875:Middle Aged; D009207:Myoclonus; D000069583:Pregabalin; D011446:Prospective Studies; D012042:Registries; D012189:Retrospective Studies; D055815:Young Adult; D005680:gamma-Aminobutyric Acid",
"nlm_unique_id": "0375403",
"other_id": null,
"pages": "36-39",
"pmc": null,
"pmid": "29111014",
"pubdate": "2017-11-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review; D000078182:Systematic Review",
"references": null,
"title": "Negative myoclonus induced by gabapentin and pregabalin: A case series and systematic literature review.",
"title_normalized": "negative myoclonus induced by gabapentin and pregabalin a case series and systematic literature review"
} | [
{
"companynumb": "KR-ACI HEALTHCARE LIMITED-2034838",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
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"activesubstancename": "GABAPENTIN"
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{
"abstract": "We report the case of a 6-year-old girl with juvenile idiopathic arthritis and anterior uveitis who was treated with two doses of intravenous methylprednisolone for acute arthritis. She developed severe ocular hypertension (intraocular pressures (IOPs) of 54 mm Hg in the right eye and 61 mm Hg in the left eye) requiring inpatient therapy with intravenous acetazolamide. The normal range of values for IOP is 12-22 mm Hg. This severe case of acute intraocular hypertension due to systemic steroids highlights the need to consider monitoring of IOPs for children on high-dose topical and systemic steroids with risk factors for raised IOP.",
"affiliations": "Department of Paediatric Orthopaedics, Bristol Royal Hospital for Children, Bristol, UK.;Department of Paediatric Rheumatology, Bristol Royal Hospital for Children, Bristol, UK.",
"authors": "Beverstock|Andrew|A|;Kelly|Alison|A|",
"chemical_list": "D000893:Anti-Inflammatory Agents; D008775:Methylprednisolone",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2019-229803",
"fulltext": "\n==== Front\nBMJ Case RepBMJ Case RepbmjcrbmjcasereportsBMJ Case Reports1757-790XBMJ Publishing Group BMA House, Tavistock Square, London, WC1H 9JR bcr-2019-22980310.1136/bcr-2019-229803Unexpected Outcome (Positive or Negative) Including Adverse Drug Reactions15061525156013721334532309317Case ReportSevere acute ocular hypertension following pulsed methylprednisolone for juvenile idiopathic arthritis Beverstock Andrew 1Kelly Alison 2\n1 \nDepartment of Paediatric Orthopaedics, Bristol Royal Hospital for Children, Bristol, UK\n\n2 \nDepartment of Paediatric Rheumatology, Bristol Royal Hospital for Children, Bristol, UK\nCorrespondence to Dr Andrew Beverstock, andrew.beverstock@uhbristol.nhs.uk2019 24 5 2019 24 5 2019 12 5 e2298038 5 2019 © BMJ Publishing Group Limited 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.2019This 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/We report the case of a 6-year-old girl with juvenile idiopathic arthritis and anterior uveitis who was treated with two doses of intravenous methylprednisolone for acute arthritis. She developed severe ocular hypertension (intraocular pressures (IOPs) of 54 mm Hg in the right eye and 61 mm Hg in the left eye) requiring inpatient therapy with intravenous acetazolamide. The normal range of values for IOP is 12–22 mm Hg. This severe case of acute intraocular hypertension due to systemic steroids highlights the need to consider monitoring of IOPs for children on high-dose topical and systemic steroids with risk factors for raised IOP.\n\npaediatrics (drugs and medicines)paediatricsrheumatologyglaucomaspecial-featureunlocked\n==== Body\nBackground\nOcular hypertension is a well-recognised side-effect of topical and systemic corticosteroid therapy, but the majority of patients have a mild rise in intraocular pressure (IOP) of less than 20 mm Hg which after withdrawal of steroids without the need for any additional treatment.1 The effect is more common with topical corticosteroid therapy.\n\nThis case is significant due to the rapid onset of the ocular hypertension and the severity of the rise. No report of such significantly elevated pressures after pulsed intravenous steroid therapy in such a young patient has been published. The case highlights the need to consider monitoring of IOPs following pulsed systemic steroids: in this case, the ocular hypertension was detected incidentally.\n\nCase presentation\nThis patient was diagnosed with oligoarticular juvenile idiopathic arthritis (JIA) at age 3 following a 1-year history of left knee stiffness. Her JIA predominantly affected her left knee, left ankle and cervical spine. She was treated initially with intravenous methylprednisolone in 2012 to achieve remission before commencing maintenance methotrexate. She was screened on a six monthly basis for uveitis over the next 2 years and had no evidence of uveitis in this time. IOPs were not routinely measured.\n\nShe was diagnosed with bilateral anterior uveitis on the 2015 on routine screening and was commenced on Pred Forte (prednisolone acetate 1% weight/volume) drops six times daily to both eyes. IOPs were not recorded due to patient distress at the time of examination. The following week, she was treated with 1000 mg intravenous methylprednisolone as a day case for a flare-up of her neck symptoms of JIA, and she was due to return the following day for a second dose. On the day her second dose was due, her mother found her to be sleepier than usual, but no visual symptoms were reported.\n\nShe had a follow-up with the ophthalmologists arranged on the same day prior to attending the hospital for her second steroid intravenous infusion. Routine tonometry was performed using iCare tonometry at this appointment. This showed significant elevation of her IOPs, with a pressure of 53.6 mm Hg in the right eye and 61.2 mm Hg in the left eye. These measurements were repeatable. Ocular examination revealed mild anterior chamber activity with 0.5+ cells in both anterior chambers.\n\nThe follow-up had been arranged prior to the administration of her systemic steroids, and thus her ocular hypertension contributed to by the intravenous methylprednisolone was picked up almost incidentally rather than through specific screening.\n\nTreatment\nDue to her extremely high IOPs, the patient was admitted for intravenous acetazolamide and topical antihypertensive therapy. After a single dose of intravenous acetazolamide her pressures improved to 25 mm Hg in the right eye and 35 mm Hg in the left eye. After two further doses her pressures were 17 mm Hg bilaterally, within the normal range. She was commenced on topical timolol, latanoprost and brinzolamide, and 7 days later, her pressures were 14 mm Hg bilaterally.\n\nSystemic steroids were discontinued, and she was commenced on adalimumab for long-term control of her arthritis and uveitis.\n\nOutcome and follow-up\nHer pressures remained low at 12 mm Hg bilaterally on long-term follow-up. Topical therapy was discontinued in January 2016 and her IOPs remained normal. Her uveitis was well controlled on adalimumab with no side effects. She had close follow-up for the next 3 years, and her IOPs remain normal.\n\nShe received an intra-articular injection of 30 mg triamcinolone acetonide but had normal IOPs before and 48 hours after the procedure.\n\nDiscussion\nMild intraocular hypertension is a well-described side effect of both topical and systemic corticosteroid therapy: mild rises in IOP occur in up to 60% of patients,2 but significant rises are uncommon. Risk factors for raised IOP following steroid administration include a previous history of uveitis,2 comorbid connective tissue disease3 and younger age.4 Severe intraocular hypertension can be vision threatening but is frequently asymptomatic; therefore, early recognition and management is important.\n\nOur case is noteworthy for several reasons: the severity of the ocular hypertension, the rapid speed of onset following the administration of intravenous steroids and due to its asymptomatic nature, being discovered almost incidentally. A previous published case described a patient with symptoms (headaches, eye pain, reduced visual acuity),5 while another described the onset following several months of therapy,6 but none described such markedly raised pressures in an asymptomatic patient.\n\nAdditionally this case highlights that significant intraocular hypertension can present very differently in children. Adults with such significant rises in IOP typically present with headaches and visual disturbance.7 The patient in this case was only fatigued, and had neither of these classical symptoms. Thus it is important to consider the diagnosis in children even in the absence of classical symptoms.\n\nThis patient developed severe ocular hypertension due to a combination of her topical prednisolone drops and pulsed intravenous methylprednisolone therapy. It is not possible to determine the precise contribution of each to her ocular hypertension, but it is likely that the severity of her ocular hypertension was related to the combination of both routes of administration. She developed this condition within 3 weeks of commencing topical steroid therapy. Had she not been followed-up for her uveitis the high pressure may have been missed. Routine measurement of IOP for patients receiving topical and intravenous steroid therapy with risk factors may be advisable to allow early detection and management of this condition.\n\nPatient’s perspective\n(Written by the patient’s mother) This was the hardest day that we have had to deal with regarding our daughter’s condition. To be told that we may have to go to London for her to have an operation on her eyes was very hard to digest. My little girl having medication that was supposed to help her that could make her go blind was so scary. If we had not have gone into the eye hospital for a routine check-up that morning then I really don’t want to think where we would be now. The adult doctor that was called didn’t believe that her pressures were up so high: he came in from home to check them himself. He said that if the pressure was up this high in an adult that they would be presenting very different to how our child was presenting. All she wanted to do was go to sleep and not open her eyes. She was very lethargic and had no energy to do anything. We want to make doctors aware that this can happen and to prevent some other family from going through what we went through.\n\nLearning points\nSteroid-induced ocular hypertension can occur in patients with juvenile idiopathic arthritis treated with systemic steroids.\n\nIt is usually asymptomatic and can be easily missed without screening. This puts patients at risk of sight-threatening glaucomatous optic neuropathy.\n\nConsider screening for ocular hypertension following pulsed intravenous methylprednisolone therapy, especially in patients using topical ocular steroids.\n\nContributors: AB wrote initial draft. AK amended the draft and approved the final version.\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\nProvenance and peer review: Not commissioned; externally peer reviewed.\n\nPatient consent for publication: Parental/guardian consent obtained.\n==== Refs\nReferences\n1 \nChy L , Dorothy SP , Jonathan CH \nCorticosteroid-induced glaucoma in children . Hong Kong Journal of Ophthalmology \n2014 ;18 :14 –19 .\n2 \nKramar M , Vu L , Whitson JT , et al \nThe effect of intravitreal triamcinolone on intraocular pressure . Curr Med Res Opin \n2007 ;23 :1253 –8 . 10.1185/030079907X187946 \n17559723 \n3 \nPhulke S , Kaushik S , Kaur S , et al \nSteroid-induced Glaucoma: An Avoidable Irreversible Blindness . J Curr Glaucoma Pract \n2017 \n11 :67 –72 . 10.5005/jp-journals-10028-1226 \n28924342 \n4 \nJonas JB , Degenring RF , Kreissig I , et al \nIntraocular pressure elevation after intravitreal triamcinolone acetonide injection . Ophthalmology \n2005 ;112 :593 –8 . 10.1016/j.ophtha.2004.10.042 \n15808249 \n5 \nFitzgerald LA , Dudley J , Inward C , et al \nUnder pressure: an ocular complication of oral corticosteroid therapy . BMJ Case Rep \n2012 ;2012 :bcr2012006955 \n10.1136/bcr-2012-006955 \n\n6 \nSousa DC , Leal I , Abegão Pinto L \nSteroid-induced protracted severe ocular hypertension in a 14-year-old girl . BMJ Case Rep \n2018 ;38 :bcr-2018-225244 \n10.1136/bcr-2018-225244 \n\n7 \nKohndkaryan A , Francis B \nAngle-closure glaucoma . BMJ Best Practice \n2018 .\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1757-790X",
"issue": "12(5)",
"journal": "BMJ case reports",
"keywords": "glaucoma; paediatrics; paediatrics (drugs and medicines); rheumatology",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D061605:Administration, Intravenous; D000893:Anti-Inflammatory Agents; D001171:Arthritis, Juvenile; D002648:Child; D005260:Female; D006801:Humans; D008775:Methylprednisolone; D009798:Ocular Hypertension; D012720:Severity of Illness Index; D014606:Uveitis, Anterior",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "31129643",
"pubdate": "2019-05-24",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "15808249;17559723;22967687;28924342;29950368",
"title": "Severe acute ocular hypertension following pulsed methylprednisolone for juvenile idiopathic arthritis.",
"title_normalized": "severe acute ocular hypertension following pulsed methylprednisolone for juvenile idiopathic arthritis"
} | [
{
"companynumb": "GB-CONCORDIA PHARMACEUTICALS INC.-E2B_00020045",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugad... |
{
"abstract": "OBJECTIVE\nTo evaluate early changes of vascular lesions and their associations with the early responses to combined photodynamic therapy (PDT) in eyes with polypoidal choroidal vasculopathy (PCV).\n\n\nMETHODS\nThis study evaluated 19 eyes of 19 patients with PCV who underwent PDT combined with anti-vascular endothelial growth factor injections and were followed for 3 months. All subjects were examined 1 week and 1, 2, and 3 months after combined PDT. \"Active\" cases were defined as recurrence or persistence of serous retinal detachment or subretinal hemorrhage detected within 3 months. Branching vascular networks (BVNs) were evaluated by optical coherence tomography angiography (OCTA) and polyps by indocyanine-green angiography.\n\n\nRESULTS\nIn total, 16%, 58%, 84%, and 89% of eyes displayed BVNs 1 week, 1, 2, and 3 months after PDT, respectively. BVNs were detected significantly more often 1 month after PDT in the \"active\" group than \"inactive\" group (89% vs. 30%, p = 0.020). There were significantly higher overall proportions of BVNs detected by OCTA in the \"active\" group than \"inactive\" group (p = 0.0058).\n\n\nCONCLUSIONS\nIn most cases, BVNs disappeared once and gradually appeared again within 3 months. Detecting BVNs using OCTA from early phases could be a helpful biomarker to assess the early responses to PDT in eyes with PCV.",
"affiliations": "Department of Ophthalmology, University of Tokyo Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.;Department of Ophthalmology, University of Tokyo Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.;Department of Ophthalmology, University of Tokyo Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.;Department of Ophthalmology, University of Tokyo Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.;Department of Ophthalmology, University of Tokyo Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.;Department of Ophthalmology, University of Tokyo Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.;Department of Ophthalmology, University of Tokyo Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.;Department of Ophthalmology, University of Tokyo Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.;Department of Ophthalmology, University of Tokyo Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan. robata-tky@umin.ac.jp.",
"authors": "Asano-Shimizu|Kimiko|K|;Asano|Shotaro|S|;Murata|Hiroshi|H|;Azuma|Keiko|K|;Nomura|Yoko|Y|;Inoue|Tatsuya|T|;Ogawa|Asako|A|;Asaoka|Ryo|R|;Obata|Ryo|R|http://orcid.org/0000-0002-1762-0797",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1007/s10792-020-01299-3",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0165-5701",
"issue": "40(6)",
"journal": "International ophthalmology",
"keywords": "Branching vascular network (BVN); Indocyanine-green angiography (ICGA); Optical coherence tomography angiography (OCTA); Photodynamic therapy (PDT); Polypoidal choroidal vasculopathy (PCV)",
"medline_ta": "Int Ophthalmol",
"mesh_terms": "D000368:Aged; D002829:Choroid; D015862:Choroid Diseases; D005260:Female; D005451:Fluorescein Angiography; D005654:Fundus Oculi; D006801:Humans; D008297:Male; D010778:Photochemotherapy; D011127:Polyps; D012171:Retinal Vessels; D012189:Retrospective Studies; D041623:Tomography, Optical Coherence",
"nlm_unique_id": "7904294",
"other_id": null,
"pages": "1335-1345",
"pmc": null,
"pmid": "32026179",
"pubdate": "2020-06",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": null,
"title": "Early changes of vascular lesions and responses to combined photodynamic therapy in patients with polypoidal choroidal vasculopathy.",
"title_normalized": "early changes of vascular lesions and responses to combined photodynamic therapy in patients with polypoidal choroidal vasculopathy"
} | [
{
"companynumb": "JP-BAUSCH-BL-2020-018849",
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"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VERTEPORFIN"
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"drugadditional": "3",
... |
{
"abstract": "Intrathecal drug delivery systems are an effective and increasingly common pain treatment modality for certain patient populations. Pumps are surgically inserted in a subcutaneous abdominal pocket and refilled with highly concentrated medication at regular intervals. Inadvertent injection of medication outside the pump is a known complication of the refill procedure. We describe the injection of hydromorphone into the pump's surrounding subcutaneous pocket, subsequent opioid overdose, and the novel application of ultrasound to visualize and aspirate the subcutaneous drug. Ultrasonography can be used as an effective modality for rapid diagnosis and treatment of an accidental pocket fill.",
"affiliations": "From the *Department of Anesthesiology, Perioperative, and Pain Medicine, Brigham & Women's Hospital, Harvard Medical School; and †Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA.",
"authors": "Peccora|Christian D|CD|;Ross|Edgar L|EL|;Hanna|George M|GM|",
"chemical_list": "D000701:Analgesics, Opioid; D009292:Narcotic Antagonists; D004091:Hydromorphone",
"country": "England",
"delete": false,
"doi": "10.1097/AAP.0000000000000008",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1098-7339",
"issue": "38(6)",
"journal": "Regional anesthesia and pain medicine",
"keywords": null,
"medline_ta": "Reg Anesth Pain Med",
"mesh_terms": "D000369:Aged, 80 and over; D000701:Analgesics, Opioid; D062787:Drug Overdose; D004867:Equipment Design; D005260:Female; D006801:Humans; D004091:Hydromorphone; D015918:Infusion Pumps, Implantable; D060186:Infusions, Spinal; D008508:Medication Errors; D009292:Narcotic Antagonists; D013396:Suction; D016896:Treatment Outcome; D018084:Ultrasonography, Interventional",
"nlm_unique_id": "9804508",
"other_id": null,
"pages": "544-6",
"pmc": null,
"pmid": "24121607",
"pubdate": "2013",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Aberrant intrathecal pump refill: ultrasound-guided aspiration of a substantial quantity of subcutaneous hydromorphone.",
"title_normalized": "aberrant intrathecal pump refill ultrasound guided aspiration of a substantial quantity of subcutaneous hydromorphone"
} | [
{
"companynumb": "US-ACTAVIS-2014-16160",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
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"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "GABAPENTIN"
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"drugadditional": null,
... |
{
"abstract": "Clinical presentation of Lyme-associated uveitis is poorly described. We reported here a case series of seven patients with uveitis related to Lyme disease and a review of the literature.\nA retrospective study in our university hospital between 1 May 2003 and 31 July 2016 on 1006 uveitis patients and review of Pubmed library.\nSeven patients (71.4% male, mean age = 53 (38-70)) were diagnosed with a Lyme-associated uveitis. All anatomical types of uveitis were found (four intermediate, three anterior, and three posterior uveitis); most were unilateral (n = 6; 85.7%), one granulomatous and two with synechiae. Peripheral retinal vasculitis was present in four patients. They all had a risk of exposure or extra-ophthalmological symptoms. Antibiotic and steroid treatment was rapidly effective in all patients. Four patients presented recurrences of uveitis, of whom two received a second antibiotic treatment, which is quite common in literature. Persistent or recurrence of symptoms can be explained by three hypotheses: (1) reinfection, (2) relapse of original infection, and (3) autoimmune reaction.\nLyme-associated uveitis appears varied. Hyalitis and involvement of the posterior segment and retinal vasculitis seem to be rather frequent. Its prognosis is mainly good, even if inflammation can be resistant or recurring.",
"affiliations": "Department of Ophthalmology, Croix-Rousse University Hospital, Hospices Civils de Lyon, University of Lyon I, Lyon, France.;Department of Internal Medicine, Hôpital de la Croix-Rousse, Hospices Civils de Lyon, University of Lyon I, Lyon, France.;Department of Ophthalmology, Croix-Rousse University Hospital, Hospices Civils de Lyon, University of Lyon I, Lyon, France.;Laboratory of Bacteriology, Croix-Rousse University Hospital, Hospices Civils de Lyon, University of Lyon I, Lyon, France.;Department of Infectious Diseases, Hôpital de la Croix-Rousse, Hospices Civils de Lyon, University of Lyon I, Lyon, France.;Department of Ophthalmology, Croix-Rousse University Hospital, Hospices Civils de Lyon, University of Lyon I, Lyon, France.;Department of Internal Medicine, Hôpital de la Croix-Rousse, Hospices Civils de Lyon, University of Lyon I, Lyon, France.;Department of Ophthalmology, Croix-Rousse University Hospital, Hospices Civils de Lyon, University of Lyon I, Lyon, France.;Department of Ophthalmology, Croix-Rousse University Hospital, Hospices Civils de Lyon, University of Lyon I, Lyon, France.",
"authors": "Bernard|Alexia|A|;Seve|Pascal|P|;Abukhashabh|Amro|A|;Roure-Sobas|Chantal|C|;Boibieux|Andre|A|;Denis|Philippe|P|;Broussolle|Christiane|C|;Mathis|Thibaud|T|;Kodjikian|Laurent|L|",
"chemical_list": "D000900:Anti-Bacterial Agents; D005938:Glucocorticoids",
"country": "United States",
"delete": false,
"doi": "10.1177/1120672119856943",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1120-6721",
"issue": "30(5)",
"journal": "European journal of ophthalmology",
"keywords": "Borrelia resistance; Lyme disease; Uveitis; antibiotic treatment; inflammatory response; relapse",
"medline_ta": "Eur J Ophthalmol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000900:Anti-Bacterial Agents; D009877:Endophthalmitis; D015818:Eye Infections, Bacterial; D005260:Female; D005938:Glucocorticoids; D006801:Humans; D008193:Lyme Disease; D008297:Male; D008875:Middle Aged; D012008:Recurrence; D031300:Retinal Vasculitis; D012189:Retrospective Studies; D014605:Uveitis",
"nlm_unique_id": "9110772",
"other_id": null,
"pages": "874-885",
"pmc": null,
"pmid": "31238716",
"pubdate": "2020-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Lyme-associated uveitis: Clinical spectrum and review of literature.",
"title_normalized": "lyme associated uveitis clinical spectrum and review of literature"
} | [
{
"companynumb": "FR-SUN PHARMACEUTICAL INDUSTRIES LTD-2020RR-267155",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CEFTRIAXONE"
},
"dru... |
{
"abstract": "Hypersensitivity reactions (HSR) to pegylated liposomal doxorubicin (PLD; Caelyx®) have been reported, and symptoms usually resolve with drug withdrawal. However, the risk of relapse of severe HSR and prevention remain poorly described. To report the management and outcome in four patients with HSR due to PLD. Patient characteristics, premedication regimen, rate of infusion, time between onset and HSR, clinical manifestations, and management were documented. A first cycle of PLD was received for cutaneous T-cell lymphoma (n = 3) and Kaposi sarcoma (n = 1). The drug was diluted in 250 mL 5% glucose and administered over one hour (4.17 mL dilution/min, i.e. 0.6 mg PLD/min for 1.8 m2 body surface area [BSA]). Grade 3 HSR occurred in the first minutes in the four patients. Because of the absence of alternative treatment for the underlying disease, PLD was resumed. Premedication was reinforced with 300 mg oral ranitidine and 50 mg hydroxyzine the night before and the morning of infusion. The rate of infusion was 1 mL dilution/min (0.14 mg PLD/min for 1.8 m2 BSA) for the first 15 minutes. No HSR occurred in three patients. In contrast, severe symptoms appeared in the first seconds of resumption in one patient. To minimise HSR to PLD, an initial reduced rate of infusion of 0.1-0.2 mg of PLD/min is warranted. In the event of HSR, alternative therapy must be privileged, and if necessary, careful re-challenge with PLD may be attempted, however relapse of HSR may occur.",
"affiliations": "Dermatology Department, APHP, Henri Mondor Hospital, Créteil, France, EA 7379 EpiDermE (Epidémiologie en Dermatologie et Evaluation des Thérapeutiques), UPEC, Créteil, France, French Study Group of Cutaneous Lymphoma (GFELC).;Department of Dermatology, Saint-André Hospital CHU Bordeaux, Bordeaux, France, INSERM U1053, Bordeaux Research in Translational Oncology University Bordeaux, Bordeaux, France.;Hematooncology Department, APHP, Saint-Louis Hospital, Paris, France, French Study Group of Cutaneous Lymphoma (GFELC).;EA 7379 EpiDermE (Epidémiologie en Dermatologie et Evaluation des Thérapeutiques), UPEC, Créteil, France, Regional Pharmacovigilance Center, APHP, Pitié-Salpêtrière Hospital, Paris, France.;Dermatology Department, APHP, Henri Mondor Hospital, Créteil, France, EA 7379 EpiDermE (Epidémiologie en Dermatologie et Evaluation des Thérapeutiques), UPEC, Créteil, France.;Pharmacy, Henri Mondor Hospital, Créteil, France.;Dermatology Department, APHP, Saint-Louis Hospital, Paris, France, French Study Group of Cutaneous Lymphoma (GFELC).;Dermatology Department, APHP, Cochin Hospital, Paris, France.;Dermatology Department, APHP, Saint-Louis Hospital, Paris, France, French Study Group of Cutaneous Lymphoma (GFELC).;Dermatology Department, APHP, Henri Mondor Hospital, Créteil, France, EA 7379 EpiDermE (Epidémiologie en Dermatologie et Evaluation des Thérapeutiques), UPEC, Créteil, France, Université Paris-Est Créteil Val de Marne (UPEC), Créteil, France.;Department of Dermatology, Saint-André Hospital CHU Bordeaux, Bordeaux, France, INSERM U1053, Bordeaux Research in Translational Oncology University Bordeaux, Bordeaux, France, French Study Group of Cutaneous Lymphoma (GFELC).",
"authors": "Ingen-Housz-Oro|Saskia|S|;Pham-Ledard|Anne|A|;Brice|Pauline|P|;Lebrun-Vignes|Bénédicte|B|;Zehou|Ouidad|O|;Reitter|Delphine|D|;Ram-Wolff|Caroline|C|;Dupin|Nicolas|N|;Bagot|Martine|M|;Chosidow|Olivier|O|;Beylot-Barry|Marie|M|",
"chemical_list": "D000903:Antibiotics, Antineoplastic; C506643:liposomal doxorubicin; D011092:Polyethylene Glycols; D004317:Doxorubicin",
"country": "France",
"delete": false,
"doi": "10.1684/ejd.2017.2986",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1167-1122",
"issue": "27(3)",
"journal": "European journal of dermatology : EJD",
"keywords": "Kaposi sarcoma; allergy; cutaneous lymphoma; hypersensitivity; pegylated liposomal doxorubicin; pseudo-allergy",
"medline_ta": "Eur J Dermatol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000903:Antibiotics, Antineoplastic; D004317:Doxorubicin; D005260:Female; D006801:Humans; D006969:Hypersensitivity, Immediate; D016410:Lymphoma, T-Cell, Cutaneous; D008297:Male; D008875:Middle Aged; D011092:Polyethylene Glycols; D011292:Premedication; D012878:Skin Neoplasms",
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"title": "Immediate hypersensitivity reaction to pegylated liposomal doxorubicin: management and outcome in four patients.",
"title_normalized": "immediate hypersensitivity reaction to pegylated liposomal doxorubicin management and outcome in four patients"
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"abstract": "Castleman's disease is a rare lymphoproliferative syndrome involving several anatomical and clinical entities. We report two cases of Castleman's disease in patients with spondyloarthritis (with and without psoriasis) treated with Tumor Necrosis Factor-alpha blockers. During follow-up, imaging examinations, carried out for disease assessment, fortuitously revealed a pelvic mass close to the psoas or an atypical cervical adenopathy. Both lesions were in moderate hypermetabolism on Positron emission tomography-computed tomography. After surgical excision and histological analysis, Castleman's disease was diagnosed without signs of malignancy. To the best of our knowledge, these are the first cases of Castleman's disease diagnosed in a context of spondyloarthritis treated with Tumor Necrosis Factor-alpha blockers. The relationship between these two pathologies and the link with Tumor Necrosis Factor-alpha blockers agents has not been explored in the literature until now.",
"affiliations": "Department of Rheumatology, CIC/CRB 1404, Rouen University Hospital, Normandie Univ, UNIROUEN, 76000 Rouen, France.;Department of Anatomy and Pathological Cytology, Henri Becquerel Center, 1 rue d'Amiens, 76000 Rouen, France.;Department of Orthopaedics and Traumatology, Rouen University Hospital, 1, rue de Germont, 76000 Rouen, France.;Department of Hematology, Henri Becquerel Center, 1, rue d'Amiens, 76000 Rouen, France.;Department of Rheumatology, CIC/CRB 1404, Rouen University Hospital, Normandie Univ, UNIROUEN, 76000 Rouen, France.;Department of Rheumatology, CIC/CRB 1404, Rouen University Hospital, Normandie Univ, UNIROUEN, 76000 Rouen, France. Electronic address: vittecoq.olivier@wanadoo.fr.",
"authors": "Renouprez|Thibaut|T|;Veresezan|Liana|L|;Dujardin|Franck|F|;Jardin|Fabrice|F|;Lequerré|Thierry|T|;Vittecoq|Olivier|O|",
"chemical_list": "D000079424:Tumor Necrosis Factor Inhibitors; D014409:Tumor Necrosis Factor-alpha",
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"issue": "87(6)",
"journal": "Joint bone spine",
"keywords": "Castleman's disease; Spondyloarthritis; TNFalpha-blocker",
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"mesh_terms": "D005871:Castleman Disease; D006801:Humans; D025241:Spondylarthritis; D000079424:Tumor Necrosis Factor Inhibitors; D014409:Tumor Necrosis Factor-alpha",
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"title": "Castleman's disease in two patients with spondyloarthritis treated by Tumor Necrosis Factor-alpha antagonists.",
"title_normalized": "castleman s disease in two patients with spondyloarthritis treated by tumor necrosis factor alpha antagonists"
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"abstract": "Metformin is a commonly used treatment modality in type 2 diabetes mellitus with lactic acidosis as a rare but life-threatening side effect. In this case report we highlight the importance of recognizing this uncommon side effect and the treatment options in a resource limited situation. We present a 14-year-old African girl who ingested an unknown amount of metformin intentionally after an argument with her mother. She was referred late to our institution in severe lactic acidosis. Lactic acidosis resolved with appropriate treatment including peritoneal dialysis. We conclude that in resource constrained settings, peritoneal dialysis may be used for metformin associated lactic acidosis with favourable outcome.",
"affiliations": "Department of Internal Medicine, Walter Sisulu University, Mthatha, South Africa.;Department of Internal Medicine, Walter Sisulu University, Mthatha, South Africa.",
"authors": "Elmezughi|Khaled|K|;Ekpebegh|Chukwuma|C|",
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"fulltext": "\n==== Front\nPan Afr Med JPan Afr Med JPAMJThe Pan African Medical Journal1937-8688The African Field Epidemiology Network PAMJ-32-11210.11604/pamj.2019.32.112.18271Case ReportMetformin-associated lactic acidosis treated successfully by peritoneal dialysis in a resource limited setting: case report Elmezughi Khaled 1&Ekpebegh Chukwuma 11 Department of Internal Medicine, Walter Sisulu University, Mthatha, South Africa& Corresponding author: Khaled Elmezughi, Department of Internal Medicine, Walter Sisulu University, Mthatha, South Africa11 3 2019 2019 32 11227 1 2019 21 2 2019 © Khaled Elmezughi et al.2019The Pan African Medical Journal - ISSN 1937-8688. 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 work is properly cited.Metformin is a commonly used treatment modality in type 2 diabetes mellitus with lactic acidosis as a rare but life-threatening side effect. In this case report we highlight the importance of recognizing this uncommon side effect and the treatment options in a resource limited situation. We present a 14-year-old African girl who ingested an unknown amount of metformin intentionally after an argument with her mother. She was referred late to our institution in severe lactic acidosis. Lactic acidosis resolved with appropriate treatment including peritoneal dialysis. We conclude that in resource constrained settings, peritoneal dialysis may be used for metformin associated lactic acidosis with favourable outcome.\n\nLactic acidosismetformin overdosemetformin toxicityperitoneal dialysisSouth Africa\n==== Body\nIntroduction\nMetformin is the recommended first-line therapy for patients with type 2 diabetes mellitus especially those who are overweight [1]. Despite its being generally safe, metformin may lead to a rare but life-threatening adverse reaction: metformin-associated lactic acidosis (MALA) [2]. MALA is defined as the presence of pH < 7.35, blood lactate >2.0 mmol/L and PaCO2 < 42 mmHg within the context of recent metformin exposure [3-5]. It is associated with a mortality rate of up to 50% [3, 6, 7]. MALA is a rare condition with an estimated incidence of 2-9 patients per 100,000 patients receiving metformin per year [3, 7]. In the largest case series published in the literature to date, the authors reported no more than dozens of cases over years of observation [8]. The etiology of lactic acidosis is multifactorial and uncertain: inhibition of gluconeogenesis by reducing hepatic lactate uptake, inhibition of pyruvate dehydrogenase activity and mitochondrial-reducing agent transport leading to increased metabolism of pyruvate into lactate [3, 9]. It also impairs lactate clearance by the liver through the inhibition of complex 1 of the mitochondrial respiratory chain [5]. MALA usually occurs with impaired renal function but may occur with preserved renal function in the setting of massive metformin ingestion [3, 4]. Voluntary poisoning is rare, and its characteristics and prognosis are seldom reported in the literature [5]. Intermittent haemodialysis is the most frequently reported treatment modality and early continuous renal replacement therapy (CRRT) has been suggested as an alternative along with supportive measures [3]. Although there is limited evidence regarding slow CRRT, it is preferred in patients with haemodynamic instability as it is better tolerated than haemodialysis [10]. Peritoneal dialysis (PD) has been used in the past as a treatment modality for acute intoxications as it is used in the settings of acute kidney injury (AKI) or end-stage renal disease (ESRD) [11], however, to our knowledge no reports have been described in using it for metformin overdose. We describe a case of MALA in a young female, who intentionally ingested an unquantifiable amount of metformin in a suicidal attempt. Although there was profound metabolic acidosis, she fully recovered with fluid resuscitation, bicarbonate administration and rapid institution of peritoneal dialysis.\n\nPatient and observation\nA 14-year old girl was referred to Nelson Mandela Academic Hospital (NMAH) from a district level Hospital few hours after intentional ingestion of a large unquantifiable amount of metformin tablets. This was following an argument with her mother who is diabetic and on metformin treatment. The patient herself was not known with diabetes or psychiatric illness and had no significant past medical history. She was not on any chronic medications. The notable findings on physical examination were acidotic breathing, sinus tachycardia of 120 beats per minute, hypotension (BP 80/45 mmHg) and abdominal tenderness. She was drowsy but arousable. Arterial blood gas on arrival to NMAH showed PH = 7.05, Po2 =115 mmHg= PCo2 = 27.5 mmHg, Base Excess = -23 mmol/L, bicarbonate = 7.6 mmol/, potassium = 6.7 mmol/L, capillary glucose reported low on the glucometer. Lactate level was rejected by the laboratory because of it was not sent on ice. Her other laboratory results at presentation were marked leukocytosis, severe metabolic acidosis, hyperkalemia, hyponatremia as well as mild elevation of the liver enzymes as depicted in Table 1. Electrocardiogram showed peaked T-waves and sinus tachycardia. Chest radiograph was unremarkable. Blood cultures and toxicology screen for paracetamol and salicylate levels were negative. A diagnosis of metformin associated lactic acidosis was made and 100 grams of activated charcoal was administered in the emergency department. She also received 20mls boluses of 50% dextrose several times and was subsequently maintained on intravenous 5% dextrose infusion. Her renal function started deteriorating on the second day after admission in keeping with AKI; (urea 12.6 mmo/L, Creatinine = 251 umol/L, K=7.2 mmol/L) most likely due to metformin toxicity. Hyperkalemia was initially treated with the combination of intravenous calcium gluconate and insulin-glucose to facilitate intracellular shift of potassium. She also received 100mls of 8.4% sodium bicarbonate via a central line. Due to lack of bed in ICU/high care, it was decided that the patient be treated in our acute peritoneal dialysis unit. Peritoneal dialysis was started because of limited availability of haemodialysis. After 45 cycles of peritoneal dialysis in 5 days, she achieved recovery of renal function with restoration of urine output, acid-base balance and complete resolution of lactic acidosis. She was discharged home on the 7th day after admission in very good condition.\n\nTable 1 Laboratory results at presentation\n\n\tPatient’s value\tNormal range\t\nHb (g/L)\t15.1\t12-15\t\nWBC [x109 /L]\t36.53\t3.9-12.6\t\nPlatelets [x109 /L]\t402\t186-454\t\nHCO3 − [Venous] [mmol/L]\t2\t23-29\t\nNa+ [mmol/L]\t133\t136-145\t\nK+ [mmol/L]\t6.9\t3.5-5.1\t\nCl− [mmol/L]\t84\t98-107\t\nAnion Gap [mmol/L]\t54\t9-16\t\nUrea [mmol/L]\t4.3\t1.4-5.4\t\nCreatinine [umol/L]\t71\t40-72\t\nTotal protein [g/L]\t86\t57-80\t\nAlbumin [g/L]\t49\t29-42\t\nBilirubin [umol/L]\t8\t5-21\t\nALT [U/L]\t38\t5-20\t\nGGT [U/L]\t35\t4-24\t\nLactate [mmol/L]\tRejected (not sent on ice)\t0.5-2.2\t\nALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT, gamma-glutamyl transferase\n\nDiscussion\nMetformin, a biguanide, was first used in the 1950s in Europe and Canada and, since 1995, in the United States. It is the most widely used oral antihyperglycemic agent in the world and is the first-line medication for the treatment of type 2 diabetes [9]. Metformin is a small 165 Da molecule with an oral availability of 55% and a distribution volume of 1-5 L/kg. The elimination half-life is 8-20 hours in individuals with normal renal function [5]. Despite the increasing use of metformin, the prevalence of MALA is uncommon; 0.03 cases per 1000 patient-years [2]. Suicide with metformin is rare. Intake of 35 g of metformin has been shown to be lethal [12], however, survival following an overdose of 63 g has been reported [13]. In cases of MALA, the serum lactate level does not correlate with prognosis, even with lactate levels as high as 35.5 mmol/L [12]. Our patient developed profound lactic acidosis that was associated with acute kidney injury, severe hyperkalemia and hypoglycemia. The high anion gap metabolic acidosis is likely due to both lactic and ureamic acidosis. Although serum lactate level was rejected by the laboratory at presentation, subsequent level was found to be still elevated (3.3 mmol/L); normal ranges between 0.5-2.2 mmol/L. Serum metformin assay is not available at our institution, however, other causes of elevated serum lactate including sepsis and tissue ischemia were excluded and there was no evidence of hepatic disease or other toxin ingestions. Our patient presented with classical symptoms of MALA within the context of metformin overdose. Although renal failure is a risk factor for MALA. Our 14-year-old patient's renal function was normal initially, however, it started deteriorating on the second day after presentation and is likely to be caused by metformin overdose. Transient hypotension in our patient responded promptly to intravenous fluids. The pathophysiologic mechanisms of hypotension in MALA include negative inotropic effects and increased systemic vascular resistance with acidosis. Profound hypotension that is unresponsive to fluid therapy may require vasopressors [5]. The use of sodium bicarbonate is controversial and not fully validated in the clinical scenario of lactic acidosis and haemodynamic instability, regardless of the aetiology [5]. Prompt treatment of acidosis in our patient with the combination of fluids, bicarbonate and peritoneal dialysis likely prevented the need for vasopressors. Metformin overdose can be treated easily with standard or high-flux haemodialysis to correct the lactic acidosis as well as to remove the medication [14]. Although mortality rate is high in cases of MALA [3, 8], our patient had a favorable clinical outcome likely from the clearance of metformin and lactate during peritoneal dialysis.\n\nConclusion\nIn resource constrained settings where haemodialysis is not readily available, peritoneal dialysis may be used for the treatment of metformin associated lactic acidosis with a favourable outcome.\n\nAcknowledgement\nThe authors are grateful to the staff of the Department of Internal Medicine at Nelson Mandela Academic Hospital (NMAH) for their kind assistance and collaboration.\n\nCompeting interests\nThe authors declare no competing interests.\n\nAuthors’ contributions\nKhaled Elmezughi and Chukwuma Ekpebegh both contributed to conception, design, drafting and revising the manuscript. Both authors read and approved the final manuscript.\n==== Refs\nReferences\n1 Turner R Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34) Lancet 1998 352 9131 854 856 9742977 \n2 Bailey CJ Turner RC Metformin N Engl J Med 1996 334 9 574 579 8569826 \nKeller G Cour M Hernu R Illinger J Robert D Argaud L Management of metformin-associated lactic acidosis by continuous renal replacement therapy PLoS One 2011 6 8 e23200 21853087 \n3 Lalau JD Race JM Metformin and lactic acidosis in diabetic humans Diabetes, Obes Metab 2000 2 3 131 137 11220548 \n4 Sánchez-Díaz JS Monares-Zepeda E Martínez-Rodríguez EA Cortés-Román JS Torres-Aguilar O Gabriela Peniche-Moguel Diaz-Gutiérrez SP Pin- Gutiérrez E Rivera-Soíis G Garcia-Méndez RC Huanca-Pacaje JM Calyeca-Sánchez Metformin-related lactic acidosis: case report Rev Colomb Anestesiol 2017 45 4 353 359 \n5 Renda F Mura P Finco G Ferrazin F Pani L Landoni Giovanni Metformin-associated lactic acidosis requiring hospitalization: a national 10 year survey and a systematic literature review Eur Rev Med Pharmacol Sci 2013 17 suppl 1 45 49 \n6 Misbin RI Green L Stadel BV Gueriguian JL Gubbi AG Alexander F Lactic Acidosis in Patients with Diabetes Treated with Metformin N Engl J Med 1998 338 4 265 266 9441244 \n7 Lalau JD Race JM Lactic acidosis in metformin-treated patientsPrognostic value of arterial lactate levels and plasma metformin concentrations Drug Saf 1999 20 4 377 384 10230584 \n8 Omar A Ellen R Sorisky A Metformin-Associated Lactic Acidosis in a Patient with Normal Renal Function Can J Diabetes 2016 40 4 280 281 27197687 \n9 Alivanis P Giannikouris I Paliuras C Arvanitis A Volanaki M Zervos A Metformin-associated lactic acidosis treated with continuous renal replacement therapy Clin Ther 2006 28 3 396 400 16750454 \n10 Lalau JD Race JM Lactic acidosis in metformin therapy Drugs 1999 58 Suppl 1 55 60 discussion 75-82 \n11 Teale KFH Devine A Stewart H Harper James The management of metformin overdose Anaesthesia 1998 53 7 698 701 9771180 \n12 Gjedde S Christiansen A Pedersen SB Rungby J Survival following a metformin overdose of 63 g: a case report Pharmacol Toxicol 2003 93 2 98 99 12899672 \n13 Bunchman T Ferris M Management of toxic ingestions with the use of renal replacement therapy Pediatr Nephrol 2011 26 4 535 41 20938691\n\n",
"fulltext_license": "CC BY",
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"issue": "32()",
"journal": "The Pan African medical journal",
"keywords": "Lactic acidosis; South Africa; metformin overdose; metformin toxicity; peritoneal dialysis",
"medline_ta": "Pan Afr Med J",
"mesh_terms": "D000140:Acidosis, Lactic; D000293:Adolescent; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents; D008687:Metformin; D010530:Peritoneal Dialysis; D016896:Treatment Outcome",
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"title": "Metformin-associated lactic acidosis treated successfully by peritoneal dialysis in a resource limited setting: case report.",
"title_normalized": "metformin associated lactic acidosis treated successfully by peritoneal dialysis in a resource limited setting case report"
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"abstract": "Coronavirus Disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) primarily affects the lungs and can lead to acute respiratory distress syndrome (ARDS). The ongoing global pandemic has created healthcare and economic crisis for almost every nation of the world. Though primarily affecting the lungs, it has also affected the kidney in various ways including acute kidney injury (AKI), proteinuria, and hematuria. It has been increasingly shown that African American (AA) individuals affected with COVID-19 and presenting with AKI and nephrotic-range proteinuria are very susceptible to focal segmental glomerulosclerosis (FSGS). The APOL-1 gene, associated with the African American population, has been increasingly recognized as a risk factor for FSGS affected with COVID-19. Our case highlights a similar case of COVID-19 in a 65-year-old AA descendant with biopsy-proven FSGS and genetically confirmed APOL-1 alleles.",
"affiliations": "Lynchburg Nephrology Physicians, 2091 Langhorne Road, Lynchburg, VA 24501, USA.;Richmond Nephrology Associates, 671 Hioaks Road, Suite B, Richmond, VA 23225, USA.;Great Plains Health, 601 W Leota St, North Platte, NE 69101, USA.;Quantum HC, Department of Internal Medicine, Navicent Health, 777 Hemlock Street, Macon, GA 31201, USA.;Quantum HC, Department of Internal Medicine, Navicent Health, 777 Hemlock Street, Macon, GA 31201, USA.;Precision Cancer Center, 122 St Christopher Dr, Ashland, KY 41101, USA.;Promedica Toledo Hospital, 2142 N Cove Blvd, Toledo, OH 43606, USA.;Adventist Medical Center, 115 Mall Drive, Hanford, CA 93230, USA.",
"authors": "Roy|Sasmit|S|https://orcid.org/0000-0002-2509-3915;Kunaparaju|Srikanth|S|;Koduri|Narayana Murty|NM|;Sangani|Vikram|V|;Pokal|Mytri|M|;Konala|Venu Madhav|VM|https://orcid.org/0000-0003-1953-8815;Balla|Mamtha|M|;Adapa|Sreedhar|S|https://orcid.org/0000-0001-5608-5654",
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"doi": "10.1155/2021/3737751",
"fulltext": "\n==== Front\nCase Rep Nephrol\nCase Rep Nephrol\nCRIN\nCase Reports in Nephrology\n2090-6641\n2090-665X\nHindawi\n\n34367703\n10.1155/2021/3737751\nCase Report\nCOVID-19 and APOL-1 High-Risk Genotype-Associated Collapsing Glomerulonephritis\nhttps://orcid.org/0000-0002-2509-3915\nRoy Sasmit docsasmit@gmail.com\n1\nKunaparaju Srikanth 2\nKoduri Narayana Murty 3\nSangani Vikram 4\nPokal Mytri 4\nhttps://orcid.org/0000-0003-1953-8815\nKonala Venu Madhav 5\nBalla Mamtha 6\nhttps://orcid.org/0000-0001-5608-5654\nAdapa Sreedhar 7\n1Lynchburg Nephrology Physicians, 2091 Langhorne Road, Lynchburg, VA 24501, USA\n2Richmond Nephrology Associates, 671 Hioaks Road, Suite B, Richmond, VA 23225, USA\n3Great Plains Health, 601 W Leota St, North Platte, NE 69101, USA\n4Quantum HC, Department of Internal Medicine, Navicent Health, 777 Hemlock Street, Macon, GA 31201, USA\n5Precision Cancer Center, 122 St Christopher Dr, Ashland, KY 41101, USA\n6Promedica Toledo Hospital, 2142 N Cove Blvd, Toledo, OH 43606, USA\n7Adventist Medical Center, 115 Mall Drive, Hanford, CA 93230, USA\nAcademic Editor: Hern n Trimarchi\n\n2021\n5 8 2021\n2021 373775126 5 2021\n28 7 2021\nCopyright © 2021 Sasmit Roy et al.\n2021\nhttps://creativecommons.org/licenses/by/4.0/ This 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.\nCoronavirus Disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) primarily affects the lungs and can lead to acute respiratory distress syndrome (ARDS). The ongoing global pandemic has created healthcare and economic crisis for almost every nation of the world. Though primarily affecting the lungs, it has also affected the kidney in various ways including acute kidney injury (AKI), proteinuria, and hematuria. It has been increasingly shown that African American (AA) individuals affected with COVID-19 and presenting with AKI and nephrotic-range proteinuria are very susceptible to focal segmental glomerulosclerosis (FSGS). The APOL-1 gene, associated with the African American population, has been increasingly recognized as a risk factor for FSGS affected with COVID-19. Our case highlights a similar case of COVID-19 in a 65-year-old AA descendant with biopsy-proven FSGS and genetically confirmed APOL-1 alleles.\n==== Body\n1. Introduction\n\nCoronavirus Disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) primarily affects the lungs and can lead to acute respiratory distress syndrome (ARDS). The kidney is another major organ affected by the virus, which can cause acute kidney injury (AKI), proteinuria, and hematuria which are the independent predictive factors for mortality [1, 2]. COVID-19 infects disproportionately minorities and people with low socioeconomic status resulting in an increased risk of hospitalization and higher mortality [3].\n\nWe describe a case report of an African American male admitted with fever and shortness of breath and was diagnosed with COVID-19, who developed worsening renal function and proteinuria. The patient was subsequently started on hemodialysis and underwent kidney biopsy.\n\nThe kidney biopsy revealed collapsing glomerulonephritis, a rare entity that has reemerged in African American patients (who have a high-risk APOL1 gene), who were infected with COVID-19.\n\n2. Case Presentation\n\nA 65-year-old African American male was admitted to the hospital with chief complaints of fever and shortness of breath. The patient was exposed to a family member who has tested positive for COVID-19 and was subsequently confirmed with SARS-CoV-2 infection by reverse transcriptase polymerase chain reaction (RT-PCR) analysis. The patient's past medical history was significant for hypertension, diabetes mellitus type 2, hyperlipidemia, and chronic kidney disease stage 3A with the baseline glomerular filtration rate (GFR) of 50 mL/min. Home medications included amlodipine 10 milligrams (mg) daily, furosemide 40 mg daily, metformin 500 mg daily, and atorvastatin 40 mg daily. Physical examination was remarkable for a temperature of 101 degrees Fahrenheit, pulse rate of 89 beats/min, blood pressure of 108/75 mm Hg, and a respiratory rate of 22 breaths/min. The patient was in moderate respiratory distress using accessory muscles, and the auscultation of the lungs was significant for bilateral (b/l) wheezing and diffuse crackles. The rest of the physical examination was insignificant. The laboratory data are detailed in Table 1 (all admission) and Table 2 (progress in hospital up to 6 weeks after discharge, renal parameters).\n\nThe renal function was worse from baseline with the serum creatinine of 6.5 mg/dl, blood urea nitrogen (BUN) of 86 mg/dl, and spot urine protein-creatinine (UPC) ratio of 15.8 gm/gm (baseline values: creatinine 1.2 mg/dl, BUN 32 mg/dl, and UPC 2gm/gm 6 months ago). Renal ultrasound revealed b/l enlarged kidneys, with no hydronephrosis. Although he had nephrotic-range proteinuria, he did not present with other classic features of nephrotic syndrome such as severe albuminemia (i.e., serum albumin <2.5 mg/dl) or peripheral edema. Ocular examination for common diabetic retinopathy features such as glaucoma, macular edema, or microaneurysm were absent. The chest X-ray revealed diffuse infiltrates in b/l lung fields consistent with COVID-19. Other serologies including antinuclear antibody (ANA), complements (C3 and C4), antineutrophil cytoplasmic antibodies (ANCAs), antiglomerular basement membrane antibody, and antiphospholipase A2 receptor (anti-PLA2R) antibodies were normal. Serologies for hepatitis B and C virus, Human Immunodeficiency Virus (HIV), Epstein–Barr Virus (EBV), Cytomegalovirus (CMV), and Parvovirus B19 were all negative.\n\nSerum immunofixation did not reveal any monoclonal protein. The patient was initially started on high-flow oxygen through a nasal cannula and was subsequently started on hemodialysis for worsening renal functions with oliguria on day five of admission.\n\nThe patient underwent renal biopsy for proteinuria and AKI to determine the etiology. Kidney biopsy revealed changes consistent with collapsing glomerulopathy, and light microscopy revealed intact glomeruli showing focal segmental sclerosis, associated with loop wrinkling, periglomerular fibrosis, and focal segmental podocyte hyperplasia with tuft collapse. No foci of endocapillary hypercellularity, crescent formation, or necrosis were identified. Out of the five glomeruli in light microscopy, one had global glomerulosclerosis, thereby suggesting roughly 20% renal tissue had global sclerosis. Around 50% globally showed collapsing lesions. The tubular epithelial cytoplasm demonstrated extensive protein resorption droplets, with the presence of focal microcystic dilatation. Interstitium revealed mild mixed inflammatory infiltrates with severe interstitial fibrosis, along with severe arterial intimal fibrosis and mild significant hyaline arteriosclerosis. Immunofluorescence did not show any significant immune deposits, while electron microscopy showed severe effacement of the podocyte foot process. No immune-type electron-dense deposits were identified on electron microscopy. Light and electron microscopy images are provided in Figures 1–5. In situ hybridization for SARS-CoV-2 was negative. Features of diabetic nephropathy such as increase in the mesangial matrix and cell content or decrease in the capillary lumen space were lacking though mild thickening of the glomerular capillary basement membrane was present.\n\nThe patient had two APOL1 risk variants detected through genetic testing which revealed compound heterozygosity for APOL1 G1 and G2 risk alleles.\n\nThe patient was subsequently treated with hydroxychloroquine, remdesivir, corticosteroids, and intravenous antibiotics during the hospital stay. The patient never needed invasive ventilation support nor intensive care unit (ICU) stay. He was discharged to the outpatient dialysis clinic on day 17 as he continued to require dialysis support. The renal function improved after six weeks, and he was taken off dialysis as his serum creatinine improved to 2.4 mg/dl with no further oliguria.\n\nThe patient continues to remain dialysis free till date, and his GFR has improved back to his baseline (pre-COVID-19 state), with the resolution of hematuria and proteinuria (Table 2). For immunosuppression, he completed a three-month course of oral prednisone with gradual tapering.\n\n3. Discussion\n\nThe involvement of the kidney by COVID-19 is frequent and manifests as acute kidney injury, proteinuria, and hematuria often progressing to End-Stage Renal Disease (ESRD) requiring dialysis. Incidents of AKI, proteinuria, and hematuria in COVID-19 patients are 10%, 40%, and 26%, respectively [1, 2].\n\nPatients with glomerulonephritis usually have hematuria, sustained proteinuria composed largely of albumin. There has been emerging evidence of collapsing glomerulopathy on kidney biopsy in genetically susceptible individuals with African ancestry, infected with COVID-19 [4, 5].\n\nCollapsing glomerulopathy presents as segmental or global glomerular collapse with a rapid deterioration in renal function. Focal segmental glomerulosclerosis (FSGS) refers to a pattern of renal injury characterized by segmental glomerular scars that involves some, but not all, glomeruli, clinically largely manifested as proteinuria. FSGS is classified based on a variety of morphologies on the biopsy finding. Among them, collapsing glomerulopathy (CG) represents an aggressive variant that is characterized by a collapse of the glomerular tuft along with hyperplasia and hypertrophy of the podocytes [6]. Acute tubular injury, inflammation of the interstitium, and tubular dilatation with accompanying microcysts are the commonly associated findings of CG [6].\n\nFSGS is more commonly seen in African Americans. Infections such as HIV, CMV, EBV, and Parvovirus B19 are commonly associated with CG. Malignancies, thrombotic microangiopathy, sickle cell disease, cholesterol embolization, genetic mutations, and certain drugs such as heroin, calcineurin inhibitors, pamidronate, and interferon can also cause CG. It is also found in inflammatory and autoimmune conditions such as hemophagocytic syndrome and systemic lupus erythematous [6].\n\nPolymorphism in the gene-encoding Apolipoprotein L1 (APOL1) is a major risk factor for nearly 10% of African Americans with nondiabetic ESRD, particularly FSGS. APOL1 alleles G1 and G2 inherited from each parent are required to increase the risk of kidney disease when compared to G0 which is considered as a low-risk allele [7]. Although, the exact mechanism on how these high-risk alleles transform the podocytes remains elusive [6]: mitochondrial dysfunction, endosome alteration, activation of protein kinases, cell membrane cation channel dysregulation, and interference with actinomycin in podocytes are the multitude of cellular mechanisms put forth based on the cell culture and transgenic mice studies [6].\n\nCOVID-19 has been found to infect a disproportionate ratio of minorities and people of low socioeconomic background leading to increased hospitalization burden and higher mortality rate in these individuals [3]. Based on their study that included combined statistical areas (poverty prone/low − income areas as per the US office of Management and Budget) in 10 major US cities such as New York City, New Orleans, Atlanta, and Chicago, they found 63.5% of the confirmed COVID-19 cases (834126 of 1312679) in the United States as of May 10, 2020, were from those areas itself. In counties with high poverty (median income range, $36,850–$88,960), those with substantially nonwhite populations had an infection rate nearly eight times that of counties with substantially white populations (RR, 7.8; 95% CI, 5.1 to 12) and a death rate more than nine times greater (RR, 9.3; 95% CI, 4.7–18.4) [3].\n\nSurprisingly, it has been found that, patients who had moderate pulmonary symptoms or who recovered from COVID-19, developed AKI and proteinuria and the AKI did not recover despite improvement in respiratory symptoms. This suggests that the effect on the lungs and kidneys are discrete [6]. Despite the initially proposed mechanism of direct renal cell infection [8–10], viral cytotoxic effect on podocyte contributing to AKI based on postmortem studies [6], and electron microscopy demonstrating possible viral particles in patients with CG [11], the follow-up case reports failed to demonstrate virus in a patient with CG by in situ hybridization studies or electron microscopy [6] or RT-PCR essay on renal tissue [12], suggesting an indirect effect of the virus on the kidneys.\n\nKudose et al. studied 17 patients with COVID-19-related AKI and their kidney biopsies and concluded that AKI in COVID-19 patients could be secondary to cytokine-mediated effects and heightened adaptive immune response but not related to direct viral injury [13]. Another multicentric study showed Acute Tubular Necrosis (ATN) and endothelial injury/thrombotic microangiopathy as a pathological process apart from collapsing GN [14].\n\nSARS-CoV-2 enters ACE2 receptors located in proximal tubules and podocytes in kidneys per postmortem histology [7, 15]. In addition to the above mentioned mechanisms, imbalanced RAS activation, hypovolemia, high PEEP, and hemodynamic changes are suggested by Ahmadian et al. [16] Also, IgA nephropathy was seen as a causative agent for AKI in COVID-19 in one case [17].\n\n3.1. Treatment\n\nTreatment of COVID-19 is still an evolving process with various guidelines and studies conducted worldwide [18]. Treatment of secondary FSGS involves management of the etiology and reduction of proteinuria. The benefit of remdesivir is not observed in patients with eGFR <30, though our patient did receive it [19]. Anecdotal evidences of steroid use in collapsing GN is there without any definitive guidelines [20].\n\n4. Conclusions\n\nKidney biopsy needs to be strongly considered, when there is clinical evidence of glomerulus involvement. Gene testing for APOL-1 should be performed if the patients are of African descent and are having nephrotic-range proteinuria with rapidly progressive renal failure. More evidence is needed through larger studies in terms of establishing prognostic markers, treatments, long-term effects of COVID-19 on the kidneys, and early interventions to improve outcomes.\n\nData Availability\n\nData were obtained from the PubMed and Google Scholar database. The authors declare the data supporting the fundings of the study are available within the article.\n\nConsent\n\nThe patient consented for publication of this study, and the written consent form is available to authors for submission if requested.\n\nConflicts of Interest\n\nThe authors have no conflicts of interest to declare.\n\nFigure 1 Focal microcystic tubular dilatation.\n\nFigure 2 No proliferative glomerular changes.\n\nFigure 3 Segmental sclerosis and periglomerular fibrosis with tuft collapse.\n\nFigure 4 Tubules with protein resorption droplets.\n\nFigure 5 Electron microscopy showing diffuse foot process effacement (arrow).\n\nTable 1 Admission labs with normal reference value.\n\n \tValue\tReference range\t\nWhite blood cell count (109/L)\t12.6\t4.5 to 11.0\t\nHemoglobin (g/dL)\t9.2\t13.5–14.5\t\nPlatelets (109/L)\t356\t150–400\t\nSodium (mmol/L)\t135\t135–145\t\nPotassium (mmol/L)\t4.0\t3.5–5.1\t\nCarbon dioxide (mmol/L)\t20\t24\t\nBUN (mg/dL)\t52\t7–20\t\nCreatinine (mg/dL)\t3.37\t0.9–1.3\t\neGFR (mL/min)\t23\t>60\t\nAlbumin (g/dL)\t3.5\t4\t\nTotal protein (g/dL)\t8.1\t6–8.3\t\nCreatinine kinase (U/L)\t996\t39–308\t\nC-reactive protein (mg/dl)\t12.5\t0.0–0.60\t\nFerritin (ng/ml)\t3624\t26–388\t\nInterleukin-6 (pg/ml)\t104.5\t0.0–15.5\t\nUPCR (g/g)\t15.8\t0.0–.02\t\nRBC on microscopy\t>100/hpf\t<3/hpf\t\n\nTable 2 Renal parameters from admission to 6-week follow-up.\n\nLaboratory value\tAdmission\tPeak\tDischarge\t6 weeks after discharge\t\nCreatinine\t3.37\t6.16\t6.46\t2.4\t\nBUN\t52\t72\t60\t34\t\nUrine protein/creatinine ratio\t15.8\t—\t—\t—\t\nHematuria\t>100/hpf\t—\t—\t—\n==== Refs\n1 Cheng Y. Luo R. Wang K. Kidney disease is associated with in-hospital death of patients with COVID-19 Kidney International 2020 97 5 829 838 10.1016/j.kint.2020.03.005 32247631\n2 Li Z. Wu M. Yao J. Caution on kidney dysfunctions of COVID-19 patients medRxiv 2020 https://www.medrxiv.org/content/10.1101/2020.02.08.20021212v2 10.1101/2020.02.08.20021212v2\n3 Adhikari S. Pantaleo N. P. Feldman J. M. Ogedegbe O. Thorpe L. Troxel A. B. Assessment of community-level disparities in coronavirus disease 2019 (COVID-19) infections and deaths in large US metropolitan areas JAMA Network Open 2020 3 7 e2016938 10.1001/jamanetworkopen.2020.16938)\n4 Shetty A. A. Tawhari I. Safar-Boueri L. COVID-19-associated glomerular disease Journal of the American Society of Nephrology 2021 32 1 33 40 10.1681/asn.2020060804 33214201\n5 Wu H. Larsen C. P. Hernandez-Arroyo C. F. AKI and collapsing glomerulopathy associated with COVID-19 and APOL1 high-risk genotype Journal of the American Society of Nephrology 2020 31 8 1688 1695 10.1681/asn.2020050558 32561682\n6 Nasr S. H. Kopp J. B. COVID-19-associated collapsing glomerulopathy: an emerging entity Kidney International Reports 2020 5 6 759 761 10.1016/j.ekir.2020.04.030 32368701\n7 Friedman D. J. COVID-19 and APOL1: understanding disease mechanisms through clinical observation Journal of the American Society of Nephrology 2021 32 1 1 2 10.1681/ASN.2020111629 33288631\n8 Su H. Yang M. Wan C. Renal histopathological analysis of 26 postmortem findings of patients with COVID-19 in China Kidney International 2020 98 1 219 227 10.1016/j.kint.2020.04.003 32327202\n9 Farkash E. A. Wilson A. M. Jentzen J. M. Ultrastructural evidence for direct renal infection with SARS-CoV-2 Journal of the American Society of Nephrology 2020 31 8 1683 1687 10.1681/asn.2020040432 32371536\n10 Diao B. Wang C. Wang R. Human kidney is a target for novel severe acute respiratory syndrome coronavirus 2 infection Nature Communications 2021 21 2506 10.1038/s41467-021-22781-1\n11 Kissling S. Rotman S. Gerber C. Collapsing glomerulopathy in a COVID-19 patient Kidney International 2020 98 1 228 231 10.1016/j.kint.2020.04.006 32471639\n12 Couturier A. Ferlicot S. Chevalier K. Indirect effects of severe acute respiratory syndrome coronavirus 2 on the kidney in coronavirus disease patients Clinical Kidney Journal 2020 13 3 347 353 10.1093/ckj/sfaa088 32695325\n13 Kudose S. Batal I. Santoriello D. Kidney biopsy findings in patients with COVID-19 Journal of the American Society of Nephrology 2020 31 9 1959 1968 10.1681/asn.2020060802 32680910\n14 Akilesh S. Nast C. C. Yamashita M. Multicenter clinicopathologic correlation of kidney biopsies performed in COVID-19 patients presenting with acute kidney injury or proteinuria American Journal of Kidney Diseases 2021 77 1 82 93 10.1053/j.ajkd.2020.10.001 33045255\n15 Chenna A. Madhav Konala V. Bose S. Acute kidney injury in a case series of patients with confirmed COVID-19 (coronavirus disease 2019): role of angiotensin-converting enzyme 2 and renin-angiotensin system blockade Case Reports in Nephrology 2020 2020 8 8811931 10.1155/2020/8811931\n16 Ahmadian E. Hosseiniyan Khatibi S. M. Razi Soofiyani S. Covid‐19 and kidney injury: pathophysiology and molecular mechanisms Reviews in Medical Virology 2020 31 3 p. e2176 10.1002/rmv.2176\n17 Huang Y. Li X.-J. Li Y.-Q. Clinical and pathological findings of SARS-CoV-2 infection and concurrent IgA nephropathy: a case report BMC Nephrology 2020 21 1 p. 504 10.1186/s12882-020-02163-3 33234164\n18 Bose S. Adapa S. Aeddula N. R. Medical management of COVID-19: evidence and experience Journal of Clinical Medicine Research 2020 12 6 329 343 10.14740/jocmr4201 32587649\n19 Beigel J. H. Tomashek K. M. Dodd L. E. Remdesivir for the treatment of covid-19-final report New England Journal of Medicine 2020 383 19 1813 1826 10.1056/nejmoa2007764\n20 Laurin L.-P. Gasim A. M. Derebail V. K. Renal survival in patients with collapsing compared with not otherwise specified FSGS Clinical Journal of the American Society of Nephrology 2016 11 10 1752 1759 10.2215/cjn.13091215 2-s2.0-85021430670 27445167\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2090-665X",
"issue": "2021()",
"journal": "Case reports in nephrology",
"keywords": null,
"medline_ta": "Case Rep Nephrol",
"mesh_terms": null,
"nlm_unique_id": "101598418",
"other_id": null,
"pages": "3737751",
"pmc": null,
"pmid": "34367703",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "32371536;33288631;32587649;32368701;33214201;32327202;33045255;32445440;32685221;32680910;32561682;32247631;27445167;32721027;32695325;33947851;32471639;33234164;33022818",
"title": "COVID-19 and APOL-1 High-Risk Genotype-Associated Collapsing Glomerulonephritis.",
"title_normalized": "covid 19 and apol 1 high risk genotype associated collapsing glomerulonephritis"
} | [
{
"companynumb": "US-LUPIN PHARMACEUTICALS INC.-2021-18421",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "HYDROXYCHLOROQUINE"
},
"drugad... |
{
"abstract": "The patient was a 65-year-old man with advanced gastric cancer, cT4bN3aM1, cStage Ⅳ. The SOX therapy was administered as the primary treatment but discontinued after 9 courses because of disease progression. The PTX plus RAM therapy was then administered for 1 courses as the secondary treatment but discontinued because of the development of peritoneal dissemination, increased number of ascites, and increased number of lymph node metastases. The nivolumab(NIV)therapy was initiated as the tertiary treatment, but the patient complained of fatigue and diplopia after 2 courses. Ptosis was observed, and transaminase and creatine kinase levels were elevated. Electrocardiography showed complete right bundle branch block. The patient showed immune-related adverse events and was diagnosed with myocarditis and myasthenia gravis due to NIV. Consequently, systemic steroids were administered. Although 2 course of CPT-11 was administered as the fourth-line treatment, the treatment was discontinued upon the patient's request. Ten months after the discontinuation of chemotherapy, the disease showed no progression. The patient is being followed-up as an outpatient. Here, we reported a case of gastric cancer with tumor shrinkage after the discontinuation of NIV.",
"affiliations": "Dept. of Medical Oncology, Ageo Central General Hospital.",
"authors": "Sato|Itaru|I|;Nakaya|Naoki|N|;Obara|Yoko|Y|;Ueno|Souichirou|S|;Nakajima|Hideo|H|",
"chemical_list": "C000708228:2-cyclohexylidenhydrazo-4-phenyl-thiazole; D013844:Thiazoles; D000077594:Nivolumab",
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-0684",
"issue": "47(12)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
"keywords": null,
"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D005743:Gastrectomy; D006801:Humans; D008207:Lymphatic Metastasis; D008297:Male; D000077594:Nivolumab; D013274:Stomach Neoplasms; D013844:Thiazoles",
"nlm_unique_id": "7810034",
"other_id": null,
"pages": "1715-1717",
"pmc": null,
"pmid": "33342990",
"pubdate": "2020-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Advanced Gastric Cancer with Tumor Shrinkage Persisting after the Discontinuation of Nivolumab-A Case Report.",
"title_normalized": "advanced gastric cancer with tumor shrinkage persisting after the discontinuation of nivolumab a case report"
} | [
{
"companynumb": "JP-LUPIN PHARMACEUTICALS INC.-2021-19559",
"fulfillexpeditecriteria": "2",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE"
},
"drugad... |
{
"abstract": "OBJECTIVE\nEzogabine (EZG) is a potassium-channel opener that has been approved as adjunctive treatment for partial-onset seizures in adults with epilepsy. This Phase I clinical study evaluated the pharmacokinetics (PK), safety, and tolerability of coadministration of EZG and a combined oral contraceptive (OC).\n\n\nMETHODS\nAn open-label drug-interaction study was conducted in healthy, female volunteers aged 18 - 55 years with regular menstrual cycles. The effects of steady-state 750 mg EZG on the PK of a combined OC agent containing 1 mg norethindrone and 0.035 mg ethinyl estradiol were evaluated, along with the effect of the contraceptive hormones on EZG PK. Safety was evaluated by clinical laboratory, vital sign, electrocardiogram, physical examination, and adverse event (AE) assessments.\n\n\nRESULTS\nOf 30 enrolled volunteers, 25 completed all treatments. OC did not affect the PK of EZG. EZG increased norethindrone area under the concentration-time curve (AUC) by 28%, with no change in the maximum plasma concentration (Cmax). Ethinyl estradiol Cmax was 21% lower with no change in AUC. The majority of AEs were mild in severity, with the most commonly reported being gastrointestinal disorders and nervous system disorders. No deaths or serious AEs were reported in this study. Five volunteers discontinued treatment due to AEs.\n\n\nCONCLUSIONS\nEZG did not have any clinically relevant impact on exposure of OC hormones in this study, and the OC hormones did not alter EZG PK parameters. This study provides PK evidence that doses of EZG and OCs do not need to be altered when co-administered.",
"affiliations": null,
"authors": "Crean|Christopher S|CS|;Tompson|Debra J|DJ|;Buraglio|Mauro|M|",
"chemical_list": "D000927:Anticonvulsants; D002219:Carbamates; D003277:Contraceptives, Oral, Combined; D010655:Phenylenediamines; C101866:ezogabine; D004997:Ethinyl Estradiol; D009640:Norethindrone",
"country": "Germany",
"delete": false,
"doi": "10.5414/CP201916",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0946-1965",
"issue": "51(11)",
"journal": "International journal of clinical pharmacology and therapeutics",
"keywords": null,
"medline_ta": "Int J Clin Pharmacol Ther",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000927:Anticonvulsants; D002219:Carbamates; D003277:Contraceptives, Oral, Combined; D004347:Drug Interactions; D004997:Ethinyl Estradiol; D005260:Female; D006801:Humans; D008875:Middle Aged; D009640:Norethindrone; D010655:Phenylenediamines; D055815:Young Adult",
"nlm_unique_id": "9423309",
"other_id": null,
"pages": "847-53",
"pmc": null,
"pmid": "24040852",
"pubdate": "2013-11",
"publication_types": "D017426:Clinical Trial, Phase I; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "The effect of ezogabine on the pharmacokinetics of an oral contraceptive agent.",
"title_normalized": "the effect of ezogabine on the pharmacokinetics of an oral contraceptive agent"
} | [
{
"companynumb": "US-JNJFOC-20131100145",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "EZOGABINE"
},
"drugadditional": null,
"... |
{
"abstract": "To report the 10-year outcome of lupus nephritis (LN) treated with mycophenolate mofetil (MMF) or tacrolimus (TAC) induction in a randomised controlled trial.\n\n\n\nPatients with active LN were treated with MMF or TAC combined with high-dose prednisolone. Responders were switched to azathioprine (AZA) at month 6. Clinical outcomes at 10 years (renal flares, renal function decline and mortality) were assessed. Factors affecting prognosis were studied by Cox regression. Urine protein-to-creatinine ratio (uPCr) and estimated glomerular filtration rate (eGFR) at different time points were evaluated for their prediction of a poor prognosis by receiver operating characteristic (ROC) analysis.\n\n\n\n150 patients were studied (age 35.5±12.8 years). Complete renal response rate was similar between MMF (59%) and TAC-treated patients (62%; p=0.71). AZA maintenance was given to 79% patients. After 118.2±42 months, proteinuric and nephritic renal flares occurred in 34% and 37% of the MMF, and 53% and 30% of the TAC groups of patients, respectively (p=0.49). The cumulative incidence of a composite outcome of ↓eGFR ≥30%, chronic kidney disease stage 4/5 or death at 10 years was 33% in both groups (p=0.90). Factors independently associated with a poor renal prognosis were first-time LN (HR 0.12 (0.031 to 0.39); p=0.01), eGFR (HR 0.98 (0.96 to 0.99); p=0.008) and no response at month 6 (HR 5.18 (1.40 to 19.1); p=0.01). ROC analysis revealed an uPCr >0.75 and eGFR of <80 mL/min at month 18 best predicted a poor renal prognosis.\n\n\n\nLong-term data confirmed non-inferiority of TAC to MMF as induction therapy of LN. An uPCr≤0.75 and eGFR of ≥80 mL/min at month 18 best predicted a favourable 10-year outcome and may be suitable targets for induction/consolidation therapy.\n\n\n\nNCT00371319.",
"affiliations": "Medicine, Tuen Mun Hospital, Hong Kong, Hong Kong ccmok2005@yahoo.com.;Medicine, Tuen Mun Hospital, Hong Kong, Hong Kong.;Department of Medicine, Princess Margaret Hospital, Hong Kong, China.;Medicine, United Christian Hospital, Hong Kong, Hong Kong.;Medicine, Tuen Mun Hospital, Hong Kong, Hong Kong.;Medicine, United Christian Hospital, Hong Kong, Hong Kong.",
"authors": "Mok|Chi Chiu|CC|0000-0003-3696-1228;Ho|Ling Yin|LY|;Ying|Shirley King Yee|SKY|;Leung|Man Chi|MC|;To|Chi Hung|CH|;Ng|Woon Leung|WL|",
"chemical_list": "D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D011239:Prednisolone; D009173:Mycophenolic Acid; D001379:Azathioprine; D016559:Tacrolimus",
"country": "England",
"delete": false,
"doi": "10.1136/annrheumdis-2020-217178",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0003-4967",
"issue": "79(8)",
"journal": "Annals of the rheumatic diseases",
"keywords": "lupus nephritis; outcomes research; systemic lupus erythematosus; treatment",
"medline_ta": "Ann Rheum Dis",
"mesh_terms": "D000328:Adult; D001379:Azathioprine; D004791:Enzyme Inhibitors; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D060828:Induction Chemotherapy; D008181:Lupus Nephritis; D060046:Maintenance Chemotherapy; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid; D011239:Prednisolone; D000067251:Symptom Flare Up; D016559:Tacrolimus; D013995:Time; D016896:Treatment Outcome",
"nlm_unique_id": "0372355",
"other_id": null,
"pages": "1070-1076",
"pmc": null,
"pmid": "32448782",
"pubdate": "2020-08",
"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial",
"references": null,
"title": "Long-term outcome of a randomised controlled trial comparing tacrolimus with mycophenolate mofetil as induction therapy for active lupus nephritis.",
"title_normalized": "long term outcome of a randomised controlled trial comparing tacrolimus with mycophenolate mofetil as induction therapy for active lupus nephritis"
} | [
{
"companynumb": "HK-ALKEM LABORATORIES LIMITED-HK-ALKEM-2020-02654",
"fulfillexpeditecriteria": "1",
"occurcountry": "HK",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "AZATHIOPRINE"
},
"dru... |
{
"abstract": "BACKGROUND\nThrombotic microangiopathy (TMA) has been reported as a complication of chemotherapy. Many antineoplastic agents have been linked to TMA, gemcitabine being one of the most frequently cited as related to this syndrome.\n\n\nMETHODS\nA retrospective search for chemotherapy-induced TMA cases among gemcitabine users in a single oncology centre from January 2009 to September 2012 was performed.\n\n\nRESULTS\nThree cases of gemcitabine-induced TMA were reported, from a total of 264 patients (incidence: 1·13%) who received the drug. From the three cases reported, two (66%) patients died as a consequence of the syndrome.\n\n\nCONCLUSIONS\nThese findings are compatible with previous analyses, which report an incidence of gemcitabine-associated TMA ranging from 0·008 to 2·2% and mortality rates from 15 to 90%. Unlike previously reported, however, cumulative dose was not predictive of risk.\n\n\nCONCLUSIONS\nGemcitabine-induced TMA is an underdiagnosed condition characterized by high mortality rates. Attention should be called for a higher level of awareness to provide early diagnosis and proper treatment.",
"affiliations": null,
"authors": "Leal|Frederico|F|;Macedo|Ligia T|LT|;Carvalheira|José Barreto C|JB|",
"chemical_list": "D000964:Antimetabolites, Antineoplastic; D003841:Deoxycytidine; C056507:gemcitabine",
"country": "England",
"delete": false,
"doi": "10.1179/1973947813Y.0000000122",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1120-009X",
"issue": "26(3)",
"journal": "Journal of chemotherapy (Florence, Italy)",
"keywords": "Chemotherapy,; Drug toxicity,; Gemcitabine,; Thrombotic microangiopathies; Thrombotic thrombocytopenic purpura,",
"medline_ta": "J Chemother",
"mesh_terms": "D000328:Adult; D000964:Antimetabolites, Antineoplastic; D003841:Deoxycytidine; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D009369:Neoplasms; D012189:Retrospective Studies; D057049:Thrombotic Microangiopathies",
"nlm_unique_id": "8907348",
"other_id": null,
"pages": "169-72",
"pmc": null,
"pmid": "24091354",
"pubdate": "2014-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Gemcitabine-related thrombotic microangiopathy: a single-centre retrospective series.",
"title_normalized": "gemcitabine related thrombotic microangiopathy a single centre retrospective series"
} | [
{
"companynumb": "BR-TEVA-515089ISR",
"fulfillexpeditecriteria": "1",
"occurcountry": "BR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CARBOPLATIN"
},
"drugadditional": null,
"d... |
{
"abstract": "Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a novel group of oral hypoglycemic agents with multiple proven beneficial effects. However, their use has been associated with euglycemic diabetic ketoacidosis (DKA), typically triggered by risk factors such as acute illness, surgery, and decreased calorie intake. Therefore, it is recommended that patients discontinue SGLT2 inhibitors at least 24 hours before surgery to minimize this risk. We report a case of a postoperative euglycemic DKA in a patient who had discontinued SGLT2 inhibitor therapy 48 hours prior to surgery.\nWe describe the clinical course of a patient with type 2 diabetes mellitus on empagliflozin therapy who was referred for coronary artery bypass graft surgery.\nA 60-year-old man with type 2 diabetes mellitus developed euglycemic DKA a few hours after coronary artery bypass graft surgery. Laboratory results showed acute postoperative elevated anion gap metabolic acidosis with normal glucose and elevated blood ketone levels. It was later revealed that the patient was treated as an outpatient with empagliflozin; the last dose was taken 48 hours prior to his procedure.\nEuglycemic DKA can occur postoperatively in patients with a history of SGLT2 inhibitor use, even 48 hours after the discontinuation of therapy. This case highlights the need to revisit the recommended time to discontinue these agents, specifically prior to major surgery, because their pharmacokinetic effects may persist after 24 hours of discontinuation, putting patients at risk for postoperative euglycemic DKA.",
"affiliations": "Department of Medicine, Maimonides Medical Center, Brooklyn, New York.;Department of Medicine, Maimonides Medical Center, Brooklyn, New York.;Division of Endocrinology, Department of Medicine, Maimonides Medical Center, Brooklyn, New York.",
"authors": "Osafehinti|Deborah A|DA|;Okoli|Ogochukwu J|OJ|;Karam|Jocelyne G|JG|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.aace.2020.11.014",
"fulltext": "\n==== Front\nAACE Clin Case Rep\nAACE Clin Case Rep\nAACE Clinical Case Reports\n2376-0605\nAmerican Association of Clinical Endocrinology\n\nS2376-0605(20)31015-4\n10.1016/j.aace.2020.11.014\nCase Report\nA Case of SGLT2 Inhibitor-Associated Euglycemic Diabetic Ketoacidosis Following Coronary Artery Bypass Surgery\nOsafehinti Deborah A. MD DOsafehinti@maimonidesmed.org\n1∗\nOkoli Ogochukwu J. MD 1\nKaram Jocelyne G. MD 2\n1 Department of Medicine, Maimonides Medical Center, Brooklyn, New York\n2 Division of Endocrinology, Department of Medicine, Maimonides Medical Center, Brooklyn, New York\n∗ Address correspondence and reprint requests to Dr Deborah A. Osafehinti, Department of Medicine, Maimonides Medical Center, 4802, Tenth Avenue, Brooklyn, NY. DOsafehinti@maimonidesmed.org\n28 12 2020\nJan-Feb 2021\n28 12 2020\n7 1 2022\nThis is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).\nObjective\n\nSodium-glucose cotransporter 2 (SGLT2) inhibitors are a novel group of oral hypoglycemic agents with multiple proven beneficial effects. However, their use has been associated with euglycemic diabetic ketoacidosis (DKA), typically triggered by risk factors such as acute illness, surgery, and decreased calorie intake. Therefore, it is recommended that patients discontinue SGLT2 inhibitors at least 24 hours before surgery to minimize this risk. We report a case of a postoperative euglycemic DKA in a patient who had discontinued SGLT2 inhibitor therapy 48 hours prior to surgery.\n\nMethods\n\nWe describe the clinical course of a patient with type 2 diabetes mellitus on empagliflozin therapy who was referred for coronary artery bypass graft surgery.\n\nResults\n\nA 60-year-old man with type 2 diabetes mellitus developed euglycemic DKA a few hours after coronary artery bypass graft surgery. Laboratory results showed acute postoperative elevated anion gap metabolic acidosis with normal glucose and elevated blood ketone levels. It was later revealed that the patient was treated as an outpatient with empagliflozin; the last dose was taken 48 hours prior to his procedure.\n\nConclusion\n\nEuglycemic DKA can occur postoperatively in patients with a history of SGLT2 inhibitor use, even 48 hours after the discontinuation of therapy. This case highlights the need to revisit the recommended time to discontinue these agents, specifically prior to major surgery, because their pharmacokinetic effects may persist after 24 hours of discontinuation, putting patients at risk for postoperative euglycemic DKA.\n\nKey words\n\neuglycemic diabetic ketoacidosis\nSGLT2 inhibitors\ntype 2 diabetes mellitus\nAbbreviations\n\nCABG, coronary artery bypass graft\nDKA, diabetic ketoacidosis\nDM, diabetes mellitus\nSGLT2, sodium-glucose cotransporter 2 inhibitor\n==== Body\nIntroduction\n\nBy 2014, and within 2 years, 3 sodium-glucose cotransporter 2 (SGLT2) inhibitors, namely canagliflozin, dapagliflozin, and empagliflozin, were approved by the U.S. Food and Drug Administration as a novel class of medications for the treatment of diabetes mellitus (DM). SGLT2 inhibitors lower serum glucose levels by blocking glucose reabsorption in the kidneys through a mechanism independent of insulin.1,2 Multiple studies have revealed that this class of medications reduces the risk of hypoglycemia, promotes weight loss, reduces cardiovascular risk, and slows the progression of albuminuria, which has resulted in a significant increase in their use over the past few years.3,4 In the U.S., SGLT2 inhibitors are only approved for the treatment of type 2 DM due to safety concerns in type 1 DM. However, off-label use in type 1 DM is common.5 SGLT2 inhibitors have been associated with an increased risk of diabetic ketoacidosis (DKA), which is characteristically associated with paradoxical normal or slightly elevated serum glucose levels, referred to as euglycemic DKA. Between March 2013 and June 2014, 20 cases of SGLT2-related euglycemic DKA were reported, causing the U.S. Food and Drug Administration to issue a safety warning.5,6\n\nSome described precipitating factors for SGLT2 inhibitor-related euglycemic DKA include acute illness, surgery, a low-calorie intake, and excessive alcohol use.1,3,4 Therefore, the American Association of Clinical Endocrinologists and the American College of Endocrinology advise that patients who are to undergo surgery should stop taking their SGLT2 inhibitors at least 24 hours before surgery to reduce the risk of euglycemic DKA in the postoperative period.5\n\nWe report a case of euglycemic DKA occurring postoperatively in a patient who stopped SGLT2 inhibitor therapy 48 hours before surgery.\n\nCase Report\n\nA 60-year-old man was referred to our hospital for coronary artery bypass graft (CABG) surgery following cardiac catheterization at the referring hospital, which revealed triple-vessel disease. His medical history was significant for coronary artery disease, hypercholesterolemia, and type 2 DM diagnosed 15 years previously. He was taking glimepiride (2 mg twice daily), metformin (1000 mg twice daily), subcutaneous semaglutide (0.25 mg weekly), and empagliflozin (10 mg orally daily). The latter 2 medications were started around a year prior to presentation at our hospital but were not on the medication list that he provided on admission.\n\nOn arrival at our hospital, he was asymptomatic, and vital signs were within normal limits. Laboratory testing revealed a white blood cell count of 7.6 K/μL (reference range: 4.8-10.8 K/μL), hemoglobin of 14.6 g/dL (14-18 g/dL), serum glucose of 157 mg/dL (59-140 mg/dL), bicarbonate of 24 mmol/L (23-32 mmol/L), anion gap of 12 mmol/L (3-11 mmol/L), troponin of 0.09 ng/mL (0.00-0.02 ng/mL), and glycated hemoglobin of 9.6% (81 mmol/mol). Urinalysis revealed glucosuria of >1000 mg/dL and ketonuria of 15 mg/dL. His oral antihyperglycemic medications were withheld, and he was placed on a subcutaneous insulin regimen for inpatient glucose control.\n\nOn the third day (around 42 hours) of admission, the patient underwent CABG surgery. Within just a few hours following surgery, the patient developed elevated anion gap metabolic acidosis with an arterial pH of 7.275, a reduced bicarbonate level of 15 mmol/L, and an increased anion gap of 25 mmol/L. The serum glucose level was normal, at 138 mg/dL (59-140 mg/dL), but the β-hydroxybutyric acid level, which was measured to evaluate the etiology of the acidosis, was elevated at 6.52 mmol/L (0.02-0.27 mmol/L). Hence, a diagnosis of euglycemic DKA was made, and the patient was started on an intravenous insulin drip with an infusion of 5% dextrose in water. He also required transient 24-hour intravenous norepinephrine for hypotension. Ketoacidosis resolved over the next 2 days (Fig.), and he transitioned to subcutaneous insulin (ie, basal and premeal insulin) with adequate glycemic control.Fig Trend of bicarbonate and glucose levels from the onset of diabetic ketoacidosis to the initiation of insulin drip/D5W infusion, and the resolution of ketoacidosis.\n\nThe etiology of elevated anion gap metabolic acidosis was initially unclear considering the patient’s normal glucose level, normal kidney function test results, normal lactic acid level, and negative results for acetaminophen, salicylate, and blood alcohol. Elevated ketone levels and the history, subsequently obtained, of home SGLT2 inhibitor therapy helped to establish the diagnosis of euglycemic DKA. Further investigation revealed that the patient had been on Invokana (canagliflozin) for many years and was switched to Jardiance (empagliflozin) about a year before presentation at our hospital. His last dose of Jardiance was the morning of his transfer to our hospital, which was about 48 hours before the CABG surgery. The remainder of his hospital stay was uneventful. At discharge, he was educated on the need to discontinue SGLT2 inhibitors at least 3 days before any procedure requiring prolonged fasting.\n\nDiscussion\n\nMost cases of SGLT2 inhibitor-related euglycemic DKA seem to have a precipitating factor. Common scenarios include infection, surgery, reduction or discontinuation of insulin, decreased oral intake, dehydration, and excessive alcohol use.1,3,4 A major cardiothoracic procedure, along with prolonged fasting on the day of surgery, were likely precipitants of the euglycemic DKA in our patient.\n\nThe precise mechanism by which SGLT2 inhibitors induce euglycemic DKA is not fully understood. A possible explanation is that SGLT2 inhibitors lower serum glucose levels through the inhibition of glucose reabsorption in the kidneys, leading to decreased insulin release and increased glucagon secretion by the pancreatic cells, both of which stimulate the production of ketones via the beta-oxidation of free fatty acids in the liver.1,4,7 Additionally, SGLT2 inhibitors directly stimulate glucagon release from the pancreas, which feeds back to more ketone production.4,7 In normal physiology, glucose stimulation of insulin release by beta cells, coupled with subsequent insulin-induced inhibition of glucagon secretion, leads to a high insulin-to-glucagon ratio in the pancreatic venous flow and portal circulation, promoting glycogenesis. The renal glucose loss observed with SGLT2 inhibitors decreases insulin stimulation and the insulin-to-glucagon ratio, leading to decreased glycogenesis, and in the setting of prolonged glucose deprivation, increased gluconeogenesis and glycogenolysis. The lack of circulating glucose results in an increased production of ketoacids. Another possible mechanism of ketoacidosis is an SGLT2 inhibitor-induced starvation state that results in increased renal reabsorption of ketone bodies.1,4 Eventually, there will be a buildup of ketosis in the presence of lower glucose levels, which is exacerbated in acute stress or when there is a low availability of carbohydrates.\n\nThe American Association of Clinical Endocrinologists and the American College of Endocrinology recommend discontinuing SGLT2 inhibitors at least 24 hours before elective surgery.5 However, because the SGLT2 inhibitors’ half-lives range from 11 to 17 hours, their pharmacodynamic effects may persist despite discontinuing the medication.3 Our patient stopped empagliflozin intake 48 hours before his CABG but still developed postoperative euglycemic DKA. Another factor that could lower the threshold of euglycemic DKA could be the anticipated stress levels associated with the procedure, which are typically extremely elevated in cardiothoracic surgeries.\n\nA delay in diagnosing euglycemic DKA is common because of the normal to mildly elevated glucose levels (eg, 138 mg/dL in our patient). It also becomes more challenging in the postoperative period, during which direct surgical complications can be mistaken as the cause of acidosis and may lead to unnecessary interventions.3 The diagnosis was also more challenging in our patient because the history of SGLT2 inhibitor use was not obtained on admission, which emphasizes the importance of a detailed medication history.\n\nMore studies are needed to guide the optimal timing of the discontinuation of these agents before elective procedures to reduce the risk of developing euglycemic DKA. An interesting finding in our patient was the presence of significant glycosuria despite normal blood glucose levels on admission. This discordance is probably indicative of a persisting SGLT2 inhibitor effect and possible increased risk of acidosis in a fasting state. A teaching point of our case would be to highlight to providers the alarming nature of persistent glycosuria in a patient treated with an SGLT2 inhibitor and undergoing a procedure. Whether glycosuria is reflecting uncontrolled hyperglycemia or a persistent SGLT2 receptor blockade, it should warrant close monitoring of glucose levels and acid-base status following a prolonged fasting state or procedure.\n\nConclusion\n\nEuglycemic DKA can occur postoperatively in patients with a history of SGLT2 inhibitor use, even 48 hours after discontinuing therapy. With the rapidly expanding use of SGLT2 inhibitors to include, in addition to diabetes, cardiac and renal indications, both providers and patients should be aware of this complication and should consider discontinuing SGLT2 inhibitors at least 48 to 72 hours prior to major surgery. Persistent glycosuria, despite discontinuation of the medication, should warrant closer monitoring for metabolic acidosis following procedures. Detailed medication history and testing for ketones in the blood are imperative to prevent a delay in insulin therapy. Preventive perioperative therapy with both glucose and insulin in patients recently treated with SGLT2 inhibitors might be an effective strategy.\n\nDisclosure\n\nThe authors have no multiplicity of interest to disclose.\n==== Refs\nReferences\n\n1 Diaz-Ramos A. Eilbert W. Marquez D. Euglycemic diabetic ketoacidosis associated with sodium-glucose cotransporter-2 inhibitor use: a case report and review of the literature Int J Emerg Med 12 2019 27 31488052\n2 Hsia D.S. Grove O. Cefalu W.T. An update on sodium-glucose co-transporter-2 inhibitors for the treatment of diabetes mellitus Curr Opin Endocrinol Diabetes Obes 24 2017 73 79 27898586\n3 Peters A.L. Buschur E.O. Buse J.B. Cohan P. Diner J.C. Hirsch I.B. Euglycemic diabetic ketoacidosis: a potential complication of treatment with sodium-glucose cotransporter 2 inhibition Diabetes Care 38 2015 1687 1693 26078479\n4 Gajjar K. Luthra P. Euglycemic diabetic ketoacidosis in the setting of SGLT2 inhibitor use and hypertriglyceridemia: a case report and review of literature Cureus 11 2019 e4384 31218148\n5 Handelsman Y. Henry R.R. Bloomgarden Z.T. American Association of Clinical Endocrinologists and American College of Endocrinology position statement on the association of SGLT-2 inhibitors and diabetic ketoacidosis Endocr Pract 22 2016 753 762 27082665\n6 FDA warns that SGLT2 inhibitors for diabetes may result in a serious condition of too much acid in the blood. U.S. Food and Drug Administration; 2015. Accessed February 7, 2020 https://www.fda.gov/media/92185/download\n7 Ogawa W. Sakaguchi K. Euglycemic diabetic ketoacidosis induced by SGLT2 inhibitors: possible mechanism and contributing factors J Diabetes Investig 7 2016 135 138\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2376-0605",
"issue": "7(1)",
"journal": "AACE clinical case reports",
"keywords": "CABG, coronary artery bypass graft; DKA, diabetic ketoacidosis; DM, diabetes mellitus; SGLT2 inhibitors; SGLT2, sodium-glucose cotransporter 2 inhibitor; euglycemic diabetic ketoacidosis; type 2 diabetes mellitus",
"medline_ta": "AACE Clin Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101670593",
"other_id": null,
"pages": "20-22",
"pmc": null,
"pmid": "33851014",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "31488052;31218148;26078479;27898586;27042263;27082665",
"title": "A Case of SGLT2 Inhibitor-Associated Euglycemic Diabetic Ketoacidosis Following Coronary Artery Bypass Surgery.",
"title_normalized": "a case of sglt2 inhibitor associated euglycemic diabetic ketoacidosis following coronary artery bypass surgery"
} | [
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"companynumb": "US-BoehringerIngelheim-2022-BI-168004",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
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"actiondrug": "6",
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"activesubstancename": "EMPAGLIFLOZIN"
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"abstract": "BACKGROUND\nDegos disease is a frequently fatal and incurable occlusive vasculopathy most commonly affecting the skin, gastrointestinal tract and brain. Vascular C5b-9 deposition and a type I interferon (IFN) rich microenvironment are held to be pathogenetically important in the evolution of the vascular changes. We recently discovered the use of eculizumab as a salvage drug in the treatment of near fatal Malignant atrophic papulosis (MAP). The effects of eculizumab on the pathology of MAP are explored.\n\n\nMETHODS\nArchival skin and gastrointestinal biopsy material was procured over a 2.5-year period before and after eculizumab therapy in our index case. Routine light microscopy and immunohistochemical assessment for C3d, C4d, C5b-9, MxA and caspase 3 were examined. Direct immunofluorescent studies were also conducted on select biopsy material.\n\n\nRESULTS\nThe patient had received eculizumab as a emergent life saving measure and following rapid improvement he continued with biweekly infusions for 4 years. Although improved he continues to have signs and symptoms of persistent abdominal disease. Pre-Eculizumab biopsies showed an active thrombotic microangiopathy associated with a high type I interferon signature and extensive vascular deposits of C5b-9 in skin and gastrointestinal biopsies. Endothelial cell apoptosis as revealed by Caspase 3 expression was noted. Inflammation comprising lymphocytes and macrophages along with mesenchymal mucin was observed as well. Post-eculizumab biopsies did not show active luminal thrombosis but only chronic sequelae of prior episodes of vascular injury. There was no discernible caspase 3 expression. After 12 months of therapy, C5b-9 was no longer detectable in tissue. The high type I IFN signature and inflammation along with mucin deposition was not altered by the drug. In addition, there was little effect of the drug on the occlusive fibrointimal arteriopathy which appears to be one characterized by extensive myofibroblastic expansion of the intima potentially as revealed by staining for smooth muscle actin without immunoreactivity for desmin and myogenin.\n\n\nCONCLUSIONS\nComplement activation and enhanced endothelial cell apoptosis play an important role in the thrombotic complications of MAP. However, the larger vessel proliferative intimal changes appear to be independent of complement activation and may be on the basis of other upstream mechanisms. Monitoring C5b-9 deposition in tissue is likely not of great value in assessing treatment response to eculizumab given the persistence of C5b-9 in tissue for several months despite clinically effective C5 blocking therapy. A more integrated approach addressing upstream and downstream pathways in addition to those attributable to complement activation are critical for the successful treatment of MAP. Eculizumab may be used as salvage therapy in critically ill patients with thrombotic microangiopathy.",
"affiliations": "Department of Pathology and Laboratory Medicine, Weill Medical College of Cornell University, Box 58, Room F-309, 1300 York Avenue, New York, New York 10065, USA. cym2003@med.cornell.edu.",
"authors": "Magro|Cynthia M|CM|;Wang|Xuan|X|;Garrett-Bakelman|Francine|F|;Laurence|Jeffrey|J|;Shapiro|Lee S|LS|;DeSancho|Maria T|MT|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D015933:Complement C3d; D050776:Complement C5b; C481642:eculizumab",
"country": "England",
"delete": false,
"doi": "10.1186/1750-1172-8-185",
"fulltext": "\n==== Front\nOrphanet J Rare DisOrphanet J Rare DisOrphanet Journal of Rare Diseases1750-1172BioMed Central 1750-1172-8-1852427961310.1186/1750-1172-8-185ResearchThe effects of Eculizumab on the pathology of malignant atrophic papulosis Magro Cynthia M 1cym2003@med.cornell.eduWang Xuan 1xuw9004@nyp.orgGarrett-Bakelman Francine 2frg9015@med.cornell.eduLaurence Jeffrey 2jlaurenc@med.cornell.eduShapiro Lee S 3leeshapiromd@gmail.comDeSancho Maria T 2mtd2002@med.cornell.edu1 Department of Pathology and Laboratory Medicine, Weill Medical College of Cornell University, Box 58, Room F-309, 1300 York Avenue, New York, New York 10065, USA2 Division of Hematology/Medical Oncology, Department of Medicine, Weill Medical College of Cornell University, New York, New York 10065, USA3 The Center for Rheumatology, LLP, 1367 Washington Ave., Suite 101, Albany, NY 12206, USA2013 26 11 2013 8 185 185 22 7 2013 9 10 2013 Copyright © 2013 Magro et al.; licensee BioMed Central Ltd.2013Magro et al.; licensee BioMed Central Ltd.This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Background\nDegos disease is a frequently fatal and incurable occlusive vasculopathy most commonly affecting the skin, gastrointestinal tract and brain. Vascular C5b-9 deposition and a type I interferon (IFN) rich microenvironment are held to be pathogenetically important in the evolution of the vascular changes. We recently discovered the use of eculizumab as a salvage drug in the treatment of near fatal Malignant atrophic papulosis (MAP). The effects of eculizumab on the pathology of MAP are explored.\n\nMethods\nArchival skin and gastrointestinal biopsy material was procured over a 2.5-year period before and after eculizumab therapy in our index case. Routine light microscopy and immunohistochemical assessment for C3d, C4d, C5b-9, MxA and caspase 3 were examined. Direct immunofluorescent studies were also conducted on select biopsy material.\n\nResults\nThe patient had received eculizumab as a emergent life saving measure and following rapid improvement he continued with biweekly infusions for 4 years. Although improved he continues to have signs and symptoms of persistent abdominal disease. Pre-Eculizumab biopsies showed an active thrombotic microangiopathy associated with a high type I interferon signature and extensive vascular deposits of C5b-9 in skin and gastrointestinal biopsies. Endothelial cell apoptosis as revealed by Caspase 3 expression was noted. Inflammation comprising lymphocytes and macrophages along with mesenchymal mucin was observed as well. Post-eculizumab biopsies did not show active luminal thrombosis but only chronic sequelae of prior episodes of vascular injury. There was no discernible caspase 3 expression. After 12 months of therapy, C5b-9 was no longer detectable in tissue. The high type I IFN signature and inflammation along with mucin deposition was not altered by the drug. In addition, there was little effect of the drug on the occlusive fibrointimal arteriopathy which appears to be one characterized by extensive myofibroblastic expansion of the intima potentially as revealed by staining for smooth muscle actin without immunoreactivity for desmin and myogenin.\n\nConclusions\nComplement activation and enhanced endothelial cell apoptosis play an important role in the thrombotic complications of MAP. However, the larger vessel proliferative intimal changes appear to be independent of complement activation and may be on the basis of other upstream mechanisms. Monitoring C5b-9 deposition in tissue is likely not of great value in assessing treatment response to eculizumab given the persistence of C5b-9 in tissue for several months despite clinically effective C5 blocking therapy. A more integrated approach addressing upstream and downstream pathways in addition to those attributable to complement activation are critical for the successful treatment of MAP. Eculizumab may be used as salvage therapy in critically ill patients with thrombotic microangiopathy. \n\nEculizumabDegos diseaseComplementC3dC5b-9Caspase 3\n==== Body\nBackground\nMalignant atrophic papulosis (MAP) falls under the alternative appellation of Degos disease and Kohlmeier-Degos disease [1-3]. It is a severe and frequently progressive angiopathy syndrome targeting certain organs, most commonly the skin, gastrointestinal tract, and central nervous system, although other organ sites including the lung and heart can be involved [4-6]. This syndromic complex has very distinctive cutaneous lesions characterized by depressed porcelain plaques with an atrophic center. Similar lesions can affect the gastrointestinal tract as well.\n\nThere are two fundamental components to the vascular disease in MAP, namely a thrombotic microangiopathy targeting capillaries and venules, and a strangulating fibrointimal arteriopathy involving small and medium-sized arteries [7]. The thrombotic microangiopathy affecting capillaries and venules is most commonly manifested in the skin and is the pathogenetic basis of the characteristic cutaneous porcelain plaques. Nevertheless, a thrombotic microangiopathy can affect any organ system and produce acute ischemic symptoms analogous to other catastrophic thrombotic microangiopathy syndromes such as antiphospholipid antibody syndrome, thrombotic thrombocytopenic purpura and hemolytic uremic syndrome [8,9]. In contradistinction, a significant component of the gastrointestinal pathology is attributable to the larger vessel fibrointimal arteriopathy of the submucosal vessels and serosa. Similar arteriopathic changes affect other organs, most notably the subdural arteries and coronary vasculature.\n\nWe have shown in previous studies that there is a role for both type I interferons as well as C5b-9 in the evolution of the microangiopathy and larger vessel arteriopathic changes that define MAP [7]. Human Myxovirus resistance protein 1 (MxA), a widely recognized and accepted marker of type I interferon bioactivity, is highly expressed in MAP, and its expression parallels the pattern of C5b-9 deposition [7]. Due to the extent of membranolytic attack complex deposition within the cutaneous vasculature, we previously hypothesized that blocking C5 through the administration of eculizumab could potentially halt disease progression and possibly even offer a cure to this once fatal disease. We discovered that the drug has a beneficial effect in catastrophic presentations of MAP. However, patients continued to experience symptoms related to the disease, especially in regards to gastrointestinal complications, indicative that the blocking of C5b-9, while significantly beneficial and potentially life saving, does not appear to be curative of MAP.\n\nThe purpose of this study is to better understand the role of complement and, more specifically, C5b-9 (i.e. the membranolytic attack complex) in the pathogenesis of MAP. It is important to delineate more precisely the sequelae of C5 blockage on the pathology of Degos disease to appreciate both the beneficial effects and inherent limitations of the drug. We had the opportunity to study multiple skin and gastrointestinal tissue samples prior to the administration of eculizumab and for up to two and a half years after the commencement of drug in one patient.\n\nMethods\nBiopsy material was available from a patient with MAP who has been receiving biweekly infusions of eculizumab since October 2009. The tissues studied included skin, small and large intestines, and pericardium. Specimens available for assessment included those before and after eculizumab therapy spanning a time period of July 2009 to December 2011. In several cases, additional tissue was available for immunofluorescent studies. The tissue was analyzed with routine light microscopy and immunohistochemical stains were performed to assess for deposition of C5b-9, C3d, and C4d in tissue. In addition, the expression of MxA was explored given the role of type I interferons in the pathogenesis of the microangiopathy. To better characterize the nature of the proliferative intimal response, smooth muscle actin, desmin, myogenin, CD34, and CD14 iimunohistochemical stains were conducted on gastrointestinal resection specimens.\n\nImmunohistochemical staining was performed on 4-μm-thick, formalin-fixed, paraffin-embedded tissue sections by using the Bond 3 Autostainer (Leica Microsystems, Buffalo Grove, IL) and the Bond Polymer Refine detection system (Leica Microsystems). Cleaved Caspase-3 (#9661, Cell Signaling Technology, Boston, MA) was used at a dilution of 1:50. C5b-9 (clone aE11, Dako, Carpinteria, CA) was used at a dilution of 1:250. Antigen retrieval was performed for Caspase-3 with Bond Epitope Retrieval Solution no. 1 (Leica Microsystems). Antigen retrieval for C5b-9 was performed using Enzyme 1 from the Bond Enzyme Pretreatment Kit (Leica Microsystems). Immunostaining was performed according to a modified manufacturer’s protocol and sections were counterstained with hematoxylin, dehydrated, and embedded in Cytoseal XYL (Thermo Scientific, Kalamazoo, MI).\n\nImmunofluorescent studies were conducted on fresh frozen tissue of the skin and gastrointestinal tract on selected cases according to previously published protocols [6].\n\nResults\nBrief clinical synopsis\n46-year-old male who initially presented with intermittent abdominal cramping and non-bloody diarrhea in 2006. In 2007, he started to develop macule- and plaque-like lesions over his upper extremities and trunk. Despite a negative lupus workup, he was given hydroxychloroquine with transient mild subjective improvement in his abdominal symptoms but no change in his skin lesions.\n\nIn July 2009, he developed worsening bilious emesis with fever and abdominal pain of several days’ duration and presented to our hospital. On a chest X-ray, he was found to have sub-diaphragmatic free air as well as pleural effusions. He was emergently sent to the operating room (OR) for exploration. During surgery, he was found to have scattered depressed whitish plaques on his colon and small intestines, mirroring the gross morphology of the skin lesions. A perforation was found in the terminal ileum, which was resected. During this hospital stay, his physical examination also revealed numerous hyperpigmented macules with central atrophy on the trunk and extremities. A few erythematous papules with scaling in the center on the neck and shoulders were also noted. Skin biopsies of these lesions showed findings consistent with Degos disease. The pathological features of the resected small intestine and skin biopsies were discussed below as pre-eculizumab changes. Post-surgery, the patient received intravenous immunoglobulin (IVIg) and was discharged home on prohylactic-dose of low molecular weight heparin.\n\nAfter discharge, he still experienced recurrent intermittent episodes of abdominal pain. In September 2009, he suffered another episode of severe abdominal pain He was diagnosed of a partial small bowel obstruction. He went to the OR and had lysis of adhesions. During surgery, that his small intestine plaques related to MAP seen at the first surgery appeared unchanged in number and distribution.\n\nIn October 2009, he was admitted to the medical intensive care unit (MICU) with left pleural and pericardial effusions complicated by cardiac tamponade. A thoracotomy performed with pericardial window chest tube placement. A concomitant pericardium biopsy showed changes consistent with MAP, the details of which are discussed below as pre-Eculizumab pericardium changes. His hospital stay was further complicated by bilateral subsegmental pulmonary emboli and biventricular failure with a left ventricular ejection fraction (LVEF) of 17%. This rapid decline in his status prompted the decision to initiate eculizumab treatment, with simultaneous support care including Dobutamin, Caspofungin for candida infection and Valganciclovir for his cytomegaloviremia. He experienced significant clinical improvement within 2–3 days of initiation of treatment, and his LVEF increased to 57%. After receiving the initial 3 cycles of Eculizumab, the patient was discharged home.\n\nHe continued eculizumab treatment as an outpatient without complications. His symptoms remained stable and he reported fewer new skin lesions in February 2010, the patient was hospitalized again for small bowel obstruction and lysis of adhesions. The ostomy was resected and the pathological findings are discussed below as post-eculizumab changes. Post surgery, he was found to have peritonitis with proteinaceous ascites, and small bowel wall thickening on imaging. A repeat skin biopsy was performed in March 2010, which showed no significant active endothelial cell necrosis. The findings of this and additional follow-up skin biopsies are detailed below as post-eculizumab changes. The patient’s symptoms again resolved with treatment and he was managed as an outpatient with biweekly infusions of Eculizumab.\n\nIn July 2011, he developed walled-off sigmoid colon perforation unresponsive to medical therapy, for which he underwent exploratory laparotomy with sigmoid colon resection, mobilization of splenic flexure and diverting ileostomy. Examination of the colon showed evidence of remote perforation, and fibro-obliterative vascular changes although without thrombosis and active vasculitis. The results are discussed in details below as the gastrointestinal findings post-Eculizumab, along with results of the concomitant skin biopsies.\n\nBy the end of 2011, the patient had received 61 cycles of eculizumab without complications, and had been largely clinically stable. He continued to experience abdominal pain; however, the pain is not severe and unaccompanied by nausea or vomiting. His skin exam shows a few healed scars along with scattered erythematous papules. However the active inflammatory lesions have not undergo evolution into an atrophic porcelain white macule. In the last year however he has had a progressively wasting course due to persistent and progressive gastrointestinal disease.\n\nHistologic results\nWe will review the biopsies sequentially and consider two time points: before and after Eculizumab therapy.\n\nSkin\nPrior to eculizumab administration: An erythematous lesion biopsied in July 2009 showed a thrombotic microangiopathy with foci of vascular drop out (Figure 1A, 1B). A scarred lesion was biopsied a few days later showed fibrosis, epidermal thinning and vascular drop out. In both biopsies prominent vascular deposition of C5b-9 (Figure 1C) was noted along with extensive immunoreactant deposition for MXA, the latter showing localization in the epidermis, endothelium and inflammatory cells (Figure 1D). There was focal nuclear staining of caspase 3 in the endothelium.\n\nFigure 1 A, B, C, and D: Skin histology pre-Eculizumab microvascular changes along with the pattern and extent of C5b-9 deposition and MXA expression in tissue. An erythematous lesion biopsied in July 2009 shows a thrombotic microangiopathy along with dermal chronic microvascular changes characterized by thickened basement membrane zones along with superficial vascular ectasia and foci of vascular drop out. The chronic microvascular changes are present in both the A (200x) and B (1000x) biopsies while intraluminal fibrin deposition is noted in B. (hematoxylin and eosin) In Figure 1A, there is a sparse perivascular lymphocytic infiltrate. The vessels appear hyalinized attributable to vascular basement membrane zone reduplication. In Figure 1B, the vessel is largely devoid of endothelium and contains a loosely adherent thrombus. The vessel is also noticeably thickened. Figure 1C exhibits the pattern of C5b-9 deposition pre-eculizumab. There is prominent deposition of C5b-9 by immunofluroescence in the vessels in the pre-eculizumab biopsy (400x). Figure 1D demonstrates MxA in skin biopsy pre-Eculizumab. There is extensive staining for MxA in the epidermis, endothelium and inflammatory cells in the pre-eculizumab biopsy indicative of a type I IFN rich microenvironment (diaminobenzidene, 1000x).\n\nPost Eculizumab administration. Subsequent to receiving eculizumab, the patient underwent 6 sequential skin biopsies 2 weeks to 25 months after commencing the drug. In none of the post-eculizumab biopsies was there vascular thrombosis (Figure 2A) but only changes reflective of antecedent microvascular injury including subepidemal fibrosis, vascular drop out, vascular basement membrane zone duplication and vascular ectasia (Figure 2A). A variable perivascular mononuclear inflammatory cell infiltrate along with mucin deposition was present in post treatmentbiopsies (Figure 2B). High levels of MxA expression similar to pretreatment biopsies was noted (Figure 2C). C5b-9 both immunohistochemically and by immunofluorescence was present for 8 months after commencing the drug. Nine months after the commencement of the drug, C5b-9 was no longer apparent (Figure 2D). The caspase 3 stains in all biopsies examined were essentially negative.\n\nFigure 2 Skin microvascular changes and immunohistochemical assessment for C5b-9 and MXA staining post-eculizumab. A. Skin histology post-eculizumab. Subsequent to receiving Eculizumab, the patient underwent 6 sequential biopsies 2 weeks to 25 months after commencing the drug. In none of the post-eculizumab biopsies is there evidence of active endothelial cell injury and vascular thrombosis. A common finding in all of the biopsies is one reflective of antecedent episodes of microvascular injury characterized by subepidemal fibrosis with vascular drop out, vascular basement membrane zone duplication and vascular ectasia (diaminobenzidene, 200x). B. Inflammatory cell infiltrate in skin biopsy post-eculizumab. A variable inflammatory cell infiltrate comprising lymphocytes and histiocytes primarily arranged around blood vessels is present in all of the biopsies. The biopsy procured in March 2011, 16 months after the commencement of eculizumab, shows a striking lymphocytic and histiocytic infiltrate with abundant mucin deposition. Despite the exuberant inflammation, active microvascular injury is not seen. In particular discernible vascular thrombosis is not observed (hematoxylin and eosin, 400x). C. MxA in skin biopsy post-eculizumab. In all post-Eculizumab biopsies, there continues to be prominent expression of MxA in the epidermis, inflammatory cells and endothelium (diaminobenzidene, 1000x). D. C5b-9 in skin biopsy post-eculizumab. Nine months after the commencement of the drug, C5b-9 was no longer apparent (diaminobenzidene, 400x).\n\nGastrointestinal specimens\nThere were a total of 3 intestinal resection specimens available for assessment. One was obtained prior to the commencement of the drug (July 2009) and two were procured 4 months (February 2010) and 21 months after starting the drug (July 2011). There were aspects of the pathology that was remarkably similar between the pre-eculizumab specimen and the one obtained 21 months after starting therapy. In both there was a striking organizing acute and chronic serositis compatible with a recent perforation. An arteriopathy affected small and medium-sized vessels of the submucosa and mesentery (Figure 3A and 3B respectively). In particular the vessels showed a mucinous fibrointimal expansion and occlusion by fibrous collagenous thrombi. The intima was focally infiltrated by macrophages There was extensive mesenchymal mucin deposition within the submucosa accompanied by a lymphocytic infiltrate Focal staining of endothelial cells and interstitial cells (i.e. fibroblasts and inflammatory cells) for caspase 3 in the pre-eculizumab resection specimens was observed although the caspase 3 stains following initiation of eculizumab were negative. There was intense staining of endothelium, smooth muscle cells, stromal cells and inflammatory cells for MxA in the before and after eculizumab resection specimens. Immunohistochemical assessment revealed marked deposition of C5b-9 in vessels of the submucosa in the pre-eculizumab specimen while the intestinal resection specimen procured 21 months after commencing therapy was devoid of endothelial and intimal vascular staining (Figure 4A and 4B).\n\nFigure 3 A and B: Submucosal vessels of intestinal resection specimens pre- and post-eculizumab, respectively. There were a total of 3 intestinal resection specimens available for assessment. One was obtained prior to the commencement of the drug (July 2009) and two were obtained 4 months (February 2010) and 21 months after starting the drug (July 2011). There are aspects of the pathology that was remarkably similar between the pre-eculizumab specimen and the one obtained 2 years after starting therapy. A striking fibro-obliterative arteriopathy affects small and medium-sized vessels of the submucosa as well as mesentery in both the pre- (A) and post-treatment (B) resection specimens (3A, hematoxylin and eosin, 200x, 3B hematoxylin and eosin, 200x). In B, the intimal proliferative changes are very striking comprising hypercellularity of the intima along with an increase in intimal matrix represented by collagen and hyaluronic acid.\n\nFigure 4 A and B: C5b-9 in submucosal vessels of intestinal resection specimens pre- and post-eculizumab, respectively. Immunohistochemical assessment reveals marked deposition of C5b-9 in vessels of the submucosa in the pre-eculizumab specimen (A, diaminobenzidene, 400x) while the intestinal resection specimen procured 21 months after commencing therapy (B, diaminobenzidene 400x) is devoid of vascular staining apart from nonspecific staining within the elastic tissue of blood vessels.\n\nThe resection specimen obtained 4 months after commencing the drug showed an obliterative fibrointimal arteriopathy without active vascular thrombosis C5b-9 were still detectable in tissue both by immunofluorescent as well as immunohistochemical assessment 4 months after commencing the drug although at 5 months post treatment an endoscopic biopsy was devoid of vascular C5b-9 deposition.\n\nPhenotypic assessment of the fibro-obliterative arteriopathy\nGiven the morphologic similarity between the arteriopathic changes in the pre-eculizumab specimen compared to the post eculizumab specimens, we conducted phenotypic studies only on the post eculizumab gastrointestinal resection specimen. The CD14 stain showed a striking influx of CD14+ monocytes throughout the gastrointestinal tract (Figure 5). In examining the diseased arteries, there was a margination of monocytes to lie in apposition to the adventitia with infiltration through the medial wall and extending into the intima; the cells exhibited a spindled morphology (Figure 6). While the desmin extensively highlighted the medial wall smooth muscle cells, the hyperplastic intima was essentially negative (Figure 7) A similar result was seen with myogenin. Very extensive staining was noted for smooth muscle actin. Staining was not observed for CD34.\n\nFigure 5 The CD14 stain shows a striking influx of CD14+ monocytes throughout the gastrointestinal tract with margination of monocytes to lie in apposition to the adventitia. Note the infiltration through the medial wall and extension into the intima (diaminobenzidene, 200x).\n\nFigure 6 While the desmin extensively highlighted the medial wall smooth muscle cells, the hyperplastic intima is essentially negative indicative that the intimal cells are not of true medial wall smooth muscle origin (diaminobenzidene, 200x).\n\nFigure 7 In this section of artery, there is very extensive staining for smooth muscle actin, an immunophenotypic profile that is common in myofibroblastic cells of stem cell hematopoietic and monocyte origin (diaminobenzidene, 200x).\n\nOther biopsies\nIn October 2009, the patient underwent a pleural biopsy along with a pericardial biopsy, which was conducted due to a large pericardial effusion. The pericardial biopsy showed a thrombogenic vasculopathy with ischemic necrosis accompanied by extensive vascular deposition of C5b-9.\n\nDiscussion\nWe have presented a case of MAP in which the patient received biweekly eculizumab infusions commencing in October 2009. We have followed the patient’s clinical course and as well performed sequential biopsies over a 2.5-year period, monitoring the effects of the drug on his disease process from both a clinical and pathological perspective. As already alluded to, there are two aspects to the vascular injury in MAP, one of which is likely preferentially targeted by eculizumab. The first is characterized by a thrombotic microangiopathy affecting capillaries and venules whereby there is discernible endothelial cell injury with endothelial cell detachment and resultant vascular thrombosis. This microangiopathy is particularly apparent in active skin lesions although it also plays a role in the pathogenesis of the ischemic complications seen in other organ sites such as the brain, gastrointestinal tract and pericardium [1-3]. In addition part of the larger vessel pathology is one reflective of a similar pattern of endothelial cell injury and thrombosis.\n\nThe drug has almost an immediate effect on ameliorating small and larger vessel endothelial cell injury and vascular thrombosis. These effects were morphologically apparent after two doses of the drug, recognizing that the symptoms that accompanied the catastrophic thrombotic microangiopathy were improved significantly with the first infusion of the drug. We postulate that the basis is likely reflective of abrogation of endothelial cell apoptosis. While caspase 3, an apoptosis marker, was discernible within the endothelium of pre-eculizumab biopsies, a significant decrement in caspase 3 expression was observed within a few weeks of receiving the drug. There is literature precedent regarding C5b-9 mediated endothelial cell apoptosis primarily in the context of experimental models of glomerulonephritis [10]. We postulate that the deposition of C5b-9 likely reflected complement activation triggered directly by type I IFNs. There are a numbers of papers that suggest that IFNα, the main type I IFN, may be a direct catalyst to the activation of complement and eventually to C5b-9 deposition [11-15]. The high type I IFN signature was revealed by the extensive staining of MxA within endothelium and perivascular and interstitial inflammatory cells.\n\nA point worthy of mention concerns the persistence of C5b-9 deposition for many months after the commencement of the drug, reflecting the slow clearance of C5b-9 previously deposited in affected tissues. Hence monitoring C5b-9 deposition in tissue is likely not of great value in assessing treatment response. From a morphologic perspective, post-eculizumab skin biopsies did not show active endothelial cell injury and/or thrombosis although more chronic change presumably on the basis of prior episodes of thrombotic microvascular injury may be quite impressive. Such changes include epidermal thinning, subepidermal fibrosis with vascular drop out, compensatory vascular ectasia and vascular basement membrane zone thickening.\n\nIn all of the biopsies, prominent MxA staining was noted in endothelium, perivascular and interstitial inflammatory cells, and vascular smooth muscle. The excessive type I IFN signature was not affected by eculizumab administration. Activated macrophages exhibiting erythrocyte phagocytosis along with mucin deposition persisted despite complement blockade, suggesting that its basis is a direct sequela of IFNα production. However, the downstream events of frank endothelial cell apoptosis and thrombosis within the vasculature appears to be halted by the drug.\n\nOur patient continued to have significant gastrointestinal disease including peritonitis and bowel perforations despite receiving biweekly infusions of the drug. In gastrointestinal tract specimens procured 4months and 2 years after commencing the drug, there was persistence of the fibromyxomatous intimal arteriopathy although without vascular thrombosis. The segments of gut were resected due to perforation. We hypothesized that the basis of the perforation was one reflective of chronic and profound ischemia due to progressive occlusive nonthrombotic fibrointimal arterial changes. The lack of overt small and or larger vessel arterial thrombosis likely accounts for the efficacy of the drug in subverting catastrophic and likely fatal ischemic events. However intimal atherosclerotic like intimal narrowing although not specifically catastrophic can lead to chronic nonfatal ischemic changes analogous to the nonocclusive atherosclerotic narrowing operational in chronic ischemic syndromes such as angina pectoris and intermittent claudication. In this regard one might surmise the drug may reduce mortality but the long term morbidity of the disease remains. Currently our patient is very unwell and is progressively wasting due to persistent and likely progressive gastrointestinal disease.\n\nThere is now an emerging body of literature on the role of type I IFN in the evolution of the atherosclerotic-like larger vessel fibrointimal changes observed in patients with systemic lupus erythematosus [8,9]. Patients with lupus erythematosus display transitional upregulation of the IFNα/interleukin-18 (IL-18) processing machinery (a.k.a. the inflammasome) [16]. IL-18 has an inhibitory effect on endothelial cell differentiation, leading to decreased vascular repair with enhanced large vessel vascular injury Elevated levels of IL-18 also correlate with increased intima and medial wall thickness [17,18]. It is possible that the arteriopathy of MAP disease is pathogenetically very similar to the larger vessel arteriopathy of systemic lupus erythematosus whereby pathways independent of complement activation may be operational [18]. A finding that is particularly intriguing in our case was the massive infiltration of his gastrointestinal tract by CD14+ monocytes which exhibited an unusual pattern of arteriocentricity including their presence in the intima of diseased vessels. Further characterization of the proliferative intima revealed marked staining for smooth muscle actin although in the absence of staining for myogenin and desmin. The phenotypic profile of the intima was one compatible therefore with spindled cells showing CD14 positivity along with myofibroblastic differentiation. It is well established that CD14+ monocytes exhibit considerable plasticity and can undergo myofibroblastic differentiation [19]. At least in this one case, the source of the intimal myofibroblast, the putative cell responsible for the hyperplastic intima, could ultimately be derived from the surrounding CD14+ monocytes. The excessive number of CD14+ monocytes in the gastrointestinal tract may reflect enhancement of monocyte recruitment triggered by type I interferons. In addition under the influence of type I interferons, CD14+ monocytes show enhanced expression of sialic acid binding IgG lectin-1 binding (Siglec-1). Increased numbers of Siglec-1+ CD14+ monocytes has been implicated in systemic sclerosis associated pulmonary hypertension, systemic sclerosis [20,21], and coronary artery disease [22].\n\nConclusions\nThe drug eculizumab aborts the severe catastrophic thrombotic microangiopathy events associated with Degos disease, likely through antiapoptotic endothelial cell effects. In this regard, the extent of thrombotic microangiopathic and larger vessel alterations are significantly attenuated although other deleterious sequelae associated with a type I interferon rich microenvironment such as endothelial repair dysfunction and enhancement of CD14+ monocyte influx with transdifferentiation into intimal myofibroblasts remain unaltered.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nAuthors’ contributions\nCMM was involved in the design of the study, interpretation and photographing of the biopsy material, and drafting and editing the manuscript. All of the other authors were involved in editing the manuscript and as well the patient was under the care of FB and MD; JL and LS provided invaluable input regarding therapy. All authors read and approved the final manuscript.\n\nAcknowledgements\nThe authors would like to thank Natalie Drucker from Yale University for editorial assitance.\n==== Refs\nSnow JL Muller SA Degos syndrome: malignant atrophic papulosis Semin Dermatol 1995 8 99 105 10.1016/S1085-5629(05)80004-5 7640203 \nTheodoridis A Makrantonaki E Zouboulis CC Malignant atrophic papulosis (Kohlmeier-Degos disease)- A review Orphanet J Rare Dis 2013 8 10 10.1186/1750-1172-8-10 23316694 \nDoutre MS Beylot C Bioulac P Busquet M Conte M Skin lesion resembling malignant atrophic papulosis in lupus erythematosus Dermatologica 1987 8 45 46 3609417 \nNotash AY Mazoochy H Mirshams M Nikoo A Lethal systemic Degos disease with prominent cardio-pulmonary involvement Saudi Med J 2008 8 133 137 18176689 \nSaglik E Baykal C Buyukbabani N Inanc M Malignant atrophic papulosis: endocardial involvement and positive anticardiolipin antibodies J Eur Acad Dermatol Venereol 2006 8 602 603 10.1111/j.1468-3083.2006.01339.x 16684293 \nMauad T De Fatima Lopes Calvo Tiberio I Baba E Andrade Junior DR Lichtenstein A Capelozzi VL Sotto MN Saldiva PH Malignant atrophic papulosis (Degos’ disease) with extensive cardiopulmonary involvement Histopathology 1996 8 84 86 10.1046/j.1365-2559.1996.t01-1-258289.x 8838127 \nMagro CM Poe JC Kim C Shapiro L Nuovo G Crow MK Crow YJ Degos disease: a C5b-9/interferon-alpha-mediated endotheliopathy syndrome Am J Clin Pathol 2011 8 599 610 10.1309/AJCP66QIMFARLZKI 21411783 \nChapman K Seldon M Richards R Thrombotic microangiopathies, thrombotic thrombocytopenic purpura, and ADAMTS-13 Semin Thromb Hemost 2012 8 47 54 22314603 \nClark WF Thrombotic microangiopathy: current knowledge and outcomes with plasma exchange Semin Dial 2012 8 214 219 10.1111/j.1525-139X.2011.01035.x 22309967 \nLiu L Qiu W Wang H Li Y Zhou J Xia M Shan K Pang R Zhou Y Zhao D Wang Y Sublytic C5b-9 complexes induce apoptosis of glomerular mesangial cells in rats with Thy-1 nephritis through role of interferon regulatory factor-1-dependent caspase 8 activation J Biol Chem 2012 8 16410 16423 10.1074/jbc.M111.319566 22427665 \nKirou KA Lee C George S Louca K Papagiannis IG Peterson MG Ly N Woodward RN Fry KE Lau AY Prentice JG Wohlgemuth JG Crow MK Coordinate overexpression of interferon-alpha-induced genes in systemic lupus erythematosus Arthritis Rheum 2004 8 3958 3967 10.1002/art.20798 15593221 \nKirou KA Lee C George S Louca K Peterson MG Crow MK Activation of the interferon-alpha pathway identifies a subgroup of systemic lupus erythematosus patients with distinct serologic features and active disease Arthritis Rheum 2005 8 1491 1503 10.1002/art.21031 15880830 \nGreenberg SA Pinkus JL Pinkus GS Burleson T Sanoudou D Tawil R Barohn RJ Saperstein DS Briemberg HR Ericsson M Park P Amato AA Interferon-alpha/beta-mediated innate immune mechanisms in dermatomyositis Ann Neurol 2005 8 664 678 10.1002/ana.20464 15852401 \nMyhr KM Sadallah S Mollnes TE Meri S Nyland HI Schifferli J Vedeler CA Interferon-alpha2a effects on complement activation and regulation in MS patients Acta Neurol Scand 2000 8 30 35 10.1034/j.1600-0404.2000.00013.x 10660149 \nSugano S Suzuki T Watanabe M Ohe K Ishii K Okajima T Retinal complications and plasma C5a levels during interferon alpha therapy for chronic hepatitis C Am J Gastroenterol 1998 8 2441 2444 10.1111/j.1572-0241.1998.00701.x 9860406 \nKahlenberg JM Thacker SG Berthier CC Cohen CD Kretzler M Kaplan MJ Inflammasome activation of IL-18 results in endothelial progenitor cell dysfunction in systemic lupus erythematosus J Immunol 2011 8 6143 6156 10.4049/jimmunol.1101284 22058412 \nHernesniemi JA Heikkilä A Raitakari OT Kähönen M Juonala M Hutri-Kähönen N Marniemi J Viikari J Lehtimäki T Interleukin-18 gene polymorphism and markers of subclinical atherosclerosis. The Cardiovascular Risk in Young Finns Study Ann Med 2010 8 3 223 230 10.3109/07853891003769940 20350254 \nLi C Zhang XL Liu H Wang ZG Yin KS Association among plasma interleukin-18 levels, carotid intima- media thickness and severity of obstructive sleep apnea Chin Med J (Engl) 2009 8 1 24 29 19187612 \nBinai N O’Reilly S Griffiths B van Laar JM Hügle T Differentiation potential of CD14+ monocytes into myofibroblasts in patients with systemic sclerosis PLoS One 2012 8 3 e33508 10.1371/journal.pone.0033508 22432031 \nChristmann RB Hayes E Pendergrass S Padilla C Farina G Affandi AJ Whitfield ML Farber HW Lafyatis R Interferon and alternative activation of monocyte/macrophages in systemic sclerosis-associated pulmonary arterial hypertension Arthritis Rheum 2011 8 6 1718 1728 10.1002/art.30318 21425123 \nYork MR Nagai T Mangini AJ Lemaire R van Seventer JM Lafyatis R A macrophage marker, Siglec-1, is increased on circulating monocytes in patientswith systemic sclerosis and induced by type I interferons and toll-like receptor agonists Arthritis Rheum 2007 8 3 1010 1020 Erratum in: Arthritis Rheum. 2007 56(5):1675 10.1002/art.22382 17328080 \nXiong YS Zhou YH Rong GH Wu WL Liang Y Yang ZX Geng HL Zhong RQ Siglec-1 on monocytes is a potential risk marker for monitoring disease severity in coronary artery disease Clin Biochem 2009 8 10–11 1057 1063 19285973\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1750-1172",
"issue": "8()",
"journal": "Orphanet journal of rare diseases",
"keywords": null,
"medline_ta": "Orphanet J Rare Dis",
"mesh_terms": "D061067:Antibodies, Monoclonal, Humanized; D015933:Complement C3d; D050776:Complement C5b; D006801:Humans; D008297:Male; D054853:Malignant Atrophic Papulosis; D008875:Middle Aged",
"nlm_unique_id": "101266602",
"other_id": null,
"pages": "185",
"pmc": null,
"pmid": "24279613",
"pubdate": "2013-11-26",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "8838127;19187612;22427665;22314603;16684293;15852401;18176689;9860406;15593221;3609417;22058412;10660149;22432031;7640203;19285973;15880830;20350254;21411783;23316694;22309967;17328080;21425123",
"title": "The effects of Eculizumab on the pathology of malignant atrophic papulosis.",
"title_normalized": "the effects of eculizumab on the pathology of malignant atrophic papulosis"
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"abstract": "BACKGROUND\nLeprosy remains infrequent in non-endemic areas. The objective of this study was to describe the cases of leprosy reviewed at a referral unit for imported diseases in Europe and to compare these findings with published data on imported leprosy.\n\n\nMETHODS\nCases of leprosy evaluated at a referral centre are described and salient features of autochthonous and imported cases are compared. A review of the literature on imported leprosy was performed.\n\n\nRESULTS\nDuring the study period, 25 patients with leprosy were followed-up (10 were autochthonous cases and 15 were considered to be imported). Regarding imported cases, the majority were diagnosed in Latin American immigrants (10/15, 67%), mean age was 42 years, there were no differences in gender distribution, estimated average time from arrival in Spain to first visit at the unit was 3 years and from symptom onset to diagnosis was 2 years. Over 80% of imported cases had multibacillary disease and over one third of patients had been previously diagnosed with leprosy. One third had received alternate incorrect diagnoses initially, <50% of patients with imported leprosy completed standard therapy and were considered cured and over one third were lost to follow-up.\n\n\nCONCLUSIONS\nLeprosy remains a complex disease for healthcare professionals unfamiliar with this infection. Manifestations are polymorphic so misdiagnoses and consequent delays in diagnosis are not infrequent and may lead to resulting disabilities. Early diagnosis and management are essential to prevent sequelae and possible transmission. Improving access to health care, especially for vulnerable groups, would be necessary to advance in the control of this disease.",
"affiliations": "National Referral Unit for Tropical Diseases, Infectious Diseases Department, Ramón y Cajal University Hospital, Instituto Ramón y Cajal de Investigación Sanitaria, Ctra. de Colmenar Km 9, Madrid 28034, Spain. Electronic address: ffnorman@gmail.com.;National Referral Unit for Tropical Diseases, Infectious Diseases Department, Ramón y Cajal University Hospital, Instituto Ramón y Cajal de Investigación Sanitaria, Ctra. de Colmenar Km 9, Madrid 28034, Spain.;National Referral Unit for Tropical Diseases, Infectious Diseases Department, Ramón y Cajal University Hospital, Instituto Ramón y Cajal de Investigación Sanitaria, Ctra. de Colmenar Km 9, Madrid 28034, Spain.;National Referral Unit for Tropical Diseases, Infectious Diseases Department, Ramón y Cajal University Hospital, Instituto Ramón y Cajal de Investigación Sanitaria, Ctra. de Colmenar Km 9, Madrid 28034, Spain.;National Referral Unit for Tropical Diseases, Infectious Diseases Department, Ramón y Cajal University Hospital, Instituto Ramón y Cajal de Investigación Sanitaria, Ctra. de Colmenar Km 9, Madrid 28034, Spain.",
"authors": "Norman|Francesca F|FF|;Fanciulli|Chiara|C|;Pérez-Molina|José-Antonio|JA|;Monge-Maillo|Begoña|B|;López-Vélez|Rogelio|R|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
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"issn_linking": "1477-8939",
"issue": "14(4)",
"journal": "Travel medicine and infectious disease",
"keywords": "Immigrant; Leprosy; Mycobacterium leprae; Neglected tropical disease; Travel",
"medline_ta": "Travel Med Infect Dis",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D002675:Child, Preschool; D003951:Diagnostic Errors; D054242:Emigrants and Immigrants; D005060:Europe; D005260:Female; D006282:Health Personnel; D006801:Humans; D007223:Infant; D007918:Leprosy; D008297:Male; D008875:Middle Aged; D009166:Mycobacterium leprae; D058069:Neglected Diseases; D013030:Spain; D013997:Time Factors; D014195:Travel",
"nlm_unique_id": "101230758",
"other_id": null,
"pages": "331-49",
"pmc": null,
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"pubdate": "2016",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Imported and autochthonous leprosy presenting in Madrid (1989-2015): A case series and review of the literature.",
"title_normalized": "imported and autochthonous leprosy presenting in madrid 1989 2015 a case series and review of the literature"
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"companynumb": "PHHY2016ES179764",
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"abstract": "Although the SAPHO (synovitis, acne, pustulosis, hyperostosis, osteitis) syndrome was defined as a distinct entity more than 20 years ago, its classification within the spectrum of inflammatory rheumatic diseases and the proper therapeutic approach are still a matter of debate. We present four patients diagnosed with the SAPHO syndrome treated and followed-up in our Department, demonstrating the diversity of their clinical courses and their responses to different therapeutic approaches. We also review the clinical, laboratory, and imaging features of the SAPHO syndrome described in the relevant literature. Despite the growing quantity of published data on the clinical features of the syndrome and the recognition of two disease patterns (inflammatory and bone remodeling disease), it is still not clear whether these possible disease subsets require different therapeutic strategies. Tumor necrosis factor-alpha (TNF-α) inhibitors have been suggested to be effective in patients with the inflammatory pattern, whereas bisphosphonates seem to be effective in patients with bone remodeling disease; however, this is still a hypothesis not yet confirmed by adequately designed clinical studies. Further research is needed to assess disease features predicting favorable response to the two therapeutic modalities beyond the first line of therapy - TNF-α inhibitors and bisphosphonates.",
"affiliations": "Ivan Padjen, MD, Department of Internal Medicine, Division of Clinical Immunology and Rheumatology, University of Zagreb School of Medicine, University Hospital Centre Zagreb, Kišpatićeva 12, 10000 Zagreb, Croatia; ivan_padjen@yahoo.ca.",
"authors": "Anić|Branimir|B|;Padjen|Ivan|I|;Mayer|Miroslav|M|;Bosnić|Dubravka|D|;Cerovec|Mislav|M|",
"chemical_list": "D004164:Diphosphonates; D014409:Tumor Necrosis Factor-alpha",
"country": "Croatia",
"delete": false,
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"issn_linking": "1330-027X",
"issue": "22(3)",
"journal": "Acta dermatovenerologica Croatica : ADC",
"keywords": null,
"medline_ta": "Acta Dermatovenerol Croat",
"mesh_terms": "D020083:Acquired Hyperostosis Syndrome; D000293:Adolescent; D000328:Adult; D015897:Comorbidity; D004164:Diphosphonates; D018450:Disease Progression; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D014409:Tumor Necrosis Factor-alpha",
"nlm_unique_id": "9433781",
"other_id": null,
"pages": "180-8",
"pmc": null,
"pmid": "25230058",
"pubdate": "2014",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Clinical features of the SAPHO syndrome and their role in choosing the therapeutic approach: report of four patients and review of the literature.",
"title_normalized": "clinical features of the sapho syndrome and their role in choosing the therapeutic approach report of four patients and review of the literature"
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"abstract": "Baclofen is a centrally acting gamma-aminobutyric acid receptor agonist with many therapeutic uses in neurology and psychiatry. An overdose of baclofen is known to cause serious side effects such as encephalopathy, seizures, respiratory depression, and delirium. Association of baclofen with psychosis has also been reported. In this case report, we are highlighting the manifestation of catatonic features in addition to psychosis following baclofen overdose.",
"affiliations": "Centre for Brain Research IISC, Bengaluru, Karnataka, India.;Department of Psychiatry, National Institute of Mental Health and Neurosciences, Bengaluru, Karnataka, India.;Department of Psychiatry, National Institute of Mental Health and Neurosciences, Bengaluru, Karnataka, India.;Department of Psychiatry, National Institute of Mental Health and Neurosciences, Bengaluru, Karnataka, India.;Department of Psychiatry, National Institute of Mental Health and Neurosciences, Bengaluru, Karnataka, India.;Department of Psychiatry, National Institute of Mental Health and Neurosciences, Bengaluru, Karnataka, India.",
"authors": "Nahar|Abhinav|A|;Shanker Reddy|Mukku Shiva|MS|;Subramaniyam|Bhaskaran Andi|BA|;Thippeswamy|Harish|H|;Chandra|Prabha S|PS|;Chaturvedi|Santosh Kumar|SK|",
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"fulltext": "\n==== Front\nIndian J Psychol MedIndian J Psychol MedIJPsyMIndian Journal of Psychological Medicine0253-71760975-1564Medknow Publications & Media Pvt Ltd India IJPsyM-39-69510.4103/IJPSYM.IJPSYM_291_17Case ReportBaclofen Overdose Presenting as Psychosis with Catatonia Nahar Abhinav Shanker Reddy Mukku Shiva 1Subramaniyam Bhaskaran Andi 1Thippeswamy Harish 1Chandra Prabha S. 1Chaturvedi Santosh Kumar 1Centre for Brain Research IISC, Bengaluru, Karnataka, India1 Department of Psychiatry, National Institute of Mental Health and Neurosciences, Bengaluru, Karnataka, IndiaAddress for correspondence: Dr. Harish Thippeswamy, Department of Psychiatry, National Institute of Mental Health and Neurosciences, Bengaluru - 560 029, Karnataka, India. E-mail: docharisht@gmail.comSep-Oct 2017 39 5 695 697 Copyright: © 2017 Indian Journal of Psychological Medicine2017This 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.Baclofen is a centrally acting gamma-aminobutyric acid receptor agonist with many therapeutic uses in neurology and psychiatry. An overdose of baclofen is known to cause serious side effects such as encephalopathy, seizures, respiratory depression, and delirium. Association of baclofen with psychosis has also been reported. In this case report, we are highlighting the manifestation of catatonic features in addition to psychosis following baclofen overdose.\n\nKey words\nBaclofencatatoniagamma-aminobutyric acid-B receptorpsychosis\n==== Body\nINTRODUCTION\nBaclofen (4-amino-3-[-4-chlorophenyl]-butanoic acid), a centrally acting gamma-aminobutyric acid (GABA) B receptor agonist, has many therapeutic uses in the field of neuropsychiatry. Therapeutic indications include spasticity resulting from conditions such as cerebral palsy, traumatic spinal injury, stroke, and multiple sclerosis.[12] It is also used as an anticraving agent in alcohol-dependence syndrome.[3] Overdose of baclofen is associated with serious adverse effects such as encephalopathy, respiratory depression, muscular hypotonia, and generalized hyporeflexia. Studies have reported that overdose >200 mg of baclofen has resulted in coma, delirium, and seizures.[4]\n\nThe psychiatric side effects of baclofen drug have not been commonly reported as compared to neurological side effects. This article describes the development of acute-onset psychosis with catatonic symptoms following an overdose of baclofen.\n\nCASE REPORT\nA 30-year-old married female with no significant family and past history of psychiatric illness presented to us with an acute-onset behavioral change. On clarification, it was found that, following an altercation with her family members, she had attempted self-harm by consuming ~300 mg of baclofen. The next day morning, she was found unconscious with frothing near mouth, following which the patient was rushed to the emergency department of a medical college, where she was given stomach wash and shifted to the Intensive Care Unit. She was on nasogastric tube feeding for the next 3 days during which the patient was conscious but not responding to any questions. From the 4th day, she was also found to be talking to self, irritable, and hostile toward family members and was found to have auditory hallucinations in the form of commenting and commanding type of voices and decreased sleep. She started having grandiose ideas that she is going to become a Goddess along with a delusion of persecution against her family members along with other patients in the ward. She was also found to be excessively cheerful and disinhibited at times. She was treated with antipsychotic and parenteral sedation (details of medication not available) for the above symptoms. Subsequently, she was referred to our hospital and on evaluation was found to be irritable and agitated with similar findings as described above. A day later, the patient was observed to have catatonic symptoms in the form of posturing, staring, negativism, reduced food intake, ambitendency, and mutism. Central nervous system examination revealed no focal neurological deficits. The catatonia severity was assessed using the Bush–Francis Catatonia Rating Scale score[5] and the score was 20. Low-dose lorazepam was started (3 mg/day in divided doses per orally) following which the patient showed a dramatic improvement and had no catatonic symptoms thereafter (Bush–Francis Catatonia Rating Scale score = 0). Tablet olanzapine 5–10 mg/day was initiated for psychotic and affective symptoms. She was discharged on tablet olanzapine 10 mg/day and tapering doses of lorazepam. Routine blood investigations and thyroid profile, erythrocyte sedimentation rate, serum Vitamin B12, and folate were within the normal limits. Magnetic resonance imaging of the brain (plain with contrast) was done, and no significant abnormality was detected. There was no history of consumption of any psychoactive substances, any herbal medications, and other over-the-counter medications. There was no history of any medical illness. The patient was evaluated during the follow-up after a month and was found to be maintaining well on 10 mg of tablet olanzapine in the absence of any psychotic or catatonic symptoms.\n\nDISCUSSION\nThe abrupt onset of psychotic and catatonic symptoms on baclofen overdose and their rapid resolution within a week on treatment in the absence of any other contributing factor suggested a diagnosis of baclofen-induced psychosis. The scoring on the Naranjo probability scale[6] suggested a probable association of baclofen with acute psychiatric symptoms in the patient. A review describing psychiatric presentation following abrupt withdrawal of baclofen highlights the symptoms mostly characterized by delirium and associated perceptual disturbances.[7] Our patient too was in an altered sensorium for the initial 4 days following an overdose but was in clear consciousness following the onset of psychotic and affective disturbance. An earlier case report has discussed about the emergence of psychosis following the therapeutic dose of baclofen and was characterized predominantly by auditory hallucinations and persecutory and referential delusions.[8] In an another case report, a patient with traumatic brain injury developed psychosis following intrathecal administration of baclofen.[9] In both the above-discussed cases, psychosis subsided once baclofen was stopped.\n\nCase reports of mania induced by therapeutic doses of baclofen have been described in the literature, and these symptoms can also arise in patients without any history of bipolar disorder.[10]\n\nThe mechanism by which baclofen can induce psychotic symptoms is not clear. Modulation of firing of dopamine neurons in the ventral tegmental area by GABA-B receptor stimulation could be contribute to the development of psychotic symptoms. In addition, its role in inducing mania-like symptoms could be due to increased noradrenergic turnover by altering the firing rate of GABAergic neurons and indirect disinhibition of 5-hydroxytryptamine (5-HT) neuron activity by presynaptic GABA-B receptors on non-5-HT neurons in the dorsal raphe nucleus.[10] The relationship between GABA-B agonist baclofen and catatonia has been described previously in a patient who was prescribed the medication for persistent lower-extremity muscle spasm following surgery for spinal cord ependymoma. The patient developed catatonic features after increase in the dose of baclofen, and there was remission of symptoms after the drug was tapered and stopped. Moreover, the symptoms re-emerged after the patient was restarted on baclofen.[11] Increased GABA-B receptor activity and reduced activity at GABA-A receptors have been proposed to cause catatonia. The balance between the GABA-A and GABA-B receptors can be disturbed by baclofen, leading to catatonic signs and symptoms.[12]\n\nCONCLUSION\nBaclofen is a commonly used drug in various neurological illnesses to reduce spasticity, and also as an anticraving agent in substance-use patients. Baclofen even though relatively safe at therapeutic doses can sometimes lead to life-threatening complications in overdose. This case demonstrates the possibility of baclofen overdose with psychosis with catatonic symptoms.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n==== Refs\nREFERENCES\n1 Standaert DG Treatment of central nervous system degenerative disorders Goodman & Gilman's the Pharmacological Basis of Therapeutics 2006 11th Edition McGraw Hill 527 45 \n2 Chang E Ghosh N Yanni D Lee S Alexandru D Mozaffar T A review of spasticity treatments: Pharmacological and interventional approaches Crit Rev Phys Rehabil Med 2013 25 11 22 25750484 \n3 Addolorato G Caputo F Capristo E Domenicali M Bernardi M Janiri L Baclofen efficacy in reducing alcohol craving and intake: A preliminary double-blind randomized controlled study Alcohol Alcohol 2002 37 504 8 12217947 \n4 Leung NY Whyte IM Isbister GK Baclofen overdose: Defining the spectrum of toxicity Emerg Med Australas 2006 18 77 82 16454779 \n5 Bush G Fink M Petrides G Dowling F Francis A Catatonia. I. Rating scale and standardized examination Acta Psychiatr Scand 1996 93 129 36 8686483 \n6 Naranjo CA Busto U Sellers EM Sandor P Ruiz I Roberts EA A method for estimating the probability of adverse drug reactions Clin Pharmacol Ther 1981 30 239 45 7249508 \n7 Leo RJ Baer D Delirium associated with baclofen withdrawal: A review of common presentations and management strategies Psychosomatics 2005 46 503 7 16288128 \n8 Chawla JM Sagar R Baclofen-induced psychosis Ann Pharmacother 2006 40 2071 3 17047139 \n9 Maneyapanda MB Driver SP Ripley DL Lloyd R Brkic N Psychosis following an increase in intrathecal baclofen PM R 2016 8 1222 4 27346089 \n10 Geoffroy PA Auffret M Deheul S Bordet R Cottencin O Rolland B Baclofen-induced manic symptoms: Case report and systematic review Psychosomatics 2014 55 326 32 24751117 \n11 Pauker SL Brown R Baclofen-induced catatonia J Clin Psychopharmacol 1986 6 387 8 3805341 \n12 Carroll BT GABAa versus GABAb hypothesis of catatonia Mov Disord 1999 14 702 3 10435515\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0253-7176",
"issue": "39(5)",
"journal": "Indian journal of psychological medicine",
"keywords": "Baclofen; catatonia; gamma-aminobutyric acid-B receptor; psychosis",
"medline_ta": "Indian J Psychol Med",
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"nlm_unique_id": "7910727",
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"pages": "695-697",
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"pmid": "29200574",
"pubdate": "2017",
"publication_types": "D002363:Case Reports",
"references": "10435515;27346089;12217947;17047139;8686483;3805341;7249508;16288128;16454779;24751117;25750484",
"title": "Baclofen Overdose Presenting as Psychosis with Catatonia.",
"title_normalized": "baclofen overdose presenting as psychosis with catatonia"
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"abstract": "A 21-year-old male with an SCN1A mutation died of cerebral herniation 3 h after a seizure occurring during physical activity. Cases of fatal cerebral edema in patients with SCN1A mutations after fever and status epilepticus have been recently reported raising the question whether sodium channel dysfunction may contribute to cerebral edema and thereby contribute to the increased premature mortality in Dravet Syndrome. We report on our patient and discuss whether the combination of hyperthermia and ion channel dysfunction may not only trigger seizures but also a fatal pathophysiological cascade of cerebral edema and herniation leading to cardiorespiratory collapse.",
"affiliations": "Department for Trauma- and Hand Surgery, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Moorenstraße 5, D-40225 Düsseldorf, Germany.;Department for Neurosurgery, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Moorenstraße 5, D-40225 Düsseldorf, Germany.;Department for Neurosurgery, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Moorenstraße 5, D-40225 Düsseldorf, Germany.;Department for Neurosurgery, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Moorenstraße 5, D-40225 Düsseldorf, Germany.;Department for Trauma- and Hand Surgery, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Moorenstraße 5, D-40225 Düsseldorf, Germany.;Department for Neurosurgery, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Moorenstraße 5, D-40225 Düsseldorf, Germany.",
"authors": "Büren|Carina|C|;Kamp|Marcel Alexander|MA|;Munoz-Bendix|Christopher|C|;Steiger|Hans-Jakob|HJ|;Windolf|Joachim|J|;Dibué-Adjei|Maxine|M|",
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"doi": "10.1016/j.ebcr.2017.12.003",
"fulltext": "\n==== Front\nEpilepsy Behav Case RepEpilepsy Behav Case RepEpilepsy & Behavior Case Reports2213-3232Elsevier S2213-3232(17)30116-010.1016/j.ebcr.2017.12.003ArticleCan the combination of hyperthermia, seizures and ion channel dysfunction cause fatal post-ictal cerebral edema in patients with SCN1A mutations? Büren Carina aKamp Marcel Alexander bMunoz-Bendix Christopher bSteiger Hans-Jakob bWindolf Joachim aDibué-Adjei Maxine maxine.dibue-adjei@livanova.combc⁎a Department for Trauma- and Hand Surgery, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Moorenstraße 5, D-40225 Düsseldorf, Germanyb Department for Neurosurgery, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Moorenstraße 5, D-40225 Düsseldorf, Germanyc LivaNova Deutschland GmbH (a LivaNova PLC-owned subsidiary), Lindberghstr 25, D-80939 Munich, Germany⁎ Corresponding author at: Department for Neurosurgery, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Moorenstraße 5, D-40225 Düsseldorf, Germany. maxine.dibue-adjei@livanova.com24 12 2017 2018 24 12 2017 9 29 32 15 8 2017 13 12 2017 18 12 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/).A 21-year-old male with an SCN1A mutation died of cerebral herniation 3 h after a seizure occurring during physical activity. Cases of fatal cerebral edema in patients with SCN1A mutations after fever and status epilepticus have been recently reported raising the question whether sodium channel dysfunction may contribute to cerebral edema and thereby contribute to the increased premature mortality in Dravet Syndrome. We report on our patient and discuss whether the combination of hyperthermia and ion channel dysfunction may not only trigger seizures but also a fatal pathophysiological cascade of cerebral edema and herniation leading to cardiorespiratory collapse.\n\nKeywords\nDravet SyndromeSCN1A mutationFatalityCerebral edemaHyperthermiaSUDEP\n==== Body\n1 Introduction\nPatients with Dravet Syndrome (DS) are at a significantly increased risk for premature death (16–17 per 1000 patient years), with sudden unexpected death in epilepsy (SUDEP) representing the leading cause of death in childhood followed by status epilepticus [1], [2]. Despite sporadic reports of acute encephalopathy in DS, cerebral edema is not traditionally considered a key pathological mechanism contributing to high mortality in DS. Recently Myers et al. report 5 fatal cases of cerebral edema occurring days after status epilepticus in children with DS. We were recently confronted with a similar case in our emergency department (ED). This was remarkable because our DS patient experienced fatal transtentorial herniation within three hours of a generalized convulsive seizure despite being immediately aborted with buccal midazolam. We therefore find it relevant to report on this case and bring to attention that there may be circumstances under which fatal cerebral edema develops rapidly in patients with DS.\n\n2 Case: 21 year-old male with SCN1A mutation\nA 21-year-old male patient with an SCN1A mutation and childhood diagnosis of DS was transferred to our ED via helicopter from a hospital nearby requiring cardiopulmonary resuscitation (CPR). According to his father his seizures could be triggered by intense emotion (especially joy) in the past but he had been seizure-free for the past 7 years with a combination of topiramate and potassium bromide. On the day of admission, a warm summer day, he had suffered from a generalized convulsive seizure of unknown duration during a 5 kilometer city run only a few meters from the finish line. Acting upon orders from the patients' father, paramedics standing by quickly applied buccal midazolam, which successfully aborted the seizure. The exact seizure duration was not reported. Upon arrival of an emergency physician the patient was asystolic but was successfully resuscitated in the ambulance. Despite having spontaneous circulation upon admission to the ED of the closest hospital, he quickly became in need of CPR again. He was therefore transferred to our hospital for tertiary care, where CPR was unsuccessfully attempted for 2 h. Arterial blood gas analysis was performed after cumulative 2 h of cardiopulmonary resuscitation. All parameters in the blood gas analysis were within the normal range except potassium (K+ [mmol/l] = 8.7) which is most likely attributable to the failed resuscitation attempts. CT revealed global cerebral edema with completely compressed ventricular cavities and no signs of traumatic brain injury, or lesions of any type. A post-mortem full body CT also did not reveal any intra- or extra-cranial signs of trauma (Fig. 1).Fig. 1 Cranial computed tomography after cumulative 3 h of cardiopulmonary resuscitation.\n\nCranial imaging revealed cerebral herniation due to global cerebral edema without any trauma signs.\n\n(with permission from the Institute of the Diagnostic und Interventional Radiology, Medical Faculty, Heinrich-Heine-University, Düsseldorf).\n\nFig. 1\n\n3 Discussion\nSUDEP is the most frequent cause of death directly related to epilepsy, and patients with Dravet Syndrome (DS) display a significantly increased SUDEP risk compared to the general epilepsy population [3]. The majority of observed SUDEP cases occur shortly after a seizure [4], [5], [6], [7], [8], however a previous seizure is not a prerequisite for SUDEP [9]. While the exact pathological mechanism contributing to SUDEP is still unresolved, the 11 cases of monitored SUDEP offer crucial insight into the events leading to SUDEP [10]: following a generalized tonic–clonic seizure (GTCS), heart rate and respiration are transiently increased before a combination of central apnoea, severe bradycardia, and most often transient asystole occurs together with postictal generalized EEG suppression, typically peaking between 1 and 3 min postictally. These observations lead to the hypothesis that SUDEP is an early post-ictal neurovegetative breakdown and potentially a consequence of years of autonomic dysfunction, a common phenomenon in epilepsy —especially in DS patients [11], [12], [13], [14]. The observation of impaired heart-rate variability in patients with DS compared to healthy controls and other epilepsy populations is of interest considering that a voltage-gated sodium channel (VGSC) such as Nav 1.1 is not expressed in cardiac tissue suggesting that cardiac dysfunction in patients with SCN1A mutations is mainly centrally mediated [15].\n\nEdema and increased intracranial pressure (ICP) are not considered a mechanism contributing to SUDEP, however if the post-ictal events occurring in this patient had been unwitnessed (e.g., at night) his death would have likely been attributed to SUDEP. Our patient displayed a similar pattern to SUDEP: fatal cardiac arrest occurring shortly after a generalized seizure. Post-ictal cerebral edema developed rapidly after an aborted seizure probably triggered by a state of prolonged hyperthermia due to physical activity on a warm day. The combination of hyperthermia, ion channel dysfunction and possibly emotional stress may trigger seizures in DS. Hyperthermia is well known to induce seizures and to influence neuronal activity in patients with SCN1A mutations and in experimental conditions involving Nav1.1 dysfunction [16], [17], [18]. Under experimental conditions, exposure to a stressor such as emotional stress increases seizure susceptibility in both SCN1A mutant animals and non-genetically altered controls [19].\n\nAccording to his father, our patient suffered from drug-resistant seizures in childhood but could ultimately be controlled with anti-seizure drug polypharmacy in adolescence and adulthood which is not uncommon in DS. At his death the patient was taking potassium bromide and topiramate, which may be of interest, as topiramate can decrease sweating and increase body temperature, leading to life-threatening dehydration especially during warm weather. In combination with the warm weather and physical activity, topiramate could have therefore contributed to hyperthermia promoting the seizure.\n\nIn neurosurgical practice, edema and raised ICP can be observed rapidly after seizures and edema as a consequence of prolonged seizures is known to represent a predictor of poor outcome [20], [21], [22]. Additionally, the combination of hyperthermia, ion channel dysfunction and possibly emotional stress may lead to fatal cerebral edema and subsequently to increased ICP with cerebral transtentorial herniation. Recently, Myers et al. reported a series of fatal cerebral edema in children with DS. Interestingly, all DS patients with fatal cerebral edema suffered from fever of ≥ 40 °C and hyperthermia-related seizures [23]. Acute encephalopathy referring to non-inflammatory cerebral edema as a complication of febrile illness has been sporadically reported for children with DS [24], [25], [26], [27]. However, pathophysiological mechanisms connecting hyperthermia-induced seizures and fatal cerebral edema have yet to be described: Three distinct possible mechanisms or a combination of thereof are considerations:(1) Hyperthermia-induced seizures may lead to an early post-ictal compromise, resulting in respiratory failure and cardiac arrest as described in the monitored SUDEP cases in the MORTEMUS study [10]. In addition to autonomic dysfunction, this may further impede CPR during cardiac arrest which promotes cerebral hypoxia. Cerebral hypoxia leads to a disturbance of ion hemostasis and in particular to a neuronal sodium ion influx [28], [29], [30]. Several studies suggested that VGSCs are important in the pathophysiology of hypoxia [28], [29], [30], [31]. It has however yet to be investigated whether SCN1A mutations in DS alter susceptibility for hypoxia and promote hypoxia-related cerebral edema by increasing neuronal sodium ion influx. Altered susceptibility to hypoxia and increased ICP from cerebral edema may impede CPR.\n\n(2) Hyperthermia-related seizures themselves may promote cerebral edema. It is widely accepted that post-ictal cerebral edema begins with excessive influx of sodium and calcium ions through their respective voltage-gated channels into neurons during the repetitive hypersynchronous glutamatergic firing due to seizure activity. Post-ictal hypoxia, energy depletion and lack of sufficient ATP ultimately cause failure of both the sodium-calcium exchange and sodium-potassium exchange further promoting sodium and calcium accumulation with hyperosmolar effects affecting the integrity of the blood-brain barrier [32]. Additionally, neuronal sodium and calcium influx will likely influence the membrane potential facilitating further ion influx through voltage-gated ion channels. Sodium influx through VGSCs during seizure activity may therefore be considered as the crucial mechanism initiating the cascade leading to cerebral edema. It is therefore likely that this cascade may be impacted by both availability of sodium ions and/or changes in the sodium ion gradient as well as altered functioning or expression of VGSCs. Increased excitability due to loss of function from mutations of SCN1A may reflect compensatory upregulation of other VGSC and voltage-gated calcium channels [33] or lack of signaling through GABA-ergic [inhibitory] interneurons in the hippocampus [34]. Increased excitability due to gain of function mutations of SCN1A also reported in DS, may reflect a lowered activation threshold of the channel or prolong channel opening increasing intracellular sodium influx and accumulation [35], [36], [37].\n\n(3) Post-ictal bradycardia and asystole as a consequence of ictal activity spreading to the cardiorespiratory nuclei of the brainstem is a proposed mechanism of SUDEP. Bradycardia is also a well-documented reaction to increased ICP (Cushing Reflex) and may further contribute to post-ictal cardio–respiratory dysfunction. Furthermore it is also possible autonomic dysfunction observed in DS patients may alter physiological compensatory mechanisms to increased ICP mediated given the complexity of brainstem-subcortical networks.\n\n\n\nThis case report is limited by the inherent nature of an isolated patient report but also by the limited documentation due to the emergency situation. However, disease-directed treatment strategies aimed at attenuating autonomic dysfunction and preventing cardiac arrest in DS patients require further investigation.\n\n4 Conclusion\nCytotoxic brain edema, neuronal swelling and subsequently Ca2 +-independent neuronal death are mediated by a sodium ion influx into neurons, which peaks during the repetitive firing of neurons underlying seizures. It is therefore possible that sodium channel dysfunction can promote fatal cerebral edema under certain circumstances including the post-ictal period. The combination of hyperthermia, ion channel dysfunction and possibly emotional stress may therefore not only trigger seizures but also facilitate a fatal pathophysiological cascade of cerebral edema leading to cerebral herniation causing cardiorespiratory collapse. Furthermore, SCN1A mutations may alter susceptibility for neuronal hypoxia. Further analyses are required to elucidate underlying pathophysiological mechanisms of SUDEP and post-ictal edema in DS patients.\n\nAcknowledgements\nNone.\n\nDisclosure of potential conflicts of interest\nMaxine Dibué-Adjei is an employee of LivaNova PLC, manufacturer of vagus nerve stimulators. All other authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers' bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements), or non-financial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this manuscript.\n\nGrant support\nThe present study was not funded.\n==== Refs\nReferences\n1 Cooper M.S. McIntosh A. Crompton D.E. McMahon J.M. Schneider A. Farrell K. Mortality in Dravet syndrome Epilepsy Res 128 2016 43 47 27810515 \n2 Skluzacek J.V. Watts K.P. Parsy O. Wical B. Camfield P. Dravet syndrome and parent associations: the IDEA League experience with comorbid conditions, mortality, management, adaptation, and grief Epilepsia 52 Suppl. 2 2011 95 101 21463290 \n3 Surges R. Thijs R.D. Tan H.L. Sander J.W. Sudden unexpected death in epilepsy: risk factors and potential pathomechanisms Nat Rev Neurol 5 2009 492 504 19668244 \n4 Ermolyuk Y.S. Alder F.G. Surges R. Pavlov I.Y. Timofeeva Y. Kullmann D.M. Differential triggering of spontaneous glutamate release by P/Q-, N- and R-type Ca2 + channels Nat Neurosci 16 2013 1754 1763 24185424 \n5 Langan Y. Sudden unexpected death in epilepsy (SUDEP): risk factors and case control studies Seizure 9 2000 179 183 10775513 \n6 Langan Y. Nashef L. Sander J.W. Sudden unexpected death in epilepsy: a series of witnessed deaths J Neurol Neurosurg Psychiatry 68 2000 211 213 10644790 \n7 Langan Y. Nashef L. Sander J.W. Case-control study of SUDEP Neurology 64 2005 1131 1133 15824334 \n8 Terrence C.F. Jr. Wisotzkey H.M. Perper J.A. Unexpected, unexplained death in epileptic patients Neurology 25 1975 594 598 1168879 \n9 Lhatoo S.D. Nei M. Raghavan M. Sperling M. Zonjy B. Lacuey N. Nonseizure SUDEP: sudden unexpected death in epilepsy without preceding epileptic seizures Epilepsia 57 2016 1161 1168 27221596 \n10 Ryvlin P. Nashef L. Lhatoo S.D. Bateman L.M. Bird J. Bleasel A. Incidence and mechanisms of cardiorespiratory arrests in epilepsy monitoring units (MORTEMUS): a retrospective study Lancet Neurol 12 2013 966 977 24012372 \n11 Nei M. Ho R.T. Abou-Khalil B.W. Drislane F.W. Liporace J. Romeo A. EEG and ECG in sudden unexplained death in epilepsy Epilepsia 45 2004 338 345 15030496 \n12 DeGiorgio C.M. DeGiorgio A.C. SUDEP and heart rate variability Epilepsy Res 90 2010 309 310 [author reply 311-2] 20399076 \n13 Delogu A.B. Spinelli A. Battaglia D. Dravet C. De Nisco A. Saracino A. Electrical and autonomic cardiac function in patients with Dravet syndrome Epilepsia 52 Suppl. 2 2011 55 58 21463281 \n14 Ergul Y. Ekici B. Tatli B. Nisli K. Ozmen M. QT and P wave dispersion and heart rate variability in patients with Dravet syndrome Acta Neurol Belg 113 2013 161 166 23065439 \n15 Zimmer T. Haufe V. Blechschmidt S. Voltage-gated sodium channels in the mammalian heart Glob Cardiol Sci Pract 2014 2014 449 463 25780798 \n16 Dravet C. Bureau M. Oguni H. Fukuyama Y. Cokar O. Severe myoclonic epilepsy in infancy: Dravet syndrome Adv Neurol 95 2005 71 102 15508915 \n17 Oakley J.C. Kalume F. Yu F.H. Scheuer T. Catterall W.A. Temperature- and age-dependent seizures in a mouse model of severe myoclonic epilepsy in infancy Proc Natl Acad Sci U S A 106 2009 3994 3999 19234123 \n18 Liautard C. Scalmani P. Carriero G. de Curtis M. Franceschetti S. Mantegazza M. Hippocampal hyperexcitability and specific epileptiform activity in a mouse model of Dravet syndrome Epilepsia 54 2013 1251 1261 23663038 \n19 Sawyer N.T. Helvig A.W. Makinson C.D. Decker M.J. Neigh G.N. Escayg A. Scn1a dysfunction alters behavior but not the effect of stress on seizure response Genes Brain Behav 15 2016 335 347 26694226 \n20 Canas N. Breia P. Soares P. Saraiva P. Calado S. Jordao C. The electroclinical-imagiological spectrum and long-term outcome of transient periictal MRI abnormalities Epilepsy Res 91 2010 240 252 20728314 \n21 Lassmann H. Petsche U. Kitz K. Baran H. Sperk G. Seitelberger F. The role of brain edema in epileptic brain damage induced by systemic kainic acid injection Neuroscience 13 1984 691 704 6527775 \n22 Gao Q. Ou-Yang T.P. Sun X.L. Yang F. Wu C. Kang T. Prediction of functional outcome in patients with convulsive status epilepticus: the END-IT score Crit Care 20 2016 46 26916702 \n23 Myers K.A. McMahon J.M. Mandelstam S.A. Mackay M.T. Kalnins R.M. Leventer R.J. Fatal cerebral edema with status epilepticus in children with Dravet syndrome: report of 5 cases Pediatrics 139 2017 \n24 Okumura A. Uematsu M. Imataka G. Tanaka M. Okanishi T. Kubota T. Acute encephalopathy in children with Dravet syndrome Epilepsia 53 2012 79 86 \n25 Takayanagi M. Haginoya K. Umehara N. Kitamura T. Numata Y. Wakusawa K. Acute encephalopathy with a truncation mutation in the SCN1A gene: a case report Epilepsia 51 2010 1886 1888 20491869 \n26 Berkovic S.F. Harkin L. McMahon J.M. Pelekanos J.T. Zuberi S.M. Wirrell E.C. De-novo mutations of the sodium channel gene SCN1A in alleged vaccine encephalopathy: a retrospective study Lancet Neurol 5 2006 488 492 16713920 \n27 Chipaux M. Villeneuve N. Sabouraud P. Desguerre I. Boddaert N. Depienne C. Unusual consequences of status epilepticus in Dravet syndrome Seizure 19 2010 190 194 20172746 \n28 Plant L.D. Marks J.D. Goldstein S.A. SUMOylation of NaV1.2 channels mediates the early response to acute hypoxia in central neurons Elife 2016 5 \n29 Fung M.L. Croning M.D. Haddad G.G. Sodium homeostasis in rat hippocampal slices during oxygen and glucose deprivation: role of voltage-sensitive sodium channels Neurosci Lett 275 1999 41 44 10554980 \n30 Fung M.L. Role of voltage-gated Na + channels in hypoxia-induced neuronal injuries Clin Exp Pharmacol Physiol 27 2000 569 574 10901384 \n31 Stys P.K. Lopachin R.M. Mechanisms of calcium and sodium fluxes in anoxic myelinated central nervous system axons Neuroscience 82 1998 21 32 9483500 \n32 Rosenberg G.A. Brain edema and disorders of cerebrospinal fluid circulation Bradley WGD R.B. Ferichel G.M. Marsden C.D. Neurology in clinical practice 2000 Butterworth Heinmann Boston 1545 1559 \n33 Yu F.H. Mantegazza M. Westenbroek R.E. Robbins C.A. Kalume F. Burton K.A. Reduced sodium current in GABAergic interneurons in a mouse model of severe myoclonic epilepsy in infancy Nat Neurosci 9 2006 1142 1149 16921370 \n34 Ogiwara I. Miyamoto H. Morita N. Atapour N. Mazaki E. Inoue I. Nav1.1 localizes to axons of parvalbumin-positive inhibitory interneurons: a circuit basis for epileptic seizures in mice carrying an Scn1a gene mutation J Neurosci 27 2007 5903 5914 17537961 \n35 Volkers L. Kahlig K.M. Verbeek N.E. Das J.H. van Kempen M.J. Stroink H. Nav 1.1 dysfunction in genetic epilepsy with febrile seizures-plus or Dravet syndrome Eur J Neurosci 34 2011 1268 1275 21864321 \n36 Rhodes T.H. Lossin C. Vanoye C.G. Wang D.W. George A.L. Jr. Noninactivating voltage-gated sodium channels in severe myoclonic epilepsy of infancy Proc Natl Acad Sci U S A 101 2004 11147 11152 15263074 \n37 Cossette P. Loukas A. Lafreniere R.G. Rochefort D. Harvey-Girard E. Ragsdale D.S. Functional characterization of the D188V mutation in neuronal voltage-gated sodium channel causing generalized epilepsy with febrile seizures plus (GEFS) Epilepsy Res 53 2003 107 117 12576172\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2213-3232",
"issue": "9()",
"journal": "Epilepsy & behavior case reports",
"keywords": "Cerebral edema; Dravet Syndrome; Fatality; Hyperthermia; SCN1A mutation; SUDEP",
"medline_ta": "Epilepsy Behav Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101614202",
"other_id": null,
"pages": "29-32",
"pmc": null,
"pmid": "29692967",
"pubdate": "2018",
"publication_types": "D002363:Case Reports",
"references": "22092154;27221596;25780798;27810515;19668244;16921370;24012372;26694226;1168879;20399076;19234123;15263074;28029095;23663038;6527775;12576172;10644790;10775513;17537961;20172746;23065439;21463281;15508915;15030496;21864321;15824334;16713920;10554980;24185424;9483500;26916702;20728314;20491869;21463290;10901384;28330972",
"title": "Can the combination of hyperthermia, seizures and ion channel dysfunction cause fatal post-ictal cerebral edema in patients with SCN1A mutations?",
"title_normalized": "can the combination of hyperthermia seizures and ion channel dysfunction cause fatal post ictal cerebral edema in patients with scn1a mutations"
} | [
{
"companynumb": "DE-GLENMARK PHARMACEUTICALS-2018GMK035231",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TOPIRAMATE"
},
"drugadditiona... |
{
"abstract": "Lacosamide (LCM) is a new generation antiepileptic drug. It has only been available in Asia in recent years. A retrospective study at two hospitals in Hong Kong was performed to investigate the post-marketing efficacy and tolerability of the drug. A total of 81 subjects were recruited, among which 88% had drug-resistant epilepsy. The most common type of epilepsy was focal with unknown etiology. All patients used LCM as adjunctive therapy. The 50% responder rate was 42% at 12 weeks after achievement of maximal dose of LCM. No specific factor correlated with responsiveness including concomitant enzyme-inducing or sodium channel blocking anticonvulsants. Withdrawal rate within first 12 weeks after drug initiation was 14% while that at any time upon follow-up was 23%. Two cases of uncommon adverse reaction of myoclonus were also reported. The mechanism was postulated to be the sodium channel inhibiting action of LCM. Our study has shown LCM to have comparable efficacy and tolerability in post-marketing experience when compared with the landmark randomized controlled trials.",
"affiliations": "Division of Neurology, Department of Medicine, Queen Mary Hospital, University of Hong Kong, Hong Kong Special Administrative Region. Electronic address: changsk@ha.org.hk.;Division of Neurology, Department of Medicine, Tseung Kwan O Hospital, Hong Kong Special Administrative Region.;Division of Neurology, Department of Medicine, Tseung Kwan O Hospital, Hong Kong Special Administrative Region.;Division of Neurology, Department of Medicine, Queen Mary Hospital, University of Hong Kong, Hong Kong Special Administrative Region.;Division of Neurology, Department of Medicine, Queen Mary Hospital, University of Hong Kong, Hong Kong Special Administrative Region.;Division of Neurology, Department of Medicine, Queen Mary Hospital, University of Hong Kong, Hong Kong Special Administrative Region.",
"authors": "Chang|Richard Shek-Kwan|RS|;Lui|Hoi Ki Kate|HKK|;Lui|Hiu Tung Colin|HTC|;Leung|C Y William|CYW|;Leung|Yu Hin Ian|YHI|;Wang|Yujie Olivia|YO|",
"chemical_list": "D000927:Anticonvulsants; D000078334:Lacosamide",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.jns.2019.116601",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0022-510X",
"issue": "409()",
"journal": "Journal of the neurological sciences",
"keywords": "Efficacy; Lacosamide; Post-marketing; Safety; Tolerability",
"medline_ta": "J Neurol Sci",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000927:Anticonvulsants; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D004827:Epilepsy; D005260:Female; D006723:Hong Kong; D006801:Humans; D000078334:Lacosamide; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "0375403",
"other_id": null,
"pages": "116601",
"pmc": null,
"pmid": "31801052",
"pubdate": "2020-02-15",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D065007:Pragmatic Clinical Trial",
"references": null,
"title": "Efficacy upon 12-weeks after achievement of maximal dose and tolerability of lacosamide as an adjunctive therapy in epilepsy: Real world clinical experience.",
"title_normalized": "efficacy upon 12 weeks after achievement of maximal dose and tolerability of lacosamide as an adjunctive therapy in epilepsy real world clinical experience"
} | [
{
"companynumb": "HK-UCBSA-2019053678",
"fulfillexpeditecriteria": "1",
"occurcountry": "HK",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "LACOSAMIDE"
},
"drugadditional": "1",
"dr... |
{
"abstract": "OBJECTIVE\nWith the increasing use of cancer chemotherapy agents, hypersensitivity reactions are commonly encountered. The allergic clinical symptoms are variable and unpredictable. The aim of this study was to identify the characteristics of hypersensitivity reactions and to assess the value of skin tests for platinum salts and pemetrexed in the treatment of patients with non-small cell lung cancers or malignant pleural mesothelioma.\n\n\nMETHODS\nA single-centre retrospective study was performed for 2 years. Patients treated with the drugs of interest for an advanced or metastatic non-small cell lung cancers or malignant pleural mesothelioma and who experienced hypersensitivity reactions symptoms were eligible for this study. Clinical symptoms of hypersensitivity reactions, population characteristics and administered chemotherapy regimens were identified.\n\n\nRESULTS\nThe hypersensitivity reactions frequency was rare (1.2%) and concerned 17 patients in our study. Typical clinical features of immediate hypersensitivity reactions associated with treatment were observed for nine patients (anaphylactic reactions for three cases, angioedema and hypotension associated with asthenia and heat in one case, respectively, and other cutaneous symptoms in the remaining four cases). Skin tests were positive in three patients, but only for platinum salts. The outcome after reintroduction of a negatively tested platinum salt allowed us to calculate a negative predictive value for platinum salt skin tests of 100%. For pemetrexed, skin tests were negative for all patients.\n\n\nCONCLUSIONS\nSkin tests could be used to diagnose hypersensitivity reactions with platinum salts or to evaluate the possibility of cross-reactions between two platinum salts. A negative skin test may predict with reasonable reliability the absence of future hypersensitivity reactions in case of reintroduction of drug infusion. Because the IgE-mediated mechanism has never been demonstrated for pemetrexed, skin tests are not valid and have no diagnostic value for this molecule. Because hypersensitivity reactions are potentially fatal adverse events, we recommend that patients who experience a hypersensitivity reactions onset should be monitored closely and clinicians must be aware of hypersensitivity reaction signs.",
"affiliations": "Aix Marseille Univ, AP-HM, Oncopharma, Hôpital Nord, Marseille, France.;Aix Marseille Univ, AP-HM, Service de Pneumologie, Hôpital Nord, Marseille, France.;Aix Marseille Univ, AP-HM, Oncologie Multidisciplinaire et Innovations Thérapeutiques, Marseille, France.;Aix Marseille Univ, AP-HM, Service de Pneumologie, Hôpital Nord, Marseille, France.;Aix Marseille Univ, AP-HM, Dermatologie, Vénéréologie et Cancérologie Cutanée, Marseille, France.;Aix Marseille Univ, AP-HM, Oncopharma, Hôpital Nord, Marseille, France.;Aix Marseille Univ, AP-HM, Oncologie Multidisciplinaire et Innovations Thérapeutiques, Marseille, France.;Aix Marseille Univ, AP-HM, Oncopharma, Hôpital Nord, Marseille, France.",
"authors": "Capelle|H|H|;Tummino|C|C|;Greillier|L|L|;Gouitaa|M|M|;Birnbaum|J|J|;Ausias|N|N|;Barlesi|F|F|;Montana|M|M|http://orcid.org/0000-0001-7423-7244",
"chemical_list": "D000970:Antineoplastic Agents; D017671:Platinum Compounds; D000068437:Pemetrexed",
"country": "England",
"delete": false,
"doi": "10.1111/jcpt.12645",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0269-4727",
"issue": "43(3)",
"journal": "Journal of clinical pharmacy and therapeutics",
"keywords": "anaphylaxis; drug hypersensitivity; lung cancer; platinum salts; skin tests",
"medline_ta": "J Clin Pharm Ther",
"mesh_terms": "D000970:Antineoplastic Agents; D002289:Carcinoma, Non-Small-Cell Lung; D003429:Cross Reactions; D004342:Drug Hypersensitivity; D006801:Humans; D008175:Lung Neoplasms; D008654:Mesothelioma; D000086002:Mesothelioma, Malignant; D000068437:Pemetrexed; D017671:Platinum Compounds; D011237:Predictive Value of Tests; D015203:Reproducibility of Results; D012189:Retrospective Studies; D012882:Skin Tests",
"nlm_unique_id": "8704308",
"other_id": null,
"pages": "320-326",
"pmc": null,
"pmid": "29092096",
"pubdate": "2018-06",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Retrospective study of hypersensitivity reactions to chemotherapeutic agents in a thoracic oncology service.",
"title_normalized": "retrospective study of hypersensitivity reactions to chemotherapeutic agents in a thoracic oncology service"
} | [
{
"companynumb": "FR-MYLANLABS-2018M1092796",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CISPLATIN"
},
"drugadditional": null,
... |
{
"abstract": "While cytokine storm develops in a minority of patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, novel treatment approaches are desperately needed for those in whom it does. Tocilizumab, an interleukin-6 receptor antibody, has been utilized for the treatment of cytokine storm in a number of severe inflammatory conditions, including in patients with severe coronavirus disease 2019 (COVID-19). Here, we present the first published case utilizing this therapy in a patient with underlying immunodeficiency. Our patient with aplastic anemia developed cytokine storm due to COVID-19 manifested by fever, severe hypoxia, pulmonary infiltrates, and elevated inflammatory markers. Following treatment with tocilizumab, cytokine storm resolved, and the patient was ultimately safely discharged from the hospital.",
"affiliations": "Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, United States.;Department of Medicine, Thomas Jefferson University Hospital, Philadelphia, PA, United States.;Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, United States.;Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, United States.;Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, United States.;Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, United States.",
"authors": "Keiffer|Gina|G|;French|Zachary|Z|;Wilde|Lindsay|L|;Filicko-O'Hara|Joanne|J|;Gergis|Usama|U|;Binder|Adam F|AF|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fonc.2020.562625",
"fulltext": "\n==== Front\nFront Oncol\nFront. Oncol.\nFrontiers in Oncology\n2234-943X Frontiers Media S.A. \n\n10.3389/fonc.2020.562625\nOncology\nCase Report\nCase Report: Tocilizumab for the Treatment of SARS-CoV-2 Infection in a Patient With Aplastic Anemia\nKeiffer Gina 1* French Zachary 2 Wilde Lindsay 1 Filicko-O'Hara Joanne 1 Gergis Usama 1 Binder Adam F. 1 1Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, United States\n2Department of Medicine, Thomas Jefferson University Hospital, Philadelphia, PA, United States\nEdited by: Massimo Libra, University of Catania, Italy\n\nReviewed by: Belinda Pinto Simoes, University of São Paulo, Brazil; Elias Hallack Atta, National Cancer Institute (INCA), Brazil\n\n*Correspondence: Gina Keiffer gina.keiffer@jefferson.eduThis article was submitted to Hematologic Malignancies, a section of the journal Frontiers in Oncology\n\n\n18 9 2020 \n2020 \n18 9 2020 \n10 56262515 5 2020 17 8 2020 Copyright © 2020 Keiffer, French, Wilde, Filicko-O'Hara, Gergis and Binder.2020Keiffer, French, Wilde, Filicko-O'Hara, Gergis and BinderThis 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.While cytokine storm develops in a minority of patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, novel treatment approaches are desperately needed for those in whom it does. Tocilizumab, an interleukin-6 receptor antibody, has been utilized for the treatment of cytokine storm in a number of severe inflammatory conditions, including in patients with severe coronavirus disease 2019 (COVID-19). Here, we present the first published case utilizing this therapy in a patient with underlying immunodeficiency. Our patient with aplastic anemia developed cytokine storm due to COVID-19 manifested by fever, severe hypoxia, pulmonary infiltrates, and elevated inflammatory markers. Following treatment with tocilizumab, cytokine storm resolved, and the patient was ultimately safely discharged from the hospital.\n\nCOVID-19SARS-CoV-2tocilizumabcytokine stormaplastic anemia\n==== Body\nIntroduction\nTo date, the novel SARS-CoV-2 has infected more than 4,500,000 people in the United States and more than three times that number worldwide. While a minority of patients develop severe symptoms from COVID-19 requiring hospitalization, treatment options for those who do are limited. There is no currently accepted standard and new approaches are desperately needed.\n\nFollowing the initial reports of COVID-19 from Wuhan, China, Huang et al. (1) described the clinical features of the disease. The subset of patients who required intensive care was found to have significant increase in inflammatory cytokines (1). Others have since shown that an increase in interleukin (IL)-6 is associated with critical illness (2) and mortality (3) in COVID-19 patients.\n\nTreatment with tocilizumab, an anti-IL-6 receptor (IL-6R) antibody, has been proposed as a strategy to control cytokine storm associated with COVID-19 (4, 5). This strategy has been utilized by others in the treatment of cytokine storm associated with SARS-CoV-2 (6–9). We describe here the first reported use of tocilizumab in a patient with underlying immune dysregulation, specifically aplastic anemia (AA). In our patient with underlying immunodeficiency, tocilizumab successfully reversed cytokine storm due to COVID-19 and the patient was successfully discharged from the hospital.\n\nCase Description\nA 72-year-old man with a past medical history of AA, amegakaryocytic thrombocytopenia and chronic kidney disease (CKD) stage 3 presented in April 2020 with high fever, cough, and progressive fatigue.\n\nAplastic anemia had been diagnosed in 2014 and initially responded to therapy with horse anti-thymocyte globulin (ATG), methylprednisolone and cyclosporine A. Nine months later, his disease progressed and he was treated with rabbit ATG, methylprednisolone, and cyclosporine A. In late 2019, his disease progressed primarily as thrombocytopenia due to acquired amegakaryocytic thrombocytopenia (AAT). He received four doses of rituximab in early 2020 for treatment of AAT without response. Bone marrow biopsy performed 2 months prior to presentation was hypocellular with 15–20% bilineage hematopoiesis and near absence of megakaryocytes without evidence of dysplasia or increased blasts. While his diagnosis is most accurately classified as AAT at the time of presentation, he had been consistently pancytopenic for 4 months despite treatment with cyclosporine A and remained dependent on platelet transfusions. Family and psycho-social history were non-contributory.\n\nPhysical examination at the time of presentation was notable for fever of 103.7F and mild tachycardia (HR 104) with normal oxygen saturation (97%) without supplemental oxygen. He appeared in mild respiratory distress, but pulmonary examination was unremarkable. His initial laboratory studies were notable for severe lymphopenia, which was different from his baseline pancytopenia and elevated C-reactive protein (CRP) and IL-6 as noted in Table 1. Chest radiograph revealed a consolidation in the left midlung, possibly representative of pneumonia (Figure 1A).\n\nTable 1 Notable laboratory studies at baseline and throughout hospitalization.\n\n\tNormal range\tBaseline Day−30\tAdmission Day 0\tDay 5\tDay 9\tTocilizumab Day 11\tDay 12\tDay 14\tDay 21\tDay 28\tDischarge Day 31\t\nWBC\t4.0–11.0 × 109 cells/L\t2.5\t2.6\t0.4\t0.7\t0.5\t0.3\t0.4\t0.1\t0.5\t0.5\t\nANC\t1.6–8.0 × 109 cells/L\t1.5\t2.36\t3.00\t5.00\t0.460\t0.220\t0.360\t–\t0.210\t0.220\t\nALC\t0.8–4.8 × 109 cells/L\t0.800\t0.080\t0.070\t0.130\t0.030\t0.050\t0.030\t–\t0.220\t0.170\t\nHb (g/dL)\t14.0–17.0 g/dL\t9.2\t8.1\t6.1\t8.2\t6.8\t8.0\t8.3\t7.4\t7.0\t6.6\t\nPlatelet\t140–400 × 109 cells/L\t24\t10\t20\t24\t9\t14\t10\t19\t24\t18\t\nCreatinine\t0.7–1.4 mg/dL\t2.34\t2.59\t2.1\t2.34\t3.04\t2.7\t1.91\t2.00\t1.31\t1.6\t\nD-dimer\t<230 ng/mL\tNR\t673\t1,005\t1,781\t1,833\t2,209\t997\t1,932\t1,010\t960\t\nPT\t9.4–13.0 s\t–\t12.4\t–\t16.5\t–\t–\t–\t16.1\t17.0\t13.5\t\naPTT\t25–36 s\t–\t29\t–\t32\t–\t–\t–\t28\t28\t29\t\nLDH\t125–240 IU/L\t267\t206\t232\t296\t–\t272\t209\t180\t142\t122\t\nFerritin\t30–400 ng/mL\tNR\t–\t4,122\t7,535\t7,291\t11,363 (Day 13)\t6,339\t2,541\t2,326\t2,533\t\nCRP\t<0.80 mg/dL\tNR\t5.10\t18.70\t34.70\t40.10\t32.60\t8.20\t7.20\t2.80\t1.4\t\nIL-6\t<5.00 pg/mL\tNR\t58.96\t–\t–\t–\t–\t–\t–\t1223.8\t–\t\nSARS-CoV-2 PCR\tNegative\tNR\tPositive\t\t\t\t\tPositive\tNegative (Day 17)\tPositive (Day 29)\t\t\nWBC, white blood cell count; ANC, absolute neutrophil count; ALC, absolute lymphocyte count; Hb, hemoglobin; PT, prothrombin time; aPTT, activated partial thromboplastin time; LDH, lactate dehydrogenase; CRP, C-reactive protein; NR, not reported.\n\nFigure 1 Select chest radiograph images during the patient's hospitalization.\n\nThe patient was treated empirically with hydroxychloroquine (400 mg twice a day for 1 day, followed by 200 mg twice a day for 4 days) for possible COVID-19 in the setting of immunosuppression. Ceftriaxone and azithromycin were added for possible community acquired pneumonia. On admission day 0, SARS-CoV-2 PCR nasal swab came back positive. For the first several days of the hospitalization, the patient had persistent fever (range 100–104F) and intermittently required oxygen up to 2 L/min via nasal cannula to maintain oxygen saturation above 94%.\n\nBy hospital day 5, he had developed progressive pancytopenia and required near daily transfusion of packed red blood cells and platelets. Due to persistent high fever, and now neutropenia, antibacterial coverage was broadened to cefepime, then meropenem, and antifungal prophylaxis with posaconazole was added. He was also started on tbo-filgrastim and eltrombopag for management of severe neutropenia and thrombocytopenia.\n\nOn hospital day 9, the patient developed lethargy and hypoxia requiring supplemental oxygen of 6 L/min via nasal cannula and subsequently Venturi mask at 50% FiO2. Repeat chest radiograph demonstrated significant worsening with bilateral pulmonary infiltrates (Figure 1B). Inflammatory markers, including ferritin and CRP were significantly increased and acute on chronic renal failure worsened (Table 1).\n\nThe clinical picture was consistent with cytokine storm due to severe COVID-19 and the patient promptly received tocilizumab 5 mg/kg (400 mg) on hospital day 11. The patient received a single dose of methylprednisolone 60 mg IV immediately prior to tocilizumab administration but did not otherwise receive corticosteroid treatment during his admission. The same day, the patient's fever resolved and he developed mild hypothermia (minimum 94.6F). Over the next several days, his temperature normalized, oxygen requirements steadily declined, inflammatory markers decreased and acute renal failure resolved. The patient remained pancytopenic and transfusion dependent. Meropenem was discontinued and he was transitioned to oral levofloxacin prophylaxis due to persistent neutropenia.\n\nOn hospital day 18, the patient developed mild recurrent fever (100.5F, repeat 100.9F). The following day, his fever increased significantly to 103.9F and his oxygen requirement increased to 10 L/min. Chest radiograph revealed new pulmonary infiltrates (Figure 1C). Cefepime was resumed and vancomycin and therapeutic voriconazole were added. Despite these efforts, the patient developed mild hypotension (BP 90/40) which resolved with fluid resuscitation. Antibiotics were further broadened to meropenem and the patient received a single dose of tobramycin. Inflammatory markers at this time were relatively stable.\n\nBy hospital day 20, the patient had again clinically improved. His blood pressure remained within normal range and his oxygen requirement decreased to 6 L/min by nasal cannula. The exact cause of his brief clinical deterioration was unclear but was presumed to be due to a secondary bacterial pneumonia. Over the subsequent days, he completed a 7-day course of meropenem and vancomycin. He remained afebrile on this treatment and his oxygen requirement slowly normalized. His repeat IL-6 level on day 28 was significantly elevated at 1223.8 pg/mL.\n\nThe patient was discharged home on hospital day 31. He remained pancytopenic and transfusion dependent at the time of hospital discharge. Notably, his SARS-CoV-2 PCR testing has remained persistently positive as of hospital day 29 (with the exception of a single negative result on day 17, which was thought to be a false negative). It is unclear whether detectable viral RNA represents persistent infectiousness or whether non-infectious RNA fragments are being detected. Twenty two days after hospital discharge, SARS-CoV-2 PCR was repeated and was negative.\n\nDiscussion\nHyperinflammatory syndromes, such as the cytokine storm observed in patients with severe SARS-CoV-2 infection, play a major role in the development of critical illness associated with viral infections. Multiple reports have identified significant increases in inflammatory markers, including IL-6, in patients with severe SARS-CoV-2 infection (1, 3, 10–12). In one retrospective analysis, elevated ferritin (mean 1297.6 vs. 614.0 ng/mL), CRP (mean 34.1 vs. 126.6 mg/L), and IL-6 levels (mean 6.8 vs. 11.4 pg/mL) have been identified as risk factors for mortality (3). Significant elevation in IL-6 has previously been identified as a significant factor in the development of cytokine release syndrome (CRS) in patients undergoing chimeric antigen receptor T cell (CAR-T) therapy, as well (13).\n\nIL-6 serves many important immunologic and hematopoietic functions, including differentiation of activated B cells to immunoglobulin-producing plasma cells, differentiation of naïve CD4+ T cells to Th17 cells and of CD8+ T cells to cytotoxic T cells, promotion of T follicular helper cell differentiation, inhibition of regulatory T cell (Treg) differentiation and stimulation of acute-phase proteins (14). In combination with erythropoietin and IL-3, IL-6 promotes formation of myeloid, erythroid, megakaryocyte, and macrophage colonies (15). Tocilizumab is a recombinant, humanized monoclonal antibody which binds and inhibits the soluble IL-6 receptor and has been utilized in the treatment of auto-inflammatory conditions (16) and CRS following CAR-T therapy (17). Based on the success of treating CAR-T-associated CRS with anti-IL-6 therapy, the same strategy has been proposed for the treatment of cytokine storm associated with severe SARS-CoV-2 infection (4, 5). Many case reports and case series support the use of tocilizumab in this setting (6–9) and multiple clinical trials investigating this treatment are underway in the United States and abroad (NCT04317092, NCT04331795, NCT04335071, NCT04356937, and others).\n\nThe most promising data thus far are from a retrospective analysis of the use of 1–2 doses of tocilizumab in 21 adult patients with severe or critical COVID-19 treated at two centers in China. Following treatment, all patients became afebrile and 70% had decreased oxygen requirements. Nineteen patients (90.5%) had been discharged from the hospital, including two critical patients, after a mean of 13.5 days following treatment with tocilizumab. No patients developed recurrent fever or symptoms of recurrent pneumonia (9).\n\nA retrospective analysis of 30 French patients age <80 years with severe COVID-19 treated with tocilizumab after at least 5 prior days of illness requiring at least 6 L/min of oxygen therapy who developed rapidly deteriorating COVID-19 pneumonia (increase by more than 3 L/min oxygen therapy in 12 h) showed that treatment with tocilizumab 8 mg/kg for 1–2 doses was associated with decreased ICU admission (OR 0.17, 95% CI 0.06–0.48, p = 0.001) and mechanical ventilation (OR 0.42, 95% CI 0.20–0.89, p = 0.025) compared to matched controls. No benefit in mortality was seen after weighted analysis (18).\n\nThe clinical response observed in our AA patient following treatment with tocilizumab is in line with previously published reports despite his underlying immunodeficiency. After a single dose of tocilizumab, his clinical and laboratory markers of severe COVID-19 had improved. While he did experience a brief clinical deterioration 7–8 days following tocilizumab administration, this was thought to be due to secondary bacterial pneumonia as evidenced by the pattern change in the chest radiologic image, and unlikely related to use of tocilizumab.\n\nBoth the development of cytokine storm and the resolution thereof following tocilizumab is particularly notable in our patient in light of his underlying immune dysfunction. Activation of aberrant T cells and monocytes, which produce large numbers of inflammatory cytokines, appears to be a driving factor and has been implicated in many patients with severe COVID-19 (9, 11, 19). Guo et al. (20) profiled the peripheral immune cells of two severe SARS-CoV-2-infected patients at three time points (severe stage: 12 h, recovery stage: 5 days and healthy stage: 7 days) following treatment with tocilizumab to better understand the immune effects of this intervention. Notably, a subpopulation of monocytes was only present in the severe stage while other distinct subpopulations were present at recovery and healthy stages. Gene expression of TNF, IL10, CCL3, and IL6 were significantly higher in the severe stage-specific monocytes, suggesting that a specific monocyte subpopulation may contribute to the inflammatory storm seen in patients with severe COVID-19. Additionally, interaction of IL-6/IL-6R ligand/receptor pairs were attenuated by tocilizumab treatment. Following treatment with tocilizumab, expression of genes involved in the acute inflammatory response and leukocyte chemotaxis were significantly decreased. B cells and effector CD8+ T cells and proliferative CD8+ T cells were significantly increased compared to controls, suggesting that anti-virus humoral and cell-mediated immune responses remained intact despite tocilizumab therapy. There was no difference in CD4+ T cells, naïve CD8+ T cells and B cells in patients vs. healthy controls (20).\n\nIL-6 level was not available immediately following tocilizumab administration in our patient due to laboratory error, however, our patient's IL-6 level was found to be significantly elevated ~2 weeks after tocilizumab administration despite clinical improvement. This trend is consistent with what has been previously reported following tocilizumab treatment in patients with rheumatoid arthritis and Castleman disease. In these patients, significant rise in IL-6 level following tocilizumab treatment has been observed. IL-6 level peaked at day 14 after therapy remained at stable elevation until day 42 (21). This phenomenon has been suggested to be due to binding of tocilizumab to IL-6R leading to delayed clearance and accumulation of IL-6 in the blood (21, 22). That this elevation persists at a stable level weeks after tocilizumab administration has been suggested to be due to continued IL-6 production at approximately the same rate as direct IL-6 degredation (21).\n\nThe totality of immune effects of SARS-CoV-2 infection and tocilizumab therapy remain to be fully understood, as does the impact of treatment with tocilizumab on the clinical course in patients with AA. It is known that IL-6 impacts the balance of Th17 and Treg cells by promoting proliferation of the former and inhibiting the later (14) and that imbalance in Th17/Treg cells is an important feature in the development of AA (23). Additionally, elevation in IL-6 has been observed in children with AA compared to healthy controls (193.48 vs. 4.58 pg/mL, p < 0.001). The degree of IL-6 elevation was associated with severity of disease and reduction in IL-6 level was associated with response to immunosuppressive therapy (IST) (24). Others have found that children with higher baseline IL-6 elevation are more likely to respond to IST (211.89 vs. 18.09 pg/mL, p = 0.005) and that an IL-6 level of at least 36.8 pg/mL had 81% sensitivity to distinguish responders from non-responders (25). There are currently no published data regarding use of tocilizumab for treatment of AA, although data on the role of IL-6 in dysregulation of Th17/Treg balance and the role of this imbalance in the development of AA suggests that tocilizumab may play a role. It remains to be seen whether our patient will benefit in his blood cell counts following tocilizumab therapy.\n\nBeing a single patient report is a major limitation. However, we felt that it's prudent to report the first use of tocilizumab to treat a cytokine storm induced severe SARSCoV-2 in a patient with underlying immunodeficiency. The findings are consistent with what has been reported in immune competent patients. The rapid clinical improvement and decline of all inflammatory markers suggests that tocilizumab was effective in reversing COVID-19-associated cytokine storm.\n\nPatient Perspective\n“I started feeling tired and had no energy even to walk short distances. I had a fever and minor cough. I went to the Emergency Room [sic] at Jefferson [sic], and I tested positive [for SARS-CoV-2] and they admitted me. The first couple of weeks (I was in the hospital for a total of 4 weeks), I slept most of the time. I was either on my back in bed or in a chair. After I started to get better, I was more awake and I became depressed and bored. I looked forward to my daily [physical therapy] visits. It is certainly difficult not having visitors. The doctors and nurses were excellent. The doctors communicated with my wife every day. I simply cannot say enough about the care I received. When released from the hospital, I came directly home and have been receiving nursing care and [physical therapy].\n\nMy case is complicated by the fact that prior to my hospitalization I required transfusions for aplastic anemia. The medical staff worked diligently to have a procedure for transfusing patients with [COVID-19] as outpatients. They were able to have a procedure set up of which I was the first. The care and attention I received at the infusion center was well-organized and excellent. My improvement is progressing and I am getting better every day.”\n\nConclusion\nUntil now, treatment of severe COVID-19 with tocilizumab has been tried in patients without pre-existing immune dysfunction. We have reported the first use of this treatment strategy in a patient with underlying immunodeficiency. It is notable that both the symptoms and signs of severe COVID-19 and the result of therapy with tocilizumab is similar to prior reports in patients with presumably normal baseline immune function. More work is desperately needed to better understand the immunological impacts of severe SARS-CoV-2 infection and the risks and benefits of tocilizumab treatment.\n\nData Availability Statement\nThe original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.\n\nEthics Statement\nEthical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.\n\nAuthor Contributions\nGK and ZF wrote the manuscript. LW, JF-O'H, UG, and AB reviewed and edited the manuscript. All authors contributed to the article and approved the submitted version.\n\nConflict of Interest\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n\nFunding. Publication of this manuscript was funded as part of employment of the authors at Sidney Kimmel Cancer Center.\n==== Refs\nReferences\n1. Huang C Wang Y Li X Ren L Zhao J Hu Y . Clinical features of patients infected with (2019) novel coronavirus in Wuhan, China\n. Lancet. (2020 ) 395 :497 –506\n. 10.1016/S0140-6736(20)30183-5 31986264 \n2. Chen X Zhao B Qu Y Chen Y Xiong J Feng Y \nDetectable serum severe acute respiratory syndrome coronavirus 2 viral load (RNAemia) is closely correlated with drastically elevated interleukin 6 level in critically Ill patients with coronavirus disease 2019\n. Clin Infect Dis . (2020 ). 10.1093/cid/ciaa449 . [Epub ahead of print].\n3. Ruan Q Yang K Wang W Jiang L Song J \nClinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China\n. Intensive Care Med . (2020 ) 46 :846 –8\n. 10.1007/s00134-020-06028-z 32125452 \n4. Mehta P McAuley DF Brown M Sanchez E Tattersall RS Manson JJ . COVID-19: consider cytokine storm syndromes and immunosuppression\n. Lancet . (2020 ) 395 :1033 –4\n. 10.1016/S0140-6736(20)30628-0 32192578 \n5. Zhang S Li L Shen A Chen Y Qi Z . Rational use of tocilizumab in the treatment of novel coronavirus pneumonia\n. Clin Drug Investig . (2020 ) 40 :511 –8\n. 10.1007/s40261-020-00917-3 32337664 \n6. Luo P Liu Y Qiu L Liu X Liu D Li J . Tocilizumab treatment in COVID-19: a single center experience\n. J Med Virol . (2020 ) 92 :814 –8\n. 10.1002/jmv.25801 32253759 \n7. Michot JM Albiges L Chaput N Saada V Pommeret F Griscelli F . Tocilizumab, an anti-IL6 receptor antibody, to treat Covid-19-related respiratory failure: a case report\n. Ann Oncol . (2020 ) 31 :961 –4\n. 10.1016/j.annonc.2020.03.300 32247642 \n8. Di Giambenedetto S Ciccullo A Borghetti A Gambassi G Landi F Visconti E . Off-label use of tocilizumab in patients with SARS-CoV-2 infection\n. J Med Virol . (2020 ). 10.1002/jmv.25897 . [Epub ahead of print].32297987 \n9. Xu X Han M Li T Sun W Wang D Fu B . Effective treatment of severe COVID-19 patients with tocilizumab\n. Proc Natl Acad Sci USA . (2020 ) 117 :10970 –5\n. 10.1073/pnas.2005615117 32350134 \n10. Wang D Hu B Hu C Zhu F Liu X Zhang J . Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China\n. JAMA . (2020 ) 323 :1061 –9\n. 10.1001/jama.2020.1585 32031570 \n11. Liu J Li S Liu J Liang B Wang X Wang H . Longitudinal characteristics of lymphocyte responses and cytokine profiles in the peripheral blood of SARS-CoV-2 infected patients\n. EBioMedicine . (2020 ) 55 :102763 . 10.1016/j.ebiom.2020.102763 32361250 \n12. Zhou F Yu T Du R Fan G Liu Y Liu Z \nClinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study\n. Lancet . (2020 ) 395 :1054 –62\n. 10.1016/S0140-6736(20)30566-3 32171076 \n13. Teachey DT Lacey SF Shaw PA Melenhorst JJ Maude SL Frey N . Identification of predictive biomarkers for cytokine release syndrome after chimeric antigen receptor T-cell therapy for acute lymphoblastic leukemia\n. Cancer Discov . (2016 ) 6 :664 –79\n. 10.1158/2159-8290.CD-16-0040 27076371 \n14. Tanaka T Narazaki M Kishimoto T \nIL-6 in inflammation, immunity, and disease\n. Cold Spring Harb Perspect Biol . (2014 ) 6 :a016295 \n10.1101/cshperspect.a016295 25190079 \n15. Madkaikar M Ghosh K Gupta M Swaminathan S Mohanty D . Ex vivo expansion of umbilical cord blood stem cells using different combinations of cytokines and stromal cells\n. Acta Haematol . (2007 ) 118 :153 –9\n. 10.1159/000108630 17890847 \n16. Tanaka T Narazaki M Ogata A Kishimoto T . A new era for the treatment of inflammatory autoimmune diseases by interleukin-6 blockade strategy\n. Semin Immunol . (2014 ) 26 :88 –96\n. 10.1016/j.smim.2014.01.009 24594001 \n17. Grupp SA Laetsch TW Buechner J Bittencourt H Maude SL Verneris MR \nAnalysis of a global registration trial of the efficacy and safety of CTL019 in pediatric and young adults with relapsed/refractory acute lymphoblastic leukemia (ALL)\n. Blood . (2016 ) 128 :221 \n10.1182/blood.V128.22.221.221 \n18. Roumier M Paule R Groh M Vallee A Ackermann F \nInterleukin-6 blockade for severe COVID-19\n. medRxiv [Preprint]. (2020 ). 10.1101/2020.04.20.20061861 \n19. Li G Fan Y Lai Y Han T Li Z Zhou P \nCoronavirus infections and immune responses\n. J Med Virol . (2020 ) 92 :424 –32\n. 10.1002/jmv.25685 31981224 \n20. Guo C Li B Ma H Wang X Cai P Yu Q . Single-cell analysis of two severe COVID-19 patients reveals a monocyte-associated and tocilizumab-responding cytokine storm\n. Nat Commun. (2020 ) 11 :3924 . 10.1038/s41467-020-17834-w 32764665 \n21. Nishimoto N Terao K Mima T Nakahara H Takagi N Kakehi T . Mechanisms and pathologic significances in increase in serum interleukin-6 (IL-6) and soluble IL-6 receptor after administration of an anti–IL-6 receptor antibody, tocilizumab, in patients with rheumatoid arthritis and Castleman disease\n. Blood . (2008 ) 112 :3959 –64\n. 10.1182/blood-2008-05-155846 18784373 \n22. Uchiyama Y Yoshida H Koike N Hayakawa N Sugita A Nishimura T \nAnti-IL-6 receptor antibody increases blood IL-6 level via the blockade of IL-6 clearance, but not via the induction of IL-6 production\n. Int Immunopharmacol . (2008 ) 8 :1595 –601\n. 10.1016/j.intimp.2008.07.002 18664393 \n23. Zeng Y Katsanis E . The complex pathophysiology of acquired aplastic anaemia\n. Clin Exp Immunol . (2015 ) 180 :361 –70\n. 10.1111/cei.12605 25683099 \n24. Gupta V Kumar S Sonowal R Singh SK . Interleukin-6 and interleukin-8 levels correlate with the severity of aplastic anemia in children\n. J Pediatr Hematol Oncol . (2017 ) 39 :214 –6\n. 10.1097/MPH.0000000000000724 28060106 \n25. Lu S Qiao X Xie X . Elevated serum interleukin-6 predicts favorable response to immunosuppressive therapy in children with aplastic anemia\n. J Pediatr Hematol Oncol . (2017 ) 39 :614 –7\n. 10.1097/MPH.0000000000000942 29068868\n\n",
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"journal": "Frontiers in oncology",
"keywords": "COVID-19; SARS-CoV-2; aplastic anemia; cytokine storm; tocilizumab",
"medline_ta": "Front Oncol",
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"title": "Case Report: Tocilizumab for the Treatment of SARS-CoV-2 Infection in a Patient With Aplastic Anemia.",
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"abstract": "We report a case of a 74-year-old man with a metastatic anaplastic pancreatic carcinoma (APC). After an early tumour progression on first-line chemotherapy with cisplatin and gemcitabine, even though it was badly tolerated, he was treated with a combination of systemic modified FOLFIRI and high-intensity focused ultrasound (HIFU) on the pancreatic mass. A tumour showing partial response with a clinical benefit was obtained. HIFU was preferred to radiotherapy because of its shorter course and minimal side effects, in order to improve the patient's clinical conditions. The patient is currently on chemotherapy, asymptomatic with a good performance status. In referral centres, with specific expertise, HIFU could be safely and successfully combined with systemic chemotherapy for treatment of metastatic pancreatic carcinoma.",
"affiliations": "Unit of Gastrointestinal Medical Oncology and Neuroendocrine Tumours, European Institute of Oncology, Milan 20141, Italy.;Unit of Gastrointestinal Medical Oncology and Neuroendocrine Tumours, European Institute of Oncology, Milan 20141, Italy.;Unit of Diagnostic Cytology, European Institute of Oncology, Milan 20141, Italy.;Unit of Gastrointestinal Medical Oncology and Neuroendocrine Tumours, European Institute of Oncology, Milan 20141, Italy.;Unit of Gastrointestinal Medical Oncology and Neuroendocrine Tumours, European Institute of Oncology, Milan 20141, Italy.;Unit of Gastrointestinal Medical Oncology and Neuroendocrine Tumours, European Institute of Oncology, Milan 20141, Italy.;Unit of Diagnostic Cytology, European Institute of Oncology, Milan 20141, Italy.;Unit of Interventional Radiology, European Institute of Oncology, Milan 20141, Italy.;Unit of Interventional Radiology, European Institute of Oncology, Milan 20141, Italy.;Unit of Gastrointestinal Medical Oncology and Neuroendocrine Tumours, European Institute of Oncology, Milan 20141, Italy.;Unit of Gastrointestinal Medical Oncology and Neuroendocrine Tumours, European Institute of Oncology, Milan 20141, Italy.;Unit of Gastrointestinal Medical Oncology and Neuroendocrine Tumours, European Institute of Oncology, Milan 20141, Italy.",
"authors": "Ungaro|Antonio|A|;Orsi|Franco|F|;Casadio|Chiara|C|;Galdy|Salvatore|S|;Spada|Francesca|F|;Cella|Chiara Alessandra|CA|;Tonno|Clementina Di|CD|;Bonomo|Guido|G|;Vigna|Paolo Della|PD|;Murgioni|Sabina|S|;Frezza|Anna Maria|AM|;Fazio|Nicola|N|",
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"doi": "10.3332/ecancer.2016.635",
"fulltext": "\n==== Front\nEcancermedicalscienceEcancermedicalscienceecancermedicalscienceecancermedicalscience1754-6605Cancer Intelligence 10.3332/ecancer.2016.635can-10-635Case ReportSuccessful palliative approach with high-intensity focused ultrasound in a patient with metastatic anaplastic pancreatic carcinoma: a case report Ungaro Antonio 1Orsi Franco 1Casadio Chiara 2Galdy Salvatore 1Spada Francesca 1Cella Chiara Alessandra 1Tonno Clementina Di 2Bonomo Guido 3Vigna Paolo Della 3Murgioni Sabina 1Frezza Anna Maria 1Fazio Nicola 11 Unit of Gastrointestinal Medical Oncology and Neuroendocrine Tumours, European Institute of Oncology, Milan 20141, Italy2 Unit of Diagnostic Cytology, European Institute of Oncology, Milan 20141, Italy3 Unit of Interventional Radiology, European Institute of Oncology, Milan 20141, ItalyCorrespondence to: Antonio Ungaro. antonio.unga@gmail.com2016 21 4 2016 10 63501 12 2015 © the authors; licensee ecancermedicalscience.2016This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.We report a case of a 74-year-old man with a metastatic anaplastic pancreatic carcinoma (APC). After an early tumour progression on first-line chemotherapy with cisplatin and gemcitabine, even though it was badly tolerated, he was treated with a combination of systemic modified FOLFIRI and high-intensity focused ultrasound (HIFU) on the pancreatic mass. A tumour showing partial response with a clinical benefit was obtained. HIFU was preferred to radiotherapy because of its shorter course and minimal side effects, in order to improve the patient’s clinical conditions.\n\nThe patient is currently on chemotherapy, asymptomatic with a good performance status.\n\nIn referral centres, with specific expertise, HIFU could be safely and successfully combined with systemic chemotherapy for treatment of metastatic pancreatic carcinoma.\n\nanaplastic pancreatic carcinomaHIFUpalliative treatmentabscopal effect\n==== Body\nIntroduction\nAnaplastic pancreatic carcinoma (APC) is a highly malignant cancer arising from epithelial lineage. It has been reported to have a high capacity to infiltrate tissues and a strong tendency to metastasise [1]. Prognosis is poor with a five-month median survival time since diagnosis and <1% five-year survival rate, irrespective of anti-tumour treatment [2]. Resective surgery if feasible, systemic chemotherapy, and chemo-radiation are usually proposed, unfortunately with a low impact on global prognosis [3].\n\nCase report\nA 74-year-old man with a history of dyslipidaemia, impaired glucose tolerance, and cholelithiasis, came to our attention because of dyspepsia and dorsal pain lasting for two months. He underwent an upper gastrointestinal (GI) endoscopy showing a submucosal nodule in the gastric antrum, and an abdomen ultrasonography (US) showing multiple gallstones and a 3 cm pancreatic body lesion.\n\nA chest-abdomen contrast medium Computed Tomography (CT)-scan detected a pancreatic body lesion of 26 mm axial diameter (Ø) with pancreatic duct dilation and perilesional lymphadenopathy with 15 mm Ø. Endoscopic US (EUS) with fine-needle aspiration (FNA) showed a 37 mm Ø hypoechoic and inhomogeneous lesion comprising mesenteric-portal axis without a clear infiltration (uT3uN0, AJCC 2010) [4]. Cytology was conclusive for anaplastic/undifferentiated pancreatic carcinoma. Immunohistochemical (IHC) analysis was positive for cytokeratin AE1-AE2, negative for S-100 protein, Melan-A, chromogranin-A (CgA), synaptophysin (Syn), and CD-56.\n\nOn this basis after discussion within the gastrointestinal multidisciplinary team (GI-MDT), a diagnostic laparoscopy plus intraoperative US were performed showing no evidence of peritoneal carcinomatosis but infiltration of splenic artery and upper mesenteric vein were seen. A peritoneal washing cytology (PWC) revealed the presence of neoplastic cells (Figure 1). Following a further multidisciplinary discussion, systemic chemotherapy was therefore proposed. The patient was asymptomatic; his performance status (PS) was 0 Eastern Cooperative Oncology Group (ECOG). Because of the particular histotype, he was not eligible for first-line chemotherapy trials, therefore a regimen with cisplatin (60 mg/mq day 1 every 21) and gemcitabine (1000 mg/mq days 1, 8, every 21) was decided on an individual scale and administered outside clinical trials (Figure 2). After day one of the second cycle, treatment was delayed because of thrombocytopaenia, and definitively discontinued because of unstable clinical status for acute lower limb peripheral neuropathy and appearance of upper abdominal pain. In the meantime, given the time from the start of chemotherapy, a restaging C-scan was performed, showing an increased pancreatic lesion (46 mm Ø) with dilatation of the Wirsung duct, and multiple pathological lymph nodes in the retroperitoneal region. As a result, we assumed that the patient had a metastatic disease, based on the radiological features (morphology, dimension, rapid growth, and contrast enhancement of paraaortic lymph nodes) and clinical evaluation (increased level of Ca 19.9, deterioration of the patient’s clinical condition and the previously positive peritoneal cytology). On this basis a third GI-MDT discussion indicated a second-line systemic chemotherapy with modified FOLFIRI (folinic acid 200 mg/mq; irinotecan 180 mg/mq; bolus fluorouracil (5-FU) 400 mg/mq; continuous infusion 5-FU 2400 mg/mq) at 70% of the conventional dose.\n\nFurthermore, because of the particular pattern of progression (expansive rather than infiltrating primary tumour growth) and its local symptomaticity, a locoregional palliative procedure was discussed.\n\nTherefore, after the fourth cycle of chemotherapy the patient underwent high-intensity focused ultrasound (HIFU) ablation on the pancreatic lesion. The treatment was performed with computerised axial scanning and power Doppler to evaluate the effect of ablation on the artery engaged. The patient was placed in a prone position on the HIFU table, and then we verified that the abdomen skin was in very close contact with degassed water. The treatment was performed with vertical scanning mode separated by 5mm-distance between each slice. HIFU ablation was performed using the JC-HIFU system (Chongquing Haifu-HIFU-Tech, Chongquing, China). The procedure was supervised by real time US; the diameter of transducer that issues US energy was 20 cm with a focal length of 15 cm and a frequency of 0.8 MHz. The software used for the real time imaging unit was MyLab70 imaging device (Esaote, Genova, Italy). This 1.0 to 8.0 MHz imaging probe is located in the centre of the HIFU transducer. Treatment was carefully monitored with US guide and finished when the lesion showed a large part of coagulation necrosis in the centre. The duration of HIFU ablation was about 90’. At the end, US revealed an extended necrosis area on the pancreatic lesion. A CT-scan performed the day after revealed a 56 mm Ø pancreatic lesion and paraaortic lymphadenopathies. After HIFU the patient received five more cycles of modified FOLFIRI. A CT-scan performed six weeks after HIFU revealed a reduction of the pancreatic head lesion (45 mm versus 56 mm Ø) and of the left paraaortic lymph nodes (15 mm versus 33 mm Ø). A restaging CT-scan after four months from the HIFU treatment revealed a further reduction of the pancreatic lesion (38 mm versus 45 mm Ø) and left paraaortic lymph nodes (8.4 mm versus 15 mm Ø).\n\nThe patient became totally asymptomatic after HIFU. Chemotherapy was well tolerated and is still ongoing.\n\nDiscussion\nClinical presentation of APC is generally unspecific, including abdominal pain, vomiting, anorexia, and weight loss [5]. Furthermore, APC can cause local complications such as bleeding and obstructive jaundice.\n\nIn the absence of literature data, a first-line therapy with gemcitabine plus cisplatin was delivered without benefit as shown from clinical worsening and radiological disease progression [6]. Furthermore its feasibility was hard because of several delays and toxicity.\n\nTherefore, a combination of fluoropyrimidine and irinotecan was proposed, based on the literature data derived from the activity of camptothecin-based therapy after platinum-based therapy in pancreatic adenocarcinoma and also on the different toxicity profile of this regimen compared with the previous one [7]. Because of the particular pattern of progression, which was mainly locoregional, with expansive rather than infiltrating picture and it being locally symptomatic, a locoregional treatment was thought would add something in terms of both local tumour growth control and quality of life (QoL) improvement.\n\nThe most common palliative locoregional treatment used in pancreatic cancer is external radiotherapy (RT). Sporadic literature data exist on intra-arterial chemotherapy [8]. Use of RT in metastatic disease is required for pain control with a palliative dose of 30 Gy. This treatment can also delay local tumour progression, but reduction is not expected. On the other hand, potential gastrointestinal toxicity induced by radiotherapy, duodenum perforation, and haematologic disorders are possible when large tumour masses are treated [9].\n\nWe chose HIFU in order to control both cancer related symptoms and reduction of local disease. Because of a shorter duration compared with radiotherapy, a less invasive approach compared to intra-arterial chemotherapy and our local interventional radiology expertise [10, 11, 12], we believed that HIFU would be the most feasible, potentially effective, and a safer approach.\n\nHIFU ablation is a non-invasive technique used for the control of localised tumour mass. It uses focused ultrasound energy to induce high temperature in the tumour and then induce necrosis and apoptosis of malignant cells. Acoustic energy is absorbed by focused target and high temperature is generated within it, but not outside the region. It is not necessary to perform any incision but light sedation or anesthesia is often suggested [13, 14].\n\nHIFU efficacy on tumour growth control is still largely debated. In a Chinese study including 251 patients treated with HIFU for advanced pancreatic carcinoma, the majority of those with locally advanced unresectable stage had an improvement of abdominal pain control and local symptoms because of reduction in tumour mass size [15].\n\nHIFU treatment differs from other locoregional treatments, such as radiotherapy or neurolysis procedure, because it requires a single session rather than multiple ones and it is not invasive.\n\nIn pancreatic cancer patients pain control is one of the most important clinical issues, usually achieved by means of opioids. A minority of patients are resistant and local treatments are usually considered. Generally more often alcohol neurolysis or external radiotherapy are considered [16]. After a multidisciplinary discussion involving interventional radiologists, surgeons, and medical oncologists, we decided to choose HIFU for the aforementioned reasons because of its one-shot technique, its previous favourable results in unresectable pancreatic cancer, and its greater suitability to be combined with chemotherapy when compared with radiation therapy. Indeed HIFU did not condition the global plan of FOLFIRI chemotherapy.\n\nThis case suggests that a multidisciplinary discussion can be useful and beneficial for patients even in a context of metastatic poor prognosis malignancy, like APC.\n\nPalliative care is a mainstay of the treatment for patients with advanced pancreatic cancer. Other than improving global QoL, it can also improve the tolerability of chemotherapy, the compliance of the patient to antitumour therapy thereby making systemic chemotherapy more feasible. In general it could even improve overall survival (OS). Improving palliative care in this clinical context means increasing the possibility that patients receiving more lines of systemic chemotherapy and possibly they could obtain an improvement of both QoL and mood, although this has not yet been demonstrated in pancreatic cancer [17].\n\nOn the other hand, HIFU ablation in this patient has had a significant effect in the control of local disease and more effect has been described in distant sites too, (paraaortic lymph nodes) away from the treated area.\n\nThis therapeutic benefit, also called ‘abscopal effect’ (from the Latin ‘ab’-position away from-and ‘scopus’-target-), has been observed and described mostly in radiation therapy [18, 19], but not in other local treatments such as HIFU ablation.\n\nIn line with the definition of abscopal effect, tumour regression is usually observed several months after treatment as a result of immunomediated events. Probably this type of cancer cell death occurs from immunogenic processes, according to the recent discovery underlying the importance of immunomodulated toxicity, especially observed with the introduction in clinical pratice of checkpoint inhibitors (combined with radiation therapy or not). Nevertheless, HIFU treatment has to be assessed in clinical studies to evaluate the potential immunomodulating effect combined or not with systemic therapy or genetic modifications which can promote this local treatment.\n\nConclusion\nIn conclusion, in advanced pancreatic carcinoma, HIFU can have a role in locally advanced unresectable disease or even in a metastatic setting, both for tumour growth control and to improve symptom control and therefore QoL. Furthermore, it can be easily combined with systemic chemotherapy. According to our case report, HIFU should be included in the multidisciplinary discussion of symptomatic patients with metastatic pancreatic cancer, i.e. is to be combined with systemic treatment. This of course will require skilled operators and therefore it should be considered only in referral institutions which have GI-MDT and interventional radiology with high expertise.\n\nFigure 1. Haematoxilin/eosin-stained pancreatic cytology revealed the presence (A) of poorly cohesive, pleomorphic, monucleated or multinucleated large cells (20x). Positivity (B) for cytokeratins AE–AE2 confirms the diagnosis of anaplastic cell carcinoma (20x). Peritoneal washing cytology (PWC) with Papanicolaou stain (C) detects cells with malignant features such as nuclear displacement, irregular nuclear membranes, small and eccentric nucleoli (40x).\nFigure 2. (A) Baseline CT scan revealed an inhomogeneous hypodense lesion in the head of pancreas; (B) after chemotherapy with gemcitabine plus cisplatin; (C) within 24 hours after HIFU pancreatic lesion shows a lump of necrotic tissue (between thrid and fourth FOLFIRI cycle); (D) CT scan at six weeks after HIFU; (E) 16 weeks after HIFU.\n==== Refs\nReferences\n1. Paal E A clinicopathologic and immunohistochemical study of 35 anaplastic carcinomas of the pancreas with a review of the literature Ann Diagn Pathol 2001 5 3 129 40 10.1053/adpa.2001.25404 11436166 \n2. Bilimoria KY Validation of the 6th edition AJCC Pancreatic Cancer Staging System: report from the National Cancer Database Cancer 2007 110 4 738 4 10.1002/cncr.22852 17580363 \n3. Krech RL Walsh D Symptoms of pancreatic cancer J Pain Symptom Manage 1991 6 6 360 7 10.1016/0885-3924(91)90027-2 1880437 \n4. AJCC Cancer Staging Manual 2010 7 New York, NY Springer 241 9 \n5. Strobel O Anaplastic pancreatic cancer: Presentation, surgical management, and outcome Surgery 2011 149 2 200 8 10.1016/j.surg.2010.04.026 20542529 \n6. Benedix F Continuous intra-arterial chemotherapy with 5-fluorouracil and cisplatin for locally advanced anaplastic carcinoma of the pancreas Int J Colorectal Dis 2008 23 7 729 31 10.1007/s00384-008-0441-0 18379798 \n7. Neuzillet C FOLFIRI regimen in metastatic pancreatic adenocarcinoma resistant to gemcitabine and platinum-salts World J Gastroenterol 2012 18 33 4533 41 10.3748/wjg.v18.i33.4533 22969226 \n8. Cantore M Phase II study of hepatic intraarterial epirubicin and cisplatin, with systemic 5-fluorouracil in patients with unresectable biliary tract tumors Cancer 2005 103 7 1402 7 10.1002/cncr.20964 15726542 \n9. Hazard L The role of radiation therapy in pancreas cancer Gastrointest Cancer Res 2009 3(1 20 8 19343134 \n10. Orgera G High intensity focused ultrasound ablation of pancreatic neuroendocrine tumours: report of two cases Cardiovasc Intervent Radiol 2011 34 419 23 10.1007/s00270-010-9884-0 20521049 \n11. Orsi F High-intensity focused ultrasound ablation: effective and safe therapy for solid tumors in difficult locations AJR Am J Roentgenol 2010 195 3 W245 52 10.2214/AJR.09.3321 20729423 \n12. Orgera G High-intensity focused ultrasound (HIFU) in patients with solid malignancies: evaluation of feasibility, local tumour response and clinical results Radiol Med 2011 116 5 734 48 10.1007/s11547-011-0634-4 21293939 \n13. Xiong LL Early clinical experience using high intensity focused ultrasound for palliation of inoperable pancreatic cancer JOP 2009 10(2) 123 9 19287104 \n14. Sofuni A The current potential of high-intensity focused ultrasound for pancreatic carcinoma J Hepatobiliary Pancreat Sci 2011 18(3) 295 303 10.1007/s00534-010-0355-4 21360084 \n15. He SX Wang GM Andrew MA Crum LA Vaezy S The noninvasive treatment of 251 cases of advanced pancreatic cancer with focused ultrasound surgery Seattle: University of Washington 2002 Proceedings from the 2nd International Symposium on Therapeutic Ultrasound 51 6 \n16. Sharma C Advances in diagnosis, treatment and palliation of pancreatic carcinoma: 1990–2010 World J Gastroenterol 2011 17 7 867 97 10.3748/wjg.v17.i7.867 21412497 \n17. Temel JS Early palliative care for patients with metastatic non-small-cell lung cancer N Engl J Med 2010 363 8 733 42 10.1056/NEJMoa1000678 20818875 \n18. Lock M Muinuddin A Kocha WI Abscopal effects: Case Report and Emerging Opportunities Cureus 2015 7 10 e344 26623199 \n19. Grass GD Krishna N Kim S The immune mechanisms of abscopal effect in radiation therapy Curr Probl Cancer 2015 20 S0147 0272 10.1016/j.currproblcancer.2015.10.003 26612692\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1754-6605",
"issue": "10()",
"journal": "Ecancermedicalscience",
"keywords": "HIFU; abscopal effect; anaplastic pancreatic carcinoma; palliative treatment",
"medline_ta": "Ecancermedicalscience",
"mesh_terms": null,
"nlm_unique_id": "101392236",
"other_id": null,
"pages": "635",
"pmc": null,
"pmid": "27170835",
"pubdate": "2016",
"publication_types": "D002363:Case Reports",
"references": "26623199;26612692;19287104;20729423;20542529;15726542;1880437;11436166;17580363;18379798;21293939;21412497;20818875;21360084;20521049;22969226;19343134",
"title": "Successful palliative approach with high-intensity focused ultrasound in a patient with metastatic anaplastic pancreatic carcinoma: a case report.",
"title_normalized": "successful palliative approach with high intensity focused ultrasound in a patient with metastatic anaplastic pancreatic carcinoma a case report"
} | [
{
"companynumb": "IT-ACCORD-040902",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CISPLATIN"
},
"drugadditional": "1",
"drugad... |
{
"abstract": "Toxic liver injury is among the major side effects of paracetamol. It is a direct effect of the drug metabolite on the liver cells and is dependent on the dose. Unintentional overdose is often the result of several days of taking excessive doses of the drug for medical use. It is fostered by patients' self-treatment, the availability of non-prescription drugs and lack of awareness of the actual composition of the medication taken. The authors of this study reported a case of hepatotoxicity in a patient treated with capecitabine for breast cancer. Capecitabine therapy was completed several days before the use of paracetamol. The detailed interview with the patient revealed that the cause of hepatic dysfunction was the fact that she took paracetamol for 3 days in a daily dose of 5.5 grams (the permissible safe dose is 4 grams) due to the viral infection. After symptomatic treatment over several days improved took place.",
"affiliations": null,
"authors": "Karczmarek-Borowska|Bozenna|B|;Drzymała|Małgorzata|M|;Golon|Kamila|K|",
"chemical_list": "D000964:Antimetabolites, Antineoplastic; D003841:Deoxycytidine; D000082:Acetaminophen; D000069287:Capecitabine; D005472:Fluorouracil",
"country": "Poland",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1426-9686",
"issue": "36(215)",
"journal": "Polski merkuriusz lekarski : organ Polskiego Towarzystwa Lekarskiego",
"keywords": null,
"medline_ta": "Pol Merkur Lekarski",
"mesh_terms": "D000082:Acetaminophen; D000964:Antimetabolites, Antineoplastic; D001943:Breast Neoplasms; D000069287:Capecitabine; D003841:Deoxycytidine; D062787:Drug Overdose; D005260:Female; D005472:Fluorouracil; D006801:Humans; D008099:Liver; D008875:Middle Aged; D014777:Virus Diseases",
"nlm_unique_id": "9705469",
"other_id": null,
"pages": "348-51",
"pmc": null,
"pmid": "24964515",
"pubdate": "2014-05",
"publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "Hepatotoxicity of acetaminophen in a patient treated with capecitabine due to breast cancer.",
"title_normalized": "hepatotoxicity of acetaminophen in a patient treated with capecitabine due to breast cancer"
} | [
{
"companynumb": "PL-RANBAXY-2014R1-84482",
"fulfillexpeditecriteria": "1",
"occurcountry": "PL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CAPECITABINE"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nPreclinical and phase I data suggest gemcitabine to be a potent radiosensitiser. This multicentre study addressed whether the addition of low dose gemcitabine to radical radiotherapy improved 2 year event-free survival in patients with medically inoperable stages I-II non-small cell lung cancer.\n\n\nOBJECTIVE\nTo determine whether low dose gemcitabine increased event-free survival in patients with T1-2 N0-1 M0 NSCLC deemed unfit for surgery.\n\n\nMETHODS\nPatients with T1-2 N0-1 M0 NSCLC deemed unfit for surgery were randomised to 3D conformal radiotherapy delivering 55 Gy in 20 fractions over 4 weeks to known sites of cancer with (Arm B) or without (Arm A) 100mg/m(2) weekly gemcitabine.\n\n\nRESULTS\nStudy entry was terminated early because of slow accrual. 111 patients were randomised between March 2003 and December 2005, of whom 4 withdrew consent and 2 were lost to follow-up. Median age was 75 (range 49-88)years and 67 (63%) were male. 86 (81%) were PS 0-1 and 31 (30%) Charlson index 2 or greater. Event-free survival in arm A and B, respectively, was 42% and 46% at 2 years and 20% and 31% at 5 years (p=0.72), while overall survival was 56% and 52% at 2 years and 20% and 33% at 5 years (p=0.87). Two deaths from accelerated interstitial lung disease were seen in arm B, but toxicity was otherwise mild.\n\n\nCONCLUSIONS\nNo evidence of an improvement in event-free survival was seen with the addition of weekly gemcitabine at this dose for patients with early stage NSCLC unfit for surgery, although the power of the study was low.",
"affiliations": "Edinburgh Cancer Centre, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK. aprice@staffmail.ed.ac.uk",
"authors": "Price|Allan|A|;Yellowlees|Ann|A|;Keerie|Catriona|C|;Russell|Susan|S|;Faivre-Finn|Corinne|C|;Gilligan|David|D|;Snee|Michael|M|;Skailes|Geraldine|G|;Hatton|Matthew|M|;Erridge|Sara|S|;Mohammed|Nazia|N|",
"chemical_list": "D011838:Radiation-Sensitizing Agents; D003841:Deoxycytidine; C056507:gemcitabine",
"country": "Ireland",
"delete": false,
"doi": "10.1016/j.lungcan.2012.05.089",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0169-5002",
"issue": "77(3)",
"journal": "Lung cancer (Amsterdam, Netherlands)",
"keywords": null,
"medline_ta": "Lung Cancer",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D002289:Carcinoma, Non-Small-Cell Lung; D059248:Chemoradiotherapy; D003841:Deoxycytidine; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D011838:Radiation-Sensitizing Agents; D016896:Treatment Outcome",
"nlm_unique_id": "8800805",
"other_id": null,
"pages": "532-6",
"pmc": null,
"pmid": "22672970",
"pubdate": "2012-09",
"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": "Radical radiotherapy with or without gemcitabine in patients with early stage medically inoperable non-small cell lung cancer.",
"title_normalized": "radical radiotherapy with or without gemcitabine in patients with early stage medically inoperable non small cell lung cancer"
} | [
{
"companynumb": "GB-CIPLA LTD.-2015GB05127",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "GEMCITABINE\\GEMCITABINE HYDROCHLORIDE"
},
"d... |
{
"abstract": "An 8-month-old child under tuberculosis treatment presented with multiple ecchymotic lesions. A severe coagulopathy was evidenced compatible with vitamin K deficiency [II (3%), VII (2%), IX (3%) and X (1%)]. It was reversed with vitamin K and plasma administration. Rifampicin-induced vitamin K deficiency is very rare, reported only once before, possibly related to an inhibition of vitamin K cycle.",
"affiliations": "From the Pediatric Infectious Diseases Unit, Department of Pediatrics, Hospital Universitario 12 de Octubre, Universidad Complutense de Madrid.;Pediatric Intensive Care Unit, Department of Pediatrics.;Pediatric Intensive Care Unit, Department of Pediatrics.;Microbiology Department, Hospital Universitario 12 de Octubre.;From the Pediatric Infectious Diseases Unit, Department of Pediatrics, Hospital Universitario 12 de Octubre, Universidad Complutense de Madrid.;From the Pediatric Infectious Diseases Unit, Department of Pediatrics, Hospital Universitario 12 de Octubre, Universidad Complutense de Madrid.;From the Pediatric Infectious Diseases Unit, Department of Pediatrics, Hospital Universitario 12 de Octubre, Universidad Complutense de Madrid.",
"authors": "Torres-Fernandez|David|D|;de Pazos Azpeitia|Blanca|B|;Gijon Mediavilla|Manuel|M|;Lopez-Roa|Paula|P|;Epalza|Cristina|C|;Grasa Lozano|Carlos Daniel|CD|;Blazquez-Gamero|Daniel|D|",
"chemical_list": "D000904:Antibiotics, Antitubercular; D014812:Vitamin K; D012293:Rifampin",
"country": "United States",
"delete": false,
"doi": "10.1097/INF.0000000000002728",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0891-3668",
"issue": "39(9)",
"journal": "The Pediatric infectious disease journal",
"keywords": null,
"medline_ta": "Pediatr Infect Dis J",
"mesh_terms": "D000904:Antibiotics, Antitubercular; D001778:Blood Coagulation Disorders; D002648:Child; D006801:Humans; D007223:Infant; D008297:Male; D010949:Plasma; D012293:Rifampin; D016896:Treatment Outcome; D014376:Tuberculosis; D014812:Vitamin K; D014813:Vitamin K Deficiency",
"nlm_unique_id": "8701858",
"other_id": null,
"pages": "833-834",
"pmc": null,
"pmid": "32453197",
"pubdate": "2020-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Severe Rifampicin-induced Vitamin K Deficiency Coagulopathy in a Child.",
"title_normalized": "severe rifampicin induced vitamin k deficiency coagulopathy in a child"
} | [
{
"companynumb": "ES-LUPIN PHARMACEUTICALS INC.-2021-15734",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "RIFAMPIN"
},
"drugadditional":... |
{
"abstract": "Impaired cellular-mediated immunity is a known risk factor for both tuberculosis and cryptococcosis. However, pulmonary cryptococcosis associated with pulmonary tuberculosis is rare. We herein describe three cases of concurrent infection with Mycobacterium tuberculosis and Cryptococcus neoformans. All patients had underlying diseases; all three had uncontrolled diabetes mellitus, and other underlying diseases were liver cirrhosis, malignancy, and rheumatoid arthritis requiring long-term steroid use. We also review other relevant reports.",
"affiliations": "Department of Infection Control Science, Graduate School of Medicine, Osaka City University, Japan.",
"authors": "Kakeya|Hiroshi|H|;Izumikawa|Koichi|K|;Yamada|Koichi|K|;Obata|Yoko|Y|;Nishino|Tomoya|T|;Takazono|Takahiro|T|;Kosai|Kosuke|K|;Kurihara|Shintaro|S|;Nakamura|Shigeki|S|;Imamura|Yoshifumi|Y|;Miyazaki|Taiga|T|;Tsukamoto|Misuzu|M|;Yanagihara|Katsunori|K|;Tashiro|Takayoshi|T|;Kohno|Shigeru|S|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": "10.2169/internalmedicine.53.1281",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0918-2918",
"issue": "53(15)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": null,
"medline_ta": "Intern Med",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D060085:Coinfection; D003453:Cryptococcosis; D003455:Cryptococcus neoformans; D003937:Diagnosis, Differential; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009169:Mycobacterium tuberculosis; D013902:Radiography, Thoracic; D014057:Tomography, X-Ray Computed; D014397:Tuberculosis, Pulmonary",
"nlm_unique_id": "9204241",
"other_id": null,
"pages": "1685-92",
"pmc": null,
"pmid": "25088887",
"pubdate": "2014",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Three cases of concurrent infection with Mycobacterium tuberculosis and Cryptococcus neoformans.",
"title_normalized": "three cases of concurrent infection with mycobacterium tuberculosis and cryptococcus neoformans"
} | [
{
"companynumb": "PHHY2014JP111586",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditional": null,
"dr... |
{
"abstract": "BACKGROUND\nThere are no data on the effects of mycophenolate mofetil (MMF) on the incidence of bronchiolitis obliterans syndrome (BOS) in lung-transplant patients. This study attempted to determine whether MMF reduces the incidence of BOS in de novo lung transplant recipients compared with azathioprine (AZA).\n\n\nMETHODS\nThis prospective, randomized, open-label, multicenter study compared the effects of MMF with AZA in combination with induction therapy, cyclosporine (Neoral) and corticosteroids in patients receiving their first lung transplant. Primary endpoint was incidence of BOS at 3 years. Secondary endpoints were incidence of acute rejection, time to first rejection event, and survival.\n\n\nRESULTS\nThe incidence of acute rejection and the time to first rejection event at 1 and 3 years did not differ between groups (54.1% vs. 53.8% and 56.6% vs. 60.3% for MMF and AZA respectively). Survival at 1 year tended to be better in patients receiving MMF (88 vs. 80%, P = 0.07). At year 3, there was no difference in survival or in the incidence, severity or time to acquisition of BOS between the two groups. Treatment was generally well tolerated, however more patients withdrew from AZA treatment than from MMF (59.6% vs. 46.5%, P = 0.02). As a result, there was an imbalance in the observation times of the two groups (876 +/- 395 vs. 947 +/- 326 days).\n\n\nCONCLUSIONS\nNo differences were seen in the incidence of acute rejection or BOS in lung transplant recipients treated with MMF or AZA. This null result may have been influenced by the shorter observation time for AZA patients.",
"affiliations": "Head of Transplant Services, The Prince Charles Hospital, Chermside, Queensland, Australia. keith_mcneil@health.qld.gov.au",
"authors": "McNeil|Keith|K|;Glanville|Allan R|AR|;Wahlers|Thorsten|T|;Knoop|Christiane|C|;Speich|Rudolf|R|;Mamelok|Richard D|RD|;Maurer|Joerg|J|;Ives|Jane|J|;Corris|Paul A|PA|",
"chemical_list": "D007166:Immunosuppressive Agents; D009173:Mycophenolic Acid; D001379:Azathioprine",
"country": "United States",
"delete": false,
"doi": "10.1097/01.tp.0000202755.33883.61",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1337",
"issue": "81(7)",
"journal": "Transplantation",
"keywords": null,
"medline_ta": "Transplantation",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D001379:Azathioprine; D001989:Bronchiolitis Obliterans; D004359:Drug Therapy, Combination; D006084:Graft Rejection; D006801:Humans; D007166:Immunosuppressive Agents; D016040:Lung Transplantation; D008875:Middle Aged; D009173:Mycophenolic Acid; D011446:Prospective Studies; D013577:Syndrome",
"nlm_unique_id": "0132144",
"other_id": null,
"pages": "998-1003",
"pmc": null,
"pmid": "16612275",
"pubdate": "2006-04-15",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Comparison of mycophenolate mofetil and azathioprine for prevention of bronchiolitis obliterans syndrome in de novo lung transplant recipients.",
"title_normalized": "comparison of mycophenolate mofetil and azathioprine for prevention of bronchiolitis obliterans syndrome in de novo lung transplant recipients"
} | [
{
"companynumb": "AU-ROCHE-1866665",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nThe concomitant antimicrobial properties of antineoplastic agents may play a role in causing pseudomembranous colitis, which has been documented for cisplatin, cyclophosphamide and 5-fluorouracil.\n\n\nMETHODS\nWe describe the first case reported in the English literature of severe pseudomembranous colitis occurring in a patient given paclitaxel as adjuvant chemotherapy for breast cancer. There was no prior antibiotic therapy. Stool culture confirmed Clostridium difficile.\n\n\nMETHODS\nOral vancomycin, metronidazole and cholestyramine led to prompt improvement of intestinal symptoms, which resolved in two weeks.\n\n\nRESULTS\nRepeat colonoscopy performed 3 months later showed total resolution of the colitis.\n\n\nCONCLUSIONS\nAwareness of pseudomembranous colitis after paclitaxel chemotherapy can avert life-threatening complications.",
"affiliations": "Department of Medical Oncology, National Cancer Centre, Singapore. dmoacs@nccs.com.sg",
"authors": "Ang|P|P|;Cheong|W K|WK|;Khoo|K S|KS|",
"chemical_list": "D000972:Antineoplastic Agents, Phytogenic; D017239:Paclitaxel",
"country": "Singapore",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0304-4602",
"issue": "29(1)",
"journal": "Annals of the Academy of Medicine, Singapore",
"keywords": null,
"medline_ta": "Ann Acad Med Singap",
"mesh_terms": "D000972:Antineoplastic Agents, Phytogenic; D001943:Breast Neoplasms; D018270:Carcinoma, Ductal, Breast; D017024:Chemotherapy, Adjuvant; D004761:Enterocolitis, Pseudomembranous; D005260:Female; D006801:Humans; D008875:Middle Aged; D017239:Paclitaxel",
"nlm_unique_id": "7503289",
"other_id": null,
"pages": "132-4",
"pmc": null,
"pmid": "10748982",
"pubdate": "2000-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Pseudomembranous colitis in a patient treated with paclitaxel for carcinoma of the breast: a case report.",
"title_normalized": "pseudomembranous colitis in a patient treated with paclitaxel for carcinoma of the breast a case report"
} | [
{
"companynumb": "SG-PFIZER INC-2017538397",
"fulfillexpeditecriteria": "1",
"occurcountry": "SG",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "DOXORUBICIN HYDROCHLORIDE"
},
"drugadditional... |
{
"abstract": "A 71-year-old woman was referred to the clinic with extensive medication-related osteonecrosis of the jaw (MRONJ) involving the mandible. She had received 7 years of zoledronate therapy. On cone beam computed tomography, the MRONJ presented as a large sequestrum spanning from the left to the right condylar process, surrounded by thick sub-periosteal bone. The sequestrum was excised via an intraoral approach, leaving the newly formed sub-periosteal bone as a neo-mandible. The patient recovered well from the operation and was discharged 5 days after surgery. She healed completely without complications. This case report presents an alternative surgical treatment that may be considered if there is clinically stable sub-periosteal bone surrounding extensive MRONJ.",
"affiliations": "Department of Oral and Maxillofacial Surgery, Medical Centre - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany. Electronic address: Rene.Rothweiler@uniklinik-freiburg.de.;Department of Oral and Maxillofacial Surgery, Medical Centre - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany. Electronic address: Pit.Voss@uniklinik-freiburg.de.;Department of Oral and Maxillofacial Surgery, Medical Centre - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany. Electronic address: Rainer.Schmelzeisen@uniklinik-freiburg.de.;Department of Oral and Maxillofacial Surgery, Medical Centre - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany. Electronic address: Marc.Metzger@uniklinik-freiburg.de.",
"authors": "Rothweiler|R|R|;Voss|P J|PJ|;Schmelzeisen|R|R|;Metzger|M C|MC|",
"chemical_list": "D050071:Bone Density Conservation Agents; D000077211:Zoledronic Acid",
"country": "Denmark",
"delete": false,
"doi": "10.1016/j.ijom.2020.07.033",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0901-5027",
"issue": "50(4)",
"journal": "International journal of oral and maxillofacial surgery",
"keywords": "bisphosphonates; medication-related osteonecrosis of the jaw (MRONJ); neo-mandible; resection of the mandible; treatment",
"medline_ta": "Int J Oral Maxillofac Surg",
"mesh_terms": "D000368:Aged; D059266:Bisphosphonate-Associated Osteonecrosis of the Jaw; D050071:Bone Density Conservation Agents; D054893:Cone-Beam Computed Tomography; D005260:Female; D006801:Humans; D008334:Mandible; D010020:Osteonecrosis; D000077211:Zoledronic Acid",
"nlm_unique_id": "8605826",
"other_id": null,
"pages": "511-515",
"pmc": null,
"pmid": "32847710",
"pubdate": "2021-04",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Medication-related osteonecrosis of the mandible: an unusual presentation and treatment.",
"title_normalized": "medication related osteonecrosis of the mandible an unusual presentation and treatment"
} | [
{
"companynumb": "NVSC2020DE237092",
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"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ZOLEDRONIC ACID"
},
"drugadditional": "3",
"... |
{
"abstract": "Still's disease is a rare, systemic inflammatory disease of unknown etiology, characterized by daily high fever, transient rash, arthritis, and organ involvement including lymphadenopathy, hepatosplenomegaly, pleuritis or pericarditis. The diagnosis of the disease is based on clinical signs and symptoms, and requires exclusion of infectious, neoplastic, and other autoimmune diseases. Treatment options include non-steroidal anti-inflammatory drugs (NSAIDs) and corticosteroids, sometimes in combination with immunosuppressive agents. We report the case of a 21-year-old man with a recent diagnosis of Still's disease. The fever, resistant to NSAIDs, resolved after treatment with paracetamol and the patient's general condition also improved. The present case has been the first to demonstrate that paracetamol may be an effective agent in adult-onset Still's disease.",
"affiliations": "Department of Internal Medicine and Clinical Pharmacology, Medical University of Silesia, Katowice, Poland. agnkedzia@poczta.onet.pl",
"authors": "Kedzia|Agnieszka|A|;Bołdys|Aleksandra|A|;Krysiak|Robert|R|;Szkróbka|Witold|W|;Okopień|Bogusław|B|",
"chemical_list": "D018712:Analgesics, Non-Narcotic; D007166:Immunosuppressive Agents; D000082:Acetaminophen",
"country": "Poland",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": null,
"issue": "119(9)",
"journal": "Polskie Archiwum Medycyny Wewnetrznej",
"keywords": null,
"medline_ta": "Pol Arch Med Wewn",
"mesh_terms": "D000082:Acetaminophen; D018712:Analgesics, Non-Narcotic; D004359:Drug Therapy, Combination; D005334:Fever; D006801:Humans; D007166:Immunosuppressive Agents; D008297:Male; D010493:Pericarditis; D016706:Still's Disease, Adult-Onset; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "0401225",
"other_id": null,
"pages": "595-8",
"pmc": null,
"pmid": "19776706",
"pubdate": "2009-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Potential benefit of paracetamol administration in adult-onset Still's disease.",
"title_normalized": "potential benefit of paracetamol administration in adult onset still s disease"
} | [
{
"companynumb": "PL-MYLANLABS-2020M1016485",
"fulfillexpeditecriteria": "1",
"occurcountry": "PL",
"patient": {
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"actiondrug": "6",
"activesubstance": {
"activesubstancename": "KETOPROFEN"
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{
"abstract": "METHODS\nThe patient we present is a 39-year-old woman with a history of hyperthyroidism who developed fast atrial fibrillation secondary to thyrotoxic storm. After the initiation of intravenous diltiazem drip, she developed hypotension, bradycardia, then asystole cardiac arrest.\nIt is well known that calcium channel blockers and beta blockers should be used with extreme caution if the patient with thyroid storm has decompensated heart failure with reduced ejection fraction. Despite this, it is recognized that guidelines for the management of thyroid storm do not include an algorithm of action in this situation. Thus, dealing with low-output failure during thyroid storm may pose a critical challenge.\n\n\nMETHODS\nA significant portion of patients with thyrotoxic storm have an underlying low-output cardiac failure. Early identification, proper hemodynamic monitoring, and administration of the agents with appropriate pharmacodynamic profile and therapeutic potentials are essential to avoid treatment-induced cardiogenic shock.",
"affiliations": "Department of Internal Medicine, Detroit Medical Center, Wayne State University School of Medicine, Detroit, MI.;Department of Internal Medicine, Detroit Medical Center, Wayne State University School of Medicine, Detroit, MI.;Department of Internal Medicine, Advocate Illinois Masonic Medical Center, Chicago, IL.",
"authors": "Subahi|Ahmed|A|;Ibrahim|Walid|W|;Abugroun|Ashraf|A|",
"chemical_list": "D000319:Adrenergic beta-Antagonists; D004110:Diltiazem",
"country": "United States",
"delete": false,
"doi": "10.1097/MJT.0000000000000739",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1075-2765",
"issue": "25(6)",
"journal": "American journal of therapeutics",
"keywords": null,
"medline_ta": "Am J Ther",
"mesh_terms": "D000319:Adrenergic beta-Antagonists; D000328:Adult; D001281:Atrial Fibrillation; D001919:Bradycardia; D019091:Critical Pathways; D004110:Diltiazem; D004452:Echocardiography; D017809:Fatal Outcome; D005260:Female; D006323:Heart Arrest; D006801:Humans; D010951:Plasma Exchange; D051437:Renal Insufficiency; D017582:Renal Replacement Therapy; D012770:Shock, Cardiogenic; D013958:Thyroid Crisis",
"nlm_unique_id": "9441347",
"other_id": null,
"pages": "e666-e669",
"pmc": null,
"pmid": "29521654",
"pubdate": "2018",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Diltiazem-Associated Cardiogenic Shock in Thyrotoxic Crisis.",
"title_normalized": "diltiazem associated cardiogenic shock in thyrotoxic crisis"
} | [
{
"companynumb": "US-MYLANLABS-2019M1032411",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "METHIMAZOLE"
},
"drugadditional": null,
... |
{
"abstract": "Nitrofurantoin has been documented as a cause of acute, sub-acute, and chronic pulmonary injury. This is a case of an 82 year-old female who presented with multiple episodes of respiratory symptoms due to recurrent pleural effusions after beginning nitrofurantoin therapy for urinary tract infection prophylaxis. Due to the rarity of pleural effusion as an adverse reaction to nitrofurantoin, the diagnosis was overlooked at first. This led to the patient undergoing multiple invasive procedures and accruing unnecessary healthcare cost before the diagnosis was made. This case demonstrates the need for physicians to remain mindful of rare adverse reactions from medications and maintain a high index of clinical suspicion with any patient presenting with a respiratory complaint while taking nitrofurantoin.",
"affiliations": "Florida State University College of Medicine, 1115 West Call St, Tallahassee, FL 32306, United States.;Capital Health Plan, 1491 Governor's Square Blvd, Tallahassee, FL 32301, United States; Florida State College of Medicine, 1115 West Call St, Tallahassee, FL 32306, United States.",
"authors": "Davis|Jared W|JW|;Jones|Lynn S|LS|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1016/j.rmcr.2016.07.009",
"fulltext": "\n==== Front\nRespir Med Case RepRespir Med Case RepRespiratory Medicine Case Reports2213-0071Elsevier S2213-0071(16)30064-810.1016/j.rmcr.2016.07.009Case ReportPleural effusion: An uncommon manifestation of nitrofurantoin-induced pulmonary injury Davis Jared W. jwd12d@gmail.coma∗Jones Lynn S. bca Florida State University College of Medicine, 1115 West Call St, Tallahassee, FL 32306, United Statesb Capital Health Plan, 1491 Governor's Square Blvd, Tallahassee, FL 32301, United Statesc Florida State College of Medicine, 1115 West Call St, Tallahassee, FL 32306, United States∗ Corresponding author. Permanent address: 2657, Sapp Rd, Cottondale, FL 32431, United States.2657, Sapp RdCottondaleFL32431United States jwd12d@gmail.com20 7 2016 2016 20 7 2016 19 65 67 24 5 2016 27 6 2016 14 7 2016 © 2016 The Authors2016This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Nitrofurantoin has been documented as a cause of acute, sub-acute, and chronic pulmonary injury. This is a case of an 82 year-old female who presented with multiple episodes of respiratory symptoms due to recurrent pleural effusions after beginning nitrofurantoin therapy for urinary tract infection prophylaxis. Due to the rarity of pleural effusion as an adverse reaction to nitrofurantoin, the diagnosis was overlooked at first. This led to the patient undergoing multiple invasive procedures and accruing unnecessary healthcare cost before the diagnosis was made. This case demonstrates the need for physicians to remain mindful of rare adverse reactions from medications and maintain a high index of clinical suspicion with any patient presenting with a respiratory complaint while taking nitrofurantoin.\n\nKeywords\nPleural effusionNitrofurantoinAdverse drug reaction\n==== Body\n1 Introduction\nNitrofurantoin has long been a staple for the treatment of urinary tract infections, either as a seven day course or as daily prophylaxis but recent guidelines has listed its use as potential first-line treatment of uncomplicated UTI. It has been an excellent alternative treatment for those with sulfa allergies, unable to tolerate trimethoprim-sulfamethoxazole. But, nitrofurantoin adverse events have been well documented throughout the literature for years. Most commonly nitrofurantoin causes gastrointestinal upset which includes nausea, vomiting, and diarrhea among others. Although rare, pulmonary adverse reactions have been the focus of many published works discussing the acute, subacute, and chronic effects of nitrofurantoin on the lungs [1], [2]. A PubMed review of clinical cases over the last ten years found discussions of reactions including pulmonary fibrosis, interstitial pneumonitis, and hypersensitivity pneumonia [3], [4]. When searching for nitrofurantoin-induced pleural disease, no cases have been documented since 2004 [5]. The objective of this report is to describe a rare but documented hypersensitivity reaction to nitrofurantoin in order to assist clinicians in identifying sequential relationships between symptoms and drug treatment to diagnose adverse drug reactions in their patients sooner rather than later.\n\n2 Case report\nAn 82 year old female presented to her primary care physician with symptoms of dyspnea and right-sided chest pain which had been ongoing for one week. The patient had been previously in good health prior to her presentation. Physical exam revealed decreased breath sounds at the right lung base with decreased fremitus but was negative for any other physical exam finding including a cutaneous rash, which has been linked to nitrofurantoin-induced Lupus. Her medical history included chronic urinary tract infections for which in the last month she had been placed on nitrofurantoin 100 mg daily for prophylaxis. Laboratory results from the initial presentation showed that the Antinuclear Antibody test (ANA) was negative which made a Lupus reaction less likely. An Erythrocyte Sedimentation Rate was checked but was within normal limits (32). Her ECG was normal and a transthoracic echocardiogram prior to her initial visit revealed normal heart structure and function with a left ventricular ejection fraction estimated at sixty percent. Therefore, cardiac cause was thought to be less likely and the patient was sent for a chest radiograph and thoracentesis with pleural fluid analysis for diagnosis. The radiograph showed significant right-sided pleural effusion. At that time she underwent a thoracentesis which removed 600 cc of clear fluid but ultimately did not find a cause for the effusion. (Table 1 shows pleural fluid analysis results). The patient was sent home with total resolution of her symptoms and a diagnosis of idiopathic pleural effusion. She was given an appointment with a pulmonologist, who also agreed in the diagnosis of idiopathic pleural effusion.\n\nThe patient remained in good health without recurrence of symptoms for one month. After one month, once again she began experiencing dyspnea and pain localized to the right chest and presented to her primary care physician. Physical exam yet again revealed decreased breath sounds at the right lung base with decreased fremitus. The patient was sent for a CT scan performed without contrast which revealed a mild to moderate right pleural effusion (Image 1).\n\nA thoracentesis was then performed, removing another 600 cc of clear yellow tinted fluid. Still no etiology was identified. After the thoracentesis the patient yet again experienced total resolution of her dyspnea and chest pain.\n\nWithin the next two weeks, the patient experienced another urinary tract infection prompting her to visit the Urologist who had prescribed the nitrofurantoin. During her visit, her medication was switched to trimethoprim-sulfamethoxazole in order to treat this breakthrough UTI. Over the next three months, the patient was not prescribed nitrofurantoin. She did not develop any pulmonary symptoms throughout this time. At a follow up visit to her primary care physician during this three month window she was found to be asymptomatic and in good health without any signs or symptoms of a recurrent pleural effusion. After this time the patient began experiencing symptoms of a urinary tract infection and she was placed back on chronic nitrofurantoin at the same dosage for prophylactic treatment.\n\nIt took three weeks after restarting the nitrofurantoin therapy for the patient to begin experiencing similar symptoms of dyspnea and chest pain. She presented to her primary care physician with the same physical exam findings as was found previously. But at this visit, both the patient and her provider now had a higher degree of suspicion for a drug induced pleural effusion once the patient had recalled the three month asymptomatic period at which time the only change was the medication taken for UTI treatment. The recurrent episodes of pleural effusion at the same time the patient began taking nitrofurantoin and the resolution of symptoms once the medication was discontinued both met the Naranjo criteria of medication induced adverse reactions. It was at this time that the patient and her primary physician decided to discontinue the nitrofurantoin. A therapeutic thoracentesis was performed and withdrew 700 cc of clear pleural fluid. Fluid analysis still could not define a specific etiology and the patient was sent home asymptomatic with plans for close follow up.\n\nOne month following, the patient presented to her primary care physician for her follow up appointment. She continued to be asymptomatic, without any difficulty in breathing or chest pain. The patient also remained off nitrofurantoin and was now taking a different medication for urinary tract infections. A chest radiograph confirmed that the patient had total resolution of the pleural effusion. A transthoracic echocardiogram was performed and remained virtually unchanged from her previous study (TTE results found in Image 2). The patient was also referred to a pulmonologist at a tertiary care center who, after examining the patient and studying her records, agreed that the recurrent pleural effusion was indeed nitrofurantoin induced. After discontinuation of the medication the patient remained asymptomatic at all of her subsequent visits to her primary care physician.\n\n3 Discussion\nThis case demonstrates a rarely documented adverse reaction to nitrofurantoin. Because pleural effusion is not often included as a potential pulmonary toxicity caused by nitrofurantoin therapy it can be easy for even the most experienced clinicians to neglect to tie the medication to the diagnosis. This case is evidence that an unexplained pleural disease, in the presence of nitrofurantoin use, should raise suspicion of a drug induced mechanism of injury.\n\nThis case scored highly on the Naranjo Scale indicating a high probability that the injury was a drug induced adverse reaction. The Naranjo Scale aids in making a diagnosis of drug induced adverse reaction when used in conjunction with clinical judgement. It is a useful tool in cases such as this when the mechanism of injury is rare and seemingly unexplained.\n\nThe case exhibits the need for physicians to remain mindful of rare adverse reactions from medications. This patient underwent multiple invasive procedures and accrued substantial healthcare cost all stemming from a reaction that resolved upon the discontinuation of a single medication. As this case proves, elderly patients are at an even higher risk of adverse reactions and drug interactions. The 2015 AGS Beers List recommended against the use of nitrofurantoin in the elderly. In those with renal impairment, the drug reaches higher systemic levels, increasing the risk for toxicities [6]. Polypharmacy is also a rather important issue in this age group which can further cloud the clinical picture. All of these factors provide further evidence for clinicians to perform a complete medication review when their patients present with unexplained symptoms, especially the elderly population. In doing so, the potential risk for harm will be lowered and patients will be less often subjected to invasive procedures which carry inherent risk of complication and increased cost.\n\nAppendix Disclosures\nThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\n\nAcknowledgements\nThe authors of this case would like to extend a thank you to Dr. Jonathan Appelbaum and Roxann Mouratidis for their guidance in planning and submission of this article.\n\nImage 1 CT Scan.\n\nImage 2 TTE Results.\n\nTable 1 Pleural fluid chemistry.\n\nPleural fluid analysis\t\nRed Blood Cells\t399\tSegmented Neutrophils\t17\t\nWhite Blood Cells\t1350\tGlucose\t127\t\nEosinophils\t9\tLDH\t167\t\nLymphocytes\t39\tProtein\t4\t\nMonocytes\t35\tpH\t7.51\n==== Refs\nReferences\n1 Reynolds T.D. Thomas J. Nitrofurantoin related pulmonary disease: a clinical reminder BMJ Case Rep. 2013 2013 \n2 Williams E.M. Triller D.M. Recurrent acute nitrofurantoin-induced pulmonary toxicity Pharmacotherapy. 26 5 2006 713 718 16718946 \n3 Syed H. Bachuwa G. Upadhaya S. Abed F. Nitrofurantoin-induced interstitial pneumonitis: albeit rare, should not be missed BMJ Case Rep. 2016 2016 \n4 Goemaere N.N. Grijm K. van Hal P.T. den Bakker M.A. Nitrofurantoin-induced pulmonary fibrosis: a case report J. Med. Case Rep. 2 2008 169 18495029 \n5 Huggins J.T. Sahn S.A. Drug-induced pleural disease Clin. Chest Med. 25 1 2004 141 153 15062606 \n6 AGS Expert Panel American Geriatrics Society 2015 updated beers criteria for potentially inappropriate medication use in older adults J. Am. Geriatr. Soc. 63 11 2015 2227 2246 26446832\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2213-0071",
"issue": "19()",
"journal": "Respiratory medicine case reports",
"keywords": "Adverse drug reaction; Nitrofurantoin; Pleural effusion",
"medline_ta": "Respir Med Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101604463",
"other_id": null,
"pages": "65-7",
"pmc": null,
"pmid": "27625984",
"pubdate": "2016",
"publication_types": "D002363:Case Reports",
"references": "26446832;18495029;23729707;16718946;15062606;26912767",
"title": "Pleural effusion: An uncommon manifestation of nitrofurantoin-induced pulmonary injury.",
"title_normalized": "pleural effusion an uncommon manifestation of nitrofurantoin induced pulmonary injury"
} | [
{
"companynumb": "US-NOVEL LABORATORIES, INC-2016-03931",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "NITROFURANTOIN"
},
"drugadditiona... |
{
"abstract": "The current study reports the case of an 80-year-old woman who experienced severe hypoglycaemia after abemaciclib administration, with a recovery time of ~46 h. Abemaciclib is a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor that is used to treat metastatic breast cancer. A side effect of abemaciclib administration is an increase in creatinine levels. The half-life (t1 / 2) of 150 mg abemaciclib in patients with breast cancer was reported to be 17.5 h (nearly lower limit), and the time to reach Cmax was ~5 h (Tmax, 4-6 h). Therefore, the total time to reach half the maximum blood concentration after abemaciclib administration is ~24 h (Tmax + t1 / 2=5+17.5=22.5 h). As abemaciclib is administered twice daily, a considerable amount (Cmax = 123 ng/ml) may persist in the blood following the initial dose. Upon repeated administration, the blood abemaciclib concentration in patients with metastatic liver tumours might increase, although their liver function remains normal. The patient described in the current study had a creatinine level of 1.05 mg/dl at the start of abemaciclib administration. At the time of emergency hospitalisation (on day 5 of abemaciclib administration), the creatinine level was 1.40 mg/dl; however, dehydration was not observed. The patient had been administered the same dose of glimepiride for >1 year and had not experienced hypoglycaemia previously. It can be speculated that the increase in blood creatinine level had some effect on glimepiride metabolism. It is thought that administered abemaciclib enhances metabolic delay in the blood in the same way as in patients with impaired liver function, and as a result, the creatinine level increases in patients with liver metastases. This causes a decrease in renal function, which in turn results in an increase in blood concentration of glimepiride, consequently leading to severe hypoglycaemia. Therefore, clinicians must be careful when using abemaciclib in patients with liver metastases, diabetes and poor renal function.",
"affiliations": "Department of Pharmacy, Oda Municipal Hospital, Oda, Shimane 694-0063, Japan.;Department of General Medicine, Shimane University Faculty of Medicine, Oda General Medicine Education Center, Oda, Shimane 694-0063, Japan.;Department of General Medicine, Shimane University Faculty of Medicine, Oda General Medicine Education Center, Oda, Shimane 694-0063, Japan.;Department of General Medicine, Shimane University Faculty of Medicine, Oda General Medicine Education Center, Oda, Shimane 694-0063, Japan.;Department of Pharmacy, Oda Municipal Hospital, Oda, Shimane 694-0063, Japan.;Department of Surgery, Oda Municipal Hospital, Oda, Shimane 694-0063, Japan.;Department of General Medicine, Shimane University Faculty of Medicine, Oda General Medicine Education Center, Oda, Shimane 694-0063, Japan.;Department of Surgery, Oda Municipal Hospital, Oda, Shimane 694-0063, Japan.;Department of General Medicine, Shimane University Faculty of Medicine, Oda General Medicine Education Center, Oda, Shimane 694-0063, Japan.",
"authors": "Horie|Tatsuo|T|;Kijima|Tsunetaka|T|;Yamaguchi|Minekazu|M|;Honda|Satoshi|S|;Horie|Miyako|M|;Ishitobi|Kazunari|K|;Yamagata|Shingo|S|;Sakano|Shigeru|S|;Kurokohchi|Kazutaka|K|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.3892/mco.2021.2223",
"fulltext": "\n==== Front\nMol Clin Oncol\nMol Clin Oncol\nMCO\nMolecular and Clinical Oncology\n2049-9450 2049-9469 D.A. Spandidos \n\nMCO-0-0-02223\n10.3892/mco.2021.2223\nArticles\nSevere hypoglycaemia under abemaciclib administration in a patient with breast cancer: A case report\nHorie Tatsuo 1 Kijima Tsunetaka 2 Yamaguchi Minekazu 23 Honda Satoshi 2 Horie Miyako 1 Ishitobi Kazunari 3 Yamagata Shingo 2 Sakano Shigeru 3 Kurokohchi Kazutaka 24 1 Department of Pharmacy, Oda Municipal Hospital, Oda, Shimane 694-0063, Japan\n2 Department of General Medicine, Shimane University Faculty of Medicine, Oda General Medicine Education Center, Oda, Shimane 694-0063, Japan\n3 Department of Surgery, Oda Municipal Hospital, Oda, Shimane 694-0063, Japan\n4 Department of General Medicine, Meiwa Hospital, Nishinomiya, Hyogo 663-8186, Japan\nCorrespondence to: Mr. Tatsuo Horie, Department of Pharmacy, Oda Municipal Hospital, 1428-3 Oda-Yosinaga, Oda, Shimane 694-0063, Japan yakuzai@ohda-hp.ohda.shimane.jp\n3 2021 \n25 1 2021 \n25 1 2021 \n14 3 6112 2 2020 11 1 2021 Copyright: © Horie et al.2020This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.The current study reports the case of an 80-year-old woman who experienced severe hypoglycaemia after abemaciclib administration, with a recovery time of ~46 h. Abemaciclib is a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor that is used to treat metastatic breast cancer. A side effect of abemaciclib administration is an increase in creatinine levels. The half-life (t1/2) of 150 mg abemaciclib in patients with breast cancer was reported to be 17.5 h (nearly lower limit), and the time to reach Cmax was ~5 h (Tmax, 4-6 h). Therefore, the total time to reach half the maximum blood concentration after abemaciclib administration is ~24 h (Tmax + t1/2=5+17.5=22.5 h). As abemaciclib is administered twice daily, a considerable amount (Cmax = 123 ng/ml) may persist in the blood following the initial dose. Upon repeated administration, the blood abemaciclib concentration in patients with metastatic liver tumours might increase, although their liver function remains normal. The patient described in the current study had a creatinine level of 1.05 mg/dl at the start of abemaciclib administration. At the time of emergency hospitalisation (on day 5 of abemaciclib administration), the creatinine level was 1.40 mg/dl; however, dehydration was not observed. The patient had been administered the same dose of glimepiride for >1 year and had not experienced hypoglycaemia previously. It can be speculated that the increase in blood creatinine level had some effect on glimepiride metabolism. It is thought that administered abemaciclib enhances metabolic delay in the blood in the same way as in patients with impaired liver function, and as a result, the creatinine level increases in patients with liver metastases. This causes a decrease in renal function, which in turn results in an increase in blood concentration of glimepiride, consequently leading to severe hypoglycaemia. Therefore, clinicians must be careful when using abemaciclib in patients with liver metastases, diabetes and poor renal function.\n\nabemaciclibcreatininecyclin-dependent kinase 4 and 6diabetesprotein-bindingrenal dysfunctionsevere hypoglycaemia\n==== Body\nIntroduction\nCancer is not the leading cause of death worldwide, but cancer associated mortality has increased in recent years (1,2). With stratification by income, it has been indicated that cancer mortality rates are steadily increasing in high-income countries compared with low-income countries (1,2). According to data from the International Agency for Research on Cancer (IARC) World Cancer Statistics GLOBOCAN, breast cancer is the most frequent cancer in women, accounted for 24% of newly diagnosed cancers in 2018 and 15% of cancer deaths, and these rates are expected to increase in the future (1,2). In addition, it is considered that the worldwide population will be aging in the future (3). Moreover, in 2019, a total of 463 million people were estimated to be living with diabetes (4), representing 9.3% of the global adult population (20-79 years), with a prevalence of 9.0% in women and 9.6% in men. The number of people living with diabetes is projected to increase by 25% to 578 million by 2030 and by 51% to 700 million by 2045 globally (4). The morbidity and mortality associated with aging, diabetes, and breast cancer are also very relevant concerns for the Japanese population. Therefore, novel therapeutic drugs for breast cancer and diabetes are continuously being developed; However, with increasing numbers of patients with comorbidities, the interactions, side effects, and adverse events of these therapeutic drugs are becoming increasingly more complicated. Under these circumstances, it is important to provide safe and secure medical care to elderly patients in particular, and it is expected that the need for a team approach to medical care consisting of many specialists, including doctors and pharmacists, will become even more important in the future. The current reports describes a case of severe hypoglycaemia in a patients with breast cancer that persisted for >24 h after the administration of abemaciclib, an antitumor agent and dual inhibitor of cyclin-dependent kinases 4 and 6 (CDK4/6). In November 2018, Japan approved the use of abemaciclib for the treatment of hormone receptor-positive and HER2-negative advanced and metastatic breast cancer (5-7). Currently, to the best of our knowledge, there have been no detailed reports regarding cases of severe hypoglycaemia associated with the use of abemaciclib to date.\n\nCase report\nIn March 2013, an 80-year-old woman who had developed multiple bone, liver, and ovarian metastases from right breast cancer (ER+: 90%, PgR8+: 90%, HER2-) was administered letrozole orally and denosumab subcutaneously. In June 2015, letrozole treatment was replaced with fulvestrant (Ful) owing to progressive disease (PD). In February 2018, haemorrhagic advanced breast cancer [Br+AX (level 1), T4N1M1, pT4bN1MX, stage IV] mastectomy was performed. Administration of Ful was continued thereafter. In July 2018, despite treatment with Ful, the patient experienced PD; therefore, bevacizumab plus paclitaxel therapy was initiated. In March 2019, due to PD as detected by computed tomography, abemaciclib plus Ful therapy was initiated. The pateent's glycated haemoglobin (HbA1c) level was 5.9% 3 weeks before the initiation of abemaciclib treatment, which commenced 4 days before hospitalisation (-day 4) at an oral dose of 150 mg, twice daily. However, adverse events such as poor physical condition, abdominal pain, and diarrhoea occurred on the second day post abemaciclib treatment (-day 3). Therefore, the dose of abemaciclib was reduced to 100 mg, twice a day, from -day 1 to hospitalisation. The patient reported tremors and insomnia that same night. Furthermore, on the following day (day 1: Day of hospitalisation), she reported subjective symptoms of diplopia, but she was able to eat a full meal three times that day. At ~21:45 h, the patient's family noticed that the patient was unfocused, with impaired speech; therefore, they contacted the emergency department of the hospital 5 min later. The patient was rushed to the hospital by her family at 22:40 h. As she was in the supine position in the back seat of the car, the staff transferred her to a stretcher with full assistance. The patient responded slightly to our call, but her level of consciousness declined, and she was unable to speak and focus. Her breathing was normal and there were no abnormal laboratory findings in her chest and abdomen during emergency room (ER) observation. The laboratory findings in the emergency outpatient clinic revealed extremely low blood glucose level of 24 mg/dl (Fig. 1A), indicating hypoglycaemia (Tables I and II). Moreover, renal dysfunction was indicated as her serum creatinine level was 1.40 mg/dl.\n\nEmergency outpatient clinical course: In the ER, the patient was not able to focus her eyes and she was unable to answer our call. As the blood tests revealed hypoglycaemia, we administered 40 ml of 40% glucose solution intravenously. The patient's level of consciousness returned to normal immediately after the injection. She could make eye contact and converse with us. After 60 min, at 23:40 h, her blood glucose level increased to 91 mg/dl (Fig. 1B), and she was able to urinate independently in the toilet and move to a wheelchair stably. The patient did not remember the time she arrived at the hospital because of hypoglycaemia. In the ER, we asked her family about her medical history and medications, including whether she had diabetes. The patient had no history of receiving antidiabetic treatment at other hospitals and had no experience of hypoglycaemia while receiving antidiabetic drugs for more than a year (Table III). Additionally, she had eaten all her meals on the day of hospitalisation (day 1). She had self-managed abemaciclib medication (Verzenio), which was recorded in the ‘Verzenio Diary’. We were able to confirm that there was no overdose of glimepiride (Gli) tablets from the patient's remaining medication.\n\nThe patient was admitted to the surgical department on the same day for hypoglycaemia treatment and follow-up. All outpatient prescription drugs were discontinued at the time of hospitalisation. The patient's clinical course after admission is shown in Fig. 1. She was conscious at 00:10 h on the second day of admission. As she complained of hunger, she was provided a banana and tea by her family. We did not detect symptoms such as diplopia, numbness, and cold sweats. The patient seemed to have independently used the toilet during the night without the aid of a nurse, as we detected a large quantity of urine in a portable toilet. The patient was asleep during the nurse's patrol. At 7:00 h, during the nurse's patrol, the patient was changing clothes on the bed, but she did not respond to the nurse's calling; moreover, she could not focus her eyes. Her blood glucose level was 38 mg/dl (Fig. 1C); thus, we immediately injected 40 ml of 40% glucose solution intravenously. Shortly after, her blood glucose level increased to 161 mg/dl (Fig. 1D), and her consciousness level returned to normal. She could maintain eye contact and we could converse with her. However, the patient did not remember any of her hypoglycaemic events. Immediately after the intravenous injection of glucose solution and oral glucose intake, her blood glucose levels increased and her consciousness improved, but the blood glucose levels later dropped back to 30-50 mg/dl. This hypoglycaemic event repeated until the third day post-admission. On all 3 days in the surgical department, the patient ate all of her meals (breakfast, lunch, and dinner). At 7:00 h on the third day of admission, her blood glucose level was 87 mg/dl, indicating no hypoglycaemia (Fig. 1Q). The patient's blood glucose level was maintained over 80 mg/dl, and there was no relapse of hypoglycaemia. Her immunoreactive insulin level was normal at 5.56 µIU/ml. In summary, the total administered glucose content from admission to recovery of severe hypoglycaemia was 48 g administered intravenously and 40 g administered orally, plus a regular meal of 1,600 kcal/day and a banana. Finally, the time required to recover from severe hypoglycaemia was ~46 h. Summary of the treatment (Table IV).\n\nDiscussion\nWe present a case report of severe hypoglycaemia under abemaciclib administration. When the patient arrived at our hospital, she had taken prescription medicines, including abemaciclib, after a full portion of dinner. We confirmed with the family regarding the absence of any overlapping medications. In this case (from -day 4 to 0), no additional new medicines were administered other than abemaciclib. The patient had been using Gli and loxoprofen sodium hydrate (Lox) since a long time, and no associated hypoglycaemic events had occurred previously. Therefore, the possibility of drug (Gli and Lox)-interaction-induced hypoglycaemia was low. Gli has a high protein-binding rate according to dosage studies in patients with type 2 diabetes (8-11). Allylpropionic acid-based Lox also has a high protein-binding rate (12-15). Therefore, when Gli is used together with Lox, the binding of Gli to blood protein is suppressed, and the free form of Gli increases (8-11). Therefore, the combined usage of Lox with Gli may enhance the hypoglycaemic effect (16). Abemaciclib, a pyrido[2,3-d]pyrimidin-7-one inhibitor, is a selective inhibitor of CDK4 and CDK6 (17-19) that phosphorylates Rb and activates transcription factor E2F1/2. Thus, abemaciclib pushes cells into the S phase and triggers DNA synthesis (20,21). The time to reach abemaciclib Cmax is ~5 h (Tmax, 4-6 h) (22,23), and the half-life of 150 mg of abemaciclib is 17.5 h (nearly lower limit: 17.4 to 38.1 h) (22,23). Therefore, the total time to reach half the maximum blood concentration after abemaciclib administration is ~24 h [Tmax + t1/2 = 5+17.5=22.5 h (22,23)]. In other words, it takes 24 h for abemaciclib blood concentration to drop by half (1/2). As abemaciclib is administered twice daily, a considerable amount of abemaciclib may persist in the blood when the second dose (~12 h later) is administered. In patients with severe liver dysfunction, the blood concentration of this drug increases (24). With repeated dosing of abemaciclib, the blood concentration of abemaciclib in patients with metastatic liver tumours may be higher than anticipated, even with normal liver function (11). Abemaciclib has been shown to have a high human plasma protein-binding rate in in vitro studies (5-7,22). Gli is primarily metabolised by the liver metabolic enzyme CYP2C9 and excreted via the kidney (urine) and liver (bile) (8-11,25), while abemaciclib is metabolised by CYP3A and excreted via the liver (24). Therefore, the possibility that they influence each other's metabolism is low. Increase in blood creatinine level has been described as an adverse event of abemaciclib (5-7,24). The patient's creatinine level was 1.05 mg/dl at the start of administration (-day 4). On the fifth day of abemaciclib administration (day 1: Day of hospitalisation), the creatinine level increased to 1.40 mg/dl; however, dehydration due to loose stools, diarrhoea, and other symptoms was not observed on admission.\n\nAbemaciclib has been shown to slow metabolism in the blood of patients with impaired liver function (5-7,24). In metastatic liver cancer, CYP2C9 metabolism in the liver decreases; therefore, the blood concentration of Gli increases (11,25). However, our patient was administered the same dose of Gli for over 1 year and had never experienced hypoglycaemia. In addition, CYP3A4 metabolism in the liver decreases in metastatic liver cancer (26,27). Consequently, the blood concentration of abemaciclib increases, which increases the creatinine level (5-7,24). Furthermore, an increase in creatinine level suggests a decrease in renal function, which is thought to increase the blood concentration of Gli (25,28-31). Although it is unclear at present whether this case is an isolated incident of the combined biochemical and genetic profile of the patient, severe hypoglycaemia may well occurs in elderly breast cancer patients with diabetes and a history of liver metastases when abemaciclib is combined used with Gli (high protein-binding affinity) and allylpropionic acid-based Lox (high protein-binding affinity). Therefore, adverse events of the drug for these patients are likely to be worth investigating in a larger population size and those awaits further elucidation. The increase in creatinine levels following abemaciclib administration does not necessarily indicate glomerular injury. However, it is difficult to argue that the increase in creatinine levels is not related to the decrease in renal function (5,23,32). Although it can not be ruled out that, the increased creatinine levels after abemaciclib treatment in patients without liver metastases, it may be lead to hyperglycemia caused by decreased water reabsorption, Low levels of Ht and BUN/Cre in the labo data indicated that the patient was not dehydrated at the time of transport. Although since this patient has liver metastasis, it is considered that the blood concentration of abemaciclib is increased due to the metabolic delay of abemaciclib and the blood creatinine level is increased. Increased creatinine levels suggested a decrease in renal function, which may have caused an increase in the blood concentration of Gli and the strong effect of Gli may have caused the patient's hypoglycaemia. Moreover, glucagon blood sugar increasing action is mainly due to the decomposition of hepatic glycogen, it is said that the effect of raising blood sugar can hardly be expected for liver metastasis patients (33). And in severe hypoglycemia with unconsciousness, it may be difficult to take glucose tablets or glucose powder. Based on the above, we must attend to the presence or absence of liver metastases, use of drugs that depend on renal excretion, blood glucose level should be carefully monitored, when we are using abemaciclib with diabetes patients. Then, if renal function is poor, it is necessary to immediately stop SU drugs such as Gli and switch to insulin.\n\nAcknowledgements\nNot applicable.\n\nFunding\nNo funding was received.\n\nAvailability of data and materials\nThe datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.\n\nAuthors' contributions\nTH, TK and KK were involved in the conception and design of the case study; TH, MY, MH, KI and SS were involved in data acquisition; TH, MY, SH, KI, SY and SS analysed and interpreted the data. TH and KK were responsible for confirming the authenticity of the raw data. The manuscript was written by TH and was critically reviewed by TH, TK, MY, SH, MH, KI, SY, SS and KK. All authors read and approved the final manuscript.\n\nEthics approval and consent to participate\nNot applicable.\n\nPatient consent for publication\nWritten informed consent was obtained from the patient for the publication of this case report.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nFigure 1 Patient's time course of blood glucose level and treatment after admission (A) day 1, 23:40 h, measurement of blood glucose and i.v. administration of 20 ml of 40% glucose solution; (B) day 1, 23:47 h, measurement of blood glucose, and the patient consumed a midnight snack; (C) day 2, 7:00 h, measurement of blood glucose and i.v. administration of 40 ml of 40% glucose solution; (D) day 2, 7:15 h, measurement of blood glucose, and the patient consumed breakfast; (E) day 2, 12:00 h, measurement of blood glucose and i.v. administration of 20 ml of 40% glucose; (F) day 2, 12:30 h, measurement of blood glucose, and the patient consumed lunch; (G) day 2, 13:45 h, measurement of blood glucose and oral administration of 10 g glucose; (H) day 2, 14:20 h, measurement of blood glucose; (I) day 2, 17:15 h, measurement of blood glucose and i.v. administration of 20 ml of 40% glucose solution; (J) day 2, 17:50 h, measurement of blood glucose and i.v. administration of 20 ml of 40% glucose; the patient consumed dinner; (K) day 2, 18:30 h, measurement of blood glucose and oral administration of 10 g glucose; (L) day 2, 21:00 h, measurement of blood glucose; (M) day 3, 0:00 h, measurement of blood glucose and oral administration of 10 g glucose; (N) day 3, 1:00 h, measurement of blood glucose; (O) day 3, 3:00 h, measurement of blood glucose and oral administration of 10 g glucose; (P) day 3, 4:00 h, measurement of blood glucose; (Q) day 3, 7:00 h, measurement of blood glucose. BS, blood sugar.\n\nTable I Observations at admission.\n\nClinical characteristics\tValue\t\nBody height\t154.5 cm\t\nBody-weight (BMI)\t57.2 kg (23.96 kg/m2)\t\nBody temperature\t34.5˚C\t\nBlood pressure\t118/52 mmHg\t\nPulse\t67/min\t\nOxygen saturation\t94%\t\nConsciousness level (GCS)\t13 = E4+V4+M5\t\nTable II Physiological data at the time of hospitalization.\n\nBlood and biochemical tests\tValue\t\nAST\t29 IU/l\t\nALT\t21 IU/l\t\nBUN\t20.4 mg/dl\t\nCr\t1.4 mg/dl\t\nCK\t108 IU/l\t\nNa\t141 mEq/l\t\nCl\t108 mEq/l\t\nCa\t8.6 mEq/l\t\nBS\t24 mg/dl\t\nWBC\t66.1x103/µl\t\nRBC\t342x104/µl\t\nHb\t108 g/dl\t\nHt\t31.40%\t\nPLT\t12.7x103/µl\t\nNeut\t55.2x102/µl\t\nLymph\t7.9x102/µl\t\nAST, aspartate aminotransferase; ALT, alanine aminotransferase; BUN, blood urea nitrogen; CK, creatine kinase; BS, blood sugar; WBC, white blood cell; RBC, red blood cell; PLT, platelet.\n\nTable III Prescription drugs: Daily dose.\n\nOral medication\tDose\t\nAbemaciclib (100 mg)\tTwice (after breakfast and dinner)\t\nGlimepiride (1 mg)\tTwice (after breakfast and dinner)\t\nLoxoprofen sodium hydrate (60 mg)\tTwice (after breakfast and dinner)\t\nRebamipide (100 mg)\tTwice (after breakfast and dinner)\t\nDoxazosin mesylate (2 mg)\tTwice (after breakfast and dinner)\t\nValsartan (80 mg)\tOnce after breakfast\t\nAmlodipine besilate (5 mg)\tOnce after breakfast\t\nPravastatin sodium (10 mg)\tOnce after dinner\t\nLoperamide hydrochloride (1 mg)\tUp to 3 times a day in case of diarrhoea\t\nBrotizolam (0.25 mg)\tBefore sleeping in case of insomnia\t\nIndomethacin patch\tTopical\t\nTable IV Summary of the treatment.\n\nA, Day 1\t\nPoint\tTime\tBlood glucose level\tTreatment\t\nA\t23:40 h\t24\t20 ml of 40% glucose solution i.v. injection\t\nB\t23:47 h\t91\tPatient ate a midnight snack\t\nB, Day 2\t\nPoint\tTime\tBlood glucose level\tTreatment\t\nC\t7:00 h\t38\t40 ml of 40% glucose solution i.v. injection\t\nD\t7:15 h\t161\tPatient ate breakfast\t\nE\t12:00 h\t49\t20 ml of 40% glucose solution i.v. injection\t\nF\t12:30 h\t102\tPatient ate lunch\t\nG\t13:45 h\t41\tOral administration of 10 g\t\nH\t14:20 h\t74\tOral administration of 10 g\t\nI\t17:15 h\t35\t20 ml of 40% glucose solution i.v. injection\t\nJ\t17:50 h\t40\t20 ml of 40% glucose solution i.v. injection\t\nK\t18:30 h\t53\tOral administration of 10 g glucose\t\nL\t21:00 h\t102\tMedical follow-up\t\nC, Day 3\t\nPoint\tTime\tBlood glucose level\tTreatment\t\nM\t0:00 h\t48\tOral administration of 10 g glucose\t\nN\t1:00 h\t102\tMedical follow-up\t\nO\t3:00 h\t55\tOral administration of 10 g glucose\t\nP\t4:00 h\t107\tMedical follow-up\t\nQ\t7:00 h\t87\tMedical follow-up\n==== Refs\nReferences\n1 Jamison DT Summers LH Alleyne G Arrow KJ Berkley S Binagwaho A Bustreo B Evans D Feachem RGA Frenk J Global health 2035: A world converging within a generation Lancet 382 1898 1955 2013 10.1016/S0140-6736(13)62105-4 24309475 \n2 Ferlay J Colombet M Soerjomataram I Mathers C Parkin DM Piñeros M Znaor A Bray F Estimating the global cancer incidence and mortality in 2018: GLOBOCAN sources and methods Int J Cancer 144 1941 1953 2019 10.1002/ijc.31937 30350310 \n3 Raftery AE Li N Ševčíková H Gerland P Heilig GK Bayesian probabilistic population projections for all countries Proc Natl Acad Sci USA 109 13915 13921 2012 10.1073/pnas.1211452109 22908249 \n4 Saeedi P Petersohn I Salpea P Malanda B Karuranga S Unwin N Colagiuri S Guariguata L Motala AA Ogurtsova K Global and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045: Results from the International Diabetes Federation Diabetes Atlas, 9(th) edition Diabetes Res Clin Pract 157 107843 2019 10.1016/j.diabres.2019.107843 31518657 \n5 Dickler MN Tolaney SM Rugo HS Cortés J Diéras V Patt D Wildiers H Hudis CA O'Shaughnessy J Zamora E MONARCH 1, a phase II study of abemaciclib, a CDK4 and CDK6 inhibitor, as a single agent, in patients with refractory HR+ /HER2- metastatic breast cancer Clin Cancer Res 23 5218 5224 2017 10.1158/1078-0432.CCR-17-0754 28533223 \n6 Sledge GW Jr Toi M Neven P Sohn J Inoue K Pivot X Burdaeva O Okera M Masuda N Kaufman PA MONARCH 2: Abemaciclib, in combination with Fulvestrant in women with HR+ /HER2- advanced breast cancer who had progressed while receiving endocrine therapy J Clin Oncol 35 2875 2884 2017 10.1200/JCO.2017.73.7585 28580882 \n7 Goetz MP Toi M Campone M Sohn J Paluch-Shimon S Huober J Park IH Trédan O Chen SC Manso L MONARCH 3: Abemaciclib, as initial therapy for advanced breast cancer J Clin Oncol 35 3638 3646 2017 10.1200/JCO.2017.75.6155 28968163 \n8 Draeger E Clinical profile of glimepiride Diabetes Res Clin Pract 28 139 146 1995 10.1016/0168-8227(95)01072-l 8529506 \n9 Draeger KE Wernicke-Panten K Lomp HJ Schüler E Rosskamp R Long-term treatment of type 2 diabetic patients with the new oral antidiabetic agent glimepiride (Amaryl): A double-blind comparison with glibenclamide Horm Metab Res 28 419 425 1996 10.1055/s-2007-979830 8911976 \n10 Badian M Korn A Lehr KH Malerczyk V Waldhäusl W Absolute bioavailability of Glimepiride (Amaryl) after oral administration Drug Metabol Drug Interact 11 331 339 1994 10.1515/dmdi.1994.11.4.331 12369756 \n11 Niemi M Cascorbi I Timm R Kroemer HK Neuvonen PJ Kivistö KT Glyburide and glimepiride pharmacokinetics in subjects with different CYP2C9 genotypes Clin Pharmacol Ther 72 326 332 2002 10.1067/mcp.2002.127495 12235454 \n12 Otagiri M Study on binding of drug to serum protein Yakugaku Zasshi 129 413 425 2009 10.1248/yakushi.129.413 (In Japanese) 19336995 \n13 Meyer MC Guttman DE The binding of drugs by plasma proteins J Pharm Sci 57 895 918 1968 10.1002/jps.2600570601 4876452 \n14 Jusko WJ Gretch M Plasma and tissue protein binding of drugs in pharmacokinetics Drug Metab Rev 5 43 140 1976 10.3109/03602537608995839 829788 \n15 Vallner JJ Binding of drugs by albumin and plasma protein J Pharm Sci 66 447 465 1977 10.1002/jps.2600660402 323460 \n16 Langtry HD Balfour JA Glimepiride. A review of its use in the management of type 2 diabetes mellitus Drugs 55 563 584 1998 10.2165/00003495-199855040-00007 9561345 \n17 Wang D Sun Y Li W Ye F Zhang Y Guo Y Zhang DY Suo J Antiproliferative effects of the CDK6 inhibitor PD0332991 and its effect on signaling networks in gastric cancer cells Int J Mol Med 41 2473 2484 2018 10.3892/ijmm.2018.3460 29436583 \n18 Toogood PL Harvey PJ Repine JT Sheehan DJ VanderWel SN Zhou H Keller PR McNamara DJ Sherry D Zhu T Discovery of a potent and selective inhibitor of cyclin-dependent kinase 4/6 J Med Chem 48 2388 2406 2005 10.1021/jm049354h 15801831 \n19 Xu H Yu S Liu Q Yuan X Mani S Pestell RG Wu K Recent advances of highly selective CDK4/6 inhibitors in breast cancer J Hematol Oncol 10 97 2017 10.1186/s13045-017-0467-2 28438180 \n20 Li B He H Tao BB Zhao ZY Hu GH Luo C Chen JX Ding XH Sheng P Dong Y Knockdown of CDK6 enhances glioma sensitivity to chemotherapy Oncol Rep 28 909 914 2012 10.3892/or.2012.1884 22736304 \n21 Malumbres M Barbacid M Cell cycle, CDKs and cancer: A changing paradigm Nat Rev Cancer 9 153 166 2009 10.1038/nrc2602 19238148 \n22 Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Phase 1 study of abemaciclib, an inhibitor of CDK 4 and 6, as a single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 78 281 288 2016 10.1007/s00280-016-3085-8 27312735 \n23 Patnaik A Rosen LS Tolaney SM Tolcher AW Goldman JW Gandhi L Papadopoulos KP Beeram M Rasco DW Hilton JF Efficacy and safety of abemaciclib, an inhibitor of CDK4 and CDK6, for patients with breast cancer, non-small cell lung cancer, and other solid tumors Cancer Discov 6 740 753 2016 10.1158/2159-8290.CD-16-0095 27217383 \n24 Tate SC Sykes AK Kulanthaivel P Chan EM Turner PK Cronier DM A population pharmacokinetic and pharmacodynamic analysis of abemaciclib, in a phase I clinical trial in cancer patients Clin Pharmacokinet 57 335 344 2018 10.1007/s40262-017-0559-8 28540640 \n25 Rosenkranz B Pharmacokinetic basis for the safety of glimepiride in risk groups of NIDDM patients Horm Metab Res 28 434 439 1996 10.1055/s-2007-979833 8911979 \n26 Kacevska M Robertson GR Clarke SJ Liddle C Inflammation and CYP3A4-mediated drug metabolism in advanced cancer: Impact and implications for chemotherapeutic drug dosing Expert Opin Drug Metab Toxicol 4 137 149 2008 10.1517/17425255.4.2.137 18248309 \n27 Fahy BN Guo T Ghose R Impact of hepatic malignancy on CYP3A4 gene expression J Surg Res 178 768 772 2012 10.1016/j.jss.2012.06.008 22763214 \n28 Rosenkranz B Profozic V Metelko Z Mrzljak V Lange C Malerczyk V Pharmacokinetics and safety of glimepiride at clinically effective doses in diabetic patients with renal impairment Diabetologia 39 1617 1624 1996 10.1007/s001250050624 8960852 \n29 Hou L Zhao T Liu Y Zhang Y Efficacy and safety of sitagliptin compared with sulfonylurea therapy in patients with type 2 diabetes showing inadequately controlled glycosylated hemoglobin with metformin monotherapy: A meta-analysis Exp Ther Med 9 1528 1536 2015 10.3892/etm.2015.2277 25780464 \n30 DeFronzo RA Pharmacologic therapy for type 2 diabetes mellitus Ann Intern Med 131 281 303 1999 10.7326/0003-4819-131-4-199908170-00008 10454950 \n31 Inzucchi SE Oral antihyperglycemic therapy for type 2 diabetes: Scientific review JAMA 287 360 372 2002 10.1001/jama.287.3.360 11790216 \n32 Levey AS Perrone RD Madias NE Serum creatinine and renal function Annu Rev Med 39 465 490 1988 10.1146/annurev.me.39.020188.002341 3285786 \n33 Pun KK Young RTT Wang C Tam CF Ho PWM The use of glucagon challenge tests in the diagnostic evaluation of hypoglycemia due to hepatoma and insulinoma J Clin Endocrinol Metab 67 546 550 1988 10.1210/jcem-67-3-546 2842361\n\n",
"fulltext_license": "CC BY-NC-ND",
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"issue": "14(3)",
"journal": "Molecular and clinical oncology",
"keywords": "abemaciclib; creatinine; cyclin-dependent kinase 4 and 6; diabetes; protein-binding; renal dysfunction; severe hypoglycaemia",
"medline_ta": "Mol Clin Oncol",
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"pages": "61",
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"pmid": "33604051",
"pubdate": "2021-03",
"publication_types": "D016428:Journal Article",
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"title": "Severe hypoglycaemia under abemaciclib administration in a patient with breast cancer: A case report.",
"title_normalized": "severe hypoglycaemia under abemaciclib administration in a patient with breast cancer a case report"
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"companynumb": "JP-TEVA-2021-JP-1952331",
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"abstract": "We describe the case of a child affected by typical symptoms of Alice in Wonderland syndrome (AIWS), related to the methylphenidate treatment he was taking for an attention deficit hyperactivity disorder (ADHD). To our knowledge, this is the first case of methylphenidate-associated AIWS.\nRetrospective single center observational case report.\nA 12-year-old boy was complaining of micropsias and macropsias. Except a disruptive ADHD treated by methylphenidate for 2 years, his medical history was banal. His symptoms coincided with a change in his treatment regimen and ceased with methylphenidate discontinuation. Unfortunately, they recurred when the medication was reimplemented by his psychiatrist. The ophthalmological examination was unremarkable. We concluded to an AIWS and prescribed ancillary testing (including blood work, electroencephalogram, and brain MRI) to rule out conditions known to be associated with this syndrome. In the meanwhile, the methylphenidate dosage was readapted, and the symptoms disappeared again. Seen this clear dechallenge and rechallenge effect and the fact that all additional tests returned normal results, we deduced that our patient's symptoms were associated to methylphenidate.\nAIWS could be a potential side effect of methylphenidate. Given the frequency of methylphenidate prescription for ADHD and its widespread misuse, it is important to consider this peculiar adverse effect. Every physician should be aware of the condition to offer reassurance and to prescribe the appropriate additional examinations, as life-threatening disorders can cause this syndrome.",
"affiliations": "Service d'Ophtalmologie, Hôpital Erasme, Brussels, Belgium.;Service d'Ophtalmologie, Hôpital Erasme, Brussels, Belgium.",
"authors": "Dugauquier|Artémise|A|https://orcid.org/0000-0003-0282-4719;Bidgoli|Sina|S|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1177/1120672120978882",
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"issn_linking": "1120-6721",
"issue": null,
"journal": "European journal of ophthalmology",
"keywords": "Pediatric ophthalmology; neuro-ophthalmic disease; pharmacology; sensory physiology/pathology; socioeconomics and education in medicine/ophthalmology; strabismus",
"medline_ta": "Eur J Ophthalmol",
"mesh_terms": null,
"nlm_unique_id": "9110772",
"other_id": null,
"pages": "1120672120978882",
"pmc": null,
"pmid": "33295214",
"pubdate": "2020-12-09",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Methylphenidate-associated Alice in Wonderland syndrome.",
"title_normalized": "methylphenidate associated alice in wonderland syndrome"
} | [
{
"companynumb": "BE-AMNEAL PHARMACEUTICALS-2020-AMRX-04044",
"fulfillexpeditecriteria": "1",
"occurcountry": "BE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHYLPHENIDATE HYDROCHLORIDE"
},
... |
{
"abstract": "OBJECTIVE\nAbout 20-25% of the testicular germ cell tumors (TGCT) are relapsed or refractory after first line therapy and optimal treatment for this group is poorly defined. We aimed to analyze the efficacy and safety of autologous stem cell transplantation (ASCT) in this patient group.Material and.\n\n\nMETHODS\n19 patients with 28 ASCT were retrospectively analyzed. All the patients were treated with BEP (Bleomycin, etoposide, cisplatin) as first line therapy and TIP(paclitexalifosfamide, cisplatin) was given as salvage chemotherapy. Stem cell collection was performed with TIP and granulocyte stimulating factor. ASCT was performed with carboplatin(700mg/m2) and etoposite(750mg /m 2). The results were provided as median(min-max). P<0.05 was accepted as statistical significant level.\n\n\nRESULTS\nAfter ASCT, complete(CR) and partial remission (PR) rates were 47.3% and 31 .5% respectively. The median overall survival(OS) and progression free survival (PFS) were 18(0-37.4 months) and 7(0-15months) months respectively. Estimated 2-year OS was 47.4% and PFS was 35.3%. Grade 3/4 toxicities including diarrhea, mucositis, and toxic hepatitis were observed in 5 patients. Only one patient died due to complication of transplantation.\n\n\nCONCLUSIONS\nAlthough the number of the patients in this study is limited, ASCT seems to be a safe and effective treatment modality in relapsed refractory non-seminomatousTGCT with an acceptable OS, PFS and mortality rates.",
"affiliations": "Department of Hematology, Izmir Katip Celebi University, Ataturk Training and Research Hospital, Izmir, Turkey.;Department of Hematology, Ege University Hospital, Izmir, Turkey.;Department of Medical Oncology, Ege University Hospital, Izmir, Turkey.;Department of Medical Oncology, Ege University Hospital, Izmir, Turkey.;Department of Medical Oncology, Ege University Hospital, Izmir, Turkey.;Department of Hematology, Ege University Hospital, Izmir, Turkey.;Department of Hematology, Ege University Hospital, Izmir, Turkey.;Department of Hematology, Ege University Hospital, Izmir, Turkey.",
"authors": "Yilmaz|F|F|;Soyer|N|N|;Uslu|R|R|;Erdogan|A P|AP|;Karaca|B|B|;Saydam|G|G|;Sahin|F|F|;Vural|F|F|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.4103/ijc.IJC_284_17",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0019-509X",
"issue": "54(2)",
"journal": "Indian journal of cancer",
"keywords": "Autologous stem cell transplantation; efficacy; germ cell tumors; safety",
"medline_ta": "Indian J Cancer",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D008297:Male; D009364:Neoplasm Recurrence, Local; D009373:Neoplasms, Germ Cell and Embryonal; D012189:Retrospective Studies; D016019:Survival Analysis; D013736:Testicular Neoplasms; D014182:Transplantation, Autologous; D055815:Young Adult",
"nlm_unique_id": "0112040",
"other_id": null,
"pages": "415-420",
"pmc": null,
"pmid": "29469069",
"pubdate": "2017",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Retrospective analysis of patients with relapsed or refractory testicular nonseminous germ cell tumors treated with autologous stem cell transplantation.",
"title_normalized": "retrospective analysis of patients with relapsed or refractory testicular nonseminous germ cell tumors treated with autologous stem cell transplantation"
} | [
{
"companynumb": "TR-PFIZER INC-2018088462",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CARBOPLATIN"
},
"drugadditional": "3",
... |
{
"abstract": "A sixty-one year old female with a past history of asthma was admitted to the emergency department because of vertigo, nausea, vomiting, chest pain and generalized erythema after taking an oral dose of cefuroxime axetil. Electrocardiography showed ST segment elevation in inferior leads. After coronary angiography, type 2 variant of Kounis Syndrome is diagnosed. We present first drug induced Kounis Syndrome in an asthmatic patient with severe anaphylactic shock. The present report also shows that atopic people expressing an amplified mast cell degranulation may have more serious hemodynamic decompensation during hypersensitivity reactions.",
"affiliations": null,
"authors": "Ilhan|Erkan|E|;Güvenç|Tolga Sinan|TS|;Poyraz|Esra|E|;Ayhan|Erkan|E|;Soylu|Ozer|O|",
"chemical_list": "D000900:Anti-Bacterial Agents; D002444:Cefuroxime; C040738:cefuroxime axetil",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.ijcard.2009.04.026",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0167-5273",
"issue": "137(3)",
"journal": "International journal of cardiology",
"keywords": null,
"medline_ta": "Int J Cardiol",
"mesh_terms": "D054058:Acute Coronary Syndrome; D000707:Anaphylaxis; D000900:Anti-Bacterial Agents; D001249:Asthma; D002444:Cefuroxime; D017023:Coronary Angiography; D003937:Diagnosis, Differential; D004342:Drug Hypersensitivity; D004562:Electrocardiography; D005260:Female; D006801:Humans; D008875:Middle Aged",
"nlm_unique_id": "8200291",
"other_id": null,
"pages": "e67-9",
"pmc": null,
"pmid": "19428133",
"pubdate": "2009-11-12",
"publication_types": "D002363:Case Reports; D016422:Letter",
"references": null,
"title": "Kounis Syndrome secondary to cefuroxime axetil use in an asthmatic patient.",
"title_normalized": "kounis syndrome secondary to cefuroxime axetil use in an asthmatic patient"
} | [
{
"companynumb": "TR-RANBAXY-2011RR-44608",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CEFUROXIME"
},
"drugadditional": null,
... |
{
"abstract": "CytoSorb hemoadsorption (CytoSorbents Inc, Monmouth Junction, NJ) was performed shortly before an urgent off-pump coronary artery bypass operation in a 58-year-old man at high risk of bleeding as a result of treatment of coronary artery disease with ticagrelor and treatment of atrial fibrillation with rivaroxaban. The patient experienced dissection of the left anterior descending artery during a percutaneous coronary intervention. Preoperatively, CytoSorb hemoadsorption was applied to eliminate the coagulative active medications. His intraoperative and postoperative courses were uneventful, with adequate bleeding control. This case highlights a promising approach for managing antiplatelet drugs and anticoagulant agents such as ticagrelor and rivaroxaban before off-pump coronary artery bypass.",
"affiliations": "Department of Cardiac Surgery, Chirurgisches Klinikum München Süd, Munich, Germany. Electronic address: helmut.mair@artemed.de.;Department of Cardiology, Internistisches Klinikum München Süd, Munich, Germany.;Department of Anesthesiology, Chirurgisches Klinikum München Süd, Munich, Germany.;Department of Cardiac Surgery, Chirurgisches Klinikum München Süd, Munich, Germany.",
"authors": "Mair|Helmut|H|;Jilek|Clemens|C|;Haas|Brigitte|B|;Lamm|Peter|P|",
"chemical_list": "D000069552:Rivaroxaban; D000077486:Ticagrelor",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.athoracsur.2020.03.108",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0003-4975",
"issue": "110(5)",
"journal": "The Annals of thoracic surgery",
"keywords": null,
"medline_ta": "Ann Thorac Surg",
"mesh_terms": "D016063:Blood Loss, Surgical; D047549:Coronary Artery Bypass, Off-Pump; D006464:Hemoperfusion; D006801:Humans; D008297:Male; D008875:Middle Aged; D000069552:Rivaroxaban; D000077486:Ticagrelor",
"nlm_unique_id": "15030100R",
"other_id": null,
"pages": "e369-e370",
"pmc": null,
"pmid": "32407851",
"pubdate": "2020-11",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Ticagrelor and Rivaroxaban Elimination With CytoSorb Adsorber Before Urgent Off-Pump Coronary Bypass.",
"title_normalized": "ticagrelor and rivaroxaban elimination with cytosorb adsorber before urgent off pump coronary bypass"
} | [
{
"companynumb": "DE-JNJFOC-20200611011",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "HEPARIN SODIUM"
},
"drugadditional": "3",
... |
{
"abstract": "Nonmyeloablative stem cell transplantation (NST) harnesses the graft-versus-tumor effect while minimizing regimen-related toxicity, and can result in donor chimerism and remission. Acute graft-versus-host disease (GVHD) and infections are major complications after sibling NST. Toxicity of unrelated-donor (UD) NST and the most appropriate GVHD prophylaxis in this setting remain poorly defined. We describe 25 patients who received UD-NST conditioned with fludarabine and cyclophosphamide. The first six patients received cyclosporine (Cs) and mycophenolate mofetil (MMF) (n=5) or methotrexate (MTX) (n=1) as GVHD prophylaxis (group 1) and all developed grade III-IV acute GVHD. The next 19 patients received the same conditioning regimen with the addition of alemtuzumab, and all received Cs/MTX post-transplant. Engraftment and donor chimerism were achieved in all but one evaluable patient. In all, 15 patients died: five of six deaths in group 1 were attributable to acute GVHD, while deaths in group 2 were due to infection or progressive disease (P=0.05). The combination of Cs/MMF is inadequate GVHD prophylaxis for UD-NST. The use of Cs, MTX, and alemtuzumab eliminated severe acute GVHD; its impact on response merits further study.",
"affiliations": "Bone Marrow and Stem Cell Transplant Programs, University of Pennsylvania Cancer Center, Philadelphia, PA, USA. awokoff@mail.med.upen.edu",
"authors": "Loren|A W|AW|;Luger|S M|SM|;Stadtmauer|E A|EA|;Tsai|D E|DE|;Schuster|S|S|;Nasta|S D|SD|;Goldstein|S C|SC|;Perl|A|A|;Orloff|G|G|;Oliver|J C|JC|;Green|J|J|;Emerson|S G|SG|;Porter|D L|DL|",
"chemical_list": "D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000912:Antibodies, Neoplasm; D000074323:Alemtuzumab; D003520:Cyclophosphamide; D014740:Vidarabine; D009173:Mycophenolic Acid; C024352:fludarabine",
"country": "England",
"delete": false,
"doi": "10.1038/sj.bmt.1704887",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0268-3369",
"issue": "35(9)",
"journal": "Bone marrow transplantation",
"keywords": null,
"medline_ta": "Bone Marrow Transplant",
"mesh_terms": "D000328:Adult; D000074323:Alemtuzumab; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000912:Antibodies, Neoplasm; D000971:Antineoplastic Combined Chemotherapy Protocols; D003520:Cyclophosphamide; D005260:Female; D006086:Graft vs Host Disease; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008232:Lymphoproliferative Disorders; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid; D018183:Transplantation Chimera; D019172:Transplantation Conditioning; D014740:Vidarabine",
"nlm_unique_id": "8702459",
"other_id": null,
"pages": "921-6",
"pmc": null,
"pmid": "15765118",
"pubdate": "2005-05",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Intensive graft-versus-host disease prophylaxis is required after unrelated-donor nonmyeloablative stem cell transplantation.",
"title_normalized": "intensive graft versus host disease prophylaxis is required after unrelated donor nonmyeloablative stem cell transplantation"
} | [
{
"companynumb": "NVSC2020US184480",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "METHOTREXATE"
},
"drugadditional": null,
"dr... |
{
"abstract": "The fluoroketolide solithromycin is 2-fold more potent in vitro than telithromycin against pneumococci (including macrolide-resistant strains) and Haemophilus influenzae and very active on pathogens causing atypical pneumonia. In contrast, it is a 30-fold less potent inhibitor of nicotinic receptors incriminated in telithromycin toxicity. In Phase II/III trials, oral solithromycin once-daily (800 mg on day 1; 400 mg on days 2-5) proved effective and safe when compared to respiratory fluoroquinolones for the treatment of community-acquired bacterial pneumonia (CABP). A Phase III intravenous trial vs. moxifloxacin has been recently completed for the same indication. Solithromycin may restore interest in ketolides as a first-line therapy for CAPB. Solithromycin safety should nevertheless be confirmed in larger populations allowing for detection of rare adverse events.",
"affiliations": "a Pharmacologie cellulaire et moléculaire , Louvain Drug Research Institute, Université catholique de Louvain , Brussels , Belgium.;a Pharmacologie cellulaire et moléculaire , Louvain Drug Research Institute, Université catholique de Louvain , Brussels , Belgium.",
"authors": "Van Bambeke|Françoise|F|;Tulkens|Paul M|PM|",
"chemical_list": "D000900:Anti-Bacterial Agents; D018942:Macrolides; D014230:Triazoles; C547755:solithromycin",
"country": "England",
"delete": false,
"doi": "10.1586/14787210.2016.1138857",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1478-7210",
"issue": "14(3)",
"journal": "Expert review of anti-infective therapy",
"keywords": "Chlamydophila pneumoniae; Haemophilus influenzae; Legionella pneumophila; Mycoplasma pneumoniae; Streptococcus pneumoniae; community-acquired bacterial pneumonia; ketolide; levofloxacin; moxifloxacin; solithromycin",
"medline_ta": "Expert Rev Anti Infect Ther",
"mesh_terms": "D000900:Anti-Bacterial Agents; D002986:Clinical Trials as Topic; D017714:Community-Acquired Infections; D006801:Humans; D018942:Macrolides; D014230:Triazoles",
"nlm_unique_id": "101181284",
"other_id": null,
"pages": "311-24",
"pmc": null,
"pmid": "26848612",
"pubdate": "2016",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": null,
"title": "The role of solithromycin in the management of bacterial community-acquired pneumonia.",
"title_normalized": "the role of solithromycin in the management of bacterial community acquired pneumonia"
} | [
{
"companynumb": "US-CIPLA LTD.-2016BE01384",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ACETAMINOPHEN"
},
"drugadditional": null,
... |
{
"abstract": "Suicide and suicidal behaviors amongst combat veterans is an important public health issue. Exposure to military combat predisposes patients to increased levels of major depression, post-traumatic stress disorder (PTSD), substance abuse, and chronic pain - all of which are important risk factors for suicide. Here, we present a case study of a young combat veteran who presented with an impulsive suicide attempt that had a high potential for lethality in the context of depression, PTSD, and substance use. On routine admission laboratory work, his serum level of testosterone was seen to be low. Given the important role that testosterone plays in the regulation of mood and behavior, we posit that it is a potentially important marker for suicide risk in an already at-risk population.",
"affiliations": null,
"authors": "Kiraly|Drew D|DD|;Sher|Leo|L|",
"chemical_list": "D013739:Testosterone",
"country": "Germany",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0334-0139",
"issue": "27(2)",
"journal": "International journal of adolescent medicine and health",
"keywords": null,
"medline_ta": "Int J Adolesc Med Health",
"mesh_terms": "D000328:Adult; D003865:Depressive Disorder, Major; D017831:Diagnosis, Dual (Psychiatry); D006801:Humans; D008297:Male; D012307:Risk Factors; D013313:Stress Disorders, Post-Traumatic; D013405:Suicide; D013739:Testosterone; D014728:Veterans",
"nlm_unique_id": "8506960",
"other_id": null,
"pages": "235-7",
"pmc": null,
"pmid": "25528760",
"pubdate": "2015-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Low testosterone in a young combat veteran with dual diagnosis and suicidal behavior: a case study.",
"title_normalized": "low testosterone in a young combat veteran with dual diagnosis and suicidal behavior a case study"
} | [
{
"companynumb": "US-APOTEX-2017AP018969",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CITALOPRAM HYDROBROMIDE"
},
"drugadditional": nu... |
{
"abstract": "Tumor-induced osteomalacia (TIO) is a rare cause of impaired bone mineralization mediated by the osteocyte-derived, phosphaturic hormone: fibroblast growth factor 23 (FGF23). The case is presented of a previously healthy 45-year-old man who developed fragility fractures at multiple sites (initially metatarsals, eventually ribs, hips, spine, scapula, and sacrum) resulting in rapid functional deterioration, weakness, and the inability to bear weight and ambulate without a walker. Workup for secondary causes of bone loss was negative except for mild hypogonadotropic hypogonadism with normal pituitary MRI and hypophosphatemia that persisted despite aggressive supplementation. Testosterone was initiated but discontinued 6 months later because of deep vein thrombosis and pulmonary embolism, likely provoked by his new sedentary state, in addition to smoking history and possibly testosterone usage. Serum FGF23 was nonelevated at 138 mRU/mL (44-215). A genetic panel for OI variants was negative for a causal mutation. At the age of 48, 3 years after his initial fracture, he was referred to our academic endocrine clinic. We ruled out additional mutations that lead to hypophosphatemic rickets, including phosphate-regulating endopeptidase homolog, X-linked. PET/CT looking for a potential TIO locus revealed uptake in the left suprapatellar recess. Biopsy was consistent with a phosphaturic mesenchymal tumor. FGF23 was repeated for a preoperative baseline and now found to be elevated at 289 mRU/mL. In retrospect, it is likely that the initial level was inappropriately elevated for the degree of hypophosphatemia. After resection, he experienced marked improvement in physical function, decreased pain, and resolution of renal phosphate wasting. The principals of establishing a robust clinical diagnosis of TIO should be emphasized, excluding other entities and avoiding pitfalls in the interpretation of laboratory testing. © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.",
"affiliations": "Department of Medicine, Division of Endocrinology and Metabolism University of North Carolina at Chapel Hill Chapel Hill NC USA.;Department of Medicine, Division of Endocrinology and Metabolism University of North Carolina at Chapel Hill Chapel Hill NC USA.;Department of Pathology Carolinas Medical Center Charlotte NC USA.;Department of Medicine, Division of Endocrinology and Metabolism University of North Carolina at Chapel Hill Chapel Hill NC USA.",
"authors": "Nandam|Neeharika|N|;Ejaz|Sadia|S|;Ahrens|William|W|;Styner|Maya|M|https://orcid.org/0000-0001-9790-8645",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1002/jbm4.10438",
"fulltext": "\n==== Front\nJBMR Plus\nJBMR Plus\n10.1002/(ISSN)2473-4039\nJBM4\nJBMR Plus\n2473-4039 John Wiley & Sons, Inc. Hoboken, USA \n\n33615107\n10.1002/jbm4.10438\nJBM410438\nOriginal Article\nOriginal Articles\nA Normal FGF23 Does Not Preclude Tumor‐Induced Osteomalacia\nA NORMAL FGF23 DOES NOT PRECLUDE TIONandam et al.Nandam Neeharika \n1\n Ejaz Sadia \n1\n Ahrens William \n2\n Styner Maya https://orcid.org/0000-0001-9790-8645\n1\nmstyner@med.unc.edu \n1 \nDepartment of Medicine, Division of Endocrinology and Metabolism\nUniversity of North Carolina at Chapel Hill\nChapel Hill\nNC\nUSA\n\n\n2 \nDepartment of Pathology\nCarolinas Medical Center\nCharlotte\nNC\nUSA\n\n* \nAddress correspondence to: Maya Styner, MD, Department of Medicine, Division of Endocrinology, University of North Carolina, CB 7170, 5003 Burnett Womack, 160 Dental Circle, Chapel Hill, NC. E‐mail: mstyner@med.unc.edu\n\n23 12 2020 \n2 2021 \n5 2 10.1002/jbm4.v5.2e1043820 6 2020 05 10 2020 15 11 2020 © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.ABSTRACT\nTumor‐induced osteomalacia (TIO) is a rare cause of impaired bone mineralization mediated by the osteocyte‐derived, phosphaturic hormone: fibroblast growth factor 23 (FGF23). The case is presented of a previously healthy 45‐year‐old man who developed fragility fractures at multiple sites (initially metatarsals, eventually ribs, hips, spine, scapula, and sacrum) resulting in rapid functional deterioration, weakness, and the inability to bear weight and ambulate without a walker. Workup for secondary causes of bone loss was negative except for mild hypogonadotropic hypogonadism with normal pituitary MRI and hypophosphatemia that persisted despite aggressive supplementation. Testosterone was initiated but discontinued 6 months later because of deep vein thrombosis and pulmonary embolism, likely provoked by his new sedentary state, in addition to smoking history and possibly testosterone usage. Serum FGF23 was nonelevated at 138 mRU/mL (44–215). A genetic panel for OI variants was negative for a causal mutation. At the age of 48, 3 years after his initial fracture, he was referred to our academic endocrine clinic. We ruled out additional mutations that lead to hypophosphatemic rickets, including phosphate‐regulating endopeptidase homolog, X‐linked. PET/CT looking for a potential TIO locus revealed uptake in the left suprapatellar recess. Biopsy was consistent with a phosphaturic mesenchymal tumor. FGF23 was repeated for a preoperative baseline and now found to be elevated at 289 mRU/mL. In retrospect, it is likely that the initial level was inappropriately elevated for the degree of hypophosphatemia. After resection, he experienced marked improvement in physical function, decreased pain, and resolution of renal phosphate wasting. The principals of establishing a robust clinical diagnosis of TIO should be emphasized, excluding other entities and avoiding pitfalls in the interpretation of laboratory testing. © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.\n\nDISORDERS OF CALCIUM/PHOSPHATE METABOLISMTUMOR‐INDUCED BONE DISEASEPTH/Vit D/FGF23OSTEOMALACIA AND RICKETSORTHOPEDIC INJURY/FRACTURE HEALINGNational Institute of Arthritis and Musculoskeletal and Skin Diseases 10.13039/100000069AR073264NIH/NCATS/NCTraCS 10.13039/100000002 source-schema-version-number2.0cover-dateFebruary 2021details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:5.9.9 mode:remove_FC converted:25.02.2021\n==== Body\nCase Presentation\nA 45‐year‐old previously healthy white man presented with multiple fragility fractures over 2 years, as well as pain and functional deficits eventually rendering him nonambulatory. He carried no previously diagnosed medical history, although he was a former smoker with a 13 pack‐year smoking history. His family history was notable for grade 1 chondrosarcoma in his mother. He initially presented to an orthopedic clinic with foot pain and hip pain after starting an exercise program. Initially, he was counseled to participate in physical therapy; however, he continued to develop progressively disabling pain. Over the course of 8 months, he was diagnosed with bilateral metatarsal and subtrochanteric femur fractures on imaging.\n\nA local endocrinologist was consulted based on suspicion for secondary causes of bone loss. His laboratory tests were notable for a low phosphorus at 2.1 mg/dL (2.7–4.5), elevated alkaline phosphatase (ALP) at 155 IU/L (34–104), elevated PTH at 211 pg/mL (12.0–72.0), low 25OHD, and 1,25(OH)2D3 at 27 ng/mL (30–80) and 12 pg/mL (20–80), respectively. However, calcium was normal at 8.8 mg/dL (8.4–10.4). Serum protein electrophoresis revealed no evidence of monoclonal gammopathy. Additional studies included a low free testosterone at 4.4 ng/mL (5–21) and luteinizing hormone at 2.2 mIU/mL (3.0–10.0). Other pituitary hormone levels and brain MRI were unremarkable.\n\nVitamin D3, calcitriol, phosphate, and testosterone were prescribed. Testosterone was discontinued 6 months later, after developing a venous thromboembolism of the left common femoral, superficial femoral, and popliteal veins, and pulmonary embolus of the left pulmonary artery. Workup for genetic causes of hypercoagulability was negative; he ultimately received anticoagulation for a year with rivaroxaban. Incidental rib fractures on a chest X‐ray at the time prompted a three‐phase 99Tc‐MDP bone scan, revealing multiple sites of uptake: ribs, scapulae, sternum, thoracolumbar spine, sacrum, bilateral ankles, and feet (Fig. 1A)\n.\n\nFig 1 Key radiologic imaging and histology sections from our patient with tumor‐induced osteomalacia (TIO). Top panel: (A) 99mtechnetium methylene diphosphonate (99mTc MDP) bone scan shows increased uptake in bilateral anterior/posterior ribs, bilateral sternoclavicular joints, right proximal intertrochanteric femur, inferior sternum, multiple bilateral lumbar transverse processes, right posterior scapula, posterior elements along upper thoracic spine, posterior elements along lumbosacral junction, right posterior sacrum, bilateral ankles, likely bilateral mid‐feet. Overall impression: Extensive multifocal regions with increased uptake likely representing subacute, remodeling, or other active stress fractures. Middle panel: (B) Computed tomography/fluorodeoxyglucose ‐positron emission tomography (CT/FDG PET) scan shows an area of suprapatellar enhancement that was suspicious for a TIO locus (C) Sagittal MR image showing the patient's hypermetabolic lesion measuring 1.7 cm in largest dimension in the left suprapatellar recess, and corresponding to hypermetabolic area on PET/CT. Bottom panel: (D) suprapatellar tumor surgical pathology specimen stained with H&E: Pattern is consistent with phosphaturic mesenchymal tumor. Arrow indicates multinucleated giant cells.\n\nLaboratory tests showed ongoing phosphate wasting, despite compliance with calcitriol 0.25 μg/d, cholecalciferol 5000 IU/d, and phosphorus 2250 mg/d in divided doses. Calculated tubular reabsorption of phosphate was 64% (>80%) and renal tubular maximal phosphate to glomerular reabsorption rate (TmP/GFR) was 1.74 mg/dL (2.5–4.5), indicating inappropriately low Pi reabsorption. Of note, it is unclear if the patient was taking phosphorus supplementation at the time of these measurements. Urine 24‐hour calcium was 244.8 mg (100–300). Testing for causal mutations in hypophosphatemic rickets and osteogenesis imperfecta was negative. Serum C‐terminal FGF23 level was tested based on concern for an acquired cause of hypophosphatemia such as TIO, and was within the reference range at 138 RU/mL (LabCorp ELISA 44–215; LabCorp, Burlington, NC, USA). At this point, 3 years after symptom onset, he was referred to our academic endocrinology practice for further workup of possible secondary causes of his phosphate wasting. His examination was remarkable only for an elevated BMI of 35, diffuse muscle and bone tenderness to palpation without evident deformities, and requirement for an ambulation‐assist device. We interpreted his normal serum FGF23 level as inappropriately high for his degree of hypophosphatemia, prompting a search for a suspected TIO locus, which was further considered based on rapid clinical deterioration in a previously healthy patient. 18F‐fluorodeoxyglucose positron emission tomography (18F‐FDG‐PET) exhibited a hypermetabolic focus at the left suprapatellar recess, which corresponded with a small 1.7‐cm mass that had previously been seen on CT 2 years prior but thought to be clinically insignificant because of its benign appearance (Fig. 1B\n). MRI demonstrated stability in size over this time period with near homogenous enhancement suggestive of a benign process; signal intensity was slightly higher than muscle with punctate areas showing low signal foci, potentially indicative of a degree of mineralization (Fig. 1C\n). Serum C‐terminal FGF23 measurement was measured with LabCorp ELISA again, and was now elevated at 289 RU/mL (44–215).\n\nBiopsy showed a phosphaturic mesenchymal tumor (Fig. 1D\n) and chromogenic in situ hybridization (Mayo Clinic, Rochester, MN, USA) was positive for FGF23 mRNA, confirming this site as a likely TIO locus (Table 1). After surgical resection of the tumor, serum C‐terminal FGF23 declined to <50 RU/mL 1‐week postoperative and was 90 RU/mL 3 weeks later (Mayo <180 RU/mL). Phosphorus and 25OHD level were rechecked at 1 month postsurgery and found to have normalized, permitting discontinuation of calcitriol and phosphorus. DEXA 8 weeks after surgery showed marked improvements, with lumbar spine T score increasing from −2.8 to −1.0 (BMD +64.29%) and femoral neck T score from −1.9 to −1.4 (BMD +26.32%). The patient also experienced significant improvement in physical function and pain after his operation.\n\nTable 1 Clinical Characteristics Prior to and After Tumor Resection\n\nTest\tYears prior to presentation\t\tWeeks after surgery\tRange\t\n3\t1\t0.5\tInitial visit\t1\t4\t12\t32\t\nPhosphorus serum (mg/dL)\t\t2.0\t2.4\t\t\t3.9\t4.1\t2.8\t2.5–5.0\t\nUrine spot ‐ Phos (mg/dL) ‐ Cr (mg/dL)\t\t\tPhos: 57 Cr: 47\t\t\t\t\t\tUrine Phos: N/A Urine Cr: 30–125\t\nTmP/GFR (mg/dL)\t\t\t1.74\t\t\t\t\t\t2.4–4.5\t\n24‐h urine calcium (mg/24 h)\t\t244.8\t\t90.0\t\t\t\t\t<100 Low Ca diet <300 Normal diet\t\nAlk phos (IU/L)\t\t166\t\t177\t99\t126\t125\t125\t34–104\t\niPTH (pg/mL)\t\t105\t\t211\t69.2\t\t\t62\t12.0–72.0\t\nCalcium (mg/dL)\t\t9.2\t\t8.7\t\t9.2\t9.3\t9.3\t8.6–10.3\t\n25OHD (ng/mL)\t\t\t\t24\t\t33\t41\t31\t30–80\t\n1,25(OH)2D (pg/mL)\t\t\t\t12.0\t\t\t\t55.6\t19.9–79.3\t\nFGF23 (mRU/mL)\t\t\t\t\t<50\t90\t\t\tMayo ELISA <180\t\n\t\t138\t289\t\t\t\t\tLabCorp ELISA 44–215\t\nPituitary hormones\tLH (mIU/mL): 2.2 ACTH (pg/mL): 24.5 TSH (mIU/mL): 2.6 Prolactin (ng/mL): 4.6\t\tLH 1.6 FSH (mIU/mL): 1.7\t\t\t\t\t\tLH: 1.2–8.6 FSH: 1.3–19.3 ACTH: 7.2–63.3 TSH: 0.3–4.5 Prolactin: 4.0–15.2\t\n24‐h urine–free cortisol (μg/dL/24 h)\t\t\t\t12.0\t\t\t\t\t0–50.0\t\nTestosterone Total (ng/dL) Free (pg/mL)\tTotal 175 Free 4.4\t\tTotal 151 Free 6.6\t\t\t\t\t\tTotal: 249–836 Free: 6.8–21.5\t\nSPEP\t\tNo monoclonal gammopathy\t\t\t\t\t\t\tN/A\t\nGenetic testing\t\tOI panel negative\tCTGT panel negative\t\t\t\t\t\t\t\nImaging studies\t\nMRI L Foot: Transverse fracture second MT, marrow edema, also medial cuneiform Hip X‐rays: Stress fractures‐ RFN & Left subtrochanteric CT and MRI lower extr: fractures as above, and with benign appearing L suprapatellar soft tissue nodule\t\n3‐phase\n99\nTc‐MDP bone scan: Multiple stress fractures MRI Brain: normal pituitary\t\t\nDEXA Spine T − 2.8 FN T − 1.9 PET‐CT: hypermetabolic L suprapatellar lesion MRI L knee: stable appearing L suprapatellar lesion\t\t\nMRI L Knee: no evidence of soft tissue lesion recurrence\t\t\nDEXA Spine T − 1.0 FN T − 1.4\t\t\nConnective tissue gene tests abnormal mineralization disorder panel, next‐generation sequencing. All coding regions for genes on the panel were analyzed for variants using Illumina (San Diego, CA, USA) MiSeq next‐generation sequencers (ALPL, ANKH, CASR, CLCN5, CYP27B1, DMP1, ENPP1, FAH, FGF23, OCRL, PHEX, SLC34A1, SLC34A3, SLC9A3R1, VDR).\n\nAbbreviations: 25OHD = calcidiol; 1,25(OH)2D = calcitriol; ACTH = adrenocorticotropic hormone; Alk phos = alkaline phosphatase; CT = computed tomography; CTGT = connective tissue gene test; DEXA = dual energy X‐ray absorptiometry; ELISA = enzyme‐linked immunosorbent assay; FSH = follicle‐stimulating hormone; iPTH = intact parathyroid hormone; LH = luteinizing hormone; MRI = magnetic resonance imaging; MT = metatarsal; OI panel = osteogenesis imperfecta panel from Invitae analyzed clinically important regions of each specified gene (COL1A1, COL1A2, CRTAP, P3H1); PRL = prolactin; SPEP = serum protein electrophoresis; TMP/GFR = tubular max reabsorption of phosphate.\n\nBackground\nIn the late 1950s the Swiss pediatric endocrinologist Andrea Prader was the first to identify a case of acquired hypophosphatemia caused by a ricketogenic substance [FGF23].(\n\n1\n, \n2\n, \n3\n\n) It would take more than 40 years to clone this humoral factor, or phosphatonin, causing renal phosphate wasting.(\n\n4\n\n) Studies of autosomal dominant hypophosphatemic rickets led to identifying FGF23 as the most common phosphatonin, crucial in both physiologic phosphate regulation and the driver of phosphate wasting in multiple diseases.(\n\n4\n, \n5\n, \n6\n\n)\n\n\nBone‐derived FGF23 is upregulated with increased serum inorganic phosphate (Pi) and downregulated in the setting of hypophosphatemia.(\n\n7\n\n) Interestingly, tight regulation of FGF23 degradation, rather than its synthesis, permits its secretion.(\n\n8\n\n) GALNT3 functions to O‐glycosylate FGF23, thus protecting FGF23 from degradation and permitting its release.(\n\n9\n\n) On the other hand, the absence of the zinc metallopeptidase phosphate‐regulating endopeptidase homolog, X‐linked (PHEX) lowers FGF23 via unclear mechanisms.(\n\n10\n\n) Intact FGF23, secreted by osteocytes and their precursors, binds with coreceptor α‐klotho to FGFR1 in the renal proximal tubule, reducing expression of the sodium‐phosphate cotransporters NaPi‐2a and NaPi‐2c, and ultimately increasing urinary phosphate excretion.(\n\n11\n\n) In addition to its effect on renal Pi handling, FGF23 suppresses renal 1‐α‐hydroxylase (CYP27B1), thereby lowering calcitriol synthesis; FGF23 also upregulates vitamin D 24‐hydroxylase (CYP24), inactivating calcitriol.(\n\n9\n, \n11\n\n) In addition to FGF23 and vitamin D, PTH is also an important phosphate regulator. PTH (via PTHR1) promotes phosphaturia by a mechanism similar to FGF23, however in contrast, upregulates CYP27B1 and suppresses CYP24.(\n\n12\n\n)\n\n\nThe presence of multiple fragility fractures in young adults merits consideration of secondary causes of bone loss. The differential diagnosis includes disorders of the collagen matrix such as osteogenesis imperfecta and disorders of calcium and vitamin D metabolism.(\n\n13\n\n) Hypophosphatemia suggests a genetic versus acquired cause of Pi loss.(\n\n14\n\n) Common acquired causes of low Pi include primary hyperparathyroidism, secondary hyperparathyroidism from vitamin D deficiency, and alcohol abuse.(\n\n12\n, \n14\n\n) Fanconi syndrome presents with glycosuria and aminoaciduria in addition to phosphaturia; it can be either inherited or secondary to medications or other illnesses, such as multiple myeloma.(\n\n12\n, \n15\n\n) Distinguishing whether hypophosphatemia is driven by renal phosphate wasting is a key part of diagnostic evaluation, and is done by calculating the tubular maximal reabsorption rate of phosphate to glomerular filtration (TmP/GFR).(\n\n16\n\n) Causes such as hyperparathyroidism and Fanconi syndrome with renally mediated Pi losses typically have low TmP/GFR values, whereas extrarenal causes such as excess phosphate binder intake and refeeding syndrome should have appropriately high TmP/GFR for the degree of hypophosphatemia.(\n\n16\n\n)\n\n\nIf investigations reveal renal‐mediated hypophosphatemia unexplained by the above causes, serum FGF23 is measured. High FGF23, or a level inappropriately normal for the degree of hypophosphatemia, might indicate a disorder of FGF23 excess. X‐linked hypophosphatemic rickets (PHEX) and autosomal dominant hypophosphatemic rickets (FGF23) are genetic disorders resulting in decreased FGF23 breakdown.(\n\n12\n\n) Of note, several patients with FGF23 mutations, especially women, may be normophosphatemic during childhood; thus testing for this mutation should be part of the workup for adult onset fragility fractures with hypophosphatemia.(\n\n12\n\n) Autosomal recessive hypophosphatemic rickets type 1 (DMP1) leads to increased transcription of FGF23.(\n\n9\n, \n12\n\n) McCune‐Albright syndrome (GNAS somatic mutation) may rarely cause FGF23 overexpression.(\n\n12\n\n) Additionally, ferric carboxymaltose administration can cause osteomalacia through an increase in FGF23.(\n\n17\n\n)\n\n\nTIO is caused by overproduction of FGF23 by small, typically benign mesenchymal tumors, leading to fragility fractures and diffuse bone and muscle pain.(\n\n18\n\n) Laboratory findings are similar to those of the FGF23 excess syndromes described above, with hypophosphatemia, renal phosphate wasting, and low to inappropriately normal 1,25(OH)2D3 for the degree of hypophosphatemia, however, without a previous history of these lab abnormalities.(\n\n19\n\n) Serum calcium, 25OHD, and PTH levels are normal, though persistently low 1,25(OH)2D3 may lead to secondary hyperparathyroidism, with elevated ALP.(\n\n19\n\n)\n\n\nThe time from symptom onset to diagnosis is over 2.5 years in most cases of TIO, in part because of delays in initial testing for hypophosphatemia, but also because of difficulty in localizing tumors.(\n\n19\n\n) Functional imaging, which takes advantage of the high expression of somatostatin receptors in TIO, is recommended and uses 111In‐octreotide or 68Gallium tetraazacyclododecanetetraacetic acid–DPhe1‐Tyr3‐octreotate (68Ga‐DOTATATE) for tumor localization.(\n\n11\n\n) DOTATATE PET/CT likely has the greatest sensitivity and specificity for TIO, with octreotide scanning also being a sensitive imaging method based on the presence of somatostatin receptors in TIO.(\n\n11\n, \n20\n\n) However, 18FDG‐PET‐CT is useful if somatostatin‐based scans are negative.(\n\n11\n, \n20\n\n) In some cases, biopsy has been discouraged based on the possibility of tumor seeding, with venous sampling being an alternate option if further diagnostic clarification is needed.(\n\n14\n\n) Successful tumor resection typically results in skeletal healing and reversal of biochemical defects; excision with wide, tumor‐free margins is essential because of the risk of tumor recurrence.(\n\n14\n, \n19\n\n) Histopathology shows a mesenchymal tumor of mixed connective tissue variant (PMT‐CT).(\n\n21\n\n) Immunohistochemical staining or RT‐PCR‐based detection of FGF23 mRNA transcription is often used to demonstrate increased FGF23 expression.(\n\n21\n, \n22\n\n) In our patientʼs case, chromogenic in situ hybridization was used to support the diagnosis.\n\nDiscussion\nThis case serves as an example of the importance of considering TIO in the differential diagnosis of fragility fractures, particularly with the constellation of new‐onset persistent renal phosphate wasting in the absence of genetic causes of hypophosphatemic osteomalacia. The presence of FGF23 level in the normal range should be interpreted as inappropriately elevated and potentially suggestive of TIO, as physiologically FGF23 should be downregulated with hypophosphatemia.\n\nInterestingly, our patient's serum FGF23 level was elevated only on recheck 5 months after his initial level. Although his tumor could have expressed higher amounts of FGF23 mRNA during this period, this case also brings into question the reproducibility of FGF23 level and sensitivity of commercially available serum assays. For example, in a study by Imel and colleagues, the test sensitivity of one C‐terminal FGF23 assay (Immutopics, Inc., San Clemente, CA, USA) was 73% in TIO; although this specific assay is different from that used for our patient, this suggests that C‐terminal assays might miss a fraction of TIO cases.(\n\n23\n\n) Imel and colleague's study also investigated the an intact FGF23 (iFGF23; Kainos Laboratories, Tokyo, Japan) assay and Immutopics intact assay (now discontinued), which had sensitivities of 86% and 23%, respectively.(\n\n23\n\n) Of note, Mayo Clinic Laboratories has recently started offering an iFGF23 assay.(\n\n24\n\n) Further research examining the sensitivities of currently available assays, including head‐to‐head comparisons of C‐terminal to iFGF23 assays, will be important for improving diagnostic accuracy in TIO. Alternatively, lowering the cutoff used for TIO diagnosis may help improve test sensitivity. For example, Proposals have been made for using iFGF23 values just above the population median as a threshold for ruling in TIO, rather than the upper limit of normal; it is possible that a similar principle may apply to C‐terminal assays.(\n\n25\n\n)\n\n\nAlternate testing modalities are needed for cases not easily diagnosed via imaging and/or FGF23 measurement. Venous sampling measuring FGF23 may have clinical utility in verifying a suspicious mass on imaging as being a TIO locus, and systematic sampling may guide locations for further imaging in patients with unrevealing radiographic studies.(\n\n26\n, \n27\n\n) Of note, current studies of venous sampling have been conducted using iFGF23 measurements, with subjects usually having elevated levels.(\n\n26\n, \n27\n\n) It is difficult to say if any of these patients would have had a normal C‐terminal FGF23, similar to our patient, if checked. Whether venous sampling may be of clinical utility in patients with normal iFGF23 or C‐terminal FGF23 levels merits further study, as this may be a relevant method in cases such as ours.\n\nIn some TIO patients with normal FGF23 levels, one may consider hypophosphatemia driven by a different paraneoplastic phosphaturic hormone, or whether FGF23 secretion may be partially responsive to serum phosphate levels in some tumors.(\n\n23\n\n) For example, matrix extracellular phosphoglycoprotein, secreted frizzled protein 4, and FGF‐7 are all additional phosphatonins that have rarely been associated with TIO.(\n\n12\n, \n28\n\n)\n\n\nOf note, this patient's family history of chondrosarcoma raises the question of a genetic predisposition to developing TIO tumors in patients with a family history of skeletal malignancy. For example, an FN1‐FGFR1 fusion gene has been identified in several TIO tumors; this gene has been hypothesized to cause tumorigenesis in TIO through FGF23 binding, leading to autocrine or paracrine activation of the receptor tyrosine kinase.(\n\n14\n, \n29\n\n) Interestingly, FGFR1 fusion genes have been identified as pathogenic in the 8p11 myeloproliferative syndrome, breast cancer, glioblastoma, and lung squamous cell carcinoma.(\n\n29\n, \n30\n\n) Additionally, similar microRNA profiles were recently noted in osteosarcomas and TIO; both show upregulation of the biomarker miR‐197 and downregulation of miR‐20b, miR‐144, and miR‐335.(\n\n31\n\n) Further genetic studies of TIO may improve our understanding of the disease and identify patients missed by currently available modalities.\n\nConclusion\nThis case illustrates a potential pitfall in the diagnosis of tumor‐induced osteomalacia (TIO), highlighting that a normal serum C‐terminal or intact FGF23 might not exclude the disorder in a patient with high clinical suspicion based on acquired hypophosphatemic osteomalacia. Rather, a normal C‐terminal or intact FGF23 must be interpreted as inappropriately high in the setting of hypophosphatemia and warrants a search for FGF23‐excess syndromes such as TIO.\n\nDisclosures\nAll authors report that there are no relevant conflicts of interest, no relevant financial or nonfinancial relationships, no patents (whether planned, pending, or issued) broadly relevant to this work, or any other relationships/conditions/circumstances that present a potential conflict of interest.\n\nAUTHOR CONTRIBUTIONS\n\nNeeharika Nandam: Conceptualization; data curation; investigation; project administration; writing‐original draft; writing‐review and editing. Sadia Ejaz: Conceptualization; writing‐original draft; writing‐review and editing. William Ahrens: Data curation; resources; software; visualization; writing‐review and editing. Maya Styner: Conceptualization; data curation; investigation; project administration; writing‐original draft; writing‐review and editing.\n\nAcknowledgments\nThis work was funded by grant no. R01AR073264 from the National Institute of Health (NIH)/National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) and grant NIH/NCATS/NCTraCS no. KL2TR002490. We would like to acknowledge and thank the NIH/NIAMS for their funding. We also thank the patient described in this report, and confirm that they provided consent for the publication of their case.\n\nAuthors' roles: Data collection: NN and MS. Photographing, formatting, and captioning of surgical pathology pictures: WA. Drafting manuscript: NN, SE, and MS. Revising manuscript content: NN, SE, and MS. Approving final version of manuscript: NN, SE, WA, and MS.\n==== Refs\nReferences\n1 \n\nPrader \nA \n, \nIllig \nR \n, \nUehlinger \nE \n, \nStalder \nG \n. Rickets following bone tumor\n. 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"pubdate": "2021-02",
"publication_types": "D016428:Journal Article",
"references": "29298794;21611969;28932769;14707860;21739089;14434619;30014155;27746322;15397919;11344269;24588013;16160135;26956379;15940367;27533306;18396126;16551733;13327668;29021995;20698924;11371627;24585932;25319834;25195776;27034530;13366213;16033853",
"title": "A Normal FGF23 Does Not Preclude Tumor-Induced Osteomalacia.",
"title_normalized": "a normal fgf23 does not preclude tumor induced osteomalacia"
} | [
{
"companynumb": "US-PFIZER INC-2020521446",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "TESTOSTERONE"
},
"drugadditional": null,
... |
{
"abstract": "Management of advanced bisphosphonate-related osteonecrosis of the jaw, particularly in cases of pathological fractures with extraoral fistulas, is a challenging responsibility for craniomaxillofacial specialists. Although a periosteal reaction is occasionally observed in cases with extensive sequestra, few reports have documented circumferential periosteal osseous formation resulting in bone repair. We present the case of a 78-year-old woman who was treated for breast cancer and received intravenous bisphosphonates. She had bisphosphonate-related osteonecrosis of the jaw with bilateral pathological fractures of the mandible. During the course of minimally invasive treatment, the necrotic segment was separated with circumferential exposure, and new bone spontaneously formed with osseous union to the unilateral fractured stump. The present case typically highlights the potential of periosteal osteogenesis to regain an acceptable state even for patients with severe \"bis-phossy jaw,\" particularly those with pathological fractures, although we do not advocate the universality of the phenomenon presented as \"phoenix jaw.\"",
"affiliations": "From the Department of Oral and Maxillofacial Surgery, Saiseikai Senri Hospital, Suita, Osaka, Japan.",
"authors": "Imai|Tomoaki|T|;Michizawa|Masahiro|M|",
"chemical_list": "D050071:Bone Density Conservation Agents; D004164:Diphosphonates",
"country": "United States",
"delete": false,
"doi": "10.1097/SCS.0000000000000595",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1049-2275",
"issue": "25(4)",
"journal": "The Journal of craniofacial surgery",
"keywords": null,
"medline_ta": "J Craniofac Surg",
"mesh_terms": "D000368:Aged; D059266:Bisphosphonate-Associated Osteonecrosis of the Jaw; D050071:Bone Density Conservation Agents; D001861:Bone Regeneration; D004164:Diphosphonates; D005260:Female; D017102:Fracture Healing; D005598:Fractures, Spontaneous; D006801:Humans; D008297:Male; D008337:Mandibular Fractures; D010012:Osteogenesis",
"nlm_unique_id": "9010410",
"other_id": null,
"pages": "e333-6",
"pmc": null,
"pmid": "24978685",
"pubdate": "2014-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "\"Phoenix jaw\"-bone regeneration of the necrotic mandible between pathological fractures: an unusual but evocative course of bisphosphonate-related osteonecrosis.",
"title_normalized": "phoenix jaw bone regeneration of the necrotic mandible between pathological fractures an unusual but evocative course of bisphosphonate related osteonecrosis"
} | [
{
"companynumb": "PHHY2015JP163643",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ZOLEDRONIC ACID"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nTo follow up on a three-site, 24-week randomized clinical trial (N = 124) comparing antipsychotic medication alone (MED) with antipsychotic medication plus parent training in the behavior management (COMB) of children with autism spectrum disorders and severe behavior problems. The COMB treatment had shown a significant advantage for child behavioral noncompliance (p = .006, d = 0.34), irritability (p = .01, d = 0.48), and hyperactivity/noncompliance (p = .04, d = 0.55) with a lower medication dose.\n\n\nMETHODS\nOne year after each participant's termination, the authors mailed an assessment packet with a return-addressed envelope; a telephone call alerted the family. Failure to return packets within 1 month elicited another contact and offers to resend.\n\n\nRESULTS\nEighty-seven of 124 families (70.2%) participated in the follow-up. The improvement difference between treatments attenuated from after treatment to follow-up for noncompliance (d = 0.32 to 0.12) and irritability (d = 0.46 to 0.03). The follow-up differences were nonsignificant (the noncompliance difference also was nonsignificant after treatment for these 87 families). Sixty-seven percent of the COMB group and 53% of the MED group were still taking risperidone, the original study medication. Most needed dose adjustments or additional medication, and the COMB group no longer had a significantly lower dose. All COMB families but only 39% of MED families reported seeking parent training after treatment. Improvements in daily living skills during treatment predicted noncompliance improvement at follow-up for the COMB children, but noncompliance deterioration and especially hyperactivity/noncompliance deterioration for the MED children.\n\n\nCONCLUSIONS\nThe study treatment experience/familiarity greatly influenced the follow-up treatment: those who had received parent training reported seeking it, whereas those who had not received it tended not to seek it. The superiority of COMB over MED after treatment attenuated by more than half at follow-up.",
"affiliations": "Nisonger Center, Ohio State University, Sunbury, OH 43074, USA. l.arnold@osumc.edu",
"authors": "Arnold|L Eugene|LE|;Aman|Michael G|MG|;Li|Xiaobai|X|;Butter|Eric|E|;Humphries|Kristina|K|;Scahill|Lawrence|L|;Lecavalier|Luc|L|;McDougle|Christopher J|CJ|;Swiezy|Naomi B|NB|;Handen|Benjamin|B|;Wilson|Krystina|K|;Stigler|Kimberly A|KA|",
"chemical_list": "D014150:Antipsychotic Agents; D010879:Piperazines; D015363:Quinolones; D000068180:Aripiprazole; D018967:Risperidone",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0890-8567",
"issue": "51(11)",
"journal": "Journal of the American Academy of Child and Adolescent Psychiatry",
"keywords": null,
"medline_ta": "J Am Acad Child Adolesc Psychiatry",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D014150:Antipsychotic Agents; D000068180:Aripiprazole; D002648:Child; D002653:Child Behavior Disorders; D002659:Child Development Disorders, Pervasive; D002675:Child, Preschool; D003131:Combined Modality Therapy; D015897:Comorbidity; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D010290:Parents; D010353:Patient Education as Topic; D010879:Piperazines; D015363:Quinolones; D018967:Risperidone; D016896:Treatment Outcome",
"nlm_unique_id": "8704565",
"other_id": null,
"pages": "1173-84",
"pmc": null,
"pmid": "23101743",
"pubdate": "2012-11",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "3993694;22215160;16014596;3158201;19858761;10591283;3434595;22265360;15060224;20377705;17667478;9711485;21822762",
"title": "Research Units of Pediatric Psychopharmacology (RUPP) autism network randomized clinical trial of parent training and medication: one-year follow-up.",
"title_normalized": "research units of pediatric psychopharmacology rupp autism network randomized clinical trial of parent training and medication one year follow up"
} | [
{
"companynumb": "US-OTSUKA-2020_011552",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ARIPIPRAZOLE"
},
"drugadditional": "3",
... |
{
"abstract": "The use and availability of cannabis for recreational and medical purposes has become more widespread with increased legalization. Adverse health outcomes of this increased use include cannabinoid hyperemesis syndrome (CHS), which is underrecognized in medical settings. Cessation of substance use is the recommendation of choice for the complete resolution of CHS. However, interventions that provide rapid relief may be necessary in treatment-refractory cases. Little evidence is available to guide care in these cases. Here we report 4 cases of treatment-refractory CHS, all of which remitted after treatment with olanzapine. Olanzapine is known to block multiple neurotransmitter receptors involved in nausea and vomiting in chemotherapy-induced nausea and vomiting. Outcomes of the cases reported here suggest that off-label use of olanzapine may be effective in the symptomatic treatment of refractory CHS and may be the preferred treatment in cases in which comorbid psychotic symptoms or agitation are present.",
"affiliations": "HSU, HERRMANN, KASHYAP, CLAASSEN: Department of Psychiatry, John Peter Smith Hospital, Fort Worth, TX.",
"authors": "Hsu|Jennifer|J|;Herrmann|Zachary|Z|;Kashyap|Saurabh|S|;Claassen|Cynthia|C|",
"chemical_list": "D002186:Cannabinoids; D000077152:Olanzapine",
"country": "United States",
"delete": false,
"doi": "10.1097/PRA.0000000000000564",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1527-4160",
"issue": "27(4)",
"journal": "Journal of psychiatric practice",
"keywords": null,
"medline_ta": "J Psychiatr Pract",
"mesh_terms": "D002186:Cannabinoids; D006801:Humans; D002189:Marijuana Abuse; D009325:Nausea; D000077152:Olanzapine; D014839:Vomiting",
"nlm_unique_id": "100901141",
"other_id": null,
"pages": "316-321",
"pmc": null,
"pmid": "34398582",
"pubdate": "2021-07-28",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Treatment of Cannabinoid Hyperemesis With Olanzapine: A Case Series.",
"title_normalized": "treatment of cannabinoid hyperemesis with olanzapine a case series"
} | [
{
"companynumb": "US-LUPIN PHARMACEUTICALS INC.-2022-00481",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "OLANZAPINE"
},
"drugadditional... |
{
"abstract": "Tolosa-Hunt syndrome is characterized by unilateral retro-orbital headaches and cranial nerve palsies, usually involving cranial nerves III-VI. It is rare for other cranial nerves to be involved, although this has previously been reported. We report a 19-year-old woman presenting with typical features of Tolosa-Hunt syndrome but ultimately developing bilateral facial nerve palsies and enhancement of both facial nerves on magnetic resonance imaging. The patient presented with unilateral retro-orbital headaches and palsies of cranial nerves III-VI. She was diagnosed with Tolosa-Hunt syndrome but was non-compliant with her corticosteroid treatment due to side effects. She returned with progressive left followed by right facial nerve palsy. Her corresponding follow-up magnetic resonance imaging scans showed sequential enhancement of the left and right facial nerves. She ultimately had clinical improvement with IV methylprednisolone. To our knowledge, Tolosa-Hunt syndrome associated with bilateral facial nerve palsy and corroborative facial nerve enhancement on magnetic resonance imaging has not previously been described. Moreover, our patient's clinical course is instructive, as it demonstrates that this atypical presentation of Tolosa-Hunt syndrome can indeed respond to corticosteroid treatment and should not be mistaken for other entities such as Bell's palsy.",
"affiliations": "Department of Radiology, Mayo Clinic, USA.;Department of Radiology, Mayo Clinic, USA.;Department of Radiology, Mayo Clinic, USA.",
"authors": "Madhavan|Ajay A|AA|https://orcid.org/0000-0003-1794-4502;DeLone|David R|DR|;Verdoorn|Jared T|JT|https://orcid.org/0000-0002-1592-1182",
"chemical_list": "D005938:Glucocorticoids; D008775:Methylprednisolone",
"country": "United States",
"delete": false,
"doi": "10.1177/1971400920939293",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1971-4009",
"issue": "33(5)",
"journal": "The neuroradiology journal",
"keywords": "Bell’s palsy; Facial nerve palsy; Tolosa–Hunt syndrome; cavernous sinus inflammation; facial nerve enhancement; pseudotumor",
"medline_ta": "Neuroradiol J",
"mesh_terms": "D003391:Cranial Nerves; D018450:Disease Progression; D005158:Facial Paralysis; D005260:Female; D005938:Glucocorticoids; D006801:Humans; D008279:Magnetic Resonance Imaging; D008775:Methylprednisolone; D020333:Tolosa-Hunt Syndrome; D055815:Young Adult",
"nlm_unique_id": "101295103",
"other_id": null,
"pages": "424-427",
"pmc": null,
"pmid": "32648510",
"pubdate": "2020-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "11606665;10849035;16776691;29169256;24059670;32332660;29623162;1419343;24207148;29415610;24059887;10668117;7436397;16492248",
"title": "Bilateral facial nerve involvement in a patient with Tolosa-Hunt syndrome.",
"title_normalized": "bilateral facial nerve involvement in a patient with tolosa hunt syndrome"
} | [
{
"companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2020R1-263328",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drug... |
{
"abstract": "Trichosporon urinary tract infection (UTI) is an unusual emerging infection, caused mostly by Trichosporon asahii, described especially in hospitalized patients. To date the interpretation and management of Trichosporon positive urinary culture remains a diagnostic and therapeutic dilemma for which there are no precise indications, and the challenge can be even more complicated in comorbid frail elderly patients. Triazoles are known to be the most effective antifungal drugs but can raise concerns about pharmacological interaction. We report a case of Trichosporon asahii nosocomial UTI in an elderly patient.",
"affiliations": "Dipartimento di Geriatria, Fondazione Policlinico Universitario A. Gemelli IRCCS, Universitá Cattolica del Sacro Cuore, Rome, Italy.;Dipartimento di Geriatria, Fondazione Policlinico Universitario A. Gemelli IRCCS, Universitá Cattolica del Sacro Cuore, Rome, Italy.;Dipartimento di Geriatria, Fondazione Policlinico Universitario A. Gemelli IRCCS, Universitá Cattolica del Sacro Cuore, Rome, Italy.;Dipartimento Scienze di Laboratorio e Infettivologiche, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy; Istituto di Microbiologia, Universitá Cattolica del Sacro Cuore, Rome, Italy.;Dipartimento Scienze di Laboratorio e Infettivologiche, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy; Istituto di Microbiologia, Universitá Cattolica del Sacro Cuore, Rome, Italy.;Dipartimento Scienze di Laboratorio e Infettivologiche, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy; Istituto di Microbiologia, Universitá Cattolica del Sacro Cuore, Rome, Italy.;Dipartimento Scienze di Laboratorio e Infettivologiche, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy; Istituto di Clinica delle Malattie Infettive, Universitá Cattolica del Sacro Cuore, Rome, Italy.",
"authors": "Acampora|Nicola|N|;Frizza|Alessandro|A|;Brau|Fabrizio|F|;Torelli|Riccardo|R|;Vella|Antonietta|A|;De Carolis|Elena|E|;Fantoni|Massimo|M|",
"chemical_list": null,
"country": "Italy",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1124-9390",
"issue": "27(1)",
"journal": "Le infezioni in medicina",
"keywords": null,
"medline_ta": "Infez Med",
"mesh_terms": "D000369:Aged, 80 and over; D016330:Frail Elderly; D006417:Hematuria; D006801:Humans; D000072742:Invasive Fungal Infections; D008297:Male; D009181:Mycoses; D014250:Trichosporon; D060586:Trichosporonosis; D014552:Urinary Tract Infections",
"nlm_unique_id": "9613961",
"other_id": null,
"pages": "93-96",
"pmc": null,
"pmid": "30882386",
"pubdate": "2019-03-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A case of Trichosporon asahii urinary tract infection in a frail elderly patient.",
"title_normalized": "a case of trichosporon asahii urinary tract infection in a frail elderly patient"
} | [
{
"companynumb": "IT-HIKMA PHARMACEUTICALS USA INC.-IT-H14001-19-46045",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "AMPICILLIN"
},
"dr... |
{
"abstract": "Hypertriglyceridemia (HTG) is an uncommon but well-established etiology of acute pancreatitis (AP) leading to significant morbidity and mortality. Hormone replacement therapy in the transgender population is an underrecognized cause of elevated triglyceride (TG) levels and may put this group at a higher risk for severe pancreatitis. We present a case of AP in a genetically male patient receiving hormone therapy for female gender transformation.A 51-year-old with a past medical history of type 2 diabetes mellitus presented with severe epigastric abdominal pain associated with nonbilious, nonbloody vomiting and anorexia for two days. The patient was diagnosed with hypertriglyceridemia-induced acute pancreatitis (HTG-AP) in the setting of elevated lipase levels of 2,083 u/L and TGs of >5,000 mg/dL. In addition, a computerized tomography scan of the abdomen showed pancreatitis without evidence of necrosis. The patient was admitted to the medical intensive care unit for the management of AP in the setting of elevated TG levels. She was treated with intravenous fluids and an insulin drip. Her home medications including estradiol and Aldactone were held. Once the TG levels were reduced to <500 mg/dL, she was taken off the Insulin drip and transitioned to a subcutaneous insulin regimen along with gemfibrozil and omega-3 fatty acid over the next three days, and then discharged to home. HTG accounts for only about 7% of pancreatitis cases and increases in severity as TG levels increase. The clinical presentation of patients suffering from HTG-AP is similar to patients with AP from other etiologies and presents in a relatively younger population compared to AP from other causes. Treatment options for HTG-AP usually utilize insulin and heparin; however, plasma exchange and venovenous filtration may be used for severe cases of HTG-AP. The goal of treatment is to lower the TG levels. Physicians should be aware of such complications and should counsel patients while utilizing hormone replacement therapy, especially in patients with a prior family history of dyslipidemia.",
"affiliations": "Internal Medicine, St. Joseph's Regional Medical Center, Paterson, USA.;Pulmonary and Critical Care Medicine, St. Joseph's Regional Medical Center, Paterson, USA.;Internal Medicine, St. Joseph's Regional Medical Center, Paterson, USA.;Internal Medicine, St. Joseph's Regional Medical Center, Paterson, USA.;Pulmonary and Critical Care Medicine, St. Joseph's Regional Medical Center, Paterson, USA.",
"authors": "Chaudhry|Arslan|A|;Yelisetti|Rishitha|R|;Millet|Christopher|C|;Biggiani|Christopher|C|;Upadhyay|Shivanck|S|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.7759/cureus.16140",
"fulltext": "\n==== Front\nCureus\nCureus\n2168-8184\nCureus\n2168-8184\nCureus Palo Alto (CA)\n\n10.7759/cureus.16140\nEndocrinology/Diabetes/Metabolism\nInternal Medicine\nGastroenterology\nAcute Pancreatitis in the Transgender Population\nMuacevic Alexander\nAdler John R\nChaudhry Arslan 1\nYelisetti Rishitha 2\nMillet Christopher 1\nBiggiani Christopher 1\nUpadhyay Shivanck 2\n1 Internal Medicine, St. Joseph’s Regional Medical Center, Paterson, USA\n2 Pulmonary and Critical Care Medicine, St. Joseph’s Regional Medical Center, Paterson, USA\nArslan Chaudhry r_chaudhrya@sjhmc.org\n3 7 2021\n7 2021\n13 7 e161403 7 2021\nCopyright © 2021, Chaudhry et al.\n2021\nChaudhry et al.\nhttps://creativecommons.org/licenses/by/3.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.\nThis article is available from https://www.cureus.com/articles/63707-acute-pancreatitis-in-the-transgender-population\nHypertriglyceridemia (HTG) is an uncommon but well-established etiology of acute pancreatitis (AP) leading to significant morbidity and mortality. Hormone replacement therapy in the transgender population is an underrecognized cause of elevated triglyceride (TG) levels and may put this group at a higher risk for severe pancreatitis. We present a case of AP in a genetically male patient receiving hormone therapy for female gender transformation.A 51-year-old with a past medical history of type 2 diabetes mellitus presented with severe epigastric abdominal pain associated with nonbilious, nonbloody vomiting and anorexia for two days. The patient was diagnosed with hypertriglyceridemia-induced acute pancreatitis (HTG-AP) in the setting of elevated lipase levels of 2,083 u/L and TGs of >5,000 mg/dL. In addition, a computerized tomography scan of the abdomen showed pancreatitis without evidence of necrosis. The patient was admitted to the medical intensive care unit for the management of AP in the setting of elevated TG levels. She was treated with intravenous fluids and an insulin drip. Her home medications including estradiol and Aldactone were held. Once the TG levels were reduced to <500 mg/dL, she was taken off the Insulin drip and transitioned to a subcutaneous insulin regimen along with gemfibrozil and omega-3 fatty acid over the next three days, and then discharged to home. HTG accounts for only about 7% of pancreatitis cases and increases in severity as TG levels increase. The clinical presentation of patients suffering from HTG-AP is similar to patients with AP from other etiologies and presents in a relatively younger population compared to AP from other causes. Treatment options for HTG-AP usually utilize insulin and heparin; however, plasma exchange and venovenous filtration may be used for severe cases of HTG-AP. The goal of treatment is to lower the TG levels. Physicians should be aware of such complications and should counsel patients while utilizing hormone replacement therapy, especially in patients with a prior family history of dyslipidemia.\n\ntransgender\ndiabetes mellitus type 2\nhormone replacement therapy\nacute pancreatitis\nhypertriglyceridemia-induced pancreatitis\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\nHypertriglyceridemia (HTG) is an uncommon but well-established etiology of acute pancreatitis (AP) leading to significant morbidity and mortality. The risk and severity of AP are suspected to increase with increasing levels of serum triglyceride (TG) levels [1]. It is crucial to identify HTG as the cause of pancreatitis and initiate an appropriate treatment plan. Hormone replacements in the transgender population are underrecognized as a cause of elevated TG levels and places this group at a higher risk for severe pancreatitis. Physicians should be aware of such complications and counsel patients while prescribing hormone replacements, especially in patients with a family history of dyslipidemia. Treatment of HTG depends on the severity of symptoms and the levels, with associated mortality. It may need aggressive interventions like plasma exchange (PLEX), especially in patients with severe pancreatitis, and resultant high mortality in these cases [1].\n\nCase presentation\n\nA 51-year-old genetic male (preferred to be addressed as she) with a past medical history of type 2 diabetes mellitus presented to the hospital with complaints of severe epigastric abdominal pain for two days. The pain was described as sudden in onset, sharp, and severe in the epigastric region. The patient rated her pain as severe in intensity, occasionally radiating to her back, and worsening in intensity while laying flat. She was unaware of any aggravating or alleviating factors. The pain was associated with episodes of nonbilious, nonbloody vomiting, and anorexia. She stated that she had a similar episode of pain about four weeks prior to the presentation which resolved within a few hours, thus the patient did not seek medical attention at that time. Home medications included Glipizide 5 mg PO QD, metformin 1,000 mg PO BID, estradiol 2 mg PO BID, and Aldactone 10 mg PO BID. At the time of presentation, her blood pressure was 145/100 mmHg, heart rate 86 beats per minute, respiratory rate 18 breaths per minute, and temperature 36.1°C. Her body mass index was 29.8 kg/m2. The patient was saturating 98% on room air. Pertinent positive findings on examination included significant epigastric tenderness and guarding without distension or rebound tenderness. Laboratory tests were significant for an elevated white blood cell count and an elevated lipase of 2,083 u/L. In addition, her TG was >5,000 mg/dL, HbA1c was 15.4%, and serum acetone was negative. Protein, albumin, alanine aminotransferase, aspartate aminotransferase, and alcohol levels were within the normal range. Furthermore, her Apache 2 score was 10 (7% estimated postoperative and 15% nonoperative mortality), Ranson score was 2 (1% predicted mortality), and neutrophil-to-lymphocyte ratio was 3.2 (a higher ratio indicating more severe pancreatitis). Table 1 lists the laboratory findings of the patient. Figure 1 shows the electrocardiogram findings of the patient which showed sinus tachycardia with no acute ST or T wave changes.\n\nTable 1 Laboratory findings.\n\nLab parameters\tPatient values\tNormal range\t\nSodium (mEq/L)\t122\t135-145\t\nPotassium (mEq/L)\t4.8\t3.5-5.0\t\nChloride (mEq/L)\t90\t98-107\t\nBicarbonate (mEq/L)\t17\t21-31\t\nGlucose (mg/dL)\t308\t70-110\t\nCalcium (mg/dL)\t8.6\t8.6-10.3\t\nPhosphorus (mEq/L)\t<1.0\t2.5-5.0\t\nMagnesium (mEq/L)\t2.0\t1.7-2.5\t\nBlood urine nitrogen (mg/dL)\t12\t7-23\t\nSerum creatinine (mg/dL)\t0.9\t0.6-1.3\t\nBilirubin total (mg/dL)\t0.4\t0.3-1.1\t\nProtein total (g/dL)\t6.3\t6.4-8.4\t\nAlbumin (g/dL)\t3.7\t3.5-5.7\t\nAlkaline phosphatase (U/L)\t77\t34-104\t\nAspartate aminotransferase (U/L)\t25\t13-39\t\nAlanine aminotransferase (U/L)\t7\t7-52\t\nTotal cholesterol (mg/dL)\t636\t<199\t\nTriglycerides (mg/dL)\t>5,000\t<149\t\nHemoglobin A1C (%)\t15.4\t4-6\t\nLipase (U/L)\t2083\t11-82\t\nC-reactive protein (mg/L)\t81.8\t≤9.9\t\nLactic acid (mmol/L)\t1.2\t0.5-2.2\t\nWhite blood cell count (×103/mm3)\t11.7\t4.5-11.0\t\nHemoglobin (g/dL)\t13.4\t13.5-17.5\t\nHematocrit (%)\t35.9\t41.0-53.0\t\nMean corpuscular volume (fL)\t86.9\t80-100\t\nPlatelet (K/mm3)\t428\t140-440\t\n\nFigure 1 Electrocardiogram showing sinus tachycardia without any acute ST or T wave changes.\n\nLimited ultrasound of the right upper abdomen was performed which showed fatty liver, adenomyomatosis in the gallbladder, and prominent pancreas. A computerized tomography scan of the abdomen revealed pancreatitis without any evidence of necrosis (Figure 2).\n\nFigure 2 Computerized tomography scan of the abdomen showing pancreatitis without evidence of necrosis.\n\nThe patient was admitted to the medical intensive care unit (ICU) for management of AP in the setting of elevated TGs. She was started on intravenous fluids and an insulin drip at a rate range of 0.1- 0.3 units/kg. She was allowed oral intake as tolerated. Her home medications including hormone replacement therapy medications, and estradiol and Aldactone were held. Once the TG levels were <500, she was taken off the insulin drip and transitioned to a subcutaneous insulin regimen over the next three days. Gemfibrozil and omega-3 fatty acid capsules were also added to the regimen. Her ICU course was complicated by the development of bilateral pleural effusions that responded to diuresis (Figure 3).\n\nFigure 3 Chest X-ray showing bilateral infiltrates with blunting of the costophrenic angles.\n\nShe was transferred to the general medical floor and was eventually discharged home and advised to take atorvastatin 40 mg daily, gemfibrozil 600 mg PO BID, and omega 3 fatty acid capsules. She is scheduled to follow up with an endocrinologist and primary care provider for further outpatient management.\n\nDiscussion\n\nGallstones and alcohol abuse are the two most common causes of AP, with HTG responsible for only about 7% of the cases. The severity of pancreatitis increases as TG levels increase. Although the exact mechanism of hypertriglyceridemia-induced acute pancreatitis (HTG-AP) is poorly understood, it is thought to be related to high levels of free fatty acids (FFA). HTG with serum TG levels of ≥500 mg/dL (≥5.65 mmol/L) increases the risk of AP [2]. HTG is categorized into primary and secondary HTG based on the etiology. Primary HTG is induced by genetic or environmental factors. Secondary HTG can be due to uncontrolled diabetes mellitus, obesity, pregnancy, and medications, etc. Here, we focus on estrogen and hormone replacement therapies as the etiology of HTG and pancreatitis. Estrogen decreases the levels of hepatic lipase and, in turn, increases the levels of TG. The regulation of lipoprotein lipase (LPL) expressed in pancreatic islet cells is altered by estrogen as well. Estrogen promotes the synthesis of TG by the liver. In addition, estrogen is proposed to have direct toxic effects on the pancreatic cells suggested by the pancreatic amylase release in rats stimulated by estrogen [3]. The acinar cells of the exocrine pancreas produce lipase. Lipase breaks down TG to produce FFA and glycerol. With high levels of FFA, they aggregate into micelles. These micelles cause ischemia in the pancreas, trigger acidosis, which in turn activates lysosomal cathepsin-B and trypsinogen to form trypsin. FFA also has direct cytotoxic effects on the acinar and vascular endothelial cells causing endothelial dysregulation, vascular leakage, and coagulation cascade activation. HTG-induced microcirculatory disturbance leads to the release of thromboxane A2/PGI2 resulting in excessive contraction of the capillary bed and aggravation of the microcirculatory disturbance. HTG decreases the production of antioxidant products like superoxide dismutase and glutathione peroxidase. The imbalance of oxidative and antioxidative species initiates an inflammatory response and aggravates the pancreatic injury. The effect of estrogen on TG depends on the route of administration. Oral estrogens may raise the TG levels but transdermal forms have a null effect or a minimal impact on the levels. Topical estrogens used vaginally for postmenopausal women had minimal systemic absorption. The levels of estrogen in postmenopausal women using vaginal estrogens remained at postmenopausal levels, and thus had no effect on TG levels [4]. The clinical presentation of patients suffering from HTG-AP is similar to patients with AP from other etiologies. HTG-AP presents in a relatively younger population compared to AP from other causes. There is inconsistent data on the relationship between the level of TG and the severity of pancreatitis [1]. In a study of 121 patients evaluating the natural course of HTG-AP, local complications were higher in patients with TG ≥1,000 mg/dL, and chronic pancreatitis was reported in 17.8% of patients. Moreover, when compared with AP from other causes, the need for ICU admission (39% versus 16%; P ≤ 0.001), systemic inflammatory response syndrome (56% versus 28%; P ≤ 0.03), and persistent organ failure (23% versus 11%; P ≤ 0.05) were significantly higher in the HTG-AP cohort [5]. In a study of 144 patients with HTG-AP conducted between 1999 and 2013, higher TG levels were associated with worse outcomes. A receiver operating characteristic curve showed that a cut-off of TG level of 2,648 mg/dL was predictive of worse outcomes. The moderately severe and severe forms of HTG-AP were found in 50% of the patients in the low-TG group and 74.36% of the patients in the high-TG group (P = 0.004). Hospital length of stay, ICU length of stay, mortality, and recurrence rates at one year, which were the secondary endpoints in this study, were noted to be higher in the high-TG group, but this did not reach statistical significance [6]. When suspecting HTG-AP, amylase levels at the time of presentation can be normal due to colorimetric interference of lipemic serum. A repeat test should be performed after diluting serum. In addition, TG levels should be measured early at the time of presentation as the levels can reduce significantly with fasting.\n\nTreatment\n\nThe cornerstone of the management of AP of any etiology is early recognition, aggressive hydration, pain management, and early enteral feeding. Scoring systems like Apache should be used for assessing the severity of pancreatitis. Severe pancreatitis should be managed in the ICU. Treatment of HTG-AP should focus on lowering the TG levels.\n\nInsulin activates the LPL promoting the degradation of chylomicrons and lowering the TG levels. Insulin lowers the TG levels by 30-50%, which is often used in acute situations to rapidly lower the TG levels. Attention must be paid to potassium levels during such high doses of insulin infusion. Patients will likely need to be on dextrose infusion to allow insulin infusion without resultant hypoglycemia. Insulin infusion can be continued until the TG levels drop to less than 1,000 mg/dL. A meta-analysis of three studies with 118 patients concluded that insulin infusion has resulted in a statistically significant decrease in the length of hospitalization and Apache scores 72 hours after treatment [7].\n\nOn the other hand, heparin causes the release of LPL from endothelial cells. Concern for a rebound HTG with heparin infusion makes it less favorable for use in the treatment of HTG. With higher TG levels, aggressive and invasive interventions like PLEX and venovenous filtration are chosen. PLEX can rapidly lower the TG and inflammatory cytokine levels, thus downregulating the inflammatory process. One session lowers the TG levels by 50-80%. PLEX is effective but can be associated with adverse reactions. According to the World Apheresis Registry Report, the risk associated with PLEX is low at about 5.7%. PLEX also needs a central venous access which carries pertinent risks [1]. There is no high-quality data available, but typically PLEX is suggested as early as possible for patients with severe HTG-AP. The American Society for Apheresis considers HTG-AP as a Grade 2C recommendation for PLEX [1].\n\nOnce the patient can tolerate diet and the TG levels are below 1,000 mg/dL, medical therapy is initiated. Medical management is not effective at TG levels above 1,000 mg/dL as the drugs work primarily by reducing the synthesis and secretion by the liver. Treatment is usually with fenofibrates which lower the TG levels by 70%. Statins can be added to the treatment regimen. Statins typically lower the TG levels by 5-15% [8]. Weight loss, aerobic exercise, and avoidance of high glycemic index foods are suggested. Alcohol consumption should be avoided in patients with severe HTG. Omega-3 fatty acids have been shown to reduce the TG levels by up to 50% [9].\n\nConclusions\n\nHTG is associated with severe pancreatitis. Identification of HTG is an essential step in the treatment of AP. Drug-induced HTG is an important category, and hormone replacement therapy is an uncommon but important etiology, especially in the transgender population. Our case depicts the possibility of such a scenario occurring in the transgender population. Exacerbation of HTG, often with AP, and failure of TG-lowering treatment can result when women with overt or covert familial HTG are given hormone therapy. It shows the need for consideration of risk before starting estrogen therapy, especially with family history screening and consideration of monitoring TG in patients who have a first-degree relative with a history of HTG, diabetes mellitus, or AP.\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 Management of hypertriglyceridemia induced acute pancreatitis Biomed Res Int Garg R Rustagi T 4721357 2018 2018 30148167\n2 The clinical relevance of omega-3 fatty acids in the management of hypertriglyceridemia Lipids Health Dis Backes J Anzalone D Hilleman D Catini J 118 15 2016 27444154\n3 Estrogens influence cholecystokinin stimulated pancreatic amylase release and acinar cell membrane cholecystokinin receptors in rat Life Sci Blevins GT Jr Huang HS Tangoku A Mckay DW Rayford PL 1565 1574 48 1991 1708070\n4 Serum lipid profile improved by ultra-low doses of 17 beta-estradiol in elderly women J Clin Endocrinol Metab Naessen T Rodriguez-Macias K Lithell H 2757 2762 86 2001 11397883\n5 Clinical Profile and Natural Course in a Large Cohort of Patients With Hypertriglyceridemia and Pancreatitis J Clin Gastroenterol Vipperla K Somerville C Furlan A 77 85 51 2017 27322530\n6 Relationship between plasma triglyceride level and severity of hypertriglyceridemic pancreatitis PLoS One Wang SH Chou YC Shangkuan WC Wei KY Pan YH Lin HC 0 11 2016\n7 Intensive insulin therapy in severe acute pancreatitis: a meta-analysis and systematic review West Indian Med J Li J Chen TR Gong HL Wan MH Chen GY Tang WF 574 579 61 2012 https://pubmed.ncbi.nlm.nih.gov/23441350/ 23441350\n8 Triglyceride-rich lipoproteins and high-density lipoprotein cholesterol in patients at high risk of cardiovascular disease: evidence and guidance for management Eur Heart J Chapman MJ Ginsberg HN Amarenco P 1345 1361 32 2011 21531743\n9 Omega-3 fatty acids for the management of hypertriglyceridemia: a science advisory from the American Heart Association Circulation Skulas-Ray AC Wilson PWF Harris WS 0 91 140 2019\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2168-8184",
"issue": "13(7)",
"journal": "Cureus",
"keywords": "acute pancreatitis; diabetes mellitus type 2; hormone replacement therapy; hypertriglyceridemia-induced pancreatitis; transgender",
"medline_ta": "Cureus",
"mesh_terms": null,
"nlm_unique_id": "101596737",
"other_id": null,
"pages": "e16140",
"pmc": null,
"pmid": "34277301",
"pubdate": "2021-07",
"publication_types": "D002363:Case Reports",
"references": "27444154;30148167;21531743;27322530;27727299;1708070;23441350;11397883;31422671",
"title": "Acute Pancreatitis in the Transgender Population.",
"title_normalized": "acute pancreatitis in the transgender population"
} | [
{
"companynumb": "US-ALVOGEN-2021-ALVOGEN-117274",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "METFORMIN HYDROCHLORIDE"
},
"drugadditi... |
{
"abstract": "Thromboembolic events (TEEs) are frequent in cancer patients, especially venous thrombosis. Arterial thrombosis is less frequent. Chemotherapy increases the risk of these TEEs. Although TEEs are often reported, intestinal ischemia is a rare complication in cancer patients treated with chemotherapy. Here we describe a rare case of a patient with small cell lung cancer, who developed intestinal ischemia during treatment with cisplatin-etoposide chemotherapy. Shock and multiple organ failure developed and an urgent laparotomy with total colectomy was necessary. This case and review of the literature show that overall arterial TEEs are not as infrequent and may rarely manifest as intestinal ischemia. A cardiovascular assessment before the start of anticancer therapy is therefore imperative for cancer patients.",
"affiliations": "Department of Pulmonology, Respiratory Oncology Unit, University Hospitals Leuven, UZ Leuven, Herestraat 49, 3000 Leuven, Belgium.;Department of Pulmonology, Respiratory Oncology Unit, University Hospitals Leuven, UZ Leuven, Herestraat 49, 3000 Leuven, Belgium.",
"authors": "Legius|Barbara|B|;Nackaerts|Kristiaan|K|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.2217/lmt-2017-0016",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1758-1966",
"issue": "6(3)",
"journal": "Lung cancer management",
"keywords": "abdominal pain; arterial thromboembolic events; cardiovascular risk assessment; cisplatin; intestinal ischemia; lung cancer",
"medline_ta": "Lung Cancer Manag",
"mesh_terms": null,
"nlm_unique_id": "101588392",
"other_id": null,
"pages": "87-91",
"pmc": null,
"pmid": "30643574",
"pubdate": "2017-12",
"publication_types": "D002363:Case Reports",
"references": "15666321;17291625;17319909;22199322;22547369;22997448;23093559;24390476;24862143;25129368;25495242;25672586;26756277;27022039;27717837;27732808;27755238;28917273",
"title": "Severe intestinal ischemia during chemotherapy for small cell lung cancer.",
"title_normalized": "severe intestinal ischemia during chemotherapy for small cell lung cancer"
} | [
{
"companynumb": "BE-TEVA-2018-BE-849789",
"fulfillexpeditecriteria": "1",
"occurcountry": "BE",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ETOPOSIDE"
},
"drugadditional": null,
... |
{
"abstract": "Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) can rarely cause alternate-sided homonymous hemianopia due to stroke-like episodes involving the occipital lobes, as reported in three previously published cases. The authors report an interesting case of a 16-year-old presenting with myoclonic epilepsy due to MELAS with the rare ND3 mitochondrial mutation T10191C, with recurrent alternate-sided homonymous hemianopia. Visual field and corresponding magnetic resonance imaging (MRI) findings are presented. To the authors' knowledge, this is the first report of recurrent alternate-sided homonymous hemianopia in MELAS with documented visual field and MRI findings with resolution between each episode.",
"affiliations": "Division of Neurology, University of Toronto , Toronto, Ontario, Canada.;Division of Neurology, University of Toronto, Toronto, Ontario, Canada; Department of Ophthalmology and Visual Sciences, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada.",
"authors": "Krysko|Kristen M|KM|;Sundaram|Arun N E|AN|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1080/01658107.2016.1224256",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0165-8107",
"issue": "41(1)",
"journal": "Neuro-ophthalmology (Aeolus Press)",
"keywords": "Case report; MELAS; mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes; recurrent alternate-sided homonymous hemianopia",
"medline_ta": "Neuroophthalmology",
"mesh_terms": null,
"nlm_unique_id": "8408966",
"other_id": null,
"pages": "30-34",
"pmc": null,
"pmid": "28228835",
"pubdate": "2017-02",
"publication_types": "D002363:Case Reports",
"references": "21443929;11456298;21045518;21850008;8517676;17204916;12790225;1422200;26095523",
"title": "Recurrent Alternate-Sided Homonymous Hemianopia Due to Mitochondrial Encephalomyopathy with Lactic Acidosis and Stroke-Like Episodes (MELAS): A Case Report.",
"title_normalized": "recurrent alternate sided homonymous hemianopia due to mitochondrial encephalomyopathy with lactic acidosis and stroke like episodes melas a case report"
} | [
{
"companynumb": "CA-UCBSA-2017007389",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VITAMIN A"
},
"drugadditional": "3",
"dru... |
{
"abstract": "Fragile X mental retardation 1 (FMR1) premutation associated phenotypes have been explored extensively since the molecular mechanism emerged involving elevated FMR1 messenger ribonucleic acid (mRNA) levels. Lowered fragile X mental retardation protein (FMRP) can also occur which may have an additive effect to the high levels of mRNA leading to neurodevelopmental problems and psychopathology. This paper was aimed to review psychosis and catatonia in premutation carriers, express the role of elevated FMR1 mRNA and lowered FMRP in the phenotype of carriers and present a case of psychosis and catatonia in a carrier. This case also demonstrates additional genetic and environmental factors which may also affect the phenotype. We review the literature and report an exemplary case of a 25 year old male premutation carrier with elevated FMR1 mRNA, low FMRP, a cytochrome P450 family 2 subfamily D polypeptide 6 (CYP2D6)*2xN mutation and a perinatal insult. This patient developed an autism spectrum disorder, psychosis, catatonia with subsequent cognitive decline after electro-convulsive therapy (ECT) for his catatonia. He had a premutation of 72 CGG repeat in FMR1, FMR1 mRNA level that was over 2.4 times normal and FMRP level at 18% of normal, and additionally, a CYP2D6 allelic variant which leads to ultrarapid metabolism (UM) of medication. There is an overlapping pathophysiological mechanism of catatonia and fragile X-associated premutation phenotypes including autism and psychosis. This case demonstrates the shared phenotype and the overlap of the pathophysiological mechanisms that can influence the intervention. Multiple genetic and environmental hits can lead to more significant involvement in premutation carriers.",
"affiliations": "MIND Institute, University of California Davis, Medical Center, Sacramento, USA; ; Center for Biomedical Research (CEBIOR), Faculty of Medicine Diponegoro University, Semarang, Indonesia;;MIND Institute, University of California Davis, Medical Center, Sacramento, USA; ; Department of Pediatrics, University of California Davis, Medical Center, Sacramento, USA;;University of Michigan Hospitals and Health Center, Ann Arbor, USA;;Department of Psychiatry and Behavioral Sciences, University of California Davis, Medical Center, Sacramento, USA.;MIND Institute, University of California Davis, Medical Center, Sacramento, USA; ; Department of Pediatrics, University of California Davis, Medical Center, Sacramento, USA;",
"authors": "Winarni|Tri Indah|TI|;Schneider|Andrea|A|;Ghaziuddin|Neera|N|;Seritan|Andreea|A|;Hagerman|Randi J|RJ|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": "10.5582/irdr.2015.01028",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2186-3644",
"issue": "4(3)",
"journal": "Intractable & rare diseases research",
"keywords": "Catatonia; fragile X syndrome; premutation; psychosis",
"medline_ta": "Intractable Rare Dis Res",
"mesh_terms": null,
"nlm_unique_id": "101586847",
"other_id": null,
"pages": "139-46",
"pmc": null,
"pmid": "26361565",
"pubdate": "2015-08",
"publication_types": "D002363:Case Reports",
"references": "16685180;24903624;24504828;8448271;14994286;16184602;16697303;23333116;21783174;17328957;8764380;23684045;10748416;23259642;9241658;10208163;25170347;23867198;3337608;11376146;23930232;23793382;17427188;14618296;20816038;21785977;12032354;22040029;15330685;24167470;16219124;12581522;25097672;16700053;19969591;21099377;12515381;17590448;22001913;8686484;21901840;21934270;16246103;10827884;10631132;22285772;23831253;12958742;21116185;20457613;9214604;12476071;12638084;12898586;20585378;10698827;17283214;21108954;20466021;19846466;11448936;11449487;24591415;23566911;11157796;21478165;16175016;12135967;15219735;25790165;22573456;19422761",
"title": "Psychosis and catatonia in fragile X: Case report and literature review.",
"title_normalized": "psychosis and catatonia in fragile x case report and literature review"
} | [
{
"companynumb": "US-ROXANE LABORATORIES, INC.-2016-RO-00613RO",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LITHIUM CARBONATE"
},
"dru... |
{
"abstract": "Malignancy after transplantation is an uncommon multifactorial occurrence. Immunosuppression to prevent graft rejection is described as a major risk factor in malignancy development in the post-transplant state. Donor-derived malignancy is a rare reported complication. Herein, we review our patient history and discuss diagnostic strategies and the implications of immunosuppression for donor-derived malignancy.\n\n\n\nThis is a 69-year-old man with post-renal-transplant urothelial carcinoma determined to be of donor origin. His course was complicated by BK virus at six years post-transplant; urothelial carcinoma was identified nine years post-transplant. Cystectomy was performed, but because of immunosuppression and underlying chronic kidney disease, the patient was considered ineligible for adjuvant chemotherapy. Two years after resection, screening MRI demonstrated retroperitoneal lymphadenopathy and a right upper pole mass in the transplanted kidney. Urine cytology confirmed the presence of malignant cells; FISH showed 2-8 copies of the X chromosome and no Y chromosome consistent with female origin of the malignant cells. CT-guided renal mass and paraaortic lymph node biopsies demonstrated that about 50 % of cells had an XY complement, while the remainder showed a XX genotype by chromosomal SNP microarray analysis. Immunosuppression was discontinued and the donor kidney removed. X/Y FISH of the urothelial carcinoma identified in the explanted kidney confirmed that the malignant cells were of female donor origin. Follow-up at 3, 6 and 12 months after discontinuation of immunosuppression and surgery demonstrated normalization of the lymphadenopathy and absence of new lesions.\n\n\n\nImmunosuppression is a major risk factor for development of malignancy in transplant recipients. Donor-derived malignancy can arise and current molecular studies allow an accurate diagnosis. Withdrawal of immunosuppression and surgical resection of the transplant kidney proved an effective treatment in our case.",
"affiliations": "Division of Hematology and Oncology, Medical University of South Carolina, 173 Ashley Ave, Suite 102 BSB, Charleston, SC 29425 USA.;Department of Pathology & Laboratory Medicine, Medical University of South Carolina, Charleston, SC USA.;Department of Pathology & Laboratory Medicine, Medical University of South Carolina, Charleston, SC USA.;Division of Hematology and Oncology, Medical University of South Carolina, 173 Ashley Ave, Suite 102 BSB, Charleston, SC 29425 USA.",
"authors": "Michel Ortega|Rosa M|RM|;Wolff|Daynna J|DJ|;Schandl|Cynthia A|CA|;Drabkin|Harry A|HA|",
"chemical_list": "D007166:Immunosuppressive Agents",
"country": "England",
"delete": false,
"doi": "10.1186/s40425-016-0167-4",
"fulltext": "\n==== Front\nJ Immunother CancerJ Immunother CancerJournal for Immunotherapy of Cancer2051-1426BioMed Central London 16710.1186/s40425-016-0167-4Case ReportUrothelial carcinoma of donor origin in a kidney transplant patient Michel Ortega Rosa M. mayela.michel@gmail.com 1Wolff Daynna J. wolffd@musc.edu 2Schandl Cynthia A. schandlc@musc.edu 2Drabkin Harry A. (843) 792-4879drabkin@musc.edu 11 Division of Hematology and Oncology, Medical University of South Carolina, 173 Ashley Ave, Suite 102 BSB, Charleston, SC 29425 USA 2 Department of Pathology & Laboratory Medicine, Medical University of South Carolina, Charleston, SC USA 18 10 2016 18 10 2016 2016 4 6314 6 2016 14 9 2016 © The Author(s). 2016\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nMalignancy after transplantation is an uncommon multifactorial occurrence. Immunosuppression to prevent graft rejection is described as a major risk factor in malignancy development in the post-transplant state. Donor-derived malignancy is a rare reported complication. Herein, we review our patient history and discuss diagnostic strategies and the implications of immunosuppression for donor-derived malignancy.\n\nCase presentation\nThis is a 69-year-old man with post-renal-transplant urothelial carcinoma determined to be of donor origin. His course was complicated by BK virus at six years post-transplant; urothelial carcinoma was identified nine years post-transplant. Cystectomy was performed, but because of immunosuppression and underlying chronic kidney disease, the patient was considered ineligible for adjuvant chemotherapy. Two years after resection, screening MRI demonstrated retroperitoneal lymphadenopathy and a right upper pole mass in the transplanted kidney. Urine cytology confirmed the presence of malignant cells; FISH showed 2-8 copies of the X chromosome and no Y chromosome consistent with female origin of the malignant cells. CT-guided renal mass and paraaortic lymph node biopsies demonstrated that about 50 % of cells had an XY complement, while the remainder showed a XX genotype by chromosomal SNP microarray analysis. Immunosuppression was discontinued and the donor kidney removed. X/Y FISH of the urothelial carcinoma identified in the explanted kidney confirmed that the malignant cells were of female donor origin. Follow-up at 3, 6 and 12 months after discontinuation of immunosuppression and surgery demonstrated normalization of the lymphadenopathy and absence of new lesions.\n\nConclusions\nImmunosuppression is a major risk factor for development of malignancy in transplant recipients. Donor-derived malignancy can arise and current molecular studies allow an accurate diagnosis. Withdrawal of immunosuppression and surgical resection of the transplant kidney proved an effective treatment in our case. \n\nKeywords\nPost-transplant malignancyImmunosuppressionSolid organ transplantationUrothelial carcinomaissue-copyright-statement© The Author(s) 2016\n==== Body\nBackground\nAccording to the Organ Procurement and Transplantation Network (OPTN), there were 17,878 kidney transplants in 2015 in the United States with 5628 of them obtained from living-donors [1]. In order for the graft to survive in the host, the recipient’s immune response to alloantigens from the graft is modulated. Otherwise, rejection would cause tissue damage and graft organ failure. Immunosuppressive drugs have made such immunomodulation feasible with 1-year graft-survival rates of 80 to 90 % [2]. However, such treatment comes at the expense of increased incidence of infection and malignancy. The most common cancers in this scenario are non-melanoma skin cancer, non-Hodgkin lymphoma and lung, liver and kidney in recipients of those organs [3]. Development of malignancy is multifactorial in this context. Commonly cited etiologies for new malignancy include decreased immunosurveillance secondary to immunosuppressive drugs, infections with oncogenic viruses, and other host-specific risk factors such as age, comorbidities and smoking and alcohol use. The risk of donor-derived transmission of disease is generally considered negligible [4].\n\nImmunosuppression controls not only anti-graft but also anti-cancer immunity, and as such is most commonly implicated while the specific immunosuppression regimen is less important. A 2010 clinical trial of cadaveric kidney transplant recipients with a 20-year follow-up period randomly allocated patients to azathioprine and prednisolone, cyclosporine monotherapy, or cyclosporine monotherapy followed by azathioprine and prednisolone after the first 3 months of post-transplant. No specific immunosuppressive drug combination was more detrimental than another [5]. Instead, factors such as increasing age and smoking status were associated with increased risk of malignancy in a multivariate analysis. This study however, did not include patients exposed to newer calcineurin inhibitors, such as tacrolimus, the mammalian target of rapamycin (mTOR) inhibitor, sirolimus or the antiproliferative agent mycophenolate mofetil.\n\nWe report on a patient that was treated with decreased immunosuppression and surgical removal of transplant kidney for management of donor-derived high-grade urothelial carcinoma.\n\nCase presentation\nA 69-year-old Caucasian male with a past medical history of hypertension and end-stage renal disease (ESRD) secondary to IgA nephropathy was managed with peritoneal dialysis (PD) for 1.5 years. His sister consented to provide a kidney and transplantation was performed in 2004. His post-transplant course was uncomplicated and immunosuppression was maintained with tacrolimus and sirolimus. In October 2010, he developed BK viremia and nephropathy, which was treated with leflunomide and a decrease in the tacrolimus dose. His course was further complicated by multiple cutaneous squamous carcinomas and a cutaneous basal cell carcinoma treated with Mohs surgery. In February 2013, he developed gross hematuria, which prompted further work-up. Masses identified by cystoscopy were sampled by transurethral resection and pathology showed high-grade invasive urothelial carcinoma of the bladder. In April 2013, he underwent radical cystectomy, prostatectomy and left pelvic lymphadenectomy (pT3pN0) with the discovery of an incidental adenocarcinoma of the prostate (Gleason 3 + 3 pT2c). Both native kidneys and ureters were removed and an ileal conduit created. He did not receive adjuvant chemotherapy because of the immunosuppression (prednisone, tacrolimus and sirolimus, which was later switched to mycophenolate mofetil) and chronic kidney disease.\n\nHe was followed with active surveillance and imaging every 6 months. In March 2015, MRI demonstrated extensive retroperitoneal abdominal and pelvic adenopathy and a mass in the right upper pole of the transplant kidney while the patient was completely asymptomatic and kidney function unchanged. Urine cytology was positive for malignant cells that were shown to be of female origin by fluorescence in situ hybridization (FISH) with 2–8 copies of the X chromosome and no copy of the Y chromosome (Fig. 1). CT-guided biopsies of the kidney mass and a lymph node were positive for urothelial cancer. SNP microarray-based chromosome analysis of the lymph node using the I Scan® System with Infinium® OExPls CytoConsortium Array BeadChip (Illumina, Inc, San Diego, CA) demonstrated about 50 % of cells had an XY complement, while the remainder showed a XX genotype. Additional chromosomal aberrations included amplification of regions of 1q, 6p, and 10p and loss of 8p, findings that are consistent with the diagnosis of urothelial cancer. However, the origin of the cancer by single nucleotide polymorphism (SNP) analysis could not be assigned due to equal percentage of the genotypes determined by equal sex chromosome distribution as mentioned above. Pathology and FISH were compared to his original high-grade urothelial carcinoma, which demonstrated aberrations common to urothelial cancer, but not identical to the more recent sample indicating a new clonal process.Fig. 1 FISH on the urine cytology sample with probes for the X chromosome centromere (red) and the Y chromosome heterochromatic region (green) (Abbott Molecular, Downers Grove, IL); large malignant urothelial carcinoma cell with four X chromosome signals and a normal male cells with one X and one Y chromosome signal\n\n\n\n\nIn June 2015, he underwent transplant nephrectomy, peritoneal dialysis catheter placement, excision of the ileal conduit and parastomal hernia repair. Pathology of the explant demonstrated a 4.6 × 4.4 × 4.1 cm, high grade urothelial carcinoma (pT3) with lymphovascular invasion in the background of severe chronic glomerulosclerosis. The malignant cells were CK7 positive, CD10 partially positive, and CD34 negative. FISH for the X and Y chromosomes performed on the urothelial carcinoma from the explanted transplant kidney confirmed that the malignant cells were of female donor origin (Fig. 2). All immunosuppression was discontinued and PD was resumed. Initial follow-up scans at 3 months demonstrated no new sites of metastasis and decrease in the size of retroperitoneal lymph nodes (LNs) with the index LN shrinking from 1.9 to 0.8 cm. Repeat scans after an additional 3 months also found no new sites of metastasis and further reduction of the index LN size to 0.7 cm. The most recent scans done 1 year after initial diagnosis continue to show no evidence of disease and stability of the index LN size at 0.7 cm. He has resumed all regular activities and has a completely normal ECOG (Eastern Cooperative Oncology Group) performance status (i.e., ECOG = 0).Fig. 2 FISH on the surgical specimen post resection with probes for X chromosome centromere (red) and the Y chromosome heterochromatic region (green) (Abbott Molecular, Downers Grove, IL) showing only X chromosome signals consistent with female donor origin of the urothelial cancer\n\n\n\n\nDiscussion\nIn the era where therapeutic reactivation of the immune system against cancer has gained significant momentum, this case points out how surgical removal of the primary donor-derived malignancy and tapering of immunosuppression to allow the body to mount a response proves to be effective therapy for at least 1 year follow-up. It is also the first documented case known to the authors to demonstrate donor-derived origin in post-transplant urothelial carcinoma by FISH.\n\nReduction of immunosuppression, the initial intervention provided to this patient, has been previously described in the management of aggressive squamous cell carcinomas [6] and aggressive undifferentiated epithelioid tumor [7] in kidney transplant recipients. Unlike these tumor types, renal cell and urinary tract carcinoma incidence did not vary significantly during the functional life of the transplant versus after transplant failure and subsequent decreased immunosuppression based on retrospective data from the Australia and New Zealand Dialysis and Transplant Registry [8].\n\nOur patient additionally underwent removal of the graft after prolonged discussion of preferred renal replacement therapy and risks and benefits of a surgical approach were addressed.\n\nHowever, decrease and/or modification of immunosuppression and, ultimately, removal of the primary malignancy, if arising in the transplanted organ, might not always be feasible as patients might be reluctant to return to dialysis.\n\nHe had a history of prior complications associated with an immunosuppressed state including BK viremia in 2010 and urothelial carcinoma that warranted surgical resection in 2013.\n\nThe oncogenic potential of BK virus remains controversial [9]. BK virus is considered to cause a subclinical primary infection, and then establishes a latent infection in the kidney and urinary tract, amongst other tissues. When it reactivates, it can cause hemorrhagic cystitis, ureteric stenosis and nephritis. It has also been associated with the development of bladder and kidney cancer, as its viral sequence and T antigen (TAg) has been detected in urothelial carcinoma cells [10]. TAg binds and inactivates p53 and pRb, resulting in aberrant cell cycle regulation [11, 12]. In contrast, Rollison et al. concluded that BK virus did not play a major role in the pathogenesis of bladder carcinoma, as only 5.5 % of the bladder cancer samples of 76 patients with urothelial carcinoma were BK positive by polymerase chain reaction (PCR) and none of them showed TAg expression. These cases were not specifically post-transplant, however, and immune state was not reported [13]. It is beyond our scope to postulate if the prior BK viremia had any impact on the development of donor-derived urothelial carcinoma in our patient. However, he did not have any other known risk factors [14] as he had only been a smoker for 2 years, less than half a pack per day- and had quit more than 40 years prior to the malignancy diagnosis.\n\nThe transmission frequency of malignancy by donors, deceased or living, is considered to be less than 1 % [4, 15]. Living donors are regularly screened and in “good health”, consequently diagnosis is frequently made only after donation. Of note, these cancers are considered donor-derived and not donor-transmitted, as the cancer was technically derived from the donor cells, but not clinically present at the time of transplant [16]. There have been at least two case reports of donor-derived urothelial carcinoma in kidney transplant recipients. Both received deceased donor kidneys, had malignancy and metastatic disease diagnosed within 1 year of transplantation, and management included paclitaxel-based chemotherapy. In the first patient, diagnosis of donor-derived malignancy was construed secondary to tempo of disease, lack of native urothelial involvement and inconclusiveness of histocompatibility testing of the tumor; this patient demonstrated no signs of disease over the 3 year follow-up period after halting immunosuppression, removal of the transplanted kidney and chemotherapy [17]. The second patient received the same treatments, but unfortunately passed away from parietal hemorrhage during chemotherapy; interestingly, the liver recipient from the same donor was also found to have disease, biopsy-proven malignant nodules, once the state organ procurement was advised of the neoplasm transmission, whereas the recipient of the other kidney did not [18]. In contrast, our patient developed donor-derived malignancy 11 years after transplantation from a living-related donor and had a sustained response 1 year after stopping immunosuppression and removal of the transplant with no chemotherapy with no current evidence of disease.\n\nOnce the clinical suspicion is present, assessment of molecular features of the tumor and/or the presence of XY or XX chromosomes discordant with the recipient’s sex, as in our case, enable the diagnosis. Male donor-derived cells in the basal layer and invasive areas of squamous cell carcinomas of three female kidney transplant recipients has been previously published [19]; however, to our knowledge; this is the first case of high grade urothelial carcinoma of donor-derived origin which is confirmed by FISH. No studies for the presence of BK virus were performed on the explant as management would not be affected.\n\nConclusions\nImmunosuppression is a major risk factor for development of malignancy in transplant recipients. Donor-derived malignancy can arise and current molecular studies allow an accurate diagnosis. Withdrawal of immunosuppression and surgical resection of the transplant kidney proved an effective treatment with ongoing surveillance and the caveat of return to PD for ESRD management. Continuous communication amongst treatment teams and the patient allowed a good outcome.\n\nAbbreviations\nCKDChronic kidney disease\n\nECOGEastern Cooperative Oncology Group\n\nESRDEnd stage renal disease\n\nFISHFluorescence in situ hybridization\n\nLNsLymph nodes\n\nmTORmammalian target of rapamycin\n\nOPTNOrgan Procurement and Transplantation Network\n\nPCRPolymerase chain reaction\n\nPDPeritoneal dialysis\n\nSNPSingle nucleotide polymorphism\n\nTAgT antigen\n\nNot applicable.\n\nFunding\nNot applicable.\n\nAvailability of data and materials\nNot applicable.\n\nAuthors’ contributions\nRMMO saw patient in clinic; wrote case and created first draft. HAD was involved in the conception of this case report, followed patient, helped with literature review and was critical in the development of the manuscript. DJW and CAS specifically reviewed the technical description and accuracy of cytogenetic studies of all samples, also reviewed the manuscript. All authors read and approved the final manuscript.\n\nAuthors’ information\nRMMO is a third year fellow in Hematology and Oncology in the Medical University of South Carolina.\n\nDJW is a Professor in the Department of Pathology & Laboratory Medicine, and Director of Cytogenetics and Molecular Genetics Laboratories in the Medical University of South Carolina.\n\nCAS is an Associate Professor in the Department of Pathology and Laboratory Medicine, and the Medical Director of Cytogenetics and Genomics Laboratories in the Medical University of South Carolina.\n\nHAD is Professor of Medicine & Gilbreth Chair in Clinical Oncology. Faculty at the Division of Hematology & Oncology in the Medical University of South Carolina.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nConsent for publication\nWritten informed consent was obtained from the patient for publication of this Case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nEthics approval and consent to participate\nNot applicable.\n==== Refs\nReferences\n1. OPTN. Transplants by Donor Type. 2016. https://optn.transplant.hrsa.gov/data/view-data-reports/national-data/##.\n2. Morris PJ Transplantation—A Medical Miracle of the 20th Century N Engl J Med 2004 351 26 2678 2680 10.1056/NEJMp048256 15616201 \n3. AlBugami M Kiberd B Malignancies: pre and post transplantation strategies Transplant Rev (Orlando) 2014 28 2 76 83 10.1016/j.trre.2013.12.002 24439783 \n4. Engels EA Cancers among US organ donors: a comparison of transplant and cancer registry diagnoses Am J Transplant 2014 14 6 1376 1382 10.1111/ajt.12683 24712385 \n5. Gallagher MP Long-term cancer risk of immunosuppressive regimens after kidney transplantation J Am Soc Nephrol 2010 21 5 852 858 10.1681/ASN.2009101043 20431040 \n6. Moloney FJ Maintenance versus reduction of immunosuppression in renal transplant recipients with aggressive squamous cell carcinoma Dermatol Surg 2004 30 4 Pt 2 674 678 15061854 \n7. Waldman AH Revision of immunosuppression in a solid organ transplant recipient leads to complete remission of metastatic undifferentiated carcinoma JAAD Case Rep 2015 1 6 S8 S11 10.1016/j.jdcr.2015.09.010 27051810 \n8. van Leeuwen MT Effect of reduced immunosuppression after kidney transplant failure on risk of cancer: population based retrospective cohort study BMJ 2010 340 c570 10.1136/bmj.c570 20150194 \n9. Abend JR Jiang M Imperiale MJ BK virus and human cancer: innocent until proven guilty Semin Cancer Biol 2009 19 4 252 260 10.1016/j.semcancer.2009.02.004 19505653 \n10. Geetha D Bladder carcinoma in a transplant recipient: evidence to implicate the BK human polyomavirus as a causal transforming agent Transplantation 2002 73 12 1933 1936 10.1097/00007890-200206270-00015 12131691 \n11. Tognon M Oncogenic transformation by BK virus and association with human tumors Oncogene 2003 22 33 5192 5200 10.1038/sj.onc.1206550 12910256 \n12. Reploeg MD Storch GA Clifford DB BK Virus: A Clinical Review Clin Infect Dis 2001 33 2 191 202 10.1086/321813 11418879 \n13. Rollison DE Lack of BK virus DNA sequences in most transitional-cell carcinomas of the bladder Int J Cancer 2007 120 6 1248 1251 10.1002/ijc.22494 17192899 \n14. Burger M Epidemiology and risk factors of urothelial bladder cancer Eur Urol 2013 63 2 234 241 10.1016/j.eururo.2012.07.033 22877502 \n15. Ison MG Donor-derived disease transmission events in the United States: data reviewed by the OPTN/UNOS Disease Transmission Advisory Committee Am J Transplant 2009 9 8 1929 1935 10.1111/j.1600-6143.2009.02700.x 19538493 \n16. Ison MG Nalesnik MA An update on donor-derived disease transmission in organ transplantation Am J Transplant 2011 11 6 1123 1130 10.1111/j.1600-6143.2011.03493.x 21443676 \n17. Milks K Krishnan S Caserta M Stratta RJ Tchelepi H Incidental Discovery of a Donor-Derived Urothelial Carcinoma Following Kidney Transplantation Int J Transplant Res Med 2015 1 006 \n18. Ferreira GF Urothelial carcinoma transmission via kidney transplantation Nephrol Dial Transplant 2010 25 2 641 643 10.1093/ndt/gfp612 20007757 \n19. Verneuil L Donor-derived stem-cells and epithelial mesenchymal transition in squamous cell carcinoma in transplant recipients Oncotarget 2015 6 39 41497 41507 26594799\n\n",
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"journal": "Journal for immunotherapy of cancer",
"keywords": "Immunosuppression; Post-transplant malignancy; Solid organ transplantation; Urothelial carcinoma",
"medline_ta": "J Immunother Cancer",
"mesh_terms": "D000368:Aged; D001739:BK Virus; D002869:Chromosome Aberrations; D006801:Humans; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents; D017404:In Situ Hybridization, Fluorescence; D016030:Kidney Transplantation; D008279:Magnetic Resonance Imaging; D008297:Male; D027601:Polyomavirus Infections; D014019:Tissue Donors; D014057:Tomography, X-Ray Computed; D014184:Transplantation, Homologous; D014412:Tumor Virus Infections; D014571:Urologic Neoplasms",
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"title": "Urothelial carcinoma of donor origin in a kidney transplant patient.",
"title_normalized": "urothelial carcinoma of donor origin in a kidney transplant patient"
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"abstract": "We present the case of a 22-year-old patient who was successfully treated with intravenous fat emulsion for severe and refractory cardiac depression after an overdose with a tricyclic antidepressant and beta-blocker.",
"affiliations": "Department of Intensive Care Medicine, Rijnstate Hospital, Arnhem, the Netherlands.",
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"title": "Case Report: Hemodynamic Instability Following Severe Metoprolol and Imipramine Intoxication Successfully Treated With Intravenous Fat Emulsion.",
"title_normalized": "case report hemodynamic instability following severe metoprolol and imipramine intoxication successfully treated with intravenous fat emulsion"
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"abstract": "A 46-year-old man with antiphospholipid syndrome (APS) and previous pulmonary embolism on anticoagulation with rivaroxaban was brought in to the hospital after a syncopal episode. He was found to be hypotensive and tachycardic and later admitted to the intensive care unit. Clinical presentation and laboratory findings were consistent with adrenal insufficiency. MRI revealed bilateral adrenal haemorrhage and he received appropriate steroid replacement therapy. Symptoms slowly subsided and anticoagulation regimen was changed to warfarin. Adrenal haemorrhage was likely caused by APS and rivaroxaban, which brings into question whether novel oral anticoagulants are safe in this patient population.",
"affiliations": "Department of Medicine, University of Miami/Jackson Memorial Hospital, Miami, Florida, USA marilyn_arosemena@hotmail.com.;Department of Medicine, University of Miami/Jackson Memorial Hospital, Miami, Florida, USA.;Internal Medicine and Pediatrics, Jackson Memorial Hospital, Miami, Florida, USA.",
"authors": "Arosemena|Marilyn A|MA|http://orcid.org/0000-0002-8185-4707;Rodriguez|Andres|A|;Ediriweera|Hasini|H|",
"chemical_list": "D000925:Anticoagulants; D014859:Warfarin; D006493:Heparin; D000069552:Rivaroxaban",
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"title": "Bilateral adrenal haemorrhage secondary to rivaroxaban in a patient with antiphospholipid syndrome.",
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"abstract": "Headache is a well-documented side effect of indomethacin in the older medical literature; however, it has rarely been commented on in indomethacin-responsive hemicrania continua. We describe the case of a 60-year-old woman with left-sided hemicrania continua whose indomethacin treatment was associated with a continuous right-sided migraine. Her indomethacin therapy was discontinued heralding a return of her left-sided hemicrania continua and a resolution of her right-sided migraine. Her hemicrania continua then responded well to melatonin, with recurrence on stopping and improvement on restarting. This is the most detailed description of headache as a side effect of indomethacin in a headache patient we are aware of, and one of only a few reported cases of melatonin-responsive hemicrania continua. We review the evidence of headache as a side effect of indomethacin in order to highlight its importance in the treatment of headache disorders. We emphasize that indomethacin headache response may be more than simply a beneficial or neutral one and might be relevant to some cases of apparently indomethacin-resistant hemicrania continua. We hope this case may encourage clinicians to inquire about headache as a potential side effect of indomethacin.",
"affiliations": "University College London Medical School, London, UK.",
"authors": "Hollingworth|Milo|M|;Young|Tim M|TM|",
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"title": "Melatonin responsive hemicrania continua in which indomethacin was associated with contralateral headache.",
"title_normalized": "melatonin responsive hemicrania continua in which indomethacin was associated with contralateral headache"
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"abstract": "Hypersexual behavior can be assumed as a rare side effect of treatment with aripiprazole and is possibly due to partial agonism on dopamine receptors or partial agonism on 5-HT1A receptors and 5 HT2A antagonism.",
"affiliations": "Vinzenz von Paul Hospital, Rottweil.",
"authors": "Kozian|Ralf|R|",
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"title": "Hypersexuality Induced by Aripiprazole.",
"title_normalized": "hypersexuality induced by aripiprazole"
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"abstract": "Complete blood count should always be considered to tailor diagnosis and appropriate management in patients with acute ischemic heart disease. We present a challenging case of recurrent acute coronary syndrome, in the context of very high thrombotic risk due to concomitant inflammatory disease. Although no general guidelines exist for the switch between antiplatelet agents, particularly in the acute setting, in specific cases, the availability of different orally- and i.v.-acting agents and platelet function tests may allow to discriminate among multiple possible mechanisms of drug failure or side effects in the individual patient.",
"affiliations": "Intensive Coronary Care Unit and De Gasperis Cardio Center, ASST Grande Ospedale Metropolitano Niguarda , Milan, Italy.;Hematology Department, ASST Grande Ospedale Metropolitano Niguarda , Milan, Italy.;Interventional cardiology and De Gasperis Cardio Center, ASST Grande Ospedale Metropolitano Niguarda , Milan, Italy.;Intensive Coronary Care Unit and De Gasperis Cardio Center, ASST Grande Ospedale Metropolitano Niguarda , Milan, Italy.;Intensive Coronary Care Unit and De Gasperis Cardio Center, ASST Grande Ospedale Metropolitano Niguarda , Milan, Italy.;Interventional cardiology and De Gasperis Cardio Center, ASST Grande Ospedale Metropolitano Niguarda , Milan, Italy.;Interventional cardiology and De Gasperis Cardio Center, ASST Grande Ospedale Metropolitano Niguarda , Milan, Italy.;Dipartimento di Scienze della Salute, Università Degli Studi di Milano , Milan, Italy.;Division of Cardiology, Ospedale Manzoni , Lecco, Italia.",
"authors": "Morici|Nuccia|N|;Cantoni|Silvia|S|;Soriano|Francesco|F|;Sacco|Alice|A|;Viola|Giovanna|G|;Esposito|Giuseppe|G|;Oreglia|Jacopo A|JA|;Cattaneo|Marco|M|;Savonitto|Stefano|S|",
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"keywords": "Antiplatelet therapy; point of care tests; stent thrombosis",
"medline_ta": "Platelets",
"mesh_terms": "D054058:Acute Coronary Syndrome; D017091:Colitis, Ischemic; D003328:Coronary Thrombosis; D005260:Female; D006470:Hemorrhage; D006801:Humans; D008875:Middle Aged",
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"title": "Recurrent stent thrombosis in a patient with acute coronary syndrome and ischemic colitis: between life-threatening thrombosis and life-threatening bleeding.",
"title_normalized": "recurrent stent thrombosis in a patient with acute coronary syndrome and ischemic colitis between life threatening thrombosis and life threatening bleeding"
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"abstract": "Hemicrania continua is an uncommon subtype of trigeminal autonomic cephalgia that exhibits dramatic therapeutic response to indomethacin. Unfortunately, indomethacin is associated with a range of adverse effects, including neuropsychiatric complications, which limits its use in many patients. Although no other effective pharmacologic agents exist, there is emerging evidence for interventional treatments such as occipital nerve and vagus nerve stimulation, which may act by modulating neural activity within the trigeminovascular system.\nWe present a 30-year-old woman with long-standing refractory hemicrania continua who suffered adverse effects to indomethacin. She experienced temporary, but near-complete, symptom resolution following piercing of the crus of the ear helix ipsilateral to her headache, whereas contralateral piercing produced no benefit.\nTo our knowledge, this case is the first to describe a therapeutic benefit following ear piercing in a patient with trigeminal autonomic cephalgia. We argue that symptom relief was obtained through a similar mechanism to occipital or vagus nerve stimulation.",
"affiliations": "Department of Neurology, Austin Health, Heidelberg, Victoria, Australia.",
"authors": "Bryson|Alexander|A|",
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"doi": "10.1136/bmjno-2021-000193",
"fulltext": "\n==== Front\nBMJ Neurol Open\nBMJ Neurol Open\nbmjno\nbmjno\nBMJ Neurology Open\n2632-6140\nBMJ Publishing Group BMA House, Tavistock Square, London, WC1H 9JR\n\nbmjno-2021-000193\n10.1136/bmjno-2021-000193\nShort Report\n1506\nTemporary resolution of hemicrania continua following ipsilateral ear piercing\nBryson Alexander\nDepartment of Neurology, Austin Health, Heidelberg, Victoria, Australia\nCorrespondence to Dr Alexander Bryson; alex.bryson@austin.org.au\n2021\n27 9 2021\n3 2 e00019314 9 2021\n© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.\n2021\nhttps://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, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.\n\nBackground\n\nHemicrania continua is an uncommon subtype of trigeminal autonomic cephalgia that exhibits dramatic therapeutic response to indomethacin. Unfortunately, indomethacin is associated with a range of adverse effects, including neuropsychiatric complications, which limits its use in many patients. Although no other effective pharmacologic agents exist, there is emerging evidence for interventional treatments such as occipital nerve and vagus nerve stimulation, which may act by modulating neural activity within the trigeminovascular system.\n\nCase\n\nWe present a 30-year-old woman with long-standing refractory hemicrania continua who suffered adverse effects to indomethacin. She experienced temporary, but near-complete, symptom resolution following piercing of the crus of the ear helix ipsilateral to her headache, whereas contralateral piercing produced no benefit.\n\nConclusions\n\nTo our knowledge, this case is the first to describe a therapeutic benefit following ear piercing in a patient with trigeminal autonomic cephalgia. We argue that symptom relief was obtained through a similar mechanism to occipital or vagus nerve stimulation.\n\nheadache\nspecial-featureunlocked\n==== Body\npmcIntroduction\n\nHemicrania continua (HC) is an uncommon but clinically striking headache syndrome that is classified as a trigeminal autonomic cephalgia (TAC).1 HC is characterised by prolonged unilateral headache accompanied by cranial autonomic phenomena such as lacrimation and ptosis.2 Crucially, HC is exquisitely sensitive to indomethacin underscoring the importance of timely diagnosis and treatment to minimise the impact on patient quality of life.\n\nUnfortunately, many patients experience adverse effects to indomethacin, yet no established prophylactic therapies exist. In some patients, an improvement with pharmacologic agents, including topiramate and melatonin, has been reported.3 More recently, interventional approaches have emerged as viable treatment options with occipital nerve stimulation and vagus nerve stimulation demonstrating benefit in small case series.4 5 These treatment strategies are thought to act by modulating neural activity within the trigeminovascular system implicated in TAC pathophysiology.6\n\nHere, we report a case of long-standing HC in which the patient experienced symptomatic improvement following ipsilateral piercing of the crus of the ear helix: a practice known as ‘Daith’ piercing.\n\nCase report\n\nA 30-year-old female patient was referred to a neurology clinic for refractory headache since the age of 16 consisting of a burning sensation over the periorbital region extending posteriorly across the scalp. The pain was exclusively left sided with sharp demarcation at the midline, and which she described as ‘splitting her head down the middle’. Her headache was constant but punctuated by severe exacerbations lasting from days to weeks with an average frequency of four exacerbations per month. There was no light or sound sensitivity, but she reported a ‘droopy’ left eyelid, periorbital swelling and rhinorrhoea during exacerbations. The patient provided written informed consent to publish her case.\n\nThe patient’s headaches did not respond to acute therapy with paracetamol, non-steroidal anti-inflammatory drugs (including ibuprofen up to 800 mg daily and celecoxib 400 mg daily) or aspirin 800 mg. She used regular propranolol 20 mg two times per day over many years for migraine prophylaxis, which was ineffective. The headaches profoundly disrupted the patient’s quality of life, and she was unemployed at the time of review. She lived in a regional setting with limited specialist access and had never previously seen a neurologist.\n\nThe patient had no other medical history and her only regular medication was propranolol. Her mother suffered from migraine without aura, but no first-degree relatives experienced headaches with similar characteristics to the patient. Cranial nerve, funduscopy and upper and lower limb neurological examinations were normal. An MRI of the brain and angiogram did not demonstrate any cerebral or vascular abnormalities. After researching alternative treatment options for migraine, the patient underwent Daith piercing of the left ear 12 months before neurology review. She noticed a rapid and dramatic symptom improvement: her severe exacerbations resolved and her background pain improved to the extent that she did not require analgesia for a 2-month period. Due to this therapeutic response, the patient then elected to undergo Daith piercing of the right ear, which provided no symptom benefit.\n\nBased on the clinical characteristics, the patient was commenced on an up-titrating dose of indomethacin for treatment of HC. At a dose of 50 mg three times per day, she experienced complete resolution of headache approximately 30 min after her third dose. Medication withdrawal several days later led to a recrudescence of her symptoms. She experimented with her indomethacin regimen and found that maintaining a daily dose of 25–50 mg reliably prevented headache recurrence. After approximately 1 month of therapy, she developed light headedness, anxiety and a distressing sensation of depersonalisation that resolved after ceasing indomethacin. She trialled topiramate 50 mg daily, which was self-ceased after 2 months due to lack of perceived benefit, and then underwent left-sided greater occipital nerve (GON) block. She reported a partial response to GON block over the following month with persistent background pain but only two mild exacerbations lasting under 24 hours, after which her headaches returned to their previous frequency and severity.\n\nDiscussion\n\nHC is an uncommon subtype of TAC that is often incorrectly diagnosed and treated. HC is under-recognised by clinicians, including neurologists, and symptoms may be confused for unrelated conditions such as dental or temporomandibular disorders.7 TACs are associated with high rates of disability, occupational absenteeism and reduced social engagement.8\n\nDue to the remarkable therapeutic response of HC to indomethacin, a misdiagnosis has profound consequence on patient quality of life. Unfortunately, indomethacin is poorly tolerated in over 30% of patients and associated with a range of adverse effects.9 Gastrointestinal disturbance is most commonly recognised but neuropsychiatric adverse effects, evident in this case report, occur in up to 3% of patients.9 Therefore, there exists an urgent need for novel treatment strategies.\n\nThe pathophysiology of TACs is complex. Pain may arise through activation of the trigeminovascular system, which consists of nociceptive fibres terminating in the trigeminocervical complex, and ascending pathways to thalamic nuclei, which project to the pain neuromatrix.10 Cranial autonomic symptoms are thought to arise from a reflex arc involving the pontine superior salivatory nucleus, and dysregulation of these pathways may be driven by the posterior hypothalamus.11 This framework provides a rationale for the use of interventional therapies in HC.12 Symptomatic improvement has been observed after sphenopalatine ganglion blockade and non-invasive vagus nerve stimulation, perhaps via modulation of the trigeminal–autonomic reflex.5 6 13 In a cross-over study of six patients receiving occipital nerve stimulation, a branch of the C2 nerve root, five patients reported significant symptom improvement.4 Here, C2 stimulation may modulate ascending trigeminal pain pathways due to afferent inputs converging within the trigeminocervical complex, perhaps through an inhibitory gate control mechanism.10\n\nDaith piercing has been reported to provide symptom benefit in migraine, but, to the best of our knowledge, this is the first case to document clinical improvement in a TAC.14 Although placebo effects are common following interventional treatment of headache, we feel this is unlikely to account for the response in this patient. Not only did contralateral piercing provided no benefit, but the patient experienced only mild improvement with GON block, which would also be expected to carry a high likelihood of placebo effect.15 The crus of the ear helix receives sensory supply from the vagus nerve and C2/C3 nerve roots via the auricular nerve, which project to the superior salivatory nucleus and spinal trigeminocervical complex, respectively. We hypothesise that symptomatic benefit was obtained through modulation of ascending pain pathways within the trigeminocervical complex, through either overlapping cervical sensory representation or via the trigeminal–autonomic reflex.6 12 It is interesting to note that the response to GON blockade was less pronounced than ear piercing in this patient. This could reflect differences in either the nature of the peripheral stimulation, or the preferential contribution of vagal afferents to the analgesic effect.\n\nConclusion\n\nThis case is the first to report a symptomatic benefit with Daith ear piercing in a patient with HC, and we propose a similar therapeutic mechanism to occipital nerve or vagus nerve stimulation. Although this case highlights the potential therapeutic mechanisms of HC, Daith piercing is not a recommended treatment modality as it is unlikely to provide persisting benefit and is associated with a risk of infection. This case also demonstrates the range of adverse effects associated with indomethacin, including neuropsychiatric complications, which are often under-recognised.\n\nData availability statement\n\nData sharing not applicable as no datasets generated and/or analysed for this study.\n\nEthics statements\n\nPatient consent for publication\n\nConsent obtained directly from patient(s).\n\nContributors: AB: acquisition of case information and drafting of manuscript.\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\nProvenance and peer review: Not commissioned; externally peer reviewed.\n==== Refs\nReferences\n\n1 Headache classification Committee of the International headache Society (IHS) the International classification of headache disorders, 3rd edition. Cephalalgia 2018;38 :1–211. 10.1177/0333102417738202\n2 CittadiniE, GoadsbyPJ. Hemicrania continua: a clinical study of 39 patients with diagnostic implications. Brain 2010;133 :1973–86. 10.1093/brain/awq137 20558416\n3 PrakashS, PatelP. Hemicrania continua: clinical review, diagnosis and management. J Pain Res 2017;10 :1493–509. 10.2147/JPR.S128472 28721092\n4 BurnsB, WatkinsL, GoadsbyPJ. Treatment of hemicrania continua by occipital nerve stimulation with a bion device: long-term follow-up of a crossover study. The Lancet Neurology 2008;7 :1001–12. 10.1016/S1474-4422(08)70217-5 18845482\n5 TsoAR, MarinJ, GoadsbyPJ. Noninvasive vagus nerve stimulation for treatment of indomethacin-sensitive headaches. JAMA Neurol 2017;74 :1266–7. 10.1001/jamaneurol.2017.2122 28846758\n6 AkermanS, SimonB, Romero-ReyesM. Vagus nerve stimulation suppresses acute noxious activation of trigeminocervical neurons in animal models of primary headache. Neurobiol Dis 2017;102 :96–104. 10.1016/j.nbd.2017.03.004 28286178\n7 VianaM, TassorelliC, AllenaM, et al . Diagnostic and therapeutic errors in trigeminal autonomic cephalalgias and hemicrania continua: a systematic review. J Headache Pain 2013;14 . 10.1186/1129-2377-14-14\n8 D’AmicoD, RaggiA, GrazziL, et al . Quality of life, and socioeconomic burden of cluster headache: a critical review of current evidence and future perspectives. Headache 2020;60 .\n9 LucasS. The pharmacology of indomethacin. Headache 2016;56 :436–46. 10.1111/head.12769 26865183\n10 BartschT, GoadsbyPJ. Increased responses in trigeminocervical nociceptive neurons to cervical input after stimulation of the dura mater. Brain 2003;126 :1801–13. 10.1093/brain/awg190 12821523\n11 BarloeseMCJ. The pathophysiology of the trigeminal autonomic cephalalgias, with clinical implications. Clin Auton Res 2018;28 :315–24. 10.1007/s10286-017-0468-9 28942483\n12 WeiDY, GoadsbyPJ. Cluster headache pathophysiology — insights from current and emerging treatments. Nat Rev Neurol 2021;17 :308–24. 10.1038/s41582-021-00477-w 33782592\n13 Michelle AndroulakisX, KrebsKA, AshkenaziA. Hemicrania continua may respond to repetitive sphenopalatine ganglion block: a case report. Headache 2016;56 :573–9. 10.1111/head.12783 26926875\n14 RizzoAC, PaolucciM, AltavillaR. Daith piercing in a case of chronic migraine: a possible vagal modulation. Front Neurol 2017;8 .\n15 DienerH-C, SchornCF, BingelU, et al . The importance of placebo in headache research. Cephalalgia 2008;28 :1003–11. 10.1111/j.1468-2982.2008.01660.x 18727647\n\n",
"fulltext_license": "CC BY-NC",
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"issue": "3(2)",
"journal": "BMJ neurology open",
"keywords": "headache",
"medline_ta": "BMJ Neurol Open",
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"title": "Temporary resolution of hemicrania continua following ipsilateral ear piercing.",
"title_normalized": "temporary resolution of hemicrania continua following ipsilateral ear piercing"
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"abstract": "The present study explored the benefit of preoperative chemoradiotherapy (PCRT) for sphincter preservation in locally advanced low-lying rectal cancer patients who underwent stapled anastomosis, especially in those with deep and narrow pelvises determined by magnetic resonance imaging.Patients with locally advanced low-lying rectal cancer (≤5 cm from the anal verge) who underwent stapled anastomosis were included. Patients were categorized into two groups (PCRT+ vs. PCRT-) according to PCRT application. Patients in the PCRT+ group were matched to those in the PCRT- group according to potential confounding factors (age, gender, clinical stage, and body mass index) for sphincter preservation. Sphincter preservation, permanent stoma, and anastomosis-related complications were compared between the groups. Pelvic magnetic resonance imaging was used to measure 12 dimensions representing pelvic cavity depth and width with which deep and narrow pelvis was defined. The impact of PCRT on sphincter preservation and permanent stoma in pelvic dimensions defined as deep and narrow pelvis was evaluated, and factors associated with sphincter preservation and permanent stoma were analyzed.One hundred sixty-six patients were one-to-one matched between the PCRT+ and PCRT- groups. Overall, sphincter-saving surgery was performed in 66.3% and the rates were not different between the 2 groups. Anastomotic complications and permanent stoma occurred nonsignificantly more frequently in the PCRT+ group. PCRT was not associated with higher rate of sphincter preservation in all pelvic dimensions defined as deep and narrow pelvis, while PCRT was related to higher rate of permanent stoma in shorter transverse diameter and interspinous distance. On logistic regression analysis, PCRT was not shown to influence both sphincter preservation and permanent stoma, while longer transverse diameter and interspinous distance were associated with lower rate of permanent stoma.PCRT had no beneficial effect on sphincter preservation in patients with locally advanced low-lying rectal cancer who had undergone stapled anastomosis. In patients with deep and narrow pelvis, PCRT had no impact on sphincter preservation but was associated with higher rate of permanent stoma.",
"affiliations": "From the Department of Colon and Rectal Surgery (IJP, CSY, S-BL, JLL, CWK, YSY, JCK); and Department of Radiology (SHP), University of Ulsan College of Medicine and Asan Medical Center, Seoul, Korea.",
"authors": "Park|In Ja|IJ|;Yu|Chang Sik|CS|;Lim|Seok-Byung|SB|;Lee|Jong Lyul|JL|;Kim|Chan Wook|CW|;Yoon|Yong Sik|YS|;Park|Seong Ho|SH|;Kim|Jin Cheon|JC|",
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"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 2714944510.1097/MD.0000000000003463034637100Research ArticleObservational StudyIs Preoperative Chemoradiotherapy Beneficial for Sphincter Preservation in Low-Lying Rectal Cancer Patients? Park In Ja MD, PhDYu Chang Sik MD, PhDLim Seok-Byung MD, PhDLee Jong Lyul MDKim Chan Wook MD, PhDYoon Yong Sik MD, PhDPark Seong Ho MD, PhDKim Jin Cheon MD, PhDZolezzi. Adrián Murillo From the Department of Colon and Rectal Surgery (IJP, CSY, S-BL, JLL, CWK, YSY, JCK); and Department of Radiology (SHP), University of Ulsan College of Medicine and Asan Medical Center, Seoul, Korea.Correspondence: Jin Cheon Kim, Department of Colon and Rectal Surgery, University of Ulsan College of Medicine and Asan Medical Center, 86 Asanbyeongwon-gil, Songpa-gu, Seoul 138-736, Korea (e-mail: jckim@amc.seoul.kr).5 2016 06 5 2016 95 18 e34632 1 2016 25 3 2016 31 3 2016 Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.2016This is an open access article distributed under the Creative Commons Attribution License 4.0, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0Supplemental Digital Content is available in the text\n\nAbstract\nThe present study explored the benefit of preoperative chemoradiotherapy (PCRT) for sphincter preservation in locally advanced low-lying rectal cancer patients who underwent stapled anastomosis, especially in those with deep and narrow pelvises determined by magnetic resonance imaging.\n\nPatients with locally advanced low-lying rectal cancer (≤5 cm from the anal verge) who underwent stapled anastomosis were included. Patients were categorized into two groups (PCRT+ vs. PCRT–) according to PCRT application. Patients in the PCRT+ group were matched to those in the PCRT– group according to potential confounding factors (age, gender, clinical stage, and body mass index) for sphincter preservation. Sphincter preservation, permanent stoma, and anastomosis-related complications were compared between the groups. Pelvic magnetic resonance imaging was used to measure 12 dimensions representing pelvic cavity depth and width with which deep and narrow pelvis was defined. The impact of PCRT on sphincter preservation and permanent stoma in pelvic dimensions defined as deep and narrow pelvis was evaluated, and factors associated with sphincter preservation and permanent stoma were analyzed.\n\nOne hundred sixty-six patients were one-to-one matched between the PCRT+ and PCRT− groups. Overall, sphincter-saving surgery was performed in 66.3% and the rates were not different between the 2 groups. Anastomotic complications and permanent stoma occurred nonsignificantly more frequently in the PCRT+ group. PCRT was not associated with higher rate of sphincter preservation in all pelvic dimensions defined as deep and narrow pelvis, while PCRT was related to higher rate of permanent stoma in shorter transverse diameter and interspinous distance. On logistic regression analysis, PCRT was not shown to influence both sphincter preservation and permanent stoma, while longer transverse diameter and interspinous distance were associated with lower rate of permanent stoma.\n\nPCRT had no beneficial effect on sphincter preservation in patients with locally advanced low-lying rectal cancer who had undergone stapled anastomosis. In patients with deep and narrow pelvis, PCRT had no impact on sphincter preservation but was associated with higher rate of permanent stoma.\n\nOPEN-ACCESSTRUE\n==== Body\nINTRODUCTION\nIt is generally expected that patients who require abdominoperineal resection would be able to preserve the sphincter via preoperative chemoradiotherapy (PCRT). Previous studies suggest that tumor downstaging and shrinkage after PCRT could increase the likelihood of sphincter preservation in rectal cancer patients.1,2\n\nMany researchers have, however, reported controversial results regarding the influence of PCRT on sphincter preservation.1–6 Although many personal series reported an increased sphincter preservation rate after PCRT,4–6 2 representative randomized controlled trials showed contrary results in terms of sphincter preservation following application of PCRT.1,3 Additionally, meta-analyses of randomized trials do not support increased rates of sphincter preservation after PCRT. A review of randomized trials revealed no difference in the rates of sphincter preservation between patients with and without PCRT.6,7 Similarly, a recent Cochrane review of 6 randomized trials found no positive effect of PCRT on the rate of sphincter preservation.8\n\nAlthough the data do not strongly support the definite benefit of PCRT for sphincter preservation, clinicians and patients still expect that application of PCRT would increase the chance of sphincter preservation by shrinkage of tumor. Sphincter preservation is, however, a very complex issue involving tumor stage and location, the patient's habitus and wishes, and the surgeon's experience. Besides a direct effect of PCRT on tumor shrinkage, these factors would also be associated with sphincter preservation. It is assumed that the beneficial effect of PCRT on sphincter preservation would be much anticipated in more technically challenging situations, such as low-lying rectal cancer undergoing stapled anastomosis or anatomically difficult cases like deep and narrow pelvis.\n\nSome studies have evaluated the operative difficulty of rectal cancer surgery according to the pelvic dimensions obtained using magnetic resonance imaging (MRI).9,10 In these reports, various pelvic dimensions were used to determine the depth and width of the pelvis. Combinations of these parameters could identify deep and narrow pelvises that could complicate sphincter preservation; however, the association of PCRT with sphincter preservation according to different pelvic dimensions was not evaluated.\n\nIn our present study, we investigated the impact of PCRT on sphincter preservation in patients with locally advanced low-lying rectal cancer who had undergone stapled anastomosis, and especially in those with deep and narrow pelvises determined by MRI.\n\nMETHODS\nPatient Identification and Definition of Outcomes\nPatients with locally advanced low-lying rectal cancer who were treated with radical resection between January 2009 and December 2012 were selected from the tumor registry of Asan Medical Center, Seoul, Korea. Patients who underwent stapled anastomosis were included. Locally advanced rectal cancer was defined as patients who were diagnosed as cT3-4 or node positive using MRI. Location of tumor was measured as distance from anal verge to lowest margin of tumor using digital rectal examination or rigid proctoscope. Low-lying rectal cancer was defined as low margin of tumor located below 5 cm from anal verge. Patients were excluded if they underwent local excision or observation after completion of PCRT or if they had manual coloanal anastomosis or intersphincteric resection.\n\nPermanent stoma was defined as stoma persisting at least 2 years after the primary tumor resection. Anastomosis-related problems such as stricture, fistula, leakage, and abscess which required medical or surgical treatment were defined as anastomotic complications.\n\nThe database of Asan Medical Center was queried to identify clinicopathological and demographic characteristics. This study was approved by the institutional review board and informed consent was waived.\n\nPatient Categorization and One-to-One Match\nPatients were categorized into 2 groups according to application of PCRT. Patients who received PCRT were classified as the PCRT+ group and those who did not receive PCRT were classified as the PCRT– group.\n\nWe made one-to-one matched group among the included patients of PCRT+ and PCRT– groups. Matched variables were age, sex, clinical T/N stage, and body mass index. Eighty three patients in each group were selected.\n\nTreatment, Pathologic Evaluation\nPatients in the PCRT+ group received external beam radiation therapy (median dose, 50.4 Gy). Intravenous fluorouracil-based chemotherapy or capecitabine was given as concomitant chemotherapy. At 6 to 8 weeks after PCRT completion, patients underwent radical resection (low anterior resection or abdominoperineal resection) according to the principles of total mesorectal excision. Total mesorectal excision was performed in the PCRT– group without preoperative treatment and adjuvant treatment was delivered according to pathologic results.\n\nIn patients who received PCRT, pathologic responses to PCRT were evaluated in the resected specimens using the tumor regression grade scored using a 5-tier system: TR, total regression with no residual tumor cells and only fibrotic mass; NTR, near-total regression with microscopic residual tumor (i.e., difficult to find) in the fibrotic tissue; moderate regression, dominant irradiation-related changes with residual tumor (i.e., easy to find); minimal regression, dominant tumor mass with obvious irradiation-related changes; and no regression and no evidence of irradiation-related changes (fibrosis, necrosis, and vascular change). Patients with TR and NTR were considered good responder and others as nonresponder.\n\nPelvic Dimensions on MRI\nBased on the preoperative staging MRI of the rectum, various pelvic dimensions were obtained. MRI was performed using a 1.5-T system (Magnetom Avanto; Siemens Medical Solutions, Erlangen, Germany); a dedicated 6-channel body phased-array coil was applied to the anterior side of the patient and another 6-channel spine coil was applied to the posterior side. The axial, sagittal, and oblique T2-weighted images of the pelvis were obtained using the following parameters: a 17 to 30 cm field of view, 3 to 4 mm section thickness, no intersection gap, 4100 to 6870 ms repetition time, 80 to 90 ms echo time, 220 × 256 matrix, and 117 echo train length. We considered various measurements of pelvic dimension as anatomical parameters that could influence sphincter preservation. Pelvic dimensions were obtained using mid-sagittal, axial, and oblique sections of the pelvis and 12 pelvic dimensions were measured (Table 1, Figure 1). Each pelvic dimension was categorized as deep and narrow pelvis when each value of pelvic dimension was lower than the median, except for angle α and D (pubic tubercle height) in which values higher than the median were considered deep and narrow pelvis.\n\nTABLE 1 Pelvic Dimensions Measured on Axial, Sagittal, and Oblique MRI\n\nFIGURE 1 Pelvic dimension measurements in an (A) axial view, (B) coronal view, and (C, D) oblique view of pelvic magnetic resonance imaging.\n\nOutline of the Study and Statistical Analysis\nWe compared demographic features and surgical outcome between PCRT+ and PCRT–. Also, the rates of sphincter preservation, permanent stoma, and anastomotic complications were compared between the 2 groups. In the next part, the association between PCRT and sphincter preservation/permanent stoma in pelvic dimensions defined as deep and narrow pelvis was analyzed. Finally, multivariate analysis was performed to evaluate factors associated with sphincter preservation and permanent stoma.\n\nNonparametric data were compared using the Wilcoxon rank sum test. Categorical data were summarized by frequency within each group, and comparisons were made using the χ2 test for proportions. Univariate analyses were conducted to identify factors associated with sphincter preservation, including pelvic dimensions, and variables with P ≤ 0.1 in univariate analyses were included in multivariate logistic regression to identify factors independently and significantly associated with sphincter-preserving surgery performance. Values of P ≤0.05 were considered statistically significant. All statistical analyses were performed using SPSS (version 21.0; IBM Statistics, Armonk, NY).\n\nRESULTS\nCharacteristics of the Study Patients\nA total of 166 patients were included in the present study. The mean age was 57.85 years (range, 29–77 years). Men were more common in this population (n = 100, 60.2%). The mean body mass index was 23.47 kg/m2 (range, 16.52–34.7 kg/m2) and 46 patients (27.7%) had a body mass index higher than 25 kg/m2. The mean distance from the anal verge was 3.7 cm (range, 1–5 cm). The distance from the anal verge and the length of the distal resection margin were also comparable between the 2 groups. In the PCRT+ group, more than half of the included patients showed a good response to PCRT (Table 2). The pelvic dimension measurements were not significantly different between the 2 groups (Supplementary Table 1).\n\nTABLE 2 Patient Characteristics\n\nSphincter Preservation, Stoma Formation, and Anastomotic Complications\nThe sphincter preservation rate was 66.3% overall, and the rates were not different between PCRT+ and PCRT– groups. Diverting stoma were made more frequently in the PCRT+ group and anastomosis-related complications, including leakage, also occurred more frequently in the PCRT+ group; however, the differences were not statistically significant compared with the PCRT– group. Reversal of diverting stoma was performed at 3 to 6 months after surgery. However, 7 patients of the PCRT+ group and 4 of the PCRT– group could not undergo reversal of diverting stoma or had to receive a stoma again after reversal because of anastomotic complications. In the PCRT+ group, 4 patients with anastomotic stenosis, 3 patients with recurrent fistula formation, and 1 patient with local recurrence could not reverse diverting stoma. In the PCRT– group, 1 patient maintained diverting colostomy due to a recurrent fistula and inflammation and the other patient with local recurrence underwent abdominoperineal resection. At the last follow-up, 36 patients in the PCRT+ group and 31 patients in the PCRT– group had permanent stoma (P = 0.43).\n\nImpact of PCRT on Sphincter Preservation and Permanent Stoma in Deep and Narrow Pelvis\nFor each pelvic dimension, the rates of sphincter preservation and permanent stoma were compared between the PCRT+ and PCRT– groups to evaluate an impact of PCRT on sphincter preservation or permanent stoma in any one of the anatomical features defined as deep and narrow pelvis (Table 3). As a result, PCRT was not associated with sphincter preservation in all pelvic dimensions. However, in patients with shorter than median transverse diameter (TD), the PCRT+ group had significantly more patients with permanent stoma than the PCRT– group (P = 0.05). The PCRT+ group also had a slightly higher permanent stoma rate than the PCRT– group in patients with shorter than median interspinous distance (ISD), but the difference was only marginally significant (P = 0.07).\n\nTABLE 3 Association of PCRT Application With Sphincter Preservation and Permanent Stoma in Each Pelvic Dimension Defined as Deep and Narrow Pelvis\n\nFactors Associated With Sphincter Preservation and Permanent Stoma\nWe performed univariate and multivariate analysis to evaluate factors associated with sphincter preservation and permanent stoma, in patients with locally advanced, low-lying rectal cancer who underwent stapled anastomosis. The factors included in multivariate analysis were application of PCRT, response to PCRT, and the pelvic dimensions (TD and ISD) that showed significant association with permanent stoma in univariate analysis. In multivariate analysis, PCRT was not associated with sphincter preservation. In addition, longer TD and ISD were associated with decreased permanent stoma. The pathologic results of nonresponder to PCRT (moderate, minimal, and no regression) were associated with higher rate of permanent stoma and lower rate of sphincter preservation in the PCRT+ group, but only with marginal significance (Table 4).\n\nTABLE 4 Factors Associated With Sphincter Preservation and Permanent Stoma\n\nDISCUSSION\nIn our present study, we showed that PCRT was not associated with increased sphincter preservation using stapled anastomosis in patients with locally advanced low-lying rectal cancer within a narrow and deep pelvis when patients were one-to-one matched for age, gender, body mass index, and clinical stage between groups classified according to application PCRT.\n\nA previous German trial did show a 20% increase in the rate of sphincter preservation in a subgroup of patients who were determined to require PCRT before abdominoperineal resection prior to randomization,1 although sphincter preservation was not found to be different in the overall study population. The NSABP R-03 trial showed that the sphincter preservation rate did not differ between PCRT and postoperative CRT.3 Some studies have investigated whether the sphincter preservation rate could be increased by modification of the PCRT protocol, such as the radiation dose or concomitant chemotherapeutic regimen.2,11,12 The Lyon R96-02 trial2 suggested that high-dose preoperative radiotherapy could increase the rate of sphincter preservation compared with a conventional dose by increasing the clinical response to preoperative radiotherapy in patients with low-lying rectal cancer. However, the oncologic outcomes, including disease-free survival and overall survival, were similar between the 2 groups. Two other randomized trials could not find a benefit from PCRT in terms of sphincter preservation. The French ACCORD (Action Concertée cancer COloRectal et Digestif) 12 trial,11 despite a trend toward an increased rate of pathological complete response, showed no significant difference in the sphincter-preservation rate between a 45 Gy/concurrent capecitabine regimen (73%) and a 50 Gy/concurrent capecitabine + oxaliplatin regimen (75%). The Italian Studio Terapia Adiuvante Retto trial,12 which compared 2 neoadjuvant regimens according to the addition of oxaliplatin to 50.4 Gy with concurrent fluorouracil, found a similar rate of sphincter-saving procedures between the 2 arms. Based on the results of these studies, there is no definite evidence that PCRT improves sphincter preservation with current standard long-course PCRT.\n\nSphincter preservation is usually more challenging in low-lying rectal cancer than in mid- and upper rectal cancer. Therefore, PCRT is expected to play a beneficial role in sphincter preservation in low-lying rectal cancer. Although the subgroup analysis by Sauer et al1 was performed for patients who were preoperatively judged suitable for PCRT, many studies evaluating the effect of PCRT on sphincter preservation included all types of rectal cancer.1,2,4–6 Therefore, the effect of PCRT on sphincter preservation in challenging conditions has not been elucidated.\n\nSphincter preservation is a complex issue in rectal cancer patients because it depends on many factors, including tumor characteristics, patient age, sex, body habitus, patient psychology, and the surgeon's experience.13–15 Usually, physicians expect PCRT-induced tumor shrinkage to be beneficial for sphincter preservation in patients with anatomical features that make operations for rectal cancer difficult. Tumor shrinkage may facilitate the tumor to retreat from the anal verge and secure operative space by reducing tumor bulk.16\n\nIn the present study, the primary goal was to evaluate if there is an impact of PCRT on sphincter preservation in locally advanced low-lying rectal cancer patients, especially in those with deep and narrow pelvises. We attempted to control for factors that are considered to affect sphincter preservation, by matching the patients according to age, sex, clinical tumor stage, and body mass index. As a result, we found out that in patients with deep and narrow pelvis, as represented by 2 pelvic dimensions (shorter than median TD and ISD), PCRT was not associated with sphincter preservation but was associated with higher rate of permanent stoma. In the final part of our analysis where multivariate analysis was performed to evaluate factors associated with sphincter preservation and permanent stoma, deep and narrow pelvis was a factor associated with permanent stoma, but not with sphincter preservation.\n\nThe fact that PCRT was associated with higher rate of permanent stoma in certain pelvic dimensions representing deep and narrow pelvis, might have been caused by a high rate of anastomosis-related complications in the PCRT+ group. Indeed, the PCRT+ group showed 2 times higher anastomosis-related complication rate than the PCRT– group.\n\nPoor tumor responses after PCRT were reported as predictive factors for the performance of abdominoperineal resection in previous studies, although this association is still controversial.13–15 In our present study, tumor regression grade assessed after PCRT was found to be associated with both sphincter preservation and permanent stoma, with marginal significance. Although further studies are needed in a larger number of patients to confirm these results, tumor regression grade after PCRT may provide practical information regarding prognosis after surgery.\n\nOur present study included only the cases who had undergone stapled anastomosis. Although stapled anastomosis is clearly not superior to hand-sewn anastomosis for coloanal anastomosis, it may be preferred if an adequate distal margin can be attained because it is associated with improved function and shorter operative time.17 It is hard to apply a stapling device in patients with low-lying bulky rectal tumors in a deep and narrow pelvis but tumor shrinkage after PCRT may facilitate stapled anastomosis in these patients, and PCRT would have a practical benefit on sphincter preservation because hand-sewn coloanal anastomosis would be less influenced by tumor bulk or pelvic anatomy than stapled anastomosis. Although earlier studies have suggested that PCRT could facilitate anastomoses for low-lying tumors, few reports have examined the effects of PCRT in a certain anastomotic method used.7,18 One study has shown that PCRT tends to increase the possibility of the performance of double-stapled anastomosis for distal rectal cancer,16 in contrast to our present findings. We found that PCRT could not increase sphincter preservation using stapled anastomosis in locally advanced low-lying rectal cancer, both in general and specifically in patients with an unfavorable pelvic dimension measured by MRI. However, the rate of permanent stoma was increased in our current PCRT group in case of deep and narrow pelvis. It may be that immoderate stapling after PCRT can result in anastomotic complications that subsequently lead to permanent stoma. PCRT has been reported to be a risk factor of anastomotic complications19,20 and our present investigation revealed a higher level of anastomotic complications in the PCRT group. These results may be of practical assistance when we make surgical decision for patients who have locally advanced low-lying rectal cancer within a deep and narrow pelvis, and had undergone PCRT, that stapled anastomosis for such patients should be carefully considered since this surgical procedure was shown to carry risk for anastomotic complications and permanent stoma.\n\nOur current study had some limitations of note. The variability in the measurement of the pelvic dimensions with pelvic MRI could have affected the outcomes, but we attempted to mitigate the interpretational bias through a central review of pelvic MRI results. Also, the fact that we included only stapled anastomosis cases in our study is another limitation. Therefore, sphincter preservation after PCRT for local excision, “wait-and-see,” and hand-sewn coloanal anastomosis approaches were not considered and the overall effect of PCRT on sphincter preservation would thus have been underestimated by our analysis. In addition, we did not include functional data, which represents the quality of life that is achieved by sphincter preservation, or qualified measurements of successful sphincter preservation.\n\nOur present study did however evaluate the effect of PCRT on sphincter preservation using stapled anastomosis according to pelvic dimensions that may influence operative difficulty. In patients with deep and narrow pelvis, we found that PCRT could not facilitate stapling anastomosis in terms of preserving sphincter function and actually interfered with stoma reversal. Our current findings thus provide practical information for the planning of operative procedure. Faced with an unfavorable pelvic anatomy, PCRT should be carefully considered for the purpose of sphincter preservation in locally advanced low-lying rectal cancer patients who undergo stapled anastomosis.\n\nIn conclusion, PCRT did not show a beneficial effect on sphincter preservation following stapled anastomosis in patients with locally advanced low-lying rectal cancer in deep and narrow pelvis. However, other surgical methods such as local excision or wait-and-see approaches were not included in our present analyses. Therefore, the results of this study are not representative of the overall influence of PCRT on sphincter preservation in rectal cancer patients. Further studies that include diverse surgical options after PCRT could help to verify the overall effect of PCRT on sphincter preservation.\n\nSupplementary Material\nSupplemental Digital Content\n Acknowledgment\nThe authors are indebted to Dr S.Y. Park, Director of Scientific Publications in Clinical Research Center, Asan Medical Center, for the pro bono review of the manuscript.\n\nAbbreviations: ISD = interspinous distance, MRI = magnetic resonance image, NCCN = the National Comprehensive Cancer Network, PCRT = preoperative chemoradiotherapy, TD = transverse diameter.\n\nIJP had full access to all of the data in the study and took responsibility for the integrity of the data and the accuracy of the data analyses.\n\nIJP and JCK created the study design, published the methodology, analyzed the data, drafted the manuscript, and conducted the literature search.\n\nJLL, YSY, CWK, SBL, CSY, and JCK conceptualized the study and collected data.\n\nAll authors critically revised the article and gave final approval of the version to be published.\n\nThe authors have no conflicts of interest to disclose.\n\nSupplemental Digital Content is available for this article.\n==== Refs\nREFERENCES\n1. Sauer R Becker H Hohenberger W \nPreoperative versus postoperative chemoradiotherapy for rectal cancer . N Engl J Med \n2004 ; 351 :1731 –1740 .15496622 \n2. Gerard JP Chapet O Nemoz C \nImproved sphincter preservation in low rectal cancer with high-dose preoperative radiotherapy: the Lyon R96-02 randomized trial . J Clin Oncol \n2004 ; 22 :2404 –2409 .15197202 \n3. Roh MS Colangelo LH O‘Connell MJ \nPreoperative multimodality therapy improves disease-free survival in patients with carcinoma of the rectum: NSABR-03 . J Clin Oncol \n2009 ; 27 :5124 –5130 .19770376 \n4. Crane CH Skibber JM Feig BW \nResponse to preoperative chemoradiation increases the use of sphincter-preserving surgery in patients with locally advanced low rectal carcinoma . Cancer \n2003 ; 97 :517 –524 .12518377 \n5. Rullier E Goffre B Bonnel C \nPreoperative radiochemotherapy and sphincter-saving resection for T3 carcinomas of the lower third of the rectum . Ann Surg \n2001 ; 234 :633 –640 .11685026 \n6. Gerard JP Rostom Y Gal J \nCan we increase the chance of sphincter saving surgery in rectal cancer with neoadjuvant treatments: lessons from a systematic review of recent randomized trials . Crit Rev Oncol Hematol \n2012 ; 81 :21 –28 .21377377 \n7. Bujko K Kepka L Michalski W \nDoes rectal cancer shrinkage induced by preoperative radio (chemo) therapy increase the likelihood of anterior resection? A systematic review of randomized trials . Radiother Oncol \n2006 ; 80 :4 –12 .16730086 \n8. McCarthy K Pearson K Fulton R \nPre-operative chemoradiation for non-metastatic locally advanced rectal cancer . Cochrane Database Syst Rev \n2012 ; 12 :CD008368 .23235660 \n9. Baik SH Kim NK Lee KY \nFactors influencing pathologic results after total mesorectal excision for rectal cancer: analysis of consecutive 100 cases . Ann Surg Oncol \n2007 ; 15 :721 –728 .18058183 \n10. Salerno G Daniels LR Brown G \nVariations in pelvic dimensions do not predict the risk of circumferential resection margin (CRM) involvement in rectal cancer . World J Surg \n2007 ; 31 :1313 –1320 .17468974 \n11. Gérard JP Azria D Gourgou-Bourgade S \nComparison of two neoadjuvant chemoradiotherapy regimens for locally advanced rectal cancer: results of the phase III trial ACCORD 12/0405-Prodige 2 . J Clin Oncol \n2010 ; 28 :1638 –1644 .20194850 \n12. Aschele C Cionini L Lonardi S \nPrimary tumor response to preoperative chemoradiation with or without oxaliplatin in locally advanced rectal cancer: pathologic results of the STAR-01 randomized phase III trial . J Clin Oncol \n2011 ; 29 :2773 –2780 .21606427 \n13. Janjan NA Khoo VS Abbruzzese J \nTumor downstaging and sphincter preservation with preoperative chemoradiation in locally advanced rectal cancer: the M.D. Anderson Cancer Center experience . Int J Radiat Oncol Biol Phys \n1999 ; 44 :1027 –1038 .10421535 \n14. Weiser MR Quah HM Shia J \nSphincter preservation in low rectal cancer is facilitated by preoperative chemoradiation and intersphincteric dissection . Ann Surg \n2009 ; 249 :236 –242 .19212176 \n15. van Leersum N Martijnse I den Dulk M \nDifferences in circumferential resection margin involvement after abdominoperineal excision and low anterior resection no longer significant . Ann Surg \n2014 ; 259 :1150 –1155 .24096756 \n16. Ihn MH Kim YH Kim DW \nEffects of preoperative chemoradiotherapy on the likelihood of sphincter preservation surgery in locally advanced distal rectal cancer: a longitudinal study based on pelvic magnetic resonance imaging . Ann Surg Oncol \n2015 ; 22 :2159 –2167 .25503346 \n17. Neutzling CB Lustosa SA Proenca IM \nStapled versus handsewn methods for colorectal anastomosis surgery . Cochrane Database Syst Rev \n2012 ; 2 :CD003144 .22336786 \n18. Kuvshinoff B Maghfoor I Miedema B \nDistal margin requirements after preoperative chemoradiotherapy for distal rectal carcinomas: are\\or = 1 cm distal margins sufficient? \nAnn Surg Oncol \n2001 ; 8 :163 –169 .11258782 \n19. Jestin P Pahlman L Gunnarsson U \nRisk factors for anastomotic leakage after rectal cancer surgery: a case-control study . Colorectal Dis \n2008 ; 10 :715 –721 .18318752 \n20. Warschkow R Steffen T Thierbach J \nRisk factors for anastomotic leakage after rectal cancer resection and reconstruction with colorectostomy. A retrospective study with bootstrap analysis . Ann Surg Oncol \n2011 ; 18 :2772 –2782 .21468782\n\n",
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"mesh_terms": "D001003:Anal Canal; D000714:Anastomosis, Surgical; D059248:Chemoradiotherapy; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D009367:Neoplasm Staging; D059351:Organ Sparing Treatments; D010043:Outcome and Process Assessment, Health Care; D010388:Pelvis; D057234:Preoperative Period; D012004:Rectal Neoplasms; D056910:Republic of Korea",
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"title": "Is Preoperative Chemoradiotherapy Beneficial for Sphincter Preservation in Low-Lying Rectal Cancer Patients?",
"title_normalized": "is preoperative chemoradiotherapy beneficial for sphincter preservation in low lying rectal cancer patients"
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"abstract": "BACKGROUND\nKosakonia cowanii, formerly known as Enterobacter cowanii, is a Gram-negative bacillus belonging to the order Enterobacterales. The species is usually recognized as a plant pathogen and has only anecdotally been encountered as a human pathogen. Here we describe the rare case of a K. cowanii infection presenting as an acute cholecystitis and provide a review of available literature. Evident difficulties in species identification by biochemical profiling suggests that potentially, K. cowanii might represent an underestimated human pathogen.\n\n\nMETHODS\nA 61-year old immunocompromised man presented to the hospital with fever and pain in the upper right abdomen. Sonography revealed an inflamed gall bladder and several gall stones. A cholecystectomy proved diagnosis of an acute cholecystitis with a partial necrosis of the gall bladder. Surgical specimen grew pure cultures of Gram-negative rods unambiguously identified as K. cowanii by MALDI-TOF, 16S-rRNA analysis and whole genome sequencing.\n\n\nCONCLUSIONS\nReporting cases of Kosakonia species can shed light on the prevalence and clinical importance of this rare cause of human infection. Our case is the first to describe an infection without prior traumatic inoculation of the pathogen from its usual habitat, a plant, to the patient. This raises the question of the route of infections as well as the pathogen's ability to colonize the human gut.",
"affiliations": "Institute for Medical Microbiology, Virology and Hygiene, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.;Department for Visceral-Surgery, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.;Institute for Medical Microbiology, Virology and Hygiene, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.;Institute for Medical Microbiology, Virology and Hygiene, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.;Institute for Medical Microbiology, Virology and Hygiene, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.;Institute for Medical Microbiology, Virology and Hygiene, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany. rohde@uke.de.",
"authors": "Berinson|Benjamin|B|;Bellon|Eugen|E|;Christner|Martin|M|;Both|Anna|A|;Aepfelbacher|Martin|M|;Rohde|Holger|H|http://orcid.org/0000-0001-8587-4433",
"chemical_list": "D012329:RNA, Bacterial; D012336:RNA, Ribosomal, 16S",
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"doi": "10.1186/s12879-020-05084-6",
"fulltext": "\n==== Front\nBMC Infect Dis\nBMC Infect. Dis\nBMC Infectious Diseases\n1471-2334 BioMed Central London \n\n5084\n10.1186/s12879-020-05084-6\nCase Report\nIdentification of Kosakonia cowanii as a rare cause of acute cholecystitis: case report and review of the literature\nBerinson Benjamin 1 Bellon Eugen 2 Christner Martin 1 Both Anna 1 Aepfelbacher Martin 1 http://orcid.org/0000-0001-8587-4433Rohde Holger rohde@uke.de 1 1 grid.13648.380000 0001 2180 3484Institute for Medical Microbiology, Virology and Hygiene, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany \n2 grid.13648.380000 0001 2180 3484Department for Visceral-Surgery, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany \n24 5 2020 \n24 5 2020 \n2020 \n20 36630 10 2019 12 5 2020 © The Author(s) 2020Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.Background\nKosakonia cowanii, formerly known as Enterobacter cowanii, is a Gram-negative bacillus belonging to the order Enterobacterales. The species is usually recognized as a plant pathogen and has only anecdotally been encountered as a human pathogen. Here we describe the rare case of a K. cowanii infection presenting as an acute cholecystitis and provide a review of available literature. Evident difficulties in species identification by biochemical profiling suggests that potentially, K. cowanii might represent an underestimated human pathogen.\n\nCase presentation\nA 61-year old immunocompromised man presented to the hospital with fever and pain in the upper right abdomen. Sonography revealed an inflamed gall bladder and several gall stones. A cholecystectomy proved diagnosis of an acute cholecystitis with a partial necrosis of the gall bladder. Surgical specimen grew pure cultures of Gram-negative rods unambiguously identified as K. cowanii by MALDI-TOF, 16S-rRNA analysis and whole genome sequencing.\n\nConclusions\nReporting cases of Kosakonia species can shed light on the prevalence and clinical importance of this rare cause of human infection. Our case is the first to describe an infection without prior traumatic inoculation of the pathogen from its usual habitat, a plant, to the patient. This raises the question of the route of infections as well as the pathogen’s ability to colonize the human gut.\n\nKeywords\nCholecystitisDiagnosticsSpecies identificationKosakonia cowaniiWhole genome sequencingCase reportissue-copyright-statement© The Author(s) 2020\n==== Body\nBackground\nFormerly, isolates of the species, now referred to as Kosakonia cowanii, had been placed within the species of Enterobacter agglomerans/Pantoea agglomerans. In the year 2000, the isolates were reclassified into the newly designated species of Enterobacter cowanii [1]. Brady et al. finally proposed the reclassification of the isolates under the name of Kosakonia cowanii based on multi-locus sequence analysis (Brady et al., 2013). K. cowanii is a well-recognized plant pathogen, causing a variety of infections resulting in e.g. wilt and dieback [2]. Although the primary description of K. cowanii as a distinct species also was based on isolates obtained from human specimens, the pathogenic potential in humans remains elusive. Only recently, K. cowanii has been described as a causative agent of rhabdomyolysis and bacteremia related to a rose thorn prick, indicating that infections from exogenous sources can occur [3]. In this report, K. cowanii was identified in two independent intraoperative samples obtained from an immunocompromised patient undergoing cholecystectomy for acute cholecystitis.\n\nCase presentation\nA 61-year-old man presented to the emergency department with recurrent fever of up to 38.9 °C since 4 days, nausea and pain in the upper right abdomen. He had a history of type 2 diabetes mellitus, adequately controlled with Metformin, hypertension and mild osteoporosis. Furthermore, he suffered from psoriatic arthritis, treated with Golimumab 50 mg once per month, Methotrexate 15 mg once per week and Prednisolone 7.5 mg daily.\n\nPhysical examination revealed a tender right upper quadrant and positive Murphy’s sign, while vital signs were normal. Sonography of the abdomen found several gallstones, sludge and thickening of the gallbladder wall of 7 mm. Leucocyte count was 11.9 × 109 /L and C reactive protein 144 mg/dl. Alkaline phosphatase was elevated at 241 U/l, gamma-glutamyl-transferase at 285 U/l and bilirubin at 2.1 mg/dl. According to local guidelines for the treatment of acute cholecystitis, antimicrobial therapy was initiated with intravenous cefuroxime and metronidazole, and a cholecystectomy was performed. Intraoperatively, the diagnosis of acute cholecystitis was confirmed. Partial necrosis of the gallbladder wall and purulent fluid in the right upper abdomen were evident. Cholecystectomy and extensive irrigation of the abdomen were performed laparoscopically without complications. Histology of the removed gallbladder revealed an ulcerophlegmonous cholecystitis with necrotic parts.\n\nThe patient became afebrile one day after surgery. The post-operative course was uncomplicated and the patient was discharged after 3 days. Antimicrobial therapy was changed to an oral application route and continued for additional seven days.\n\nMicrobiology\nTwo independent samples were collected during surgery, one swab from the inside of the gallbladder and one bile sample. Specimens were sent for routine microbiology diagnostics and streaked onto Columbia blood agar and MacConkey agar for aerobic and Schaedler agar for anaerobic incubation, respectively (all media Oxoid, Basingstoke, UK). After 24 h of aerobic and anaerobic incubation at 37 °C, both samples grew pure cultures of a Gram-negative bacillus, identified by matrix-assisted laser desorption ionization/time off light mass spectrometry fingerprinting (MALDI-TOF; Bruker, Bremen, Germany) as K. cowanii.\n\nSpecies identification was confirmed by partial sequencing of the 16S ribosomal RNA (rRNA) gene, which showed 100% identity of non-ambiguous bases to the 16S rRNA of K. cowanii type strain 888–76 (GenBank accession number CP019445.1) [4]. Notably, biochemical species-level identification, performed with VITEK2 GN ID card (Biomerieux, Marcy-l’Etoile, France), incorrectly identified the strain as Pantoea spp. with a certainty of 98%.\n\nMinimal inhibitory concentrations (MICs) were determined by gradient diffusion (Etest, Biomerieux, Marcy-l’Etoile, France; Liofilchem, Roseto degli Abruzzi, Italy), and verified by broth microdilution (Micronaut-S MDR MRGN-Screening 2 and Micronaut-S β-Lactamases, Merlin Diagnostika, Bornheim, Germany) (Table 1).\nTable 1 Antimicrobial susceptibility profile of K. cowanii from a cholecystitis\n\nAntibiotic substance\tMICa [mg/mL]\tInterpretationb\t\nAmpicillin\t≥ 256\tR\t\nAmpicillin/Sulbactam\t≤ 2\tS\t\nCefoxitin\t4\tWildtype\t\nPiperacillin\t8\tS\t\nPiperacillin/Tazobactam\t≤ 0,5\tS\t\nFosfomycin\t≥ 64\tR\t\nMeropenem\t≤ 0.0032\tS\t\nCiprofloxacin\t≤ 0.04\tS\t\nColistin\t≤ 1\tS\t\naMICs as determined by Etest and broth microdilution for K. cowanii clinical isolate\n\nbInterpretation according to EUCAST criteria for Enterobacterales (The European Committee on Antimicrobial Susceptibility Testing. Breakpoint tables for interpretation of MICs and zone diameters. Version 9.0, 2018. http://eucast.org)\n\n\n\nWhole genome sequencing of the isolate was performed using the Illumina NextSeq platform. Reads were assembled with spades [5] and annotated with prokka [6]. The draft genome comprises 50 contigs larger than 200 base pairs with a total length of 4.9 million base pairs and a G + C-content of 56.2%. Bioinformatic analysis showed 98.4% average nucleotide identity to K. cowanii 888–76 [7], and a genome to genome distance between the two strains corresponding to a DNA-DNA hybridization relative binding ratio of 86.7% [8], thus confirming MALDI-TOF- and 16S-based species-level identification. The virulence gene profile determined with abricate (https://github.com/tseemann/abricate) and the virulence factor database [9] matched the profile of the K. cowanii type strain 887–76, which also originates from a clinical sample. In agreement with phenotypic testing (Table 1) resistance gene profiling identified a class A beta-lactamase showing 98.6% amino acid identity to the beta-lactamase of K. cowanii 888–76 (Genebank accession number APZ06536.1) but no class C beta-lactamase as typically encountered in other Enterobacter-like species. Sequencing reads have been deposited in NCBI’s small reads archive (SRR8572161). The strain was deposited at the German Collection of Microorganisms and Cell Cultures GmbH (DSMZ) (reference number DSM 108916).\n\nDiscussion and conclusions\nAcute cholecystitis, which is a sudden inflammation of the gallbladder, is a common diagnosis worldwide. This disease is in more than 90% of the cases a complication of a cholecystolithiasis, complicated by an infection with predominantly Gram-negative bacteria of the order of Enterobacterales [10]. In Germany more than 63.000 cases of cholecystitis were reported in 2010 [11]. Cholecystitis is regarded as a typical endogenous infection caused by pathogens derived from the patient’s microbiota.\n\nHere we describe the first case of cholecystitis caused by K. cowanii in an immunocompromised man. Conventionally, K. cowanii is regarded as a plant pathogen and probably only rarely causes human infections. In fact, to our knowledge only one case report so far unambiguously identified K. cowanii as a causative agent in the context of a human infection. In that patient, rhabdomyolysis and bacteremia occurred after a rose thorn prick, i.e. most likely resulted from an exogenous source potentially contaminated with K. cowanii [3]. In contrast, in our case K. cowanii caused an endogenous infection. This could have potentially resulted from ingestion of food containing K. cowanii, resulting in a transient colonization of the patient’s gut. Studies in the past have shown, that K. cowanii is a food contaminant, shown by its presence in powdered infant formula milk and on edible flowers or basil leaves [12, 13]. Further studies are needed to clarify if K. cowanii also might be able to permanently colonize the human intestine.\n\nAs so far described, patients receiving a powerful immunomodulatory medication of Golimumab and Methotrexate develop more infections than a placebo controlled group. Higher rates of infections also occurred with higher doses of Golimumab. These infections usually consist of respiratory infections up to pneumonia or urinary tract, but cases of acute cholecystitis also have been described [14, 15]. One can therefore argue that the administered medication might have facilitated the development of the infection with this rather uncommon pathogen.\n\nIt needs to be stressed that the species most probably will be misidentified if conventional biochemical differentiation systems are being employed, potentially leading to an underestimation of K. cowanii’s true importance as a human pathogen. Intriguingly, a retrospective study identified 53 pediatric cases of infection with Pantoea agglomerans, of which 7 had a penetrating trauma with a plant thorn, stick or glass shard [16]. A more thorough analysis of infections in which Pantoea agglomerans is tentatively identified as the causative agent might in fact reveal K. cowanii as the real pathogen. As already observed with other pathogens, the broad implementation of MALDI-TOF whole cell mass fingerprinting technology as the first line technique for routine microbiological differentiation might also shed light on the prevalence of K. cowanii and other plant pathogens in human infections.\n\nAbbreviations\nMALDI-TOFMatrix-assisted laser desorption/ionization - time of flight\n\nDSMZGerman Collection of Microorganisms and Cell Cultures GmbH\n\nMICminimal inhibitory concentration\n\nrRNAribosomal ribonucleic acid\n\nDNADeoxyribonucleic acid\n\nEUCASTEuropean Committee on Antimicrobial Susceptibility Testing\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nNot applicable.\n\nAuthors’ contributions\nBB analyzed data and wrote the manuscript. EB added clinical data and contributed to manuscript preparation. MC analyzed the whole genome sequencing data. AB analyzed data and wrote the manuscript. MA and HR designed the study and wrote the manuscript. All authors read and approved the final manuscript.\n\nFunding\nNone.\n\nAvailability of data and materials\nThe isolate was submitted to the German Collection of Microorganisms and Cell Cultures (DSMZ) as DSM 108916.\n\nThe isolate’s 16S sequence was deposited to NCBI GenBank under accession number MK517531.\n\nNext generation sequencing data was deposited to NCBI’s sequence read archive (SRA) under BioProject number PRJNA522304.\n\nEthics approval and consent to participate\nThe study was conducted in accordance to §12 of the Hamburg Hospital Law (HmbKHG) from 17.04.1991, therefore no ethics committee approval was needed.\n\nConsent for publication\nPatient’s written informed consent to publish potentially identifying images and clinical details was obtained.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n==== Refs\nReferences\n1. Inoue K Sugiyama K Kosako Y Sakazaki R Yamai S Enterobacter cowaniisp. Nov., a new species of the family Enterobacteriaceae Curr Microbiol 2000 41 6 417 420 10.1007/s002840010160 11080391 \n2. Brady CL Venter SN Cleenwerck I Engelbeen K de Vos P Wingfield MJ Telechea N Coutinho TA Isolation of Enterobacter cowanii from Eucalyptus showing symptoms of bacterial blight and dieback in Uruguay Lett Appl Microbiol 2009 49 4 461 465 10.1111/j.1472-765X.2009.02692.x 19674289 \n3. Washio K Yamamoto G Ikemachi M Fujii S Ohnuma K Masaki T Rhabdomyolysis due to bacteremia from Enterobacter cowanii caused by a rose thorn prick J Dermatol 2018 45 11 e313 e314 10.1111/1346-8138.14341 29696688 \n4. Yang XJ Wang S Cao JM Hou JH Complete genome sequence of human pathogen Kosakonia cowanii type strain 888-76(T) Braz J Microbiol 2018 49 1 16 17 10.1016/j.bjm.2017.03.010 28774637 \n5. Bankevich A Nurk S Antipov D Gurevich AA Dvorkin M Kulikov AS Lesin VM Nikolenko SI Pham S Prjibelski AD SPAdes: a new genome assembly algorithm and its applications to single-cell sequencing J Comput Biol 2012 19 5 455 477 10.1089/cmb.2012.0021 22506599 \n6. Seemann T Prokka: rapid prokaryotic genome annotation Bioinformatics 2014 30 14 2068 2069 10.1093/bioinformatics/btu153 24642063 \n7. Yoon SH Ha SM Lim J Kwon S Chun J A large-scale evaluation of algorithms to calculate average nucleotide identity Antonie Van Leeuwenhoek 2017 110 10 1281 1286 10.1007/s10482-017-0844-4 28204908 \n8. Meier-Kolthoff JP Auch AF Klenk HP Goker M Genome sequence-based species delimitation with confidence intervals and improved distance functions BMC Bioinformatics 2013 14 60 10.1186/1471-2105-14-60 23432962 \n9. Chen L Yang J Yu J Yao Z Sun L Shen Y Jin Q VFDB: a reference database for bacterial virulence factors Nucleic Acids Res 2005 33 Database issue D325 D328 10.1093/nar/gki008 15608208 \n10. Liu J Yan Q Luo F Shang D Wu D Zhang H Shang X Kang X Abdo M Liu B Acute cholecystitis associated with infection of Enterobacteriaceae from gut microbiota Clin Microbiol Infect 2015 21 9 851 10.1016/j.cmi.2015.05.017 \n11. Gotzky K Landwehr P Jahne J Epidemiology and clinical presentation of acute cholecystitis Chirurg 2013 84 3 179 184 10.1007/s00104-012-2355-1 23404248 \n12. Wetzel K Lee J Lee CS Binkley M Comparison of microbial diversity of edible flowers and basil grown with organic versus conventional methods Can J Microbiol 2010 56 11 943 951 10.1139/W10-082 21076485 \n13. Mardaneh J Soltan-Dallal MM Isolation and identification of E. cowanii from powdered infant formula in NICU and determination of antimicrobial susceptibility of isolates Iran J Pediatr 2014 24 3 261 266 25562018 \n14. Tesser J Kafka S DeHoratius RJ Xu S Hsia EC Turkiewicz A Efficacy and safety of intravenous golimumab plus methotrexate in patients with rheumatoid arthritis aged < 65 years and those >/= 65 years of age Arthritis Res Ther 2019 21 1 190 10.1186/s13075-019-1968-x 31429794 \n15. Kay J Fleischmann R Keystone E Hsia EC Hsu B Mack M Goldstein N Braun J Kavanaugh A Golimumab 3-year safety update: an analysis of pooled data from the long-term extensions of randomised, double-blind, placebo-controlled trials conducted in patients with rheumatoid arthritis, psoriatic arthritis or ankylosing spondylitis Ann Rheum Dis 2015 74 3 538 546 10.1136/annrheumdis-2013-204195 24344160 \n16. Cruz AT Cazacu AC Allen CH Pantoea agglomerans, a plant pathogen causing human disease J Clin Microbiol 2007 45 6 1989 1992 10.1128/JCM.00632-07 17442803\n\n",
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"keywords": "Case report; Cholecystitis; Diagnostics; Kosakonia cowanii; Species identification; Whole genome sequencing",
"medline_ta": "BMC Infect Dis",
"mesh_terms": "D002763:Cholecystectomy; D041881:Cholecystitis, Acute; D004755:Enterobacteriaceae; D004756:Enterobacteriaceae Infections; D005704:Gallbladder; D042882:Gallstones; D006801:Humans; D016867:Immunocompromised Host; D008297:Male; D008875:Middle Aged; D009336:Necrosis; D012329:RNA, Bacterial; D012336:RNA, Ribosomal, 16S; D035583:Rare Diseases; D016896:Treatment Outcome; D000073336:Whole Genome Sequencing",
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"title": "Identification of Kosakonia cowanii as a rare cause of acute cholecystitis: case report and review of the literature.",
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"abstract": "The yellow fever vaccines on the market are contraindicated for immunocompromised and elderly patients. A case of yellow fever vaccine used in a 27-year-old Slovenian male with psoriatic arthritis during treatment with methotrexate is described. We demonstrate a positive case, since there were no adverse effects in concurrent administration of yellow fever vaccine and methotrexate. This patient did not show severe adverse reactions and did not contract yellow fever despite potential exposure. More research is needed on possible adverse effects of concurrent administration of yellow fever vaccine and methotrexate to determine the potential of this method for more frequent use.",
"affiliations": "Department of Clinical Pharmacy, Ormož Hospital, Ormož, Slovenia. Corresponding author: matejstuhec@gmail.com.",
"authors": "Stuhec|Matej|M|",
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"title": "Yellow fever vaccine used in a psoriatic arthritis patient treated with methotrexate: a case report.",
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"abstract": "We examined the efficacy and tolerability of calcitonin gene-related peptide-targeted monoclonal antibodies (CGRP-targeted mAbs) as add-on therapy for patients with chronic migraine (CM) undergoing treatment with onabotulinumtoxinA (onabot) who require additional preventive therapy.\n\n\n\nWe reviewed medical records of patients with CM receiving treatment with onabot who were subsequently prescribed a CGRP-targeted mAb medication. The primary outcome was the change in number of monthly headache days (MHDs) reported. Secondary outcomes were change in headache pain severity, discontinuation due to lack of tolerability, and severe adverse events.\n\n\n\nOf 153 patients, 111 (72.5%) reported a decrease in either MHDs or headache pain severity, with documentation of MHDs in 66 patients. Among these 66 patients, the average number of MHDs before initiation of onabot treatment was 25.7. After onabot treatment, an average decrease of 10.9 MHDs was reported (P < 0.001). After the addition of a CGRP-targeted mAb medication, patients experienced a further decrease of 5.7 MHDs (P < 0.001). With combined therapy, patients reported a total decrease of 16.6 MHDs (P < 0.001). Adverse effects occurred in 13 patients (8.5%) after addition of the CGRP-targeted mAb and included constipation, injection site reaction, and fatigue. No serious adverse events were reported.\n\n\n\nAdding a CGRP-targeted mAb to onabot in patients with CM was associated with further reductions in MHDs without major tolerability issues across a range of mAbs. This retrospective review supports the conduct of a well-designed double-blind study adding a CGRP-targeted mAb or placebo to onabot.",
"affiliations": "Department of Medicine, Montefiore Medical Center and the Albert Einstein College of Medicine, Bronx, New York.;Department of Neurology, Montefiore Medical Center and the Albert Einstein College of Medicine, Bronx, New York.;Department of Neurology, Montefiore Medical Center and the Albert Einstein College of Medicine, Bronx, New York.;Department of Neurology, Columbia University Medical Center, New York, New York, USA.",
"authors": "Cohen|Fred|F|0000-0003-3436-2846;Armand|Cynthia|C|;Lipton|Richard B|RB|;Vollbracht|Sarah|S|",
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"keywords": "Calcitonin Gene–Related Peptide; Chronic Migraine; Efficacy; OnabotulinumtoxinA; Tolerability",
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"mesh_terms": "D000911:Antibodies, Monoclonal; D019274:Botulinum Toxins, Type A; D002116:Calcitonin; D015740:Calcitonin Gene-Related Peptide; D006801:Humans; D008881:Migraine Disorders; D012189:Retrospective Studies; D016896:Treatment Outcome",
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"title": "Efficacy and Tolerability of Calcitonin Gene-Related Peptide-Targeted Monoclonal Antibody Medications as Add-on Therapy to OnabotulinumtoxinA in Patients with Chronic Migraine.",
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"abstract": "Immune checkpoint inhibitors can be potentially cardiotoxic. It has not been frequently reported in the literature. Cardiomyopathy with these agents can have early onset and may start with non-specific symptoms like fatigue, weakness before presenting with obvious features of acute heart failure. Rapid progression and fulminant course of this disease necessitate high index of clinical suspicion and early diagnosis. High-dose steroids should be instituted early to blunt the immune response against myocardium. Further bigger studies are needed to fully understand the pathogenesis of this condition.",
"affiliations": "Department of Advanced Heart Failure and Pulmonary Hypertension, Hackensack University Medical Center, NJ, USA.;Department of Internal Medicine, Rutgers-NJMS, NJ, USA.;Department of Advanced Heart Failure and Pulmonary Hypertension, Hackensack University Medical Center, NJ, USA.",
"authors": "Sharma|Munish|M|;Suero-Abreu|Giselle A|GA|;Kim|Bernard|B|",
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"fulltext": "\n==== Front\nCardiol ResCardiol ResElmer PressCardiology Research1923-28291923-2837Elmer Press 10.14740/cr838Case ReportA Case of Acute Heart Failure due to Immune Checkpoint Blocker Nivolumab Acute Heart Failure due to NivolumabSharma Munish acSuero-Abreu Giselle A. bKim Bernard aa Department of Advanced Heart Failure and Pulmonary Hypertension, Hackensack University Medical Center, NJ, USAb Department of Internal Medicine, Rutgers-NJMS, NJ, USAc Corresponding Author: Munish Sharma, Department of Advanced Heart Failure and Pulmonary Hypertension, Hackensack University Medical Center, NJ 07601, USA. Email: munishs1@hotmail.com4 2019 11 4 2019 10 2 120 123 28 1 2019 15 2 2019 Copyright 2019, Sharma et al.2019This article is distributed under the terms of the Creative Commons Attribution Non-Commercial 4.0 International License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Immune checkpoint inhibitors can be potentially cardiotoxic. It has not been frequently reported in the literature. Cardiomyopathy with these agents can have early onset and may start with non-specific symptoms like fatigue, weakness before presenting with obvious features of acute heart failure. Rapid progression and fulminant course of this disease necessitate high index of clinical suspicion and early diagnosis. High-dose steroids should be instituted early to blunt the immune response against myocardium. Further bigger studies are needed to fully understand the pathogenesis of this condition.\n\nImmune checkpoint inhibitorCardiomyopathyAcute heart failure\n==== Body\nIntroduction\nImmune checkpoint inhibitors consist of ipilimumab, an anti-cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) antibody, nivolumab and pembrolizumab, which are anti-programmed death-1 (PD-1) antibodies. Nivolumab inhibits PD-1 receptor on T cells and blocks PD-1 pathway-mediated anti-tumor immune response inhibition [1]. Apart from malignant melanoma, non-small cell lung cancer (NSCLC) and renal cell carcinoma (RCC), nivolumab has been found to exhibit effective antitumor activity in patients with relapsed or refractory B- and T-cell lymphomas who received pretreatment [2]. Due to aberrant activity of autoreactive T cells, immune checkpoint inhibitors have been found to be associated with dermatitis, endocrinopathies, colitis, pneumonitis and hepatitis [3]. Cardiotoxicity associated with immune checkpoint inhibitors when used alone or in combination is rare and has been reported only in a few case reports and case series studies [3, 4]. We present a case of acute heart failure in a patient started on nivolumab for treatment of angioimmunoblastic T-cell lymphoma (AITL).\n\nCase Report\nA 76-year-old female patient with history of psoriatic arthritis treated with methotrexate and ustekinumab in the past, seizure disorder on leviteracetam and AITL with central nervous system (CNS) involvement was admitted to our hospital on July 19, 2018 due to extreme fatigue and worsening shortness of breath (SOB) over a period of 1 week. Her SOB was new and rapidly worsened to be present even with minimal exertion. She complained of orthopnea but no paroxysmal nocturnal dyspnea. Patient was diagnosed with AITL in January 2018 and was treated with brentuximab vedotin, cyclophosphamide, doxorubicin, prednisone, and etoposide along with intrathecal methotrexate for CNS involvement. She was started on a combination of brentuximab and nivolumab 22 days prior to this hospitalization. On our initial examination in cardiac care unit, her blood pressure was 67/48 mm Hg, heart rate 104 beats per minute (bpm), temperature 97.2 Fahrenheit, respiratory rate 31/min and saturation 96 % on 1.5 liters of oxygen via nasal cannula. Her total leucocyte count was 11 × 103 cells/mL (reference range: 4 - 11 × 103), hemoglobin 9.7 g/dL (reference range: 12 - 15.5), blood urea nitrogen (BUN) 30 mg/dL (reference range: 5 - 24), creatinine 1.2 mg/dL (reference range: 0.3 - 1.5), serum sodium 128 mmol/L (reference range: 134 - 146), potassium 5.3 mmol/L (reference range: 3.5 - 5.2), carbon dioxide (CO2) 22 mmol/L (reference range: 24 - 32), troponin I 0.060 ng/mL (reference range: 0.0 - 0.030) and brain natriuretic peptide (BNP) 892 pg/mL (reference range: 0 - 100). Electrocardiogram (ECG) showed sinus tachycardia with no ST-T changes (Fig. 1). Chest X-ray revealed interstitial edema and bibasilar pleural parenchymal opacification. Transthoracic echocardiogram (TTE) was significant for severely reduced left ventricular ejection fraction (LVEF) of less than 20 %, moderate pericardial effusion, moderate mitral regurgitation (MR), severe tricuspid regurgitation (TR) and mildly dilated right ventricular cavity (Fig. 2a, b). TTE in June 14, 2018 had revealed LVEF of 55 %, grade I diastolic dysfunction, mild MR/TR with no pericardial effusion (Table 1, Fig. 3a-c). Computed tomography (CT) chest showed bilateral small pleural effusions and a small new pericardial effusion (Fig. 4). Viral serology from peripheral blood was non-reactive for adenovirus, enterovirus, Coxsackie virus, Ebstein-Barr virus (EBV) and cytomegalovirus (CMV). She was negative for hepatitis B/hepatitis C and human immune deficiency virus (HIV) in the recent past. Thyroid-stimulating hormone (TSH) was 2.612 uIU/L (reference range: 0.5 - 5.0) and serum protein electrophoresis did not reveal any monoclonal protein peak.\n\nFigure 1 ECG on July 27, 2018: left axis deviation, sinus tachycardia and low voltage.\n\nFigure 2 Echocardiogram obtained during hospital admission showing low ejection fraction.\n\nTable 1 Two-Dimensional Transthoracic Echogardiogram (TTE) Report on July 21, 2018\nPericardium\tModerate pericardial effusion\t\nLeft ventricle\tSeverely reduced systolic function, ejection fraction estimated at less than 20%, unable to assess left ventricle diastolic function (tachycardia), mild asymmetric hypertrophy\t\nRight ventricle\tCavity mildly dilated\t\nRight atrium\tCavity mildly dilated\t\nInferior vena cava\tDilated (> 2.1 cm) with less than 50% respiratory collapse with an estimated right atrial pressure of 15 mm Hg\t\nMitral valve\tMild to moderate regurgitation on color-flow PW Doppler\t\nTricuspid valve\tModerate to severe regurgitation on color-flow PW Doppler\t\nAortic valve\tThe aortic valve is sclerotic without reduced excursion, no stenosis, trace regurgitation on color-flow PW Doppler\t\nPulmonic valve\tThe pulmonic valve was not well visualized, trace regurgitation on color-flow PW Doppler\t\nIn comparison to the previous study dated June 14, 2018, there is significant change noted (moderate pericardial effusion is seen and LVEF is severely reduced at < 20%).\n\nFigure 3 (a) Echocardiogram done on June 14, 2018 showing normal ejection fraction by biplane. (b, c) Echocardiogram done on June 14, 2018.\n\nFigure 4 CT chest showing bilateral pleural effusion.\n\nA Swann-Ganz catheter was placed to monitor cardiac hemodynamics. Her cardiac index was 1.5 L/min/m2. Patient was started on milrinone drip. Timely mixed venous oxygen saturation was drawn and milrinone was up-titrated to up to 0.6 mg/kg/min to achieve optimal cardiac output. Patient was also on norephinephrine drip to maintain a mean arterial pressure of 65 mm Hg or more. She was also treated with 1 mg/kg of intravenous solumedrol. After 3 days, patient did not show any sign of improvement on inotrope support and underwent implantation of right-sided axillary Impella 5.0 and Impella RP. Repeat TTE on July 28 showed LVEF of less than 20 %, severely dilated right ventricle and mild pericardial effusion. Patient continued to remain sedated and ventilated after Impella implantation. An extensive discussion was done between the patient’s family members including her power of attorney, primary oncologist and cardiologist. In view of extremely poor prognosis of her widely spread T-cell lymphoma and acute de novo heart failure, family opted to terminally extubate the patient.\n\nDiscussion\nImmune checkpoint inhibitors have been found to be promising in inducing antitumor activity in malignancies including melanoma, NSCLC, RCC and T- and B-cell lymphomas but overall immune-mediated adverse reactions have been found to be as high as 40% [5]. These agents can have significant cardiac adverse effects that can manifest as autoimmune myocarditis, cardiomyopathy, cardiac fibrosis, heart failure and cardiac arrest [4]. Cardiac toxicity per se has been estimated to occur in less than 1% patients receiving this immunotherapy. Combination of ipilimumab and nivolumab has been found to produce more severe and frequent cardiotoxicity compared to patients on nivolumab alone [3]. It has been previously reported that two or more organs systems can have simultaneous immune-mediated manifestations with ipilimumab (7%) and ipilimumab-nivolumab (31%). Thus special attention needs to be paid for development of cardiotoxicity in those patients who have already experienced an immune-mediated reaction but in absence of predictive biomarkers it is difficult to prevent an impending immune-mediated reaction [6]. The mechanism of adverse events related to immune checkpoint inhibitors has not been fully understood. Studies in mice have shown that deficiency of CTLA-4 induces severe myocarditis due to rampant lymphocytic infiltration [7]. Since PD-1 is known to be cardio-protective as it inhibits tissue inflammation and myocardial damage, studies have shown that mice with PD1−/− CD8+ T cells compared to mice with PD1+/+ CD8+ T cells tend to develop severe myocarditis [8]. Spontaneous autoimmune dilated cardiomyopathy can also be seen in mice with PL-1 deficiency [9]. Thus, checkpoint inhibitors likely lower the threshold of activation of T cells against the self-antigen in the heart [4].\n\nIn a case series of eight patients, cardiotoxicity occurred within 4 - 22 weeks after initiation of check point inhibitors alone or in combination [4]. In another case series of two patients, fulminant myocarditis occurred within 12 - 15 days of initial therapy. All of these patients were started at 1 mg/kg of nivolumab alone or in combination [3, 4]. In our case, patient presented with low output cardiogenic shock within 22 days of initiation of nivolumab 1 mg/kg, which was her only new medication. Endomyocardial biopsy can show features of interstitial inflammation suggested by infiltration of lymphocytes and interstitial fibrosis. Cardiac magnetic resonance imaging (MRI) can reveal enhanced T2 signal suggestive of underlying myocardial edema suggestive of myocarditis. Our patient presented with cardiogenic shock and could not be subjected to endomyocardial biopsy but cardiac MRI could have been contemplated if she had stabilized during the course of treatment. Significant drop in LVEF in echocardiography in absence of other identifiable causes can indicate immune-mediated cardiotoxicity in patients recently started on immune therapy. Though there is no definite treatment protocol in general, smaller studies have shown improvement in LVEF with intravenous methyl prednisone 1 - 2 mg/kg while in the hospital. This can be transitioned to oral prednisone on discharge and tapered over a period of month [4]. There are no bigger studies conducted so far to determine the prognosis of such cases but few case series have shown recovery in around 60 % cases with some permanent decrease in LVEF [3, 4].\n\nConclusions\nClinicians must be aware of the potential cardiotoxicity of immune checkpoint inhibitors. It can have early onset and may start with non-specific symptoms like fatigue, weakness before presenting with obvious features of acute heart failure. Rapid progression and fulminant course of this disease necessitate high index of clinical suspicion and early diagnosis. Endomyocardial biopsy can reveal features of myocarditis and fibrosis, but due to its invasive nature, may not be a suitable test in critically ill patients. Careful history, examination and interpretation of basic non-invasive test like echocardiography can give clue to diagnosis. High-dose steroids should be instituted early to blunt the immune response against myocardium. Further bigger studies are needed to fully understand the pathogenesis of this condition so that more specific and effective treatment strategies can be devised.\n\nConflict of Interest\nAuthors declare no conflict of interest.\n==== Refs\nReferences\n1 Andorsky DJ Yamada RE Said J Pinkus GS Betting DJ Timmerman JM Programmed death ligand 1 is expressed by non-hodgkin lymphomas and inhibits the activity of tumor-associated T cells Clin Cancer Res 2011 17 13 4232 4244 10.1158/1078-0432.CCR-10-2660 21540239 \n2 Lesokhin AM Ansell SM Armand P Scott EC Halwani A Gutierrez M Millenson MM et al Nivolumab in patients with relapsed or refractory hematologic malignancy: preliminary results of a phase Ib study J Clin Oncol 2016 34 23 2698 2704 10.1200/JCO.2015.65.9789 27269947 \n3 Johnson DB Balko JM Compton ML Chalkias S Gorham J Xu Y Hicks M et al Fulminant myocarditis with combination immune checkpoint blockade N Engl J Med 2016 375 18 1749 1755 10.1056/NEJMoa1609214 27806233 \n4 Heinzerling L Ott PA Hodi FS Husain AN Tajmir-Riahi A Tawbi H Pauschinger M et al Cardiotoxicity associated with CTLA4 and PD1 blocking immunotherapy J Immunother Cancer 2016 4 50 10.1186/s40425-016-0152-y 27532025 \n5 Postow MA Chesney J Pavlick AC Robert C Grossmann K McDermott D Linette GP et al Nivolumab and ipilimumab versus ipilimumab in untreated melanoma N Engl J Med 2015 372 21 2006 2017 10.1056/NEJMoa1414428 25891304 \n6 Voskens CJ Goldinger SM Loquai C Robert C Kaehler KC Berking C Bergmann T et al The price of tumor control: an analysis of rare side effects of anti-CTLA-4 therapy in metastatic melanoma from the ipilimumab network PLoS One 2013 8 1 e53745 10.1371/journal.pone.0053745 23341990 \n7 Tivol EA Borriello F Schweitzer AN Lynch WP Bluestone JA Sharpe AH Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4 Immunity 1995 3 5 541 547 10.1016/1074-7613(95)90125-6 7584144 \n8 Tarrio ML Grabie N Bu DX Sharpe AH Lichtman AH PD-1 protects against inflammation and myocyte damage in T cell-mediated myocarditis J Immunol 2012 188 10 4876 4884 10.4049/jimmunol.1200389 22491251 \n9 Nishimura H Okazaki T Tanaka Y Nakatani K Hara M Matsumori A Sasayama S et al Autoimmune dilated cardiomyopathy in PD-1 receptor-deficient mice Science 2001 291 5502 319 322 10.1126/science.291.5502.319 11209085\n\n",
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"issue": "10(2)",
"journal": "Cardiology research",
"keywords": "Acute heart failure; Cardiomyopathy; Immune checkpoint inhibitor",
"medline_ta": "Cardiol Res",
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"title": "A Case of Acute Heart Failure due to Immune Checkpoint Blocker Nivolumab.",
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"abstract": "Central vein disease is defined as at least 50% narrowing up to total occlusion of central veins of the thorax including superior vena cava, brachiocephalic, subclavian, and internal jugular vein. Thrombosis due to intravascular leads occurs in approximately 30% to 45% of patients early or late after implantation of a pacemaker by transvenous access.In this case, we report a male patient, 65-years old, hypertensive, type 2 diabetic, with atherosclerotic disease, coronary artery disease, underwent coronary artery bypass surgery in the past 10 years, having already experienced an acute myocardial infarction, bearer automatic implantable cardioverter defibrillator for 8 years after an episode of aborted sudden death due to ischemic cardiomyopathy, presenting left superior vena cava syndrome. The use of clopidogrel and rivaroxaban for over a year had no benefit on symptoms improvement.After atrial and ventricular leads extraction, a new shock lead was positioned in the right ventricle using active fixation and a new atrial lead was positioned in the right atrium, passing inside of the stents. Two days after the procedure the patient was asymptomatic and was discharged.",
"affiliations": "From the Cardiac Surgery Division, Department of Medicine, Universidade Federal Fluminense, Niterói (MGK, GRDS); Cardiac Surgery Department (MGK, GRDS); Vascular Surgery Department, Hospital Regional Darcy Vargas, Rio Bonito, RJ, Brazil (RLLA, HBS); Department of Cardiology, Shanghai First People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China (SC); Fellowship of European Heart Rhythm Association/European Society of Cardiology, Department of Cardiology, Elisabethinen University Teaching Hospital Linz, Linz, Austria (SC); and Cardiology Division, Department of Medicine, Universidade Federal Fluminense, Niterói, RJ, Brazil (HVJ).",
"authors": "Kiuchi|Márcio Galindo|MG|;Andrade|Ricardo Luiz Lima|RLL|;Silva|Gustavo Ramalho da|GRD|;Souto|Hanry Barros|HB|;Chen|Shaojie|S|;Junior|Humberto Villacorta|HV|",
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"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 2640280310.1097/MD.0000000000001481014813400Research ArticleClinical Case ReportICD Leads Extraction and Clearing of Access Way in a Patient With Superior Vena Cava Syndrome Building A TunnelKiuchi Márcio Galindo MD, MSc, PhDAndrade Ricardo Luiz Lima MDda Silva Gustavo Ramalho MDSouto Hanry Barros MDChen Shaojie MD, PhDJunior Humberto Villacorta MD, PhDVitarelli. Antonio From the Cardiac Surgery Division, Department of Medicine, Universidade Federal Fluminense, Niterói (MGK, GRDS); Cardiac Surgery Department (MGK, GRDS); Vascular Surgery Department, Hospital Regional Darcy Vargas, Rio Bonito, RJ, Brazil (RLLA, HBS); Department of Cardiology, Shanghai First People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China (SC); Fellowship of European Heart Rhythm Association/European Society of Cardiology, Department of Cardiology, Elisabethinen University Teaching Hospital Linz, Linz, Austria (SC); and Cardiology Division, Department of Medicine, Universidade Federal Fluminense, Niterói, RJ, Brazil (HVJ).Correspondence: Marcio Galindo Kiuchi, Universidade Federal Fluminense, Niteroi, Rio de Janeiro, Brazil (e-mail: marciokiuchi@gmail.com).9 2015 25 9 2015 94 38 e14819 7 2015 3 8 2015 9 8 2015 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.2015This is an open access article 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 the author is credited and the new creations are licensed under the identical terms. http://creativecommons.org/licenses/by-nc-sa/4.0Abstract\nCentral vein disease is defined as at least 50% narrowing up to total occlusion of central veins of the thorax including superior vena cava, brachiocephalic, subclavian, and internal jugular vein. Thrombosis due to intravascular leads occurs in approximately 30% to 45% of patients early or late after implantation of a pacemaker by transvenous access.\n\nIn this case, we report a male patient, 65-years old, hypertensive, type 2 diabetic, with atherosclerotic disease, coronary artery disease, underwent coronary artery bypass surgery in the past 10 years, having already experienced an acute myocardial infarction, bearer automatic implantable cardioverter defibrillator for 8 years after an episode of aborted sudden death due to ischemic cardiomyopathy, presenting left superior vena cava syndrome. The use of clopidogrel and rivaroxaban for over a year had no benefit on symptoms improvement.\n\nAfter atrial and ventricular leads extraction, a new shock lead was positioned in the right ventricle using active fixation and a new atrial lead was positioned in the right atrium, passing inside of the stents. Two days after the procedure the patient was asymptomatic and was discharged.\n\nOPEN-ACCESSTRUE\n==== Body\nCentral vein disease is defined as at least 50% narrowing up to total occlusion of central veins of the thorax including superior vena cava, brachiocephalic, subclavian, and internal jugular vein.1 Obstruction can be caused by invasion or external compression of the superior vena cava by adjacent pathologic processes involving the lung, lymph nodes, and other mediastinal structures or by thrombosis within the superior vena cava.2 In the past, infectious lesions were common causes; however, nowadays malignancy and the use of intravascular devices and cardiac pacemakers have become the main causes.2,3 Thrombosis due to intravascular leads occurs in approximately 30% to 45% of patients early or late after implantation of a pacemaker by a transvenous access.4 Several patients may be asymptomatic because they develop efficient collateral circulation. The incidence of pacemaker-induced superior vena cava syndrome has been reported to be less than 0.1%.5 In the meantime, the superior vena cava syndrome associated with internal leads may be a benign condition, or a debilitating and sometimes intractable complication. Furthermore, there is no consensus on a standard care management.6\n\nAngioplasty and stent placement have been established as a less invasive but equally effective alternative to open surgical treatment.7 Meanwhile, angioplasty is potentially associated with lead damage and dysfunction. The trapping and crushing of leads by a stent would be an insolvable situation if the device gets infected. A percutaneous approach consisting of lead removal, stent implantation, and reimplantation of leads has been described with good results over the short and medium term follow-up.8 Long-term efficacy of this approach is still unknown. A recent study reported that percutaneous stent implantation after lead removal followed by reimplantation of leads is a feasible alternative therapy for pacemaker-induced superior vena cava syndrome, although some cases may require repeat intervention.9\n\nIn this case, we report a male patient, 65-years old, hypertensive, type 2 diabetic, with atherosclerotic disease, coronary artery disease, underwent coronary artery bypass surgery in the past 10 years, having already experienced an acute myocardial infarction, bearer automatic implantable cardioverter defibrillator (ICD) (Fig. 1) for 8 years after an episode of aborted sudden death due to ischemic cardiomyopathy, presenting left superior vena cava syndrome with the following symptoms: arms, neck, and face edema, besides development of swollen collateral veins on the chest wall, shortness of breath, and cough (the ethics committee composed by Paola Baars Gomes Moises, Luis Marcelo Rodrigues Paz, Humberto Cesar Tinoco e Jonny Shogo Takahashi, approved the execution of the case). Informed consent was signed by the patient.\n\nFIGURE 1 Previous automatic implantable cardioverter defibrillator (A), (B), (C), and (D).\n\nThe use of clopidogrel and rivaroxaban for over a year had no benefit on symptoms improvement. The computed tomography angiography of the thoracic venous system showed a noted marked diameter reduction with irregular opacification in the brachiocephalic veins and distal half of the superior vena cava. This structure had normal caliber and was well opacified from the confluence with the azygos vein continuing along the jugular and subclavian veins. Exuberant collateral circulation was noted through the superficial veins in the chest wall, intercostal veins, paraspinal, and mediastinal. The strategy adopted was the extraction of the “double coil” shock lead positioned in the ventricle and the explant of the atrial lead, as well as the generator, to perform the patency of the route and the consequent improvement of symptoms. The leads were extracted after the introduction of the guides on both electrodes, dilation of the initial and middle portions of the left subclavian vein, clockwise and counterclockwise rotation of the leads, besides manual traction. The leads were extracted without any complications and the brachiocephalic vein where they were placed was partially obstructed, confirmed after infusion of non-iodinated contrast (Fig. 2). We opted first of lead extraction because the implantation of stents in this vein could fracture the electrodes.\n\nFIGURE 2 Leads extraction without (A), (B), (C) and the left subclavian and brachiocephalic veins where they were placed has been partially unobstructed, confirmed after infusion of non-iodinated contrast (D).\n\nThe puncture of the right subclavian vein and the right femoral vein were performed, with an introduction of a short sheath 6F in each vein. Thereupon, hydrophilic wire guide (Aqualiner, Nipro Corporation, Japan) was introduced, as well as, an “over the wire” pig tail catheter. Venography with non-iodinated contrast through both accesses was performed. The superior vena cava had an unbridgeable thrombus (Fig. 3A and B) just above the right atrium, with only a tortuous and very narrow path between the superior vena cava and the brachiocephalic vein. The guidewire Aqualiner was replaced by another wire (road runner, Cook Medical, Rio de Janeiro, Brazil) due to this increased support and the femoral short sheath was replaced by 6F long sheath with 90 cm. A hydrophilic tip catheter (Slip-Cath Beacon Tip Hydrophilic Catheter, Cook Medical) was inserted to overcome the occlusion with success at this stage of the procedure (Fig. 3C–E). After several tries, this catheter was captured by a lassoer catheter (Multi-Snare, B. Braun Interventional Systems Inc., Rio de Janeiro, Brazil) inserted into the brachiocephalic vein through the left subclavian vein puncture (Fig. 3F). The guide wire was replaced by a fixed core wire guide (Fig. 3G and H) (Amplatz, Cook Medical) and angioplasty was performed with noncompliant balloon catheter, thus requiring the implantation of 2 self-expanding stents 28 mm × 60 mm (sinus-XL Stent, Optimed, Medizinische Instrumente GmbH, Ettlingen, Germany) in the left subclavian vein, brachiocephalic trunk, and the superior vena cava followed by dilation with balloon catheter of 26 mm × 4 cm (Zelos PTA – Balloon Catheter, Optimed, Medizinische Instrumente GmbH, Ettlingen, Germany). A venography ensured the access to ICD implantation (Fig. 4A–F).\n\nFIGURE 3 Angiography of the venous system showing the superior vena cava with an unbridgeable thrombus just above the right atrium (A) and (B). A tip hydrophilic catheter was inserted to overcome the occlusion, with success at this stage of the procedure (C), (D), and (E). The tip hydrophilic catheter was captured by a lassoer catheter inserted into the brachiocephalic vein through the left subclavian vein puncture (F). The guide wire was replaced by a fixed core wire guide (G) and (H).\n\nFIGURE 4 Angioplasty with noncompliant balloon catheter (A) and (B). Implantation of 2 self-expanding stents (C), in the left subclavian vein, brachiocephalic trunk, and the superior vena cava, followed by dilation with balloon catheter (D), and venography (E) and (F), ensuring the access to ICD implantation. A new “mono coil” shock lead was positioned in the apex of the right ventricle (G) and a new atrial lead was positioned in the right atrium (H), passing inside of the stents.\n\nA new “mono coil” shock lead was positioned in the apex of the right ventricle using active fixation and a new atrial lead was positioned in the right atrium, passing inside of the stents. Both were fixed in the pectoral muscles and connected to the ICD generator (Fortify ICD DR, St. Jude Medical, Rio de Janeiro, Brazil) (Fig. 4G and H). In the day after the procedure, the symptoms were no longer present and the patient was discharged on the second day after the procedure. Until the present time of follow-up (3 months) the patient remained asymptomatic. The patient was discharged using aspirin, clopidogrel, and rivaroxaban.\n\nAcknowledgments\nThe authors thank Mr. Sérgio Oliveira for their technical support.\n\nThe authors have no funding and conflicts of interest to disclose.\n==== Refs\nREFERENCES\n1. Modabber M Kundu S \nCentral venous disease in hemodialysis patients: an update . Cardiovasc Intervent Radiol \n2013 ; 36 :898 –903 .23073561 \n2. Wilson LD Detterbeck FC Yahalom J \nSuperior vena cava syndrome with malignant causes . N Engl J Med \n2007 ; 356 :1862 –1869 .17476012 \n3. Rice TW Rodriguez RM Light RW \nThe superior vena cava syndrome: clinical characteristics and evolving etiology . Medicine \n2006 ; 85 :37 –42 .16523051 \n4. Spittell PC Hayes DL \nVenous complications after insertion of atransvenous pacemaker . Mayo Clin Proc \n1992 ; 67 :258 –265 .1545594 \n5. Mazzetti H Dussaut A Tentori C \nSuperiorvena cava occlusion and/or syndrome related to pacemaker leads . Am Heart J \n1993 ; 125 :831 –837 .8438712 \n6. Riley RF Petersen SE Ferguson JD \nManaging superiorvena cava syndrome as a complication of pacemaker implantation: a pooled analysis of clinical practice . Pacing Clin Electrophysiol \n2010 ; 33 :420 –425 .20051021 \n7. Rizvi AZ Kalra M Bjarnason H \nBenign superior vena cava syndrome: stenting is now the first lineof treatment . J Vasc Surg \n2008 ; 47 :372 –380 .18241760 \n8. Chan AW Bhatt DL Wilkoff BL \nPercutaneous treatment for pacemaker-associatedsuperior vena cava syndrome . Pacing Clin Electrophysiol \n2002 ; 25 :1628 –1633 .12494623 \n9. Fu HX Huang XM Zhong L \nOutcome and management of pacemaker-induced superior vena cava syndrome . Pacing Clin Electrophysiol \n2014 ; 37 :1470 –1476 .25040311\n\n",
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"mesh_terms": "D000368:Aged; D002405:Catheterization, Central Venous; D017147:Defibrillators, Implantable; D020878:Device Removal; D004567:Electrodes, Implanted; D006801:Humans; D008297:Male; D010690:Phlebography; D013479:Superior Vena Cava Syndrome; D013927:Thrombosis; D016896:Treatment Outcome; D014683:Vena Cava, Superior",
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"title": "ICD Leads Extraction and Clearing of Access Way in a Patient With Superior Vena Cava Syndrome: Building A Tunnel.",
"title_normalized": "icd leads extraction and clearing of access way in a patient with superior vena cava syndrome building a tunnel"
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"abstract": "A 52-year-old woman presented with idiopathic active scleritis not responding to oral cyclophosphamide, azathioprine, and oral steroid. Her intraocular pressure in the left eye was 45 mm of Hg in spite of using combination of brinzolamide 1% and brimonidine 0.2% (thrice a day), timolol maleate 0.5% (twice a day) eye drops in both eyes and oral acetazolamide. She was administered subcutaneous golimumab 50 mg injection every 4 weeks along with oral methotrexate 15 mg/week. The scleral inflammation responded and she underwent Ahmed glaucoma valve implantation after two months of initiation of golimumab therapy. After one week of surgery her IOP in left eye was the reduced to 8 mm of Hg. The index case showed that Golimumab can be a useful drug in the management of necrotizing scleritis refractory to the conventional therapy.",
"affiliations": "Department of Uvea, Medical and Vision Research Foundations, Sankara Nethralaya, Chennai, Tamil Nadu, India.;Department of Glaucoma, Medical and Vision Research Foundations, Sankara Nethralaya, Chennai, Tamil Nadu, India.;Department of Glaucoma, Medical and Vision Research Foundations, Sankara Nethralaya, Chennai, Tamil Nadu, India.;Department of Rheumatology, Apollo Hospital, Chennai, Tamil Nadu, India.",
"authors": "Dutta Majumder|Parthopratim|P|;|||;David|Rathini Lilian|RL|;Kaushik|Viswanath|V|",
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"fulltext": "\n==== Front\nIndian J OphthalmolIndian J OphthalmolIJOIndian Journal of Ophthalmology0301-47381998-3689Wolters Kluwer - Medknow India 31332143IJO-67-136010.4103/ijo.IJO_2081_18Case ReportsA case of idiopathic necrotizing scleritis with secondary glaucoma treated successfully with golimumab and Ahmed valve implantation Dutta Majumder Parthopratim Jayshree 1David Rathini Lilian 1Kaushik Viswanath 2Department of Uvea, Medical and Vision Research Foundations, Sankara Nethralaya, Chennai, Tamil Nadu, India1 Department of Glaucoma, Medical and Vision Research Foundations, Sankara Nethralaya, Chennai, Tamil Nadu, India2 Department of Rheumatology, Apollo Hospital, Chennai, Tamil Nadu, IndiaCorrespondence to: Dr. Parthopratim Dutta Majumder, Department of Uvea, Sankara Nethralaya, 18, College Road, Nungambakkam, Chennai - 600 006, Tamil Nadu, India. E-mail: drparthopratim@gmail.com8 2019 67 8 1360 1362 29 12 2018 15 3 2019 Copyright: © 2019 Indian Journal of Ophthalmology2019This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.A 52-year-old woman presented with idiopathic active scleritis not responding to oral cyclophosphamide, azathioprine, and oral steroid. Her intraocular pressure in the left eye was 45 mm of Hg in spite of using combination of brinzolamide 1% and brimonidine 0.2% (thrice a day), timolol maleate 0.5% (twice a day) eye drops in both eyes and oral acetazolamide. She was administered subcutaneous golimumab 50 mg injection every 4 weeks along with oral methotrexate 15 mg/week. The scleral inflammation responded and she underwent Ahmed glaucoma valve implantation after two months of initiation of golimumab therapy. After one week of surgery her IOP in left eye was the reduced to 8 mm of Hg. The index case showed that Golimumab can be a useful drug in the management of necrotizing scleritis refractory to the conventional therapy.\n\nGlaucoma surgerygolimumabimmunosuppressive agentsintraocular pressurenecrotizing scleritis\n==== Body\nThe management of glaucoma in patients with scleritis always remains a challenge. The surgical intervention to control the intraocular pressure (IOP) in necrotizing scleritis, the most common subtypes of scleritis associated with secondary glaucoma further adds to the challenge.[1] The higher chances of globe-perforation because of extensive scleral thinning are often the main limiting factor in such cases. Also, reactivation of scleral inflammation following surgery is a major concern for the treating ophthalmologist. Literature on surgical management of glaucoma associated with necrotizing scleritis is sparse. There has been only two reports on Ahmed glaucoma valve (AGV) implantation in patients with necrotizing scleritis available in literature.[23]\n\nGolimumab (GLM) is a fully human anti-tumour necrosis factor (TNF)-α monoclonal antibody. Since its first reported use in the treatment of non-infectious uveitis in 2011,[4] various reports on efficacy of the drug in the management of ocular inflammatory diseases have been published. We present a refractory case of necrotizing scleritis with secondary glaucoma, where subcutaneous injection of GLM with oral methotrexate helped to attain resolution of scleral inflammation and IOP control was achieved with an AGV implantation. To the best of our knowledge, the index case is the first report on potential use of GLM in patients with scleritis.\n\nCase Report\nA 52-year-old woman presented to our clinic with complaints of recurrent attacks of ocular pain and redness in both eyes for last 6 years. She received a diagnosis of necrotising scleritis, and was extensively investigated. A thorough systemic evaluation for syphilis, tuberculosis, and sarcoidosis was unrevealing. Results of laboratory investigations for vasculitis and rheumatologic disorders were within reference limits. She had undergone phacoemulsification with intraocular lens implantation. She was treated with topical and oral corticosteroid and various immunosuppressives – methotrexate, azathioprine, cyclophosphamide, cyclosporine in these years; but failed to achieve a steroid-free remission. Her best corrected visual acuity was 6/36 in right eye and 6/9 in left eye. Slit-lamp examination of the right eye revealed 360 degree scleral thinning with peripheral corneal thinning and opacity in right eye with a quiet anterior chamber and pseudophakia [Fig. 1a]. In left eye, diffuse scleral thinning was noted with dilated deeper episcleral vessels, which did not blanch with topical vasoconstrictor [Fig. 1b-d]. Slit-lamp examination of the left eye also revealed cells 1+, flare 1+ in anterior chamber. IOP measured with Goldman applanation tonometry was 26 mm of Hg in right eye and 45 mm of Hg in left eye. Fundus examination showed clear media with no evidence of posterior segment inflammation. Optic nerve examination revealed increased vertical cup: Disc ratios of 0.8 with bipolar thinning in the right eye and 0.9 with near total cupping in left eye. She was on oral corticosteroid (10 mg every day), oral cyclophosphamide (50 mg twice a day), oral azathioprine (50 mg twice a day). She was also using a combination of brinzolamide 1% and brimonidine 0.2% (thrice a day), timolol maleate 0.5% (twice a day) eye drops in her both eyes and was on oral acetazolamide 250 mg four times a day. A decision to insert Ahmed glaucoma valve was suggested after proper control of scleritis. She was subsequently administered subcutaneous golimumab 50 mg and started on oral methotrexate (15 mg/week) under the care of a rheumatologist. It was decided to repeat the subcutaneous golimumab 50 mg injection every 4 weeks. She was advised to continue anti-glaucoma medications. Follow-up examination 2 months later revealed complete resolution of scleritis with a quiet anterior chamber in left eye. IOP in right and left eye was 14 and 28 mm of Hg respectively. Subsequently she underwent Ahmed glaucoma valve implantation in her left eye. One week after the surgery, her IOP in left eye was 8 mm of Hg [Fig. 2]. A third injection of subcutaneous golimumab 50 mg injection was administered and she was advised to continue oral methotrexate 15 mg/week.\n\nFigure 1 (a) Slit-lamp photograph of the right eye showing 360 degree scleral thinning and peripheral corneal thinning and opacity. (b-d) Slit-lamp photograph of the left eye showing diffuse scleral thinning with dilated deeper episcleral vessels, which did not blanch with topical vasoconstrictor\n\nFigure 2 Slit-lamp photograph of the left eye showing Ahmed glaucoma valve in superotemporal quadrant and tube in situ\n\n\nDiscussion\nThe cause of glaucoma in scleritis patients can be multi-factorial and can be due to obstruction of the trabecular meshwork by inflammatory cells, peripheral anterior synechiae and/or posterior synechiae related or due to steroid response.[5] The concurrent anterior uveitis, presence of synechia, previous cataract surgery and corneal involvements are the other reported risk factors for increased IOP in patients with scleritis.[1]\n\nOver the last few years, drainage implants have become popular and increasingly being advocated for the treatment of uveitic glaucoma with high published success rates. However, the literature on AGV implantation in patients with necrotizing scleritis is sparse. Ranjan and Rao[2] described a case of necrotizing scleritis with extensive staphylomas and secondary glaucoma in a 35-year-old one eyed female. The patient underwent AGV implant and had good control IOP post-operatively. After three and half months, she presented with recurrence of scleral inflammation with scleral melt leading to exposure of the valve for which she required patch graft.[2] Goel et al.[3] described a patient with bilateral idiopathic healed sclerokeratouveitis with ciliary and intercalary staphyloma where phacoemulsification with intraocular lens implantation and AGV implant were performed as a single-stage procedure for complicated cataract and secondary glaucoma in the left eye. A cadaveric scleral graft was used to cover the AGV and the post-operative outcome was good except for severe anterior chamber inflammation on the second day.[3]\n\nNecrotising scleritis, though rare, is the most severe form of the scleral inflammation. Immunosuppressive agents are often considered as first-line of therapy in the management of necrotizing scleritis. Though, reported to have a higher association with systemic rheumatic diseases than other subtypes of scleritis, necrotizing scleritis can be idiopathic.[6] Management of necrotizing scleritis, refractory to the conventional immunosuppressive therapy is challenging. In our case, it was further complicated by the secondary glaucoma. Various biological agents has been successfully used in the management of refractory necrotizing scleritis.[78] The scleral inflammation in our patient was resistant to conventional immunosuppressives, but responded to subcutaneous injection of GLM which helped us to perform AGV implantation. GLM, which requires once a month injection, has been found to be effective in the management of recalcitrant cases of uveitis.[910] Our report suggests that GLM can be a useful drug in the management of necrotizing scleritis refractory to the conventional therapy. However, further research is needed to ensure the safety and efficacy of the drug in patients with necrotizing scleritis.\n\nDeclaration of patient consent\nThe authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n==== Refs\n1 Heinz C Bograd N Koch J Heiligenhaus A Ocular hypertension and glaucoma incidence in patients with scleritis Graefes Arch Clin Exp Ophthalmol 2013 251 139 42 22820814 \n2 Ranjan A Rao A Ahmed glaucoma valve surgery for necrotizing scleritis with secondary glaucoma Int Ophthalmol 2014 34 327 9 23636673 \n3 Goel R Thangkhiew L Yadava U Kumar S Management of bilateral idiopathic healed sclerokeratouveitis with ciliary and intercalary staphyloma with complicated cataract and secondary glaucoma Indian J Ophthalmol 2010 58 444 20689209 \n4 Cordero-Coma M Salom D Díaz-Llopis M López-Prats MJ Calleja S Golimumab for uveitis Ophthalmology 2011 118 1892.e3 4 \n5 Schlote T Zierhut M Ocular hypertension and glaucoma associated with scleritis and uveitis. Aspects of epidemiology, pathogenesis and therapy Dev Ophthalmol 1999 30 91 109 10627919 \n6 Wilhelmus KR Grierson I Watson PG Histopathologic and clinical associations of scleritis and glaucoma Am J Ophthalmol 1981 91 697 705 6166197 \n7 de Fidelix TS Vieira LA de Freitas D Trevisani VF Biologic therapy for refractory scleritis: A new treatment perspective Int Ophthalmol 2015 35 903 12 26319144 \n8 Bogdanic-Werner K Fernandez-Sanz G Alejandre Alba N Ferrer Soldevila P Romero-Bueno FI Sanchez-Pernaute O Rituximab therapy for refractory idiopathic scleritis Ocul Immunol Inflamm 2013 21 329 32 23662782 \n9 Miserocchi E Modorati G Pontikaki I Meroni P Gerloni V Golimumab treatment for complicated uveitis Clin Exp Rheumatol 2013 31 320 1 23331715 \n10 Miserocchi E Modorati G Pontikaki I Meroni PL Gerloni V Long-term treatment with golimumab for severe uveitis Ocul Immunol Inflamm 2014 22 90 5 24143896\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0301-4738",
"issue": "67(8)",
"journal": "Indian journal of ophthalmology",
"keywords": "Glaucoma surgery; golimumab; immunosuppressive agents; intraocular pressure; necrotizing scleritis",
"medline_ta": "Indian J Ophthalmol",
"mesh_terms": "D000911:Antibodies, Monoclonal; D005260:Female; D005901:Glaucoma; D020327:Glaucoma Drainage Implants; D006801:Humans; D007279:Injections, Subcutaneous; D007429:Intraocular Pressure; D008875:Middle Aged; D019919:Prosthesis Implantation; D015423:Scleritis; D014065:Tonometry, Ocular",
"nlm_unique_id": "0405376",
"other_id": null,
"pages": "1360-1362",
"pmc": null,
"pmid": "31332143",
"pubdate": "2019-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "24143896;23331715;26319144;6166197;23636673;23662782;10627919;22820814;21889663;20689209",
"title": "A case of idiopathic necrotizing scleritis with secondary glaucoma treated successfully with golimumab and Ahmed valve implantation.",
"title_normalized": "a case of idiopathic necrotizing scleritis with secondary glaucoma treated successfully with golimumab and ahmed valve implantation"
} | [
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"companynumb": "IN-MYLANLABS-2020M1004367",
"fulfillexpeditecriteria": "1",
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"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "AZATHIOPRINE"
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... |
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